General Notices

Contents of the General Notices

Part IIIItalic introductionGeneral Notices of the European

Pharmacopoeia

1.1 General StatementsConventional terms

1.2 Other Provisions Applying to GeneralChapters and Monographs

QuantitiesApparatus and proceduresWater-bathDrying and ignition to constant massReagentsSolventsExpression of contentTemperature

1.3 General ChaptersContainers

1.4 MonographsTitlesRelative atomic and molecular massesDefinition

Limits of contentVegetable drugs

ProductionCharacters

SolubilityIdentificationTests and assays

ScopeCalculationLimitsIndication of permitted limits of impuritiesVegetable drugsEquivalents

StorageLabellingWarningsImpuritiesCritical physical propertiesReference substances, reference

preparations and reference spectraChemical reference substancesBiological reference preparationsReference spectra

1.5 Abbreviations and Symbols

1.6 Units of the International System (SI)Used in the Pharmacopoeia andEquivalence with Other Units

Part IItalic introductionEuropean Pharmacopoeia

Part IIItalic introductionOfficial StandardsExpression of StandardsTemperatureWeights and MeasuresAtomic WeightsConstant WeightExpression of ConcentrationsWater BathReagentsIndicatorsCaution StatementsTitlesChemical FormulaeDefinitionProductionManufacture of Formulated

PreparationsFreshly and Recently PreparedMethods of SterilisationWaterExcipientsColouring AgentsAntimicrobial PreservativesCharacteristicsSolubilityIdentificationAssays and TestsBiological Assays and TestsStorageLabellingAction and UseCrude Drugs

General Notices

Part I The British Pharmacopoeia comprises the entire text within this publication.The word ‘official’ is used in the Pharmacopoeia to signify ‘of the Pharmaco-poeia’. It applies to any title, substance, preparation, method or statementincluded in the general notices, monographs and appendices of the Pharmaco-poeia. The abbreviation for British Pharmacopoeia is BP.

European Pharmacopoeia

Monographs of the European Pharmacopoeia are reproduced in thisedition of the British Pharmacopoeia by incorporation of the textpublished under the direction of the Council of Europe (Partial Agree-ment) in accordance with the Convention on the Elaboration of a Euro-pean Pharmacopoeia (Treaty Series No. 32 (1974) CMND 5763) asamended by the Protocol to the Convention (Treaty Series No MISC16(1990) CMND 1133). They are included for the convenience of users

of the British Pharmacopoeia. In cases of doubt or disputereference should be made to the Council of Europe text.

Monographs of the European Pharmacopoeia are distinguishedby a chaplet of stars against the title and by an italicised statementpreceding the Definition. The beginnning and end of text from the

European Pharmacopoeia are denoted by means of horizontallines with the symbol ‘Ph Eur’ ranged left and right, respectively.

Inclusion of a triangle within the chaplet of stars denotes mono-graphs that have been adopted by the European PharmacopoeiaCommission following their preparation according to a procedure ofharmonisation agreed between the bodies responsible for the EuropeanPharmacopoeia and those of Japan and the United States of America.

The general provisions of the European Pharmacopoeia relating todifferent types of dosage form are included in the appropriate generalmonograph in that section of the British Pharmacopoeia entitled Mono-graphs: Formulated Preparations. These general provisions apply to alldosage forms of the type defined, whether an individual monograph isincluded in the British Pharmacopoeia or not.

Texts of the European Pharmacopoeia are governed by the GeneralNotices of the European Pharmacopoeia. These are reproduced as PartIII of these notices.

Part II The following general notices apply to the statements made in the monographsof the British Pharmacopoeia other than those reproduced from the EuropeanPharmacopoeia and to the statements made in the Appendices of the BritishPharmacopoeia other than when a method, test or other matter described inan appendix is invoked in a monograph reproduced from the EuropeanPharmacopoeia.

Official Standards The requirements stated in the monographs of the Pharmacopoeiaapply to articles that are intended for medicinal use but not necessarilyto articles that may be sold under the same name for other purposes. Anarticle intended for medicinal use that is described by means of anofficial title must comply with the requirements of the relevant mono-graph. A formulated preparation must comply throughout its assignedshelf-life (period of validity). The subject of any other monograph mustcomply throughout its period of use.

A monograph is to be construed in accordance with any generalmonograph or notice or any appendix, note or other explanatorymaterial that is contained in this edition and that is applicable to thatmonograph. All statements contained in the monographs, except wherea specific general notice indicates otherwise and with the exceptionsgiven below, constitute standards for the official articles. An article isnot of Pharmacopoeial quality unless it complies with all of the require-ments stated. This does not imply that a manufacturer is obliged toperform all the tests in a monograph in order to assess compliance withthe Pharmacopoeia before release of a product. The manufacturer mayassure himself that a product is of Pharmacopoeial quality by othermeans, for example, from data derived from validation studies of themanufacturing process, from in-process controls or from a combinationof the two. Parametric release in appropriate circumstances is thus notprecluded by the need to comply with the Pharmacopoeia. The generalnotice on Assays and Tests indicates that analytical methods other thanthose described in the Pharmacopoeia may be employed for routinepurposes.

Requirements in monographs have been framed to provide appropri-ate limitation of potential impurities rather than to provide against allpossible impurities. Material found to contain an impurity not detect-able by means of the prescribed tests is not of Pharmacopoeial quality ifthe nature or amount of the impurity found is incompatible with goodpharmaceutical practice.

The status of any statement given under the side-headings Definition,Production, Characteristics, Storage, Labelling or Action and use isdefined within the general notice relating to the relevant side-heading.In addition to any exceptions indicated by one of the general noticesreferred to above, the following parts of a monograph do not constitutestandards: (a) a graphic or molecular formula given at the beginning ofa monograph; (b) a molecular weight; (c) a Chemical Abstracts ServiceRegistry Number; (d) any information given at the end of a monographconcerning impurities known to be limited by that monograph; (e)information in any annex to a monograph. Any statement containingthe word ‘should’ constitutes non-mandatory advice orrecommendation.

The expression ‘unless otherwise justified and authorised’ means thatthe requirement in question has to be met, unless a competent authorityauthorises a modification or exemption where justified in a particularcase. The term ‘competent authority’ means the national, supranationalor international body or organisation vested with the authority formaking decisions concerning the issue in question. It may, for example,be a licensing authority or an official control laboratory. For a formula-ted preparation that is the subject of monograph in the British

Pharmacopoeia any justified and authorised modification to, orexemption from, the requirements of the relevant general monograph ofthe European Pharmacopoeia is stated in the individual monograph.For example, the general monograph for Tablets requires that UncoatedTablets, except for chewable tablets, disintegrate within 15 minutes; forCalcium Lactate Tablets a time of 30 minutes is permitted.

Many of the general monographs for formulated preparations includestatements and requirements additional to those of the EuropeanPharmacopoeia that are applicable to the individual monographs of theBritish Pharmacopoeia. Such statements and requirements apply to allmonographs for that dosage form included in the Pharmacopoeia unlessotherwise indicated in the individual monograph.

Where a monograph on a biological substance or preparation refers toa strain, a test, a method, a substance, etc., using the qualifications‘suitable’ or ‘appropriate’ without further definition in the text, thechoice of such strain, test, method, substance, etc., is made in accord-ance with any international agreements or national regulations affectingthe subject concerned.

Expression of Standards

Where the standard for the content of a substance described in amonograph is expressed in terms of the chemical formula for thatsubstance an upper limit exceeding 100% may be stated. Such an upperlimit applies to the result of the assay calculated in terms of theequivalent content of the specified chemical formula. For example, thestatement ‘contains not less than 99.0% and not more than 101.0% ofC20H24N2O2,HCl’ implies that the result of the assay is not less than99.0% and not more than 101.0%, calculated in terms of the equivalentcontent of C20H24N2O2,HCl.

Where the result of an assay or test is required to be calculated withreference to the dried, anhydrous or ignited substance, the substancefree from a specified solvent or to the peptide content, the determin-ation of loss on drying, water content, loss on ignition, content of thespecified solvent or peptide content is carried out by the methodprescribed in the relevant test in the monograph.

Temperature The Celsius thermometric scale is used in expressing temperatures.

Weights and Measures The metric system of weights and measures is employed; SI Units havegenerally been adopted. Metric measures are required to have beengraduated at 20° and all measurements involved in the analyticaloperations of the Pharmacopoeia are intended, unless otherwise stated,to be made at that temperature. Graduated glass apparatus used inanalytical operations should comply with Class A requirements of theappropriate specification issued by the British Standards Institution.

Atomic Weights The atomic weights adopted are the values given in the Table of Relat-ive Atomic Weights 1989 published by the International Union of Pureand Applied Chemistry. The values are based on the carbon-12 scale(Appendix XXII).

Constant Weight The term ‘constant weight’, used in relation to the process of drying orthe process of ignition, means that two consecutive weighings do notdiffer by more than 0.5 milligram, the second weighing being madeafter an additional period of drying or ignition under the specified

conditions appropriate to the nature and quantity of the residue (1hour is usually suitable).

Expression of Concentrations

The term ‘per cent’ or more usually the symbol ‘%’ is used with one offour different meanings in the expression of concentrations according tocircumstances. In order that the meaning to be attached to theexpression in each instance is clear, the following notation is used.

Per cent w/w (% w/w) (percentage weight in weight) expresses thenumber of grams of solute in 100 g of product.

Per cent w/v (% w/v) (percentage weight in volume) expresses thenumber of grams of solute in 100 ml of product.

Per cent v/v (% v/v) (percentage volume in volume) expresses thenumber of millilitres of solute in 100 ml of product.

Per cent v/w (% v/w) (percentage volume in weight) expresses thenumber of millilitres of solute in 100 g of product.

Usually the strength of solutions of solids in liquids is expressed aspercentage weight in volume, of liquids in liquids as percentage volumein volume and of gases in liquids as percentage weight in weight.

When the concentration of a solution is expressed as parts per million(ppm), it means weight in weight, unless otherwise specified.

When the concentration of a solution is expressed as parts of dissolvedsubstance in parts of the solution, it means parts by weight (g) of a solidin parts by volume (ml) of the final solution; or parts by volume (ml) ofa liquid in parts by volume (ml) of the final solution; or parts by weight(g) of a gas in parts by weight (g) of the final solution.

When the concentration of a solution is expressed in molarity designa-ted by the symbol M preceded by a number, it denotes the number ofmoles of the stated solute contained in sufficient Purified Water (unlessotherwise stated) to produce 1 litre of solution.

Water Bath The term ‘water bath’ means a bath of boiling water, unless water atsome other temperature is indicated in the text. An alternative form ofheating may be employed providing that the required temperature isapproximately maintained but not exceeded.

Reagents The reagents required for the assays and tests of the Pharmacopoeia aredefined in appendices. The descriptions set out in the appendices donot imply that the materials are suitable for use in medicine.

Indicators Indicators, the colours of which change over approximately the samerange of pH, may be substituted for one another but in the event ofdoubt or dispute as to the equivalence of indicators for a particularpurpose, the indicator specified in the text is alone authoritative.

The quantity of an indicator solution appropriate for use in acid—basetitrations described in assays or tests is 0.1 ml unless otherwise stated inthe text.

Any solvent required in an assay or test in which an indicator is speci-fied is previously neutralised to the indicator, unless a blank test isprescribed.

Caution Statements A number of materials described in the monographs and some of thereagents specified for use in the assays and tests of the Pharmacopoeiamay be injurious to health unless adequate precautions are taken. Theprinciples of good laboratory practice and the provisions of any appro-

priate regulations such as those issued in the United Kingdom inaccordance with the Health and Safety at Work etc. Act (1974) shouldbe observed at all times in carrying out the assays and tests of thePharmacopoeia.

Attention is drawn to particular hazards in certain monographs bymeans of an italicised statement; the absence of such a statement shouldnot however be taken to mean that no hazard exists.

Titles Subsidiary titles, where included, have the same significance as the maintitles. An abbreviated title constructed in accordance with the directionsgiven in Appendix XXI A has the same significance as the main title.

Titles that are derived by the suitable inversion of words of a main orsubsidiary title, with the addition of a preposition if appropriate, are alsoofficial titles. Thus, the following are all official titles: Aspirin Tablets,Tablets of Aspirin; Ginger Tincture, Tincture of Ginger; AtropineInjection, Injection of Atropine.

A title of a formulated preparation that includes the full nonpro-prietary name of the active ingredient or ingredients, where this is notincluded in the title of the monograph, is also an official title. Forexample, the title Promethazine Hydrochloride Oral Solution has thesame significance as Promethazine Oral Solution and the title Brom-pheniramine Maleate Tablets has the same significance as Bromphenir-amine Tablets.

Where the English title at the head of a monograph in the EuropeanPharmacopoeia is different from that at the head of the text incorpora-ted into the British Pharmacopoeia, the European Pharmacopoeia titleis given in an italicised statement at the head of the incorporated text.The titles and subsidiary titles (if any) of such incorporated texts havebeen declared Approved Synonyms in accordance with section 65(8) ofthe Medicines Act 1968 and are thus official titles. A cumulative list ofsuch Approved Synonyms is provided in Appendix XXI B.

Where the names of Pharmacopoeial substances, preparations andother materials occur in the text they are printed with capital initialletters and this indicates that materials of Pharmacopoeial quality mustbe used. Words in the text that name a reagent or other material, aphysical characteristic or a process that is described or defined in anappendix are printed in italic type, for example, methanol, absorbance,gas chromatography, and these imply compliance with the requirementsspecified in the appropriate appendix.

Chemical Formulae When the chemical composition of an official substance is known orgenerally accepted, the graphic and molecular formulae, the molecularweight and the Chemical Abstracts Service Registry Number are norm-ally given at the beginning of the monograph for information. Thisinformation refers to the chemically pure substance and is not to beregarded as an indication of the purity of the official material. Else-where, in statements of standards of purity and strength and in descrip-tions of processes of assay, it is evident from the context that the formu-lae denote the chemically pure substances.

Where the absolute stereochemical configuration is specified, theInternational Union of Pure and Applied Chemistry (IUPAC) R/S andE/Z systems of designation have been used. If the substance is an enan-tiomer of unknown absolute stereochemistry the sign of the optical

rotation, as determined in the solvent and under the conditions speci-fied in the monograph, has been attached to the systematic name. Anindication of sign of rotation has also been given where this is incorpor-ated in a trivial name that appears on an IUPAC preferred list.All amino acids, except glycine, have the L-configuration unless other-wise indicated. The three-letter and one-letter symbols used for aminoacids in peptide and protein sequences are those recommended by theJoint Commission on Biochemical Nomenclature of the InternationalUnion of Pure and Applied Chemistry and the International Union ofBiochemistry.

In the graphic formulae the following abbreviations are used:

Me i –CH3 i Bus –CH(CH3)CH2CH3 i

Et i –CH2CH3 i Bun –CH2CH2CH2CH3 i

Pri –CH(CH3)2 i But –C(CH3)3 i

Prn –CH2CH2CH3 i Ph i –C6H5 i

Bui –CH2CH(CH3)2 i Ac i –COCH3 i

Definition Statements given under the side-heading Definition constitute an officialdefinition of the substance, preparation or other article that is thesubject of the monograph. They constitute instructions or requirementsand are mandatory in nature.

Certain medicinal or pharmaceutical substances and other articles aredefined by reference to a particular method of manufacture. A state-ment that a substance or article is prepared or obtained by a certainmethod constitutes part of the official definition and implies that othermethods are not permitted. A statement that a substance may beprepared or obtained by a certain method, however, indicates that this isone possible method and does not imply that other methods areproscribed.

Additional statements concerning the definition of formulated prepar-ations are given in the general notice on Manufacture of FormulatedPreparations.

Production Statements given under the side-heading Production draw attention toparticular aspects of the manufacturing process but are not necessarilycomprehensive. They constitute mandatory instructions to manu-facturers. They may relate, for example, to source materials, to themanufacturing process itself and its validation and control, to in-processtesting or to testing that is to be carried out by the manufacturer on thefinal product (bulk material or dosage form) either on selected batchesor on each batch prior to release. These statements cannot necessarilybe verified on a sample of the final product by an independent analyst.The competent authority may establish that the instructions have beenfollowed, for example, by examination of data received from the manu-facturer, by inspection or by testing appropriate samples.

The absence of a section on Production does not imply that attentionto features such as those referred to above is not required. A substance,preparation or article described in a monograph of the Pharmacopoeia isto be manufactured in accordance with the principles of good manu-facturing practice and in accordance with relevant international agree-ments and supranational and national regulations governing medicinalproducts.

Where in the section under the side-heading Production a mono-graph on a vaccine defines the characteristics of the vaccine strain tobe used, any test methods given for confirming these characteristicsare provided as examples of suitable methods. The use of thesemethods is not mandatory.

Additional statements concerning the production of formulatedpreparations are given in the general notice on Manufacture ofFormulated Preparations.

Manufacture of Formulated Preparations

Attention is drawn to the need to observe adequate hygienic precautionsin the preparation and dispensing of pharmaceutical formulations. Theprinciples of good pharmaceutical manufacturing practice should beobserved.

The Definition in certain monographs for pharmaceutical prepara-tions is given in terms of the principal ingredients only. Any ingredient,other than those included in the Definition, must comply with thegeneral notice on Excipients and the product must conform with thePharmacopoeial requirements.

The Definition in other monographs for pharmaceutical preparationsis presented as a full formula. No deviation from the stated formula ispermitted except those allowed by the general notices on ColouringAgents and Antimicrobial Preservatives. Where additionally directionsare given under the side-heading Extemporaneous Preparation these areintended for the extemporaneous preparation of relatively small quanti-ties for short-term supply and use. When so prepared, no deviationfrom the stated directions is permitted. If, however, such apharmaceutical preparation is manufactured on a larger scale with theintention that it may be stored, deviations from the stated directions arepermitted provided that the final product meets the following criteria:

(1) compliance with all of the requirements stated in the monograph;

(2) retention of the essential characteristics of the preparation madestrictly in accordance with the directions of the Pharmacopoeia.

Monographs for yet other pharmaceutical preparations include both aDefinition in terms of the principal ingredients and, under the side-heading Extemporaneous Preparation, a full formula together with, insome cases, directions for their preparation. Such full formulae anddirections are intended for the extemporaneous preparation of relativelysmall quantities for short-term supply and use. When so prepared, nodeviation from the stated formula and directions is permitted. If, how-ever, such a pharmaceutical preparation is manufactured on a largerscale with the intention that it may be stored, deviations from the form-ula and directions stated under the side-heading ExtemporaneousPreparation are permitted provided that any ingredient, other thanthose included in the Definition, complies with the general notice onExcipients and that the final product meets the following criteria:

(1) accordance with the Definition stated in the monograph;

(2) compliance with all of the requirements stated in the monograph;

(3) retention of the essential characteristics of the preparation madestrictly in accordance with the formula and directions of thePharmacopoeia.

In the manufacture of any official preparation on a large scale withthe intention that it should be stored, in addition to following anyinstruction under the side-heading Production, it is necessary toascertain that the product is satisfactory with respect to its physical andchemical stability and its state of preservation over the claimed shelf-life. This applies irrespective of whether the formula of thePharmacopoeia and any instructions given under the side-headingExtemporaneous Preparation are followed precisely or modified.Provided that the preparation has been shown to be stable in otherrespects, deterioration due to microbial contamination may beinhibited by the incorporation of a suitable antimicrobial preservative.In such circumstances the label states appropriate storage conditions,the date after which the product should not be used and the identityand concentration of the antimicrobial preservative.

Freshly and Recently Prepared

The direction, given under the side-heading ExtemporaneousPreparation, that a preparation must be freshly prepared indicates that itmust be made not more than 24 hours before it is issued for use. Thedirection that a preparation should be recently prepared indicates thatdeterioration is likely if the preparation is stored for longer than about 4weeks at 15° to 25°.

Methods of Sterilisation

The methods of sterilisation used in preparing the sterile materialsdescribed in the Pharmacopoeia are given in Appendix XVIII. Foraqueous preparations, steam sterilisation (heating in an autoclave) is themethod of choice wherever it is known to be suitable. Any method ofsterilisation must be validated with respect to both the assurance ofsterility and the integrity of the product and to ensure that the finalproduct complies with the requirements of the monograph.

Water The term Water used without qualification in formulae for formulatedpreparations means either potable water freshly drawn direct from thepublic supply and suitable for drinking or freshly boiled and cooledPurified Water. The latter should be used if the public supply is from alocal storage tank or if the potable water is unsuitable for a particularpreparation.

Excipients Where an excipient for which there is a Pharmacopoeial monograph isused in preparing an official preparation it shall comply with that mono-graph. Any substance added in preparing an official preparation shall beinnocuous, shall have no adverse influence on the therapeutic efficacy ofthe active ingredients and shall not interfere with the assays and tests ofthe Pharmacopoeia. Particular care should be taken to ensure that suchsubstances are free from harmful organisms.

Colouring Agents If in a monograph for a formulated preparation defined by means of afull formula a specific colouring agent or agents is prescribed, suitablealternatives approved in the country concerned may be substituted.

Antimicrobial Preservatives

When the term ‘suitable antimicrobial preservative’ is used it is impliedthat the preparation concerned will be effectively preserved according to

the appropriate criteria applied and interpreted as described in the testfor efficacy of antimicrobial preservation (Appendix XVI C). In certainmonographs for formulated preparations defined by means of a fullformula, a specific antimicrobial agent or agents may be prescribed;suitable alternatives may be substituted provided that their identity andconcentration are stated on the label.

Characteristics Statements given under the side-heading Characteristics are not to beinterpreted in a strict sense and are not to be regarded as officialrequirements. Statements on taste are provided only in cases where thisproperty is a guide to the acceptability of the material (for example, amaterial used primarily for flavouring). The status of statements onsolubility is given in the general notice on Solubility.

Solubility Statements on solubility given under the side-headingCharacteristics are intended as information on the approximatesolubility at a temperature between 15° and 25°, unless otherwisestated, and are not to be considered as official requirements.

Statements given under side-headings such as Solubility in ethanolexpress exact requirements and constitute part of the standards for thesubstances under which they occur.

The following table indicates the meanings of the terms used in state-ments of approximate solubilities.

Descriptive term Approximate volume ofsolvent in millilitres pergram of solute

very soluble less than 1freely soluble from 1 to 10soluble from 10 to 30sparingly soluble from 30 to 100slightly soluble from 100 to 1000very slightly soluble from 1000 to 10,000practically insoluble more than 10,000

The term ‘partly soluble’ is used to describe a mixture of which onlysome of the components dissolve.

Identification The tests described or referred to under the side-heading Identificationare not necessarily sufficient to establish absolute proof of identity. Theyprovide a means of verifying that the identity of the material beingexamined is in accordance with the label on the container.

Unless otherwise prescribed, identification tests are carried out at atemperature between 15° and 25°.

When tests for infrared absorption are applied to material extractedfrom formulated preparations, strict concordance with the specifiedreference spectrum may not always be possible, but nevertheless a closeresemblance between the spectrum of the extracted material and thespecified reference spectrum should be achieved.

Assays and Tests The assays and tests described are the official methods upon which thestandards of the Pharmacopoeia depend. The analyst is not precludedfrom employing alternative methods, including methods of micro-

analysis, in any assay or test if it is known that the method used willgive a result of equivalent accuracy. Local reference materials may beused for routine analysis, provided that these are calibrated against theofficial reference materials. In the event of doubt or dispute, themethods of analysis, the reference materials and the reference spectra ofthe Pharmacopoeia are alone authoritative.

Where the solvent used for a solution is not named, the solvent isPurified Water.

Unless otherwise prescribed, the assays and tests are carried out at atemperature between 15° and 25°.

A temperature in a test for Loss on drying, where no temperaturerange is given, implies a range of ± 2° about the stated value.

Visual comparative tests, unless otherwise prescribed, are carried outusing identical tubes of colourless, transparent, neutral glass with a flatbase. The volumes of liquid prescribed are for use with tubes 16 mm ininternal diameter; tubes with a larger internal diameter may be used butthe volume of liquid examined must be increased so that the depth ofliquid in the tubes is not less than that obtained when the prescribedvolume of liquid and tubes 16 mm in internal diameter are used. Equalvolumes of the liquids to be compared are examined down the verticalaxis of the tubes against a white background or, if necessary, against ablack background. The examination is carried out in diffuse light.

Where a direction is given that an analytical operation is to be carriedout ‘in subdued light’, precautions should be taken to avoid exposure todirect sunlight or other strong light. Where a direction is given that ananalytical operation is to be carried out ‘protected from light’, precau-tions should be taken to exclude actinic light by the use of low-actinicglassware, working in a dark room or similar procedures.

For preparations other than those of fixed strength, the quantity to betaken for an assay or test is usually expressed in terms of the activeingredient. This means that the quantity of the active ingredientexpected to be present and the quantity of the preparation to be takenare calculated from the strength stated on the label.

In assays the approximate quantity to be taken for examination isindicated but the quantity actually used must not deviate by more than10% from that stated. The quantity taken is accurately weighed ormeasured and the result of the assay is calculated from this exactquantity. Reagents are measured and the procedures are carried outwith an accuracy commensurate with the degree of precision implied bythe standard stated for the assay.

In tests the stated quantity to be taken for examination must be usedunless any divergence can be taken into account in conducting the testand calculating the result. The quantity taken is accurately weighed ormeasured with the degree of precision implied by the standard or, wherethe standard is not stated numerically (for example, in tests for Clarityand colour of solution), with the degree of precision implied by thenumber of significant figures stated. Reagents are measured and theprocedures are carried out with an accuracy commensurate with thisdegree of precision.

The limits stated in monographs are based on data obtained in normalanalytical practice; they take account of normal analytical errors, ofacceptable variations in manufacture and of deterioration to an extent

considered acceptable. No further tolerances are to be applied to thelimits prescribed to determine whether the article being examinedcomplies with the requirements of the monograph.

In determining compliance with a numerical limit, the calculatedresult of a test or assay is first rounded to the number of significantfigures stated, unless otherwise prescribed. The last figure is increasedby one when the part rejected is equal to or exceeds one half-unit,whereas it is not modified when the part rejected is less than a half-unit.

In certain tests, the concentration of impurity is given in parentheseseither as a percentage or in parts per million by weight (ppm). Inchromatographic tests such concentrations are stated as a percentageirrespective of the limit. In other tests they are usually stated in ppmunless the limit exceeds 500 ppm. In those chromatographic tests inwhich a secondary spot or peak in a chromatogram obtained with asolution of the substance being examined is described as correspondingto a named impurity and is compared with a spot or peak in a chroma-togram obtained with a reference solution of the same impurity, thepercentage given in parentheses indicates the limit for that impurity. Inthose chromatographic tests in which a spot or peak in a chromatogramobtained with a solution of the substance being examined is described interms other than as corresponding to a named impurity (commonly, forexample, as any (other) secondary spot or peak) but is compared with aspot or peak in a chromatogram obtained with a reference solution of anamed impurity, the percentage given in parentheses indicates animpurity limit expressed in terms of a nominal concentration of thenamed impurity. In chromatographic tests in which a comparison ismade between spots or peaks in chromatograms obtained with solutionsof different concentrations of the substance being examined, the per-centage given in parentheses indicates an impurity limit expressed interms of a nominal concentration of the medicinal substance itself. Insome monographs, in particular those for certain formulated prepara-tions, the impurity limit is expressed in terms of a nominal concentra-tion of the active moiety rather than of the medicinal substance itself.Where necessary for clarification the terms in which the limit isexpressed are stated within the monograph.

In all cases where an impurity limit is given in parentheses, the figuresgiven are approximations for information only; conformity with therequirements is determined on the basis of compliance or otherwisewith the stated test.

The use of a proprietary designation to identify a material used in anassay or test does not imply that another equally suitable material maynot be used.

Biological Assays and Tests

Methods of assay described as Suggested methods are not obligatory,but when another method is used its precision must be not less thanthat required for the Suggested method.

For those antibiotics for which the monograph specifies a micro-biological assay the potency requirement is expressed in the monographin International Units (IU) per milligram. The material is not ofpharmacopoeial quality if the upper fiducial limit of error is less than thestated potency. For such antibiotics the required precision of the assay

is stated in the monograph in terms of the fiducial limits of error aboutthe estimated potency.

For other substances and preparations for which the monographspecifies a biological assay, unless otherwise stated, the precision of theassay is such that the fiducial limits of error, expressed as a percentageof the estimated potency, are within a range not wider than thatobtained by multiplying by a factor of ten the square roots of the limitsgiven in the monograph for the fiducial limits of error about the statedpotency.

In all cases fiducial limits of error are based on a probability of 95%(P = 0.95).

Where the biological assay is being used to ascertain the purity of thematerial, the stated potency means the potency stated on the label interms of International Units (IU) or other Units per gram, per milligramor per millilitre. When no such statement appears on the label, thestated potency means the fixed or minimum potency required in themonograph. This interpretation of stated potency applies in all casesexcept where the monograph specifically directs otherwise.

Where the biological assay is being used to determine the total activityin the container, the stated potency means the total number of Interna-tional Units (IU) or other Units stated on the label or, if no such state-ment appears, the total activity calculated in accordance with theinstructions in the monograph.

Wherever possible the primary standard used in an assay or test is therespective International Standard or Reference Preparation establishedby the World Health Organization for international use and the biologi-cal activity is expressed in International Units (IU).

In other cases, where Units are referred to in an assay or test, the Unitfor a particular substance or preparation is, for the United Kingdom,the specific biological activity contained in such an amount of therespective primary standard as the appropriate international or nationalorganisation indicates. The necessary information is provided with theprimary standard.

Unless otherwise directed, animals used in an assay or a test arehealthy animals, drawn from a uniform stock, that have not previouslybeen treated with any material that will interfere with the assay or test.Unless otherwise stated, guinea-pigs weigh not less than 250 g or, whenused in systemic toxicity tests, not less than 350 g. When used in skintests they are white or light coloured. Unless otherwise stated, miceweigh not less than 17 g and not more than 22 g.

Certain of the biological assays and tests of the Pharmacopoeia aresuch that in the United Kingdom they may be carried out only inaccordance with the Animals (Scientific Procedures) Act 1986.Instructions included in such assays and tests in the Pharmacopoeia,with respect to the handling of animals, are therefore confined to thoseconcerned with the accuracy and reproducibility of the assay or test.

Storage Statements under the side-heading Storage constitute non-mandatoryadvice. The substances and preparations described in the Pharmaco-poeia are to be stored under conditions that prevent contamination and,as far as possible, deterioration. Precautions that should be taken inrelation to the effects of the atmosphere, moisture, heat and light areindicated, where appropriate, in the monographs. Further precautions

may be necessary when some materials are stored in tropical climatesor under other severe conditions. The expression ‘protected frommoisture’ means that the product is to be stored in an airtightcontainer. Care is to be taken when the container is opened in a dampatmosphere. A low moisture content may be maintained, if necessary,by the use of a desiccant in the container provided that direct contactwith the product is avoided. The expression ‘protected from light’means that the product is to be stored either in a container made of amaterial that absorbs actinic light sufficiently to protect the contentsfrom change induced by such light or in a container enclosed in anouter cover that provides such protection or stored in a place fromwhich all such light is excluded. The expression ‘tamper-evidentcontainer’ means a closed container fitted with a device that revealsirreversibly whether the container has been opened.

Labelling The labelling requirements of the Pharmacopoeia are not compre-hensive and laws governing the statements to be declared on labels ofofficial articles should also be met. In the United Kingdom the provis-ions of regulations issued in accordance with the Medicines Act 1968,together with those of regulations for the labelling of hazardousmaterials, should be met.

Only those statements in monographs given under the side-headingLabelling that are necessary to demonstrate compliance or otherwisewith the monograph are mandatory. Any other statements are includedas recommendations.

Such matters as the exact form of wording to be used and whether aparticular item of information should appear on the primary label andadditionally, or alternatively, on the package or exceptionally in a leafletare, in general, outside the scope of the Pharmacopoeia. When the term‘label’ is used in Labelling statements of the Pharmacopoeia, decisionsas to where the particular statement should appear should therefore bemade in accordance with relevant legislation.

The label of every official article states (i) the name at the head of themonograph and (ii) a reference consisting of either figures or letters, ora combination of figures and letters, by which the history of the articlemay be traced.

The label of every official formulated preparation other than those offixed strength also states the content of the active ingredient or ingredi-ents expressed in the terms required by the monograph. Where thecontent of active ingredient is required to be expressed in terms otherthan the weight of the official medicinal substance used in making theformulation, this is specifically stated under the side-heading Labelling.Thus, where no specific requirement is included under the side-headingLabelling, it is implied that the content of active ingredient is expressedin terms of the weight of the official medicinal substance used inmaking the formulation. For example, for Ampicillin Injection, whichcontains Ampicillin Sodium but for which the content is expressed interms of the equivalent amount of ampicillin, a specific requirement tothis effect is included under the side-heading Labelling. ForAmitriptyline Tablets which contain Amitriptyline Hydrochloride andfor which the result of the assay is expressed in terms of amitriptylinehydrochloride no specific statement is included under the side-heading

Labelling; these Tablets are thus labelled with the nominal weight ofAmitriptyline Hydrochloride.

These requirements do not necessarily apply to the labelling of articlessupplied in compliance with a prescription.

Action and Use The statements given under this side-heading in monographs areintended only as information on the principal pharmacological actionsor the uses of the materials in medicine or pharmacy. It should not beassumed that the substance has no other action or use. The statementsare not intended to be binding on prescribers or to limit their discretion.

Crude Drugs The macroscopical characteristics of a crude drug includes those feat-ures that can be seen by the unaided eye or by the use of a hand lens.

Vegetable drugs are required to be free from insects and other animalmatter, and from animal excreta. Not more than traces of foreignorganic matter may be present in powdered vegetable drugs. Microbialcontamination should be minimal.

In determining the content of active principle, Acid-insoluble ash,Ash, Extractive soluble in ethanol, Loss on drying, Sulphated ash,Water, Water-soluble ash and Water-soluble extractive of vegetabledrugs, the calculations are made with reference to the drug that has notbeen specially dried unless otherwise prescribed in the monograph.

In the assays for alkaloids in crude drugs and their preparations,definite quantities of solvents are specified. The quantities are given asbeing suitable for typical cases; they may, however, be varied wherenecessary to overcome the difficulties that may be encountered inspecial instances, provided that the effect of the prescribed directions isensured.

When it is found necessary to dry a crude drug before it can bereduced to powder for the purpose of assay, a correction is made for theloss on drying and the alkaloidal content is calculated with reference tothe undried drug.

Part III Monographs and other texts of the European Pharmacopoeia that areincorporated in this edition of the British Pharmacopoeia are governed by thegeneral notices of the European Pharmacopoeia; these are reproduced below.

GENERAL NOTICES OF THE EUROPEANPHARMACOPOEIA

Text in [ ] does not form part of the General Notices of the EuropeanPharmacopoeia but has been added for the convenience of the user of theBritish Pharmacopoeia.

1.1. GENERAL STATEMENTS

The General Notices apply to all monographs and other texts of theEuropean Pharmacopoeia.

In the texts of the European Pharmacopoeia, the word ‘Pharmaco-poeia’ without qualification means the European Pharmacopoeia. Theofficial abbreviation Ph. Eur. may be used to indicate the EuropeanPharmacopoeia.

The use of the title or the subtitle of a monograph implies that thearticle complies with the requirements of the relevant monograph. Such

references to monographs in the texts of the Pharmacopoeia are shownusing the monograph title and serial number in italics.

A pharmaceutical preparation must comply throughout its period ofvalidity. The subject of any other monograph must comply throughoutits period of use. The period of validity that is assigned to any givenarticle and the time from which that period is to be calculated aredecided by the competent authority in the light of experimental resultsof stability studies.

Unless otherwise indicated in the General Notices or in the mono-graphs, statements in monographs constitute mandatory requirements.General chapters [Appendices] become mandatory when referred to in amonograph, unless such reference is made in a way that indicates that itis not the intention to make the text referred to mandatory but rather tocite it for information or guidance.

The active ingredients (medicinal substances), excipients (auxiliarysubstances), pharmaceutical preparations and other articles described inthe monographs are intended for human and veterinary use (unlessexplicitly restricted to one of these uses). An article is not of Pharma-copoeia quality unless it complies with all the requirements stated in themonograph. This does not imply that performance of all the tests in amonograph is necessarily a prerequisite for a manufacturer in assessingcompliance with the Pharmacopoeia before release of a product. Themanufacturer may obtain assurance that a product is of Pharmacopoeiaquality from data derived, for example, from validation studies of themanufacturing process and from in-process controls. Parametric releasein circumstances deemed appropriate by the competent authority is thusnot precluded by the need to comply with the Pharmacopoeia.

The tests and assays described are the official methods upon which thestandards of the Pharmacopoeia are based. With the agreement of thecompetent authority, alternative methods of analysis may be used forcontrol purposes, provided that the methods used enable an unequivocaldecision to be made as to whether compliance with the standards of themonographs would be achieved if the official methods were used. In theevent of doubt or dispute, the methods of analysis of the Pharmacopoeiaare alone authoritative.

Certain materials that are the subject of a pharmacopoeial monographmay exist in different grades suitable for different purposes. Unlessotherwise indicated in the monograph, the requirements apply to allgrades of the material. In some monographs, particularly those onexcipients, a list of critical properties that are important for the use ofthe substance may be appended to the monograph for information andguidance. Test methods for determination of one or more of thesecritical properties may be given, also for information and guidance.

The general monographs on dosage forms apply to all preparations ofthe type defined. The requirements are not necessarily comprehensivefor a given specific preparation and requirements additional to thoseprescribed in the general monograph may be imposed by the competentauthority.

Conventional terms The term ‘competent authority’means the national, supranational orinternational body or organisation vested with the authority for makingdecisions concerning the issue in question. It may, for example, be a

national pharmacopoeia authority, a licensing authority or an officialcontrol laboratory.

The expression ‘unless otherwise justified and authorised’ means thatthe requirements have to be met, unless the competent authorityauthorises a modification or an exemption where justified in a particularcase.

Statements containing the word ‘should’ are informative or advisory.In certain monographs or other texts, the terms ‘suitable’ and ‘appro-

priate’ are used to describe a reagent, micro-organism, test method etc.;if criteria for suitability are not described in the monograph, suitabilityis demonstrated to the satisfaction of the competent authority.

1.2. OTHER PROVISIONS APPLYING TO GENERALCHAPTERS [APPENDICES] AND MONOGRAPHS

Quantities In tests with numerical limits and assays, the quantity stated to be takenfor examination is approximate. The amount actually used, which maydeviate by not more than 10 per cent from that stated, is accuratelyweighed or measured and the result is calculated from this exactquantity. In tests where the limit is not numerical, but usually dependsupon comparison with the behaviour of a reference in the same condi-tions, the stated quantity is taken for examination. Reagents are used inthe prescribed amounts.

Quantities are weighed or measured with an accuracy commensuratewith the indicated degree of precision. For weighings, the precisioncorresponds to plus or minus 5 units after the last figure stated (forexample, 0.25 g is to be interpreted as 0.245 g to 0.255 g). For themeasurement of volumes, if the figure after the decimal point is a zeroor ends in a zero (for example, 10.0 ml or 0.50 ml), the volume ismeasured using a pipette, a volumetric flask or a burette, as appropriate;otherwise, a graduated measuring cylinder or a graduated pipette maybe used. Volumes stated in microlitres are measured using a micro-pipette or microsyringe. It is recognised, however, that in certain casesthe precision with which quantities are stated does not correspond tothe number of significant figures stated in a specified numerical limit.The weighings and measurements are then carried out with a suffi-ciently improved accuracy.

Apparatus and procedures

Volumetric glassware complies with Class A requirements of theappropriate International Standard issued by the InternationalOrganisation for Standardisation.

Unless otherwise prescribed, analytical procedures are carried out at atemperature between 15°C and 25°C.

Unless otherwise prescribed, comparative tests are carried out usingidentical tubes of colourless, transparent, neutral glass with a flat baseand an internal diameter of 16 mm. Equal volumes of the liquids to becompared are examined down the vertical axis of the tubes against awhite background, or if necessary against a black background. Theexamination is carried out in diffuse light.

Any solvent required in a test or assay in which an indicator is to beused is previously neutralised to the indicator, unless a blank test isprescribed.

Water-bath The term ‘water-bath’ means a bath of boiling water unless water atanother temperature is indicated. Other methods of heating may besubstituted provided the temperature is near to but not higher than100°C or the indicated temperature.

Drying and ignition to constant mass

The terms ‘dried to constant mass’ and ‘ignited to constant mass’mean that two consecutive weighings do not differ by more than 0.5mg, the second weighing following an additional period of drying orof ignition respectively appropriate to the nature and quantity of theresidue.

Where drying is prescribed using one of the expressions ‘in a desic-cator’ or ‘in vacuo’, it is carried out using the conditions describedunder 2.2.32. Loss on drying [Appendix IX D].

Reagents The proper conduct of the analytical procedures described in thePharmacopoeia and the reliability of the results depend, in part, uponthe quality of the reagents used. The reagents are described in generalchapter 4 [Appendix I]. It is assumed that reagents of analytical gradeare used; for some reagents, tests to determine suitability are included inthe specifications.

Solvents Where the name of the solvent is not stated, the term ‘solution’ impliesa solution in water. Where the use of water is specified or implied in theanalytical procedures described in the Pharmacopoeia or for the prepar-ation of reagents, water complying with the requirements of the mono-graph on Purified water (8) is used. The term ‘distilled water’ indicatespurified water prepared by distillation.

The term ‘ethanol’ without qualification means absolute alcohol. Theterm ‘alcohol’ without qualification means alcohol containing about 96per cent V/V of ethanol (C2H6O). Other dilutions of ethanol are indi-cated by the term ‘alcohol’ followed by a statement of the percentage byvolume of ethanol (C2H6O) required.

Expression of content In defining content, the expression ‘per cent’ is used according tocircumstances with one of two meanings:

— per cent m/m (percentage, mass in mass) expresses the number ofgrams of substance in 100 grams of final product.

— per cent V/V (percentage, volume in volume) expresses the numberof millilitres of substance in 100 millilitres of final product.

The expression ‘parts per million (ppm)’ refers to mass in mass,unless otherwise specified.

Temperature Where an analytical procedure describes temperature without a figure,the general terms used have the following meaning:

In a deep-freeze below –15°C

In a refrigerator 2°C to 8°C

Cold or cool 8°C to 15°C

Room temperature 15°C to 25°C

1.3. GENERAL CHAPTERS [incorporated in the Appendices ofthe British Pharmacopoeia]

Containers Materials used for containers are described in general chapter 3[Appendix XX]. General names used for materials, particularly plasticsmaterials, each cover a range of products varying not only in theproperties of the principal constituent but also in the additives used.The test methods and limits for materials depend on the formulationand are therefore applicable only for materials whose formulation iscovered by the preamble to the specification. The use of materials withdifferent formulations and the test methods and limits applied to themare subject to agreement by the competent authority.

The specifications for containers in general chapter 3 [AppendixXIX], have been developed for general application to containers of thestated category but in view of the wide variety of containers availableand possible new developments, the publication of a specification doesnot exclude the use, in justified circumstances, of containers thatcomply with other specifications, subject to agreement by the competentauthority.

Reference may be made within the monographs of the Pharmacopoeiato the definitions and specifications for containers provided in thissection. The general monographs for pharmaceutical dosage forms may,under the heading Definition/Production, require the use of certaintypes of container; certain other monographs may, under the headingStorage, indicate the type of container that is recommended for use.

1.4. MONOGRAPHS

Titles Monograph titles are in English and French in the respective versions[published by the Council of Europe] and there is a Latin subtitle whichmay be used in place of the English or French title as may any synonymsdeclared equivalent by the competent authority [see ApprovedSynonyms, Appendix XXI B].

Relative atomic and The relative atomic mass (Ar) or the relative molecular mass (Mr) ismolecular masses shown, as and where appropriate, at the beginning of each monograph.

The relative atomic and molecular masses and the molecular andgraphic formulae do not constitute analytical standards for thesubstances described.

Definition Statements under the heading Definition constitute an official definitionof the substance, preparation or other article that is the subject of themonograph.

Limits of content Where limits of content are prescribed, they arethose determined by the method described under Assay.

Vegetable drugs In monographs on vegetable drugs, the definitionindicates whether the subject of the monograph is, for example, thewhole drug or the drug in powdered form. Where a monograph appliesto the drug in several states, for example both to the whole drug and thedrug in powdered form, the definition states this.

Production Statements under the heading Production draw attention to particularaspects of the manufacturing process but are not necessarily compre-hensive. They constitute instructions to manufacturers. They mayrelate, for example, to source materials, to the manufacturing process

itself and its validation and control, to in-process testing or to testingthat is to be carried out by the manufacturer on the final article eitheron selected batches or on each batch prior to release. These statementscannot necessarily be verified on a sample of the final article by anindependent analyst. The competent authority may establish that theinstructions have been followed, for example, by examination of datareceived from the manufacturer, by inspection of manufacture or bytesting appropriate samples.

The absence of a section on Production does not imply that attentionto features such as those referred to above is not required. A productdescribed in a monograph of the Pharmacopoeia is manufactured inaccordance with the principles of good manufacturing practice and inaccordance with relevant international agreements and supranationaland national regulations governing products for human or veterinaryuse.

Where in the section under the heading Production a monograph on avaccine defines the characteristics of the vaccine strain to be used, anytest methods given for confirming these characteristics are provided forinformation as examples of suitable methods.

Characters The statements under the heading Characters are not to be interpretedin a strict sense and are not requirements.

Solubility In statements of solubility in the section headed Characters,the terms used have the following significance referred to a temperaturebetween 15°C and 25°C.

Descriptive term Approximate volume ofsolvent in millilitres pergram of solute

very soluble less than 1freely soluble from 1 to 10soluble from 10 to 30sparingly soluble from 30 to 100slightly soluble from 100 to 1000very slightly soluble from 1000 to 10,000practically insoluble more than 10,000

The term ‘partly soluble’ is used to describe a mixture where onlysome of the components dissolve. The term ‘miscible’ is used todescribe a liquid that is miscible in all proportions with the statedsolvent.

Identification The tests given in the identification section are not designed to give afull confirmation of the chemical structure or composition of theproduct; they are intended to give confirmation, with an acceptabledegree of assurance, that the article conforms to the description on thelabel.

Certain monographs have subdivisions entitled ‘First identification’and ‘Second identification’. The test or tests that constitute the ‘Secondidentification’ may be used instead of the test or tests of the ‘Firstidentification’ provided it can be demonstrated that the substance orpreparation is fully traceable to a batch certified to comply with all therequirements of the monograph.

Tests and assays Scope The requirements are not framed to take account of all possibleimpurities. It is not to be presumed, for example, that an impurity thatis not detectable by means of the prescribed tests is tolerated if commonsense and good pharmaceutical practice require that it be absent. Seealso below under Impurities.

Calculation Where the result of a test or assay is required to becalculated with reference to the dried or anhydrous substance or onsome other specified basis, the determination of loss on drying, watercontent or other property is carried out by the method prescribed in therelevant test in the monograph.

Limits The limits prescribed are based on data obtained in normalanalytical practice; they take account of normal analytical errors, ofacceptable variations in manufacture and compounding and of deterio-ration to an extent considered acceptable. No further tolerances are tobe applied to the limits prescribed to determine whether the articlebeing examined complies with the requirements of the monograph.

In determining compliance with a numerical limit, the calculatedresult of a test or assay is first rounded to the number of significantfigures stated, unless otherwise prescribed. The last figure is increasedby one when the part rejected is equal to or exceeds one half-unit,whereas it is not modified when the part rejected is less than a half-unit.

Indication of permitted limit of impurities The approximatecontent of impurity tolerated, or the sum of impurities, may be indica-ted in parentheses for information only. If the use of a referencesubstance for the named impurity is not prescribed, this content may beexpressed as a nominal concentration of the substance used to preparethe reference solution specified in the monograph, unless otherwisedescribed. Acceptance or rejection is determined on the basis of compli-ance or non-compliance with the stated test.

Vegetable drugs For vegetable drugs, the sulphated ash, total ash,water-soluble matter, alcohol-soluble matter, water content, content ofessential oil and content of active principle are calculated with referenceto the drug that has not been specially dried, unless otherwise prescri-bed in the monograph.

Equivalents Where an equivalent is given, for the purposes of thePharmacopoeia only the figures shown are to be used in applying therequirements of the monograph.

Storage The information and recommendations given under the heading Storagedo not constitute a pharmacopoeial requirement but the competentauthority may specify particular storage conditions that must be met.

The articles described in the Pharmacopoeia are stored in such a wayas to prevent contamination and, as far as possible, deterioration. Wherespecial conditions of storage are recommended, including the type ofcontainer (see General Notice on Containers above) and limits oftemperature, they are stated in the monograph.

The following expressions are used in monographs under Storage withthe meaning shown.

Protected from moisture means that the product is stored in an airtightcontainer. Care is to be taken when the container is opened in a dampatmosphere. A low moisture content may be maintained, if necessary,

by the use of a desiccant in the container provided that direct contactwith the product is avoided.

Protected from light means that the product is stored either in acontainer made of a material that absorbs actinic light sufficiently toprotect the contents from change induced by such light or in a containerenclosed in an outer cover that provides such protection or stored in aplace from which all such light is excluded.

Labelling In general, labelling is subject to supranational and national regulationand to international agreements. The statements under the headingLabelling therefore are not comprehensive and, moreover, for thepurposes of the Pharmacopoeia only those statements that are necessaryto demonstrate compliance or non-compliance with the monograph aremandatory. Any other labelling statements are included as recommend-ations. When the term ‘label’ is used in the Pharmacopoeia, the label-ling statements may appear on the container, the package or a leafletaccompanying the package, as decided by the competent authority.

Warnings Materials described in monographs and reagents specified for use in thePharmacopoeia may be injurious to health unless adequate precautionsare taken. The principles of good quality control laboratory practice andthe provisions of any appropriate regulations are to be observed at alltimes. Attention is drawn to particular hazards in certain monographsby means of a warning statement; absence of such a statement is not tobe taken to mean that no hazard exists.

Impurities A list of all known and potential impurities that have been shown to becontrolled by the tests in a monograph may be given for information.The list may be divided into two sublists entitled ‘Qualified impuri-ties’and ‘Other detectable impurities’. Qualified impurities are thosepreviously accepted by the competent authority as being qualified;impurities deemed qualified by other means (for example, impuritieswhich occur as natural metabolites) may also be included. Otherdetectable impurities are those potential impurities that have not beendetected in any samples of the substance during elaboration of themonograph or that occur in amounts below 0.1 per cent, but that havebeen shown to be limited by the tests.

Critical physical properties

A list of critical physical properties that are not the subject of officialrequirements but which are nevertheless important for the use of asubstance may be appended to a monograph, for information andguidance (see also above 1.1. General statement).

Reference substances, reference preparations and reference spectra

Certain monographs require the use of a reference substance, areference preparation or a reference spectrum. These are chosen withregard to their intended use as prescribed in the monographs of thePharmacopoeia and are not necessarily suitable in other circumstances.The European Pharmacopoeia Commission does not acceptresponsibility for any errors arising from use other than as prescribed.

The reference substances, the reference preparations and the referencespectra are established by the European Pharmacopoeia Commissionand may be obtained from the Technical Secretariat. They are the

official reference materials to be used in cases of arbitration. A list ofreference substances, reference preparations and reference spectra maybe obtained from the Technical Secretariat.

Local reference materials may be used for routine analysis, providedthey are calibrated against the materials established by the EuropeanPharmacopoeia Commission.

Any information necessary for proper use of the reference substanceor reference preparation is given on the label or in the accompanyingleaflet or brochure. Where no drying conditions are stated in the leafletor on the label, the substance is to be used as received. No certificate ofanalysis or other data not relevant to the prescribed use of the productare provided. No expiry date is indicated: the products are guaranteedto be suitable for use when despatched and can normally be used for notless than 6 months after receipt if the containers are stored unopened asdescribed in the accompanying leaflet; beyond this period, it is neces-sary to seek advice from the Technical Secretariat. The stability of thecontents of opened containers cannot be guaranteed.

Chemical Reference Substances The abbreviation CRS indicates aChemical Reference Substance established by the European Pharmaco-poeia Commission. Some Chemical Reference Substances are used forthe microbiological assay of antibiotics and their activity is stated, inInternational Units, on the label or on the accompanying leaflet anddefined in the same manner as for Biological Reference Preparations.

Biological Reference Preparations The majority of the primarybiological reference preparations referred to in the European Pharmaco-poeia are the appropriate International Standards and Reference Prepar-ations established by the World Health Organisation. Because thesereference materials are usually available only in limited quantities, theCommission has established Biological Reference Preparations (indica-ted by the abbreviation BRP) where appropriate. Where applicable, thepotency of the Biological Reference Preparations is expressed in Inter-national Units. For some Biological Reference Preparations, where aninternational standard or reference preparation does not exist, thepotency is expressed in European Pharmacopoeia Units.

Reference spectra The reference spectrum is accompanied byinformation concerning the conditions used for sample preparation andrecording the spectrum.

1.5 ABBREVIATIONS AND SYMBOLS

A Absorbancecentper 1

mc 1A Specific absorbance

A1 Relative atomic mass

[ ]α D20 Specific optical rotation

bp Boiling point

BRP Biological Reference Preparation

CRS Chemical Reference Substance2020d Relative density

I.U. International Unit

l Wavelength

M Molarity

Mr Relative molecular mass

mp Melting point20Dn Refractive index

Ph. Eur. U. European Pharmacopoeia Unit

ppm Parts per million

R Substance or solution defined under“Reagents”

Rf Used in chromatography to indicate the ratioof the distance travelled by a substance tothe distance travelled by the solvent front

Rst Used in chromatography to indicate the ratioof the distance travelled by a substance tothe distance travelled by a referencesubstance

PD50 The statistically determined dose of avaccine that, in the conditions of the tests,may be expected to protect 50 per cent ofthe animals against a challenge dose ofthe micro-organisms or toxins against whichit is active.

ED50 The statistically determined dose of avaccine that, in the conditions of the tests,may be expected to induce specificantibodies in 50 per cent of the animals forthe relevant vaccine antigens.

PFU Pock-forming units or plaque-forming units.

SPF Specified-pathogen-free.

COLLECTIONS OF MICRO-ORGANISMS

ATTC American Type Culture Collection10810 University BouldevardManassas, Virginia 20110-2209, USA

C.I.P. Collection de l’Institut Pasteur (strains ofbacteria)

B.P. 52, 25 rue de Docteur Roux75724 Paris Cedex 15, France

IMI International Mycological InstituteBakeham LaneSurrey TW20 9TY, Great Britain

I.P. Institut Pasteur (strains of other micro-organisms)

Service de la Collection Nationale deCulture de Micro-organismes (C.N.C.M.)25, rue du Docteur-RouxF-75015 Paris, France

NCIMB National Collection of Industrial and MarineBacteria Ltd23 St Machar DriveAberdeen AB24 3RY, Great Britain

NCPF National Collection of Pathogenic FungiLondon School of Hygiene & TropicalMedicineKeppel StreetLondon WC1E 7HT, Great Britain

NCTC National Collection of Type CulturesCentral Public Health LaboratoryColindale AvenueLondon NW9 5HT, Great Britain

NCYC National Collection of Yeast CulturesAFRC Food Reserach InstituteColney LaneNorwich NR4 7UA, Great Britain

S.S.I. Statens Serum Institut80 Amager Boulevard, Copenhagen,Denmark

[See also Appendix XXIV]

RV Substance used as a primary standard involumetric analysis

ABBREVIATIONS USED IN THEMONOGRAPHS ON IMMUNOGLOBINS,IMMUNOSERA AND VACCINES

LD50 The statistically determined quantity of asubstance that, when administered by thespecific route, may be expected to causethe death of 50 per cent of the test animalswithin a given period.

MLD Minimum lethal dose

L+/10 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, causes the death of thetest animals within a given period.

L+ dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with 1I.U. of antitoxin and administered by thespecific route, causes the death of thetest animals within a given period.

Lr/100 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.01 I.U. of antitoxin and injectedintracutaneously causes a characteristicreaction at the site of injection within agiven period.

Lp/10 dose The smallest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, causes paralysis in thetest animals within a given period.

Lo/10 dose The largest quantity of a toxin that, in thecondition of the test, when mixed with0.1 I.U. of antitoxin and administered bythe specific route, does not causesymptoms of toxicity in the test animalswithin a given period.

Lf dose The quantity of toxin or toxoid thatflocculates in the shortest time with 1 I.U.of antitoxin.

CCID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the cell cultures to which it isadded.

EID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of fertilised eggs into which it isinoculated.

ID50 The statistically determined quantity ofvirus that may be expected to infect 50 percent of the animals into which it isinoculated.

1.6. UNITS OF THE INTERNATIONAL SYSTEM (SI) USEDIN THE PHARMACOPOEIA AND EQUIVALENCE WITHOTHER UNITS

International System of Units (SI)

The International System of Units comprises three classes of units,namely base units, derived units and supplementary units.1 The baseunits and their definitions are set out in Table 1.6-1.

The derived units may be formed by combining the base unitsaccording to the algebraic relationships linking the correspondingquantities. Some of these derived units have special names andsymbols. The SI units used in the European Pharmacopoeia are shownin Table 1.6-2.

Some important and widely used units outside the InternationalSystem are shown in Table 1.6-3.

The prefixes shown in Table 1.6-4 are used to form the names andsymbols of the decimal multiples and submultiples of SI units.

Table 1.6–1 SI Base Units

Quantity Unit Definition

Name Symbol Name Symbol

Length L metre m The metre is the length of the path travelled by light in a vacuumduring a time interval of 1/299,792,458 of a second.

Mass M kilogram kg The kilogram is equal to the mass of the international prototype ofthe kilogram

Time T second s The second is the duration of 9,192,631,770 periods of theradiation corresponding to the transition between the two hyperfinelevels of the ground state of the caesium-133 atom.

Electric current I ampere A The ampere is that constant current which, maintained in twostraight parallel conductors of infinite length, of negligible circularcross section and placed 1 metre apart in vacuum would producebetween these conductors a force equal to 2 × 10–7newton permetre of length.

Thermodynamictemperature

T kelvin K The kelvin is the fraction 1/273.16 of the thermodynamictemperature of the triple point of water.

Amount of substance N mole mol The mole is the amount of substance of a system containing asmany elementary entities as there are atoms in 0.012 kilogram ofcarbon-12*

Luminous intensity Iv candela cd The candela is the luminous intensity in a given direction of asource emitting monochromatic radiation with a frequency of540 × 1012 hertz and whose energy intensity in that direction is1/683 watt per steradian.

* When the mole is used, the elementary entities must be specified and may be atoms, molecules, ions, electrons, other particles orspecified groups of such particles.

1The definitions of the units used in the International System aregiven in the booklet Le Système International d’Unités (SI)published by the Bureau International des Poids et Mesures,Pavillon de Breteuil, F-92310 Sevres, France

Table 1.6–2 SI Units used in the European Pharmacopoeia and Equivalence with Other Units

Quantity Unit Conversion of other unitsinto SI units

Name Symbol Name Symbol Expression inSI base units

Expression inother SI units

Wave number ν one per metre 1/m m–1

Wavelength λ micrometre µm 10–6 m

nanometre nm 10–9 m

Area A, S square metre m2 m2

Volume V cubic metre m3 m3 1 ml = 1 cm3 = 10–6 m3

Frequency ν hertz Hz s–1

Density ρρρρρρρρρρρρρρρρρρρρρρρρρ kilogram percubic metre

kg/m3 Kg·m–3 1 g/ml = 1 g/cm3 =103 kg·m–3

Velocity ν metre per second m/s m·s–1

Force F newton N m·kg·s–2 1 dyne = 1g·cm·s–2 =10–5 N1 kp = 9.806 65 N

Pressure ρ pascal Pa m–1·kg·s–2 N·m–2 1 dyne/cm2 = 10–1 Pa =10–1 N·m–2

1 atm = 101 325 Pa =101.325 kPa1 bar = 105 Pa = 0.1 MPa1 mm Hg = 133.322 387 Pa1 Torr = 133.322 368 Pa1 psi = 6.894 757 kPa

Dynamic viscosity η pascal second Pa·s m–1·kg·s–1 N·s·m–2 1 P = 10–1 Pa·s =10–1 N·s·m–2

1 cP = 1 mPa·s

Kinematicviscocity

ν square metreper second

m2 /s m2·s–1 Pa·s·m2·kg–1

N·m·s·kg–11 St = 1 cm2·s–1 = 10–4 m2·s–1

Energy W joule J m2·kg·s–2 N·m 1 erg = 1 cm2·g·s–2 =1 dyne·cm = 10–1 J

1 cal = 4.1868 J

PowerRadiant flux

P watt W m2·kg·s–3 N·m·s–1

J·s–11 erg/s = 1 dyne·cm·s–1 =10–7 W = 10–7 N·m·s–1 =10–7 J·s–1

Absorbed dose(of radiant energy)

D gray Gy m2?s–2 J·kg–1 1 rad = 10–2 Gy

Electric potential,electromotive force

U volt V m2·kg·s–3·A–1 W·A–1

Electric resistance R ohm Ω m2·kg·s–3·A–2 V·A–1

Quantity of electricity Q coulomb C A·s

Activity of aradionuclide

A becquerel Bq s–1 1 Ci = 37 ×× 109 Bq =37 ×× 109 s–1

Concentration(of amount ofsubstance)

Molar concentration c mole per cubicmetre

mol/m3 mol·m–3 1 mol/l = 1M = 1 mol/dm3 =103 mol·m–1

Mass concentration ρρρρρρρρρρρρρρρρρρρρρρρρρ kilogram per cubicmetre

kg/m3 kg·m–3 1 g/l = 1 g/dm3 = 1 kg·m–3

Table 1.6–3 Units used with the International System

Quantity Unit Value in SI units

Time Symbol

Time minute min 1 min = 60 s

hour h 1 h = 60 mins = 3600 s

day d 1 d = 24 h = 86 4000 s

Plane angle degree ° 1° = (π ⁄ 180) rad

Volume litre l 1 l = 1 dm3 = 10−3 m3

Mass tonne t 1 t = 103 kg

Rotationalfrequency

revolutionper minute

r ⁄⁄ min 1 r ⁄ min = (1 ⁄ 60) s−1

Table 1.6–4 Decimal Multiples and Sub-multiples of Units

Factor Prefix Symbol Factor Prefix Symbol

1018 exa E 10−1 deci d

1015 peta P 10−2 centi c

1012 tera T 10−3 milli m

109 giga G 10−6 micro µ106 mega M 10−9 nano n

103 kilo k 10−12 pico p

102 hecto h 10−15 femto f

101 deca da 10−18 atto a

NOTES

1. In the Pharmacopoeia the Celsius temperature is used (symbol t). This is defined by the equation

t = T - To

where To = 273.15 K by definition. The Celsius or centigrade temperature is expressed in degree Celsius (symbol°C). The unit “degree Celsius” is equal to the unit “kelvin”.

2. The practical expressions of concentrations used in the Pharmacopoeia are defined in the General Notices.

3. The radian is the plane angle between two radii of a circle which cut off on the circumference an arc equal in lengthto the radius.

4. In the Pharmacopoeia conditions of centrifugation are defined by reference to the acceleration due to gravity (g):g = 9.806 65 mvs–2

5. Certain quantities without dimensions are used in the Pharmacopoeia: relative density (2.2.5), absorbance (2.2.25),specific absorbance (2.2.25) and refractive index (2.2.6) as well as quantities expressed in other units such as thespecific optical rotation (2.2.7).

6. The microkatal is defined as the enzymic activity which, under defined conditions, produces the transformation(e.g. hydrolysis) of 1 micromole of the substrate per second.

Monographs

Formulated Preparations:General Monographs

45-2

FORMULATED PREPARATIONS:GENERAL MONOGRAPHS

GLOSSARY

A glossary of terms relating to formulated preparations is included in the 3rd edition of the European Pharma-copoeia [1502]. This glossary is reproduced below.

Ph Eru ___________________________________________________________________________________________________________

The following introductory text provides definitions and/or explanations of terms that may be found in, or usedin association with, the general monographs on dosage forms, but that are not defined within them. Whererelevant, reference is made to other equivalent terms that may be found in other publications or contexts.

This glossary is given for information.

Standard Term

Standard Terms for describing the pharmaceutical form of a medicinal product, the routes ofadministration and the containers used have been established by the European PharmacopoeiaCommission and are provided in a separate publication on Standard Terms.

Active substance

The active substance is any component of a medicinal product intended to furnish pharmacologicalactivity or another direct effect in the diagnosis, treatment or prevention of disease, or to affect thestructure or function of the human or animal body by pharmacological means. A medicinal productmay contain more than one active substance. Equivalent terms: active ingredient, drug substance,medicinal substance.

Excipient

An excipient is any component, other than the active substance(s), present in a medicinal product orused in the manufacture of the product. The intended function of an excipient is to act as the carrier(vehicle or basis) or as a component of the carrier of the active substance(s) and, in so doing, tocontribute to product attributes such as stability, biopharmaceutical profile, appearance and patientacceptability and to the ease with which the product can be manufactured. Usually, more than oneexcipient is used in the formulation of a medicinal product.

Vehicle

A vehicle is the carrier, composed of one or more excipients, for the active substance(s) in a liquidpreparation.

Basis

A basis is the carrier, composed of one or more excipients, for the active substance(s) in semi-solidand solid preparations.

Conventional-release dosage forms

Conventional-release dosage forms are preparations showing a release of the active substance(s)which is not deliberately modified by a special formulation design and/or manufacturing method. Inthe case of a solid dosage form, the dissolution profile of the active substance depends essentially onits intrinsic properties. Equivalent term: immediate-release dosage form.

Modified-release dosage formsModified-release dosage forms are preparations where the rate and/or place of release of the activesubstance(s) is different from that of a conventional-release dosage form administered by the sameroute. This deliberate modification is achieved by a special formulation design and/or manufacturingmethod. Modified-release dosage forms include prolonged-release, delayed-release and pulsatile-release dosage forms.

Prolonged-release dosage forms

Prolonged-release dosage forms are modified-release dosage forms showing a slower release of theactive substance(s) than that of a conventional-release dosage form administered by the same route.Prolonged-release is achieved by a special formulation design and/or manufacturing method. Equiva-lent term: extended-release dosage form.

Delayed-release dosage forms

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Delayed-release dosage forms are modified-release dosage forms showing a release of the activesubstance(s) which is delayed. Delayed release is achieved by a special formulation design and/ormanufacturing method. Delayed-release dosage forms include gastro-resistant preparations as definedin the general monographs on solid oral dosage forms.

Pulsatile-release dosage forms

Pulsatile-release dosage forms are modified-release dosage forms showing a sequential release of theactive substance(s). Sequential release is achieved by a special formulation design and/ormanufacturing method.

Large-volume parenterals

Infusions and injections supplied in containers with a nominal content of more than 100 ml.

Small-volume parenterals

Infusions and injections supplied in containers with a nominal content of 100 ml or less.__________________________________________________________________________________________________________ Ph Eur

45-4

CAPSULES

revised 1/01

Capsules comply with the requirements of the 3rd edition of the European Pharmacopoeia [0016]. Theserequirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

The requirements of this monograph do not necessarily apply to preparations that are presented as capsulesintended for use other than by oral administration. Requirements for such preparations may be found, whereappropriate, in other general monographs, for example Rectal preparations (1145) and Vaginal preparations(1164).

DEFINITION

Capsules are solid preparations with hard or soft shells of various shapes and capacities, usuallycontaining a single dose of active substance. They are intended for oral administration.

The capsule shells are made of gelatin or other substances, the consistency of which may beadjusted by the addition of substances such as glycerol or sorbitol. Excipients such as surface-activeagents, opaque fillers, antimicrobial preservatives, sweeteners, colouring matter authorised by thecompetent authority and flavouring substances may be added. The capsules may bear surfacemarkings.

The contents of capsules may be solid, liquid or of a paste-like consistency. They consist of one ormore active substances with or without excipients such as solvents, diluents, lubricants anddisintegrating agents. The contents do not cause deterioration of the shell. The shell, however, isattacked by the digestive fluids and the contents are released.

Where applicable, containers for capsules comply with the requirements of Materials used for themanufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of capsules may be distinguished:— hard capsules,— soft capsules,— gastro-resistant capsules,— modified-release capsules,— cachets.

PRODUCTION

In the manufacture, packaging, storage and distribution of capsules, suitable means are taken toensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, capsuleswith a content of active substance less than 2 mg or less than 2 per cent of the total mass comply withtest B for uniformity of content of single-dose preparations. If the preparation has more than oneactive substance, the requirement applies only to those ingredients which correspond to the aboveconditions.

Uniformity of mass (2.9.5). Capsules comply with the test for uniformity of mass of single-dosepreparations. If the test for uniformity of content is prescribed for all the active substances, the testfor uniformity of mass is not required.

Dissolution A suitable test may be carried out to demonstrate the appropriate release of the activesubstance(s), for example one of the tests described in Dissolution test for solid dosage forms (2.9.3).

Where a dissolution test is prescribed, a disintegration test may not be required.

STORAGE

Store in a well-closed container, at a temperature not exceeding 30°C.

LABELLING

The label states the name of any added antimicrobial preservative.

Hard Capsules

DEFINITION

Hard capsules have shells consisting of two prefabricated cylindrical sections one end of which isrounded and closed, the other being open.

45-5

PRODUCTION

The active substance(s) usually in solid form (powder or granules) are filled into one of thesections which is then closed by slipping the other section over it. The security of the closure maybe strengthened by suitable means.

TESTS

Disintegration Hard capsules comply with the test for disintegration of tablets and capsules(2.9.1). Use water R as the liquid medium. When justified and authorised, 0.1M hydrochloric acid orartificial gastric juice R may be used as the liquid medium. If the capsules float on the surface of thewater, a disc may be added. Operate the apparatus for 30 min, unless otherwise justified andauthorised and examine the state of the capsules. The capsules comply with the test if all six havedisintegrated.

Soft Capsules

DEFINITION

Soft capsules have thicker shells than those of hard capsules. The shells consist of one part and areof various shapes.

PRODUCTION

Soft capsules are usually formed, filled and sealed in one operation but for extemporaneous use,the shell may be prefabricated. The shell material may contain an active substance.

Liquids may be enclosed directly; solids are usually dissolved or dispersed in a suitable vehicle togive a solution or dispersion of a paste-like consistency.

There may be partial migration of the constituents from the capsule contents into the shell and viceversa because of the nature of the materials and the surfaces in contact.

TESTS

Disintegration Soft capsules comply with the test for disintegration of tablets and capsules (2.9.1).Use water R as the liquid medium. When justified and authorised, 0.1M hydrochloric acid or artificialgastric juice R may be used as the liquid medium. Add a disc to each tube. Liquid active substancesdispensed in soft capsules may attack the disc; in such circumstances and where authorised, the discmay be omitted. Operate the apparatus for 30 min, unless otherwise justified and authorised andexamine the state of the capsules. If the capsules fail to comply because of adherence to the discs,repeat the test on a further six capsules omitting the discs. The capsules comply with the test if all sixhave disintegrated.

Modified-Release Capsules

DEFINITION

Modified-release capsules are hard or soft capsules in which the contents or the shell or both containspecial excipients or are prepared by a special process designed to modify the rate, the place or thetime at which the active substance(s) are released.

Modified release capsules include prolonged-release capsules and delayed-release capsules.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Gastro-Resistant Capsules

DEFINITION

Gastro-resistant capsules are delayed-release capsules that are intended to resist the gastric fluid andto release their active substance or substances in the intestinal fluid. Usually they are prepared byfilling capsules with granules or with particles covered with a gastro-resistant coating or in certaincases, by providing hard or soft capsules with a gastro-resistant shell (enteric capsules).

PRODUCTION

For capsules filled with granules or filled with particles covered with a gastro-resistant coating, asuitable test is carried out to demonstrate the appropriate release of the active substance(s).

TESTS

Disintegration For capsules with a gastro-resistant shell carry out the test for disintegration (2.9.1)with the following modifications. Use 0.1M hydrochloric acid as the liquid medium and operate theapparatus for 2 h, or other such time as may be authorised, without the discs. Examine the state ofthe capsules. The time of resistance to the acid medium varies according to the formulation of thecapsules to be examined. It is typically 2 h to 3 h but even with authorised deviations it must not beless than 1 h. No capsule shows signs of disintegration or rupture permitting the escape of the

45-6

contents. Replace the acid by phosphate buffer solution pH 6.8 R. When justified and authorised, abuffer solution of pH 6.8 with added pancreas powder (for example, 0.35 g of pancreas powder Rper 100 ml of buffer solution) may be used. Add a disc to each tube. Operate the apparatus for 60min and examine the state of the capsules. If the capsules fail to comply because of adherence tothe discs, repeat the test on a further six capsules omitting the discs. The capsules comply with thetest if all six have disintegrated.

Dissolution For capsules prepared from granules or particles already covered with a gastro-resistant coating, a suitable test is carried out to demonstrate the appropriate release of the activesubstance(s), for example the test described in Dissolution test for solid dosage forms (2.9.3).

Cachets

DEFINITION

Cachets are solid preparations consisting of a hard shell containing a single dose of one or moreactive substances. The cachet shell is made of unleavened bread usually from rice flour and consistsof two prefabricated flat cylindrical sections. Before administration, the cachets are immersed inwater for a few seconds, placed on the tongue and swallowed with a draught of water.

LABELLING

The label states the method of administration of the cachets.__________________________________________________________________________________________________________ Ph Eur

Capsules of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosecapsules that are the subject of an individual monograph in the British Pharmacopoeia.

When presented as granules the contents of the requisite number of capsules should be mixed andpowdered before performing the Assay and tests described in the monograph.

Content of active ingredient in capsules The range for the content of active ingredient stated inthe monograph is based on the requirement that 20 capsules, or such other number as may beindicated in the monograph, are used in the Assay. In the circumstances where 20 capsules cannot beobtained, a smaller number, which must not be less than 5, may be used, but to allow for samplingerrors the tolerances are widened in accordance with Table I.

The requirements of Table I apply when the stated limits are 90 to 110%. For limits other than 90to 110%, proportionately smaller or larger allowances should be made.

Disintegration For those Hard Capsules or Soft Capsules for which a requirement for Dissolution isincluded in the individual monograph, the requirement for Disintegration does not apply.

Uniformity of content Details of the analytical method to be employed for determining the contentof active ingredient may be included in certain monographs. Unless otherwise stated in themonograph the limits are as given in test B for uniformity of content, Appendix XII H.

Any capsules that when examined individually show a gross deviation from the prescribed or statedcontent are not official.

Labelling The label states (1) the quantity of the active ingredient contained in each Capsule; (2)the date after which the Capsules are not intended to be used; (3) the conditions under which theCapsules should be stored.

The following capsules are the subject of an individual monograph in the British Pharmacopoeia.

Acebutolol CapsulesAmantadine CapsulesAmoxicillin CapsulesAmpicillin CapsulesAzapropazone CapsulesBromocriptine CapsulesCalcitriol CapsulesCefaclor CaspulesCefadroxil CapsulesCefalexin CapsulesCefradine CapsulesChloramphenicol CapsulesChlordiazepoxide CapsulesClindamycin CapsulesClobazam CapsulesClofazimine Capsules

45-7

Clofibrate CapsulesClomethiazole CapsulesClomipramine CapsulesCloxacillin CapsulesCo-beneldopa CapsulesCo-danthrusate CapsulesCo-fluampicil CapsulesDemeclocycline CapsulesDextropropoxyphene CapsulesDisopyramide CapsulesDisopyramide Phosphate CapsulesDocusate CapsulesDosulepin Capsules/Dothiepin CapsulesDoxepin CapsulesDoxycycline CapsulesErythromycin Estolate CapsulesEstramustine Phosphate CapsulesEthosuximide CapsulesEtodolac CapsulesEtoposide CapsulesFenbufen CapsulesFerrous Fumarate CapsulesFlucloxacillin CapsulesFluoxetine CapsulesFlurazepam CapsulesGemfibrozil CapsulesHalibut-liver Oil CapsulesHaloperidol CapsulesHydroxycarbamide Capsules/Hydroxyurea CapsulesIndometacin CapsulesIsotretinoin CapsulesKetoprofen CapsulesLevodopa CapsulesLincomycin CapsulesLomustine CapsulesLoperamide CapsulesLymecycline CapsulesMefenamic Acid CapsulesMetyrapone CapsulesMexiletine CapsulesNaftidrofuryl CapsulesNifedipine CapsulesNortriptyline CapsulesOxytetracycline CapsulesPentazocine CapsulesPeppermint Oil Capsules, Gastro-resistantPhenoxybenzamine CapsulesPhenytoin CapsulesPiroxicam CapsulesPropranolol Capsules, Prolonged-releaseRifampicin CapsulesTetracycline CapsulesTriamterene CapsulesUrsodeoxycholic Acid Capsules

45-8

MEDICATED CHEWING GUMS

corrected 1/01

Medicated Chewing Gums comply with the requirements of the 3rd edition of the European Pharmacopoeia[1239]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Medicated chewing gums are solid, single-dose preparations with a base consisting mainly of gumthat are intended to be chewed but not swallowed.

They contain one or more active substances which are released by chewing. After dissolution ordispersion of the active substances in saliva, chewing gums are intended to be used for:— local treatment of mouth diseases,— systemic delivery after absorption through the buccal mucosa or from the gastrointestinal tract.

PRODUCTION

Medicated chewing gums are made with a tasteless masticatory gum base that consists of natural orsynthetic elastomers. They may contain other excipients such as fillers, softeners, sweetening agents,flavouring substances, stabiliser and plasticisers and authorised colouring matter.

Medicated chewing gums are manufactured by compression or by softening or melting the gumbases and adding successively the other substances. In the latter case, chewing gums are then furtherprocessed to obtain the desired gum presentation. The medicated chewing gums may be coated, forexample, if necessary to protect from humidity and light.

Unless otherwise justified and authorised, a suitable test is carried out to demonstrate theappropriate release of the active ingredient(s).

In the manufacture, packaging, storage and distribution of medicated chewing gums, suitablemeans must be taken to ensure their microbial quality; recommendations related to this aspect areprovided in the general chapter on Microbiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, medicatedchewing gums with a content of active ingredient less than 2 mg or less than 2 per cent of the totalmass comply with test A for uniformity of content of single-dose preparations. If the preparationcontains more than one active substance, the requirement applies only to those active substanceswhich correspond to the above conditions.

Uniformity of mass (2.9.5). Uncoated medicated chewing gums and, unless otherwise justified andauthorised, coated medicated chewing gums comply with the test for uniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed for all the active substances, thetest for uniformity of mass is not required.

STORAGE

Store uncoated medicated chewing gums protected from humidity and light.__________________________________________________________________________________________________________ Ph Eur

45-9

LIQUIDS FOR CUTANEOUS APPLICATION

LIQUID PREPARATIONS FOR CUTANEOUS APPLICATION revised 1/01

Liquids for Cutaneous Application comply with the requirements of the 3rd edition of the European Pharma-copoeia [0927] for Liquid Preparations for Cutaneous Application. These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Where justified and authorised, the requirements of this monograph do not apply to liquid preparations forcutaneous application intended for systemic use.

DEFINITION

Liquid preparations for cutaneous application are preparations of a variety of viscosities intended tobe applied to the skin (including the scalp) or nails in order to obtain a local action or transdermalactivity. They are solutions, emulsions or suspensions which may contain one or more activesubstances in a suitable vehicle. They may contain suitable antimicrobial preservatives, antioxidantsand other excipients such as stabilisers, emulsifiers and thickeners.

Emulsions may show evidence of phase separation but are readily redispersed on shaking.Suspensions may show a sediment which is readily dispersed on shaking to give a suspension which issufficiently stable to enable a homogeneous preparation to be delivered.

Where applicable, containers for liquid preparations for cutaneous application comply with therequirements of Materials used for the manufacture of containers (3.1 and subsections) and Containers(3.2 and subsections).

When liquid preparations for cutaneous application are dispensed in pressurised containers, thecontainers comply with the requirements of the monograph on Pressurised pharmaceutical preparations(0523).

Preparations specifically intended for use on severely injured skin are sterile.

Several categories of liquid preparations for cutaneous application may be distinguished:— shampoos,— cutaneous foams.

PRODUCTION

During the development of a liquid preparation for cutaneous application, the formulation for whichcontains an antimicrobial preservative, the effectiveness of the chosen preservative shall bedemonstrated to the satisfaction of the competent authority. A suitable test method together withcriteria for judging the preservative properties of the formulation are provided in the text on Efficacyof antimicrobial preservation (5.1.3).

In the manufacture, packaging, storage and distribution of liquid preparations for cutaneousapplication, suitable means are taken to ensure their microbial quality; recommendations on thisaspect are provided in the text on Microbiological quality of pharmaceutical preparations (5.1.4).

Sterile liquid preparations for cutaneous application are prepared using materials and methodsdesigned to ensure sterility and to avoid the introduction of contaminants and the growth of micro-organisms; recommendations on this aspect are provided in the text on Methods of preparation of sterileproducts (5.1.1).

In the manufacture of liquid preparations for cutaneous application containing dispersed particles,measures are taken to ensure a suitable and controlled particle size with regard to the intended use.

TESTS

Deliverable mass or volume (2.9.28). Liquid preparations for cutaneous application supplied insingle-dose containers comply with the test.

Sterility (2.6.1). Where the label indicates that the preparation is sterile, it complies with the test forsterility.

STORAGE

Store in a well-closed container. If the preparation is sterile, store in a sterile, airtight, tamper-proofcontainer.

LABELLING

The label states:— the name of any added antimicrobial preservative,— where applicable, that the preparation is sterile.

Shampoos

DEFINITION

Shampoos are liquid or, occasionally semi-solid preparations intended for application to the scalp and

45-10

subsequent washing away with water. Upon rubbing with water they usually form a foam.

They are emulsions, suspensions or solutions. Shampoos normally contain surface active agents.

Cutaneous Foams

DEFINITION

Cutaneous foams comply with the requirements of the monograph on Medicated foams (1105).__________________________________________________________________________________________________________ Ph Eur

Liquids for Cutaneous Application of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyapplication, collodion, liniment, lotion or paint that is the subject of an individual monograph in the BritishPharmacopoeia and to the solutions listed below.

APPLICATIONSLabelling The label states (1) that the Application is intended for external use only; (2) the dateafter which the Application is not intended to be used; (3) the conditions under which theApplication should be stored; (4) the directions for using the Application; (5) any special precautionsassociated with the use of the Application.

COLLODIONSDefinition Collodions are Liquids for Cutaneous Application, usually containing Pyroxylin in amixture of Ether and Ethanol. When they are allowed to dry, a flexible film is formed at the site ofapplication.

Storage Collodions should be stored at temperatures not exceeding 25° and remote from fire.

Labelling The label states (1) that the Collodion is intended for external use only; (2) the date afterwhich the Collodion is not intended to be used; (3) the conditions under which the Collodion shouldbe stored; (4) the directions for using the Collodion; (5) any special precautions associated with theuse of the Collodion.

LINIMENTSDefinition Liniments are Liquids for Cutaneous Application that are intended to be applied to theunbroken skin with friction.

Storage Certain plastic containers, such as those made from polystyrene, are unsuitable forLiniments.

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that theLiniment is intended for external use only; (3) if appropriate, that the contents of the containershould be shaken before use; (4) the date after which the Liniment is not intended to be used; (5) theconditions under which the Liniment should be stored; (6) the directions for using the Liniment; (7)any special precautions associated with the use of the Liniment.

LOTIONSDefinition Lotions are Liquids for Cutaneous Application that are intended to be applied to theunbroken skin without friction.

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that theLotion is intended for external use only; (3) that the Lotion should be shaken before use; (4) the dateafter which the Lotion is not intended to be used; (5) the conditions under which the Lotion shouldbe stored; (6) the directions for using the Lotion; (7) any special precautions associated with the useof the Lotion.

NAIL SOLUTIONSLabelling The label states (1) the name and concentration of the active ingredient; (2) that the NailSolution is intended for external use only; (3) the date after which the Nail Solution is not intendedto be used; (4) the conditions under which the Nail Solution should be stored; (5) the directions forusing the Nail Solution; (6) any special precautions associated with use of the Nail Solution.

PAINTSDefinition Paints are solutions or dispersions of one or more active ingredients. They are intendedfor application to the skin or, in some cases, mucous membranes.

Storage Paints should be kept in airtight containers.

Labelling The label states (1) the names and concentrations of the active ingredients; (2) the dateafter which the Paint is not intended to be used; (3) the conditions under which the Paint should be

45-11

stored; (4) the directions for using the Paint; (5) any special precautions associated with the use ofthe Paint.

The following liquids for cutaneous application are the subject of an individual monograph in the BritishPharmacopoeia.

ApplicationsBenzyl Benzoate ApplicationBetamethasone Valerate Scalp ApplicationMinoxidil Scalp ApplicationSelenium Sulphide Scalp Application

CollodionsFlexible CollodionSalicylic Acid Collodion

LinimentsMethyl Salicylate LinimentWhite Liniment

LotionsBenzoyl Peroxide LotionBetamethasone Valerate LotionCalamine LotionCarbaryl LotionCrotamiton LotionZinc Sulphate Lotion

Nail SolutionsTioconazole Nail Solution

PaintsPodophyllin Paint, Compound

SolutionsNote: Certain formulated preparations other than the ones listed below are the subject of anindividual monograph in the British Pharmacopoeia with the title Solution. As confirmed by theabsence of a cross reference to the general monograph for Liquids for Cutaneous Application, suchsolutions are outside the scope of this general monograph.

Adrenaline Solution/Epinephrine SolutionCetrimide SolutionChlorinated Lime and Boric Acid SolutionChloroxylenol SolutionIodine Solution, AlcoholicLidocaine Solution, SterilePovidone–Iodine SolutionSilver Nitrate Solution, SterileSodium Chloride SolutionSodium Hypochlorite Solution, DiluteTretinoin Solution

45-12

EAR PREPARATIONS

revised 1/01

Ear Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia [0652].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Ear preparations are liquid, semi-solid or solid preparations intended for instillation, for spraying, forinsufflation, for application to the auditory meatus or as an ear wash.

Ear preparations usually contain one or more active substances in a suitable vehicle. They maycontain excipients, for example, to adjust tonicity or viscosity, to adjust or stabilise the pH, toincrease the solubility of the active substances, to stabilise the preparation or to provide adequateantimicrobial properties. The excipients do not adversely affect the intended medicinal action of thepreparation or, at the concentrations used, cause toxicity or undue local irritation.

Preparations for application to the injured ear, particularly where the ear-drum is perforated, orprior to surgery are sterile, free from antimicrobial preservatives and supplied in single-dosecontainers.

Ear preparations are supplied in multi-dose or single-dose containers, provided, if necessary, with asuitable administration device which may be designed to avoid the introduction of contaminants.

Unless otherwise justified and authorised, aqueous ear preparations supplied in multidosecontainers contain a suitable antimicrobial preservative at a suitable concentration, except where thepreparation itself has adequate antimicrobial properties.

Where applicable, containers for ear preparations comply with the requirements of Materials usedfor the manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of ear preparations may be distinguished:— ear-drops and sprays,— semi-solid ear preparations,— ear powders,— ear washes,— ear tampons.

PRODUCTION

During the development of an ear preparation, the formulation for which contains an antimicrobialpreservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction ofthe competent authority. A suitable test method together with criteria for judging the preservativeproperties of the formulation are provided in the text on Efficacy of antimicrobial preservation (5.1.3).

In the manufacture, packaging, storage and distribution of ear preparations, suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

Sterile ear preparations are prepared using materials and methods designed to ensure sterility andto avoid the introduction of contaminants and the growth of micro-organisms; recommendations onthis aspect are provided in the text on Methods of preparation of sterile products (5.1.1).

In the manufacture of ear preparations containing dispersed particles, measures are taken to ensurea suitable and controlled particle size with regard to the intended use.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-doseear preparations with a content of active substance less than 2 mg or less than 2 per cent of the totalmass comply with test B for uniformity of content of single-dose preparations. If the preparation hasmore than one active substance, the requirement applies only to those ingredients that correspond tothe above conditions.

Uniformity of mass (2.9.5). Single-dose ear preparations comply with the test for uniformity ofmass of single-dose preparations. If the test for uniformity of content is prescribed for all the activesubstances, the test for uniformity of mass is not required.

Sterility (2.6.1). Where the label indicates that the ear preparation is sterile, it complies with the testfor sterility.

STORAGE

Store in a well-closed container. If the preparation is sterile, store in a sterile, airtight, tamper-proofcontainer.

45-13

LABELLING

The label states:— the name of any added antimicrobial preservative,— where applicable, that the preparation is sterile,— for multidose containers, the period after opening the container after which the contents must

not be used. This period does not exceed 4 weeks, unless otherwise justified and authorised.

Ear-Drops and Sprays

DEFINITION

Ear-drops and sprays are solutions, emulsions or suspensions of one or more active substances inliquids suitable for application to the auditory meatus without exerting harmful pressure on the ear-drum (for example, water, glycols or fatty oils). They may also be placed in the auditory meatus bymeans of a tampon impregnated with the liquid.

Emulsions may show evidence of phase separation but are readily redispersed on shaking.Suspensions may show a sediment which is readily dispersed on shaking to give a suspension whichremains sufficiently stable to enable the correct dose to be delivered.

Ear drops are usually supplied in multidose containers of glass or suitable plastic material that arefitted with an integral dropper or with a screw cap of suitable materials incorporating a dropper andrubber or plastic teat. Alternatively, such a cap assembly is supplied separately. Sprays are usuallysupplied in multi-dose containers fitted with an appropriate applicator. When sprays are supplied inpressurised containers, these comply with the requirements of the monograph on Pressurisedpharmaceutical preparations (0523).

Semi-Solid Ear Preparations

DEFINITION

Semi-solid ear preparations are intended for application to the external auditory meatus, if necessaryby means of a tampon impregnated with the preparation.

Semi-solid ear preparations comply with the requirements of the monograph on Semi-solid prepara-tions for cutaneous application (0132).

They are supplied in containers fitted with a suitable applicator.

Ear Powders

DEFINITION

Ear powders comply with the requirements of the monograph on Powders for cutaneous application(1166).

They are supplied in containers fitted with a suitable device for application or insufflation.

Ear Washes

DEFINITION

Ear washes are preparations intended to cleanse the external auditory meatus. They are usuallyaqueous solutions with a pH within physiological limits.

Ear washes intended for application to injured parts or prior to a surgical operation are sterile.

TESTS

Deliverable mass or volume (2.9.28). Ear washes supplied in single-dose containers comply withthe test.

Ear Tampons

DEFINITION

Ear tampons are intended to be inserted into the external auditory meatus. They comply with therequirements of the monograph on Medicated tampons (1155).

__________________________________________________________________________________________________________ Ph Eur

Ear Preparations of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to thoseear drops that are the subject of an individual monograph in the British Pharmacopoeia.

EAR DROPS

Storage Ear Drops are supplied in containers of glass or suitable plastic that are fitted with an

45-14

integral dropper or with a screw cap of suitable materials incorporating a dropper and rubber orplastic teat. Alternatively, such a cap assembly is supplied separately.

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that theEar Drops are intended for external use only; (3) the date after which the Ear Drops are not intendedto be used; (4) the conditions under which the Ear Drops should be stored.

The following ear drops are the subject of an individual monograph in the British Pharmacopoeia.

Almond Oil Ear DropsAluminium Acetate Ear DropsChloramphenicol Ear DropsCholine Salicylate Ear DropsHydrocortisone Acetate and Neomycin Ear DropsOlive Oil Ear DropsSodium Bicarbonate Ear Drops

45-15

EXTRACTS

Extracts comply with the requirements of the 3rd edition of the European Pharmacopoeia [0765]. Theserequirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Extracts are concentrated preparations of liquid, solid or intermediate consistency, usually obtainedfrom dried vegetable or animal matter. For some preparations, the matter to be extracted mayundergo a preliminary treatment, for example, inactivation of enzymes, grinding or defatting.

Extracts are prepared by maceration, percolation or other suitable, validated methods using ethanolor another suitable solvent. After extraction, unwanted matter is removed, if necessary.

PRODUCTION

Production by percolation If necessary, reduce the matter to be extracted to pieces of suitable size.Mix thoroughly with a portion of the prescribed extraction solvent and allow to stand for anappropriate time. Transfer to a percolator and allow the percolate to flow slowly making sure that thematter to be extracted is always covered with the remaining extraction solvent. The residue may bepressed out and the expressed fluid combined with the percolate.

Production by maceration Unless otherwise prescribed, reduce the matter to be extracted topieces of suitable size, mix thoroughly with the prescribed extraction solvent and allow to stand in aclosed container for an appropriate time. The residue is separated from the extraction solvent, and ifnecessary, pressed out. In the latter case, the two liquids obtained are combined.

Concentration to the intended consistency is carried out using suitable methods, generally underreduced pressure and at a temperature at which deterioration of the constituents is at a minimum.The residual solvents in the extract do not exceed the prescribed limits.

Standardised extracts are adjusted to the defined content of constituents using suitable inertmaterials or using another extract of the vegetable or animal matter used for the preparation.

Liquid Extracts

DEFINITION

Liquid extracts are fluid preparations of which, in general, one part by mass or volume is equivalentto one part by mass of the original dried drug. These preparations are adjusted, if necessary, so thatthey satisfy the requirements for content of solvent, for constituents or for dry residue.

Liquid extracts may be prepared by the methods described above using only ethanol of suitableconcentration or water or by dissolving a soft or dry extract in one of these solvents and, if necessary,filtering; whatever their method of preparation, the extracts obtained have a comparable composition.A slight sediment may form on standing and that is acceptable as long as the composition is notchanged significantly.

Liquid extracts may contain suitable antimicrobial preservatives.

TESTS

Relative density (2.2.5). Where applicable, the liquid extract complies with the limits prescribed inthe monograph.

Ethanol content (2.9.10). For alcoholic liquid extracts, carry out the determination of ethanolcontent. The ethanol content complies with that prescribed.

Methanol and 2-propanol (2.9.11). For alcoholic liquid extracts, not more than 0.05 per cent V/Vof methanol and not more than 0.05 per cent V/V of 2-propanol, unless otherwise prescribed.

Dry residue Where applicable, the liquid extract complies with the limits prescribed in the mono-graph. In a flat-bottomed dish about 50 mm in diameter and about 30 mm in height, introducerapidly 2.00 g or 2.0 ml of the extract to be examined. Evaporate to dryness on a water-bath and dryin an oven at 100°C to 105°C for 3 h. Allow to cool in a desiccator over diphosphorus pentoxide R andweigh. Calculate the result as a mass percentage or in grams per litre.

STORAGE

Store in a well-closed container, protected from light.

LABELLING

The label states:— the vegetable or animal matter used,— where applicable, that fresh vegetable or animal matter was used,— the name and the ethanol content in per cent V/V of the solvent used for the preparation,

45-16

— where applicable, the ethanol content in per cent V/V in the final extract,— the content of active principle and/or the ratio of starting material to final liquid extract,— the name and concentration of any added antimicrobial preservative.

Soft Extracts

DEFINITION

Soft extracts are preparations of an intermediate consistency, between liquid and dry extracts. Theyare obtained by partial evaporation of the solvent used for preparation. Only ethanol of suitableconcentration or water is used. Soft extracts generally have a dry residue of not less than 70 per centby mass. They may contain suitable antimicrobial preservatives.

TESTS

Dry residue Where applicable, the soft extract complies with the limits prescribed in the mono-graph. In a flat-bottomed dish about 50 mm in diameter and about 30 mm in height, weigh rapidly2.00 g of the extract to be examined. Heat to dryness on a water-bath and dry in an oven at 100°C to105°C for 3 h. Allow to cool in a desiccator over diphosphorus pentoxide R and weigh. Calculate theresult as a mass percentage.

STORAGE

Store in a well-closed container, protected from light.

LABELLING

The label states:— the vegetable or animal matter used,— where applicable, that fresh vegetable or animal matter was used,— the name and the ethanol content in per cent V/V of the solvent used for the preparation,— the content of active principle and/or the ratio of starting material to final soft extract,— the name and concentration of any added antimicrobial preservative.

Dry Extracts

DEFINITION

Dry extracts are solid preparations obtained by evaporation of the solvent used for their production.Dry extracts generally have a dry residue of not less than 95 per cent by mass. Suitable inert materialsmay be added.

Standardised dry extracts are adjusted to the defined content of constituents, using suitable inertmaterials or a dry extract of the vegetable or animal matter used for the preparation.

Where applicable, the monograph on a dry extract prescribes a limit test for the solvent used forextraction.

TESTS

Loss on drying (2.2.32). Where applicable, the dry extract complies with the limits prescribed in themonograph. In a flat-bottomed dish about 50 mm in diameter and about 30 mm in height, weighrapidly 0.50 g of the extract to be examined, finely powdered. Dry in an oven at 100°C to 105°C for3 h. Allow to cool in a desiccator over diphosphorus pentoxide R and weigh. Calculate the result as amass percentage.

STORAGE

Store in an airtight container, protected from light.

LABELLING

The label states:— the name and amount of any inert material used,— the vegetable or animal matter used,— where applicable, that fresh vegetable or animal matter was used,— the name and the ethanol content in per cent V/V of the solvent used for the preparation,— the content of active principle and/or the ratio of starting material to final dry extract.

__________________________________________________________________________________________________________ Ph Eur

Extracts of the British Pharmacopoeia

The following extracts are the subject of an individual monograph in the British Pharmacopoeia. Thosedistinguished by the symbol ‘ ’ in the list below are monographs of the European Pharmacopoeia.

Aloes Dry Extract, Standardised Belladonna Leaf Dry Extract, Standardised

45-17

Cascara Dry ExtractFrangula Bark Dry Extract, Standardised Ipecacuanha Liquid ExtractLiquorice Ethanolic Liquid Extract, StanardisedLiquorice Liquid ExtractQuillaia Liquid ExtractSenna Leaf Dry Extract, Standardised Senna Liquid ExtractSquill Liquid Extract

45-18

EYE PREPARATIONS

revised 1/01

Eye Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia [1163].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Eye preparations are sterile liquid, semi-solid or solid preparations intended for administration uponthe eyeball and/or to the conjunctiva or for insertion in the conjunctival sac.

Where applicable, containers for eye preparations comply with the requirements of Materials usedfor the manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of eye preparations may be distinguished:— eye drops,— eye lotions,— powders for eye drops and eye lotions,— semi-solid eye preparations,— ophthalmic inserts.

PRODUCTION

During the development of an eye preparation, the formulation for which contains an antimicrobialpreservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction ofthe competent authority. A suitable test method together with criteria for judging the preservativeproperties of the formulation are provided in the text on Efficacy of antimicrobial preservation (5.1.3).

Eye preparations are prepared using materials and methods designed to ensure sterility and toavoid the introduction of contaminants and the growth of micro-organisms; recommendations on thisaspect are provided in the text on Methods of preparation of sterile products (5.1.1).

In the manufacture of eye preparations containing dispersed particles, measures are taken to ensurea suitable and controlled particle size with regard to the intended use.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-doseeye preparations with a content of active substance less than 2 mg or less than 2 per cent of the totalmass comply with test B for uniformity of content of single-dose preparations. If the preparation hasmore than one active substance, the requirement applies only to those substances that correspond tothe above conditions.

Uniformity of mass (2.9.5). Single-dose eye preparations comply with the test for uniformity ofmass of single-dose preparations. If the test for uniformity of content is prescribed for all the activesubstances, the test for uniformity of mass is not required.

Sterility (2.6.1). Eye preparations comply with the test for sterility. Applicators supplied separatelyalso comply with the test for sterility. Remove the applicator with aseptic precautions from itspackage and transfer it to a tube of culture medium so that it is completely immersed. Incubate andinterpret the results as described in the test for sterility.

Deliverable mass or volume (2.9.28). Liquid and semi-solid eye preparations supplied in single-dose containers comply with the test.

STORAGE

Unless otherwise prescribed, store in a sterile, airtight, tamper-proof container.

LABELLING

The label states the name of any added antimicrobial preservative.

Eye-drops

DEFINITION

Eye-drops are sterile aqueous or oily solutions or suspensions of one or more active substancesintended for instillation into the eye.

Eye-drops may contain excipients, for example, to adjust the tonicity or the viscosity of the prepa-ration, to adjust or stabilise the pH, to increase the solubility of the active substance, or to stabilisethe preparation. These substances do not adversely affect the intended medicinal action or, at theconcentrations used, cause undue local irritation.

Aqueous preparations supplied in multidose containers contain a suitable antimicrobialpreservative in appropriate concentration except when the preparation itself has adequate

45-19

antimicrobial properties. The antimicrobial preservative chosen must be compatible with the otheringredients of the preparation and must remain effective throughout the period of time during whicheye-drops are in use.

If eye-drops are prescribed without antimicrobial preservatives they are supplied wherever possiblein single-dose containers. Eye-drops intended for use in surgical procedures do not containantimicrobial preservatives and are supplied in single-dose containers.

Eye-drops that are solutions, examined under suitable conditions of visibility, are practically clearand practically free from particles.

Eye-drops that are suspensions may show a sediment that is readily redispersed on shaking to give asuspension which remains sufficiently stable to enable the correct dose to be delivered.

Multidose preparations are supplied in containers that allow successive drops of the preparation tobe administered. The containers contain at most 10 ml of the preparation, unless otherwise justifiedand authorised.

TESTS

Particle size Unless otherwise justified and authorised, eye-drops in the form of a suspension complywith the following test: introduce a suitable quantity of the suspension into a counting cell or with amicropipette onto a slide, as appropriate, and scan under a microscope an area corresponding to 10 µgof the solid phase. For practical reasons, it is recommended that the whole sample is first scanned atlow magnification (e.g. × 50) and particles greater than 25 µm are identified. These larger particlescan then be measured at a larger magnification (e.g. × 200 to × 500). For each 10 µg of solid activesubstance, not more than twenty particles have a maximum dimension greater than 25 µm, and notmore than two of these particles have a maximum dimension greater than 50 µm. None of theparticles has a maximum dimension greater than 90 µm.

LABELLING

The label states:— where applicable, the name of any added antimicrobial preservative,— for multidose containers, the period after opening the container after which the contents must

not be used. This period does not exceed 4 weeks, unless otherwise justified and authorised.

Eye Lotions

DEFINITION

Eye lotions are sterile aqueous solutions intended for use in washing or bathing the eye or forimpregnating eye dressings.

Eye lotions may contain excipients, for example to adjust the tonicity or the viscosity of the prepara-tion or to adjust or stabilise the pH. These substances do not adversely affect the intended action or,at the concentrations used, cause undue local irritation.

Eye lotions supplied in multidose containers contain a suitable antimicrobial preservative inappropriate concentration except when the preparation itself has adequate antimicrobial properties.The antimicrobial preservative chosen is compatible with the other ingredients of the preparation andremains effective throughout the period of time during which the eye lotions are in use.

If eye lotions are prescribed without an antimicrobial preservative, they are supplied in single-dosecontainers. Eye lotions intended for use in surgical procedures or in first-aid treatment do not containan antimicrobial preservative and are supplied in single-dose containers.

Eye lotions examined under suitable conditions of visibility, are practically clear and practically freefrom particles.

The containers for multidose preparations do not contain more than 200 ml of eye lotion, unlessotherwise justified and authorised.

LABELLING

The label states:— where applicable, that the contents are to be used on one occasion only,— for multidose preparations, the period after opening the container after which the contents must

not be used. This period does not exceed 4 weeks, unless otherwise justified and authorised.

Powders for Eye-Drops and Powders for Eye Lotions

DEFINITION

Powders for the preparation of eye-drops and eye lotions are supplied in a dry, sterile form to bedissolved or suspended in an appropriate liquid vehicle at the time of administration. They maycontain excipients to facilitate dissolution or dispersion, to prevent caking, to adjust the tonicity, toadjust or stabilise the pH or to stabilise the preparation.

After dissolution or suspension in the prescribed liquid, they comply with the requirements for eye-drops or eye lotions, as appropriate.

45-20

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dose powders for eye-drops and eye lotions with a content of active substance less then 2 mg orless than 2 per cent of the total mass comply with test B for uniformity of content of single-dosepreparations. If the preparation has more than one active substance, the requirement applies onlyto those substances which correspond to the above condition.

Uniformity of mass (2.9.5). Single-dose powders for eye-drops and eye lotions comply with thetest for uniformity of mass of single-dose preparations. If the test for uniformity of content isprescribed for all the active substances, the test for uniformity of mass is not required.

Semi-Solid Eye Preparations

DEFINITION

Semi-solid eye preparations are sterile ointments, creams or gels intended for application to theconjunctiva. They contain one or more active substances dissolved or dispersed in a suitable basis.They have a homogeneous appearance.

Semi-solid eye preparations comply with the requirements of the monograph on Semi-solid prepara-tions for cutaneous application (0132). The basis should be non-irritant to the conjunctiva.

Semi-solid eye preparations are packed in small, sterilised collapsible tubes fitted or provided with acannula and having a content of not more than 5 g of the preparation. The tubes must be well-closedto prevent microbial contamination. Semi-solid eye preparations may also be packed in suitablydesigned single-dose containers. The containers, or the nozzles of tubes, are of such a shape as tofacilitate administration without contamination. Tubes are tamper-proof.

TESTS

Particle size Semi-solid eye preparations containing dispersed solid particles comply with thefollowing test: spread gently a quantity of the preparation corresponding to at least 10 µg of solidactive substance as a thin layer. Scan under a microscope the whole area of the sample. For practicalreasons, it is recommended that the whole sample is first scanned at a small magnification (e.g. × 50)and particles greater than 25 µm are identified. These larger particles can then be measured at alarger magnification (e.g. × 200 to × 500). For each 10 µg of solid active substance, not more thantwenty particles have a maximum dimension greater than 25 µm, and not more than two of theseparticles have a maximum dimension greater than 50 µm. None of the particles has a maximumdimension greater than 90 µm.

Ophthalmic Inserts

DEFINITION

Ophthalmic inserts are sterile, solid or semi-solid preparations of suitable size and shape, designed tobe inserted in the conjunctival sac, to produce an ocular effect. They generally consist of a reservoirof active substance embedded in a matrix or bounded by a rate-controlling membrane. The activesubstance, which is more or less soluble in physiological fluids, is released over a determined periodof time.

Ophthalmic inserts are individually distributed into sterile containers.

PRODUCTION

In the manufacture of ophthalmic inserts, means must be taken to ensure a suitable dissolutionbehaviour.

TESTS

Uniformity of content (2.9.6). Ophthalmic inserts comply, where applicable, with test A foruniformity of content.

LABELLING

The label states:— where applicable, the total quantity of active substance per insert,— where applicable, the dose released per unit time.

__________________________________________________________________________________________________________ Ph Eur

Eye Preparations of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyeye drops, eye lotion or eye ointment that is the subject of an individual monograph in the British Pharmaco-poeia.

45-21

EYE DROPS

Definition Definition of particular Eye Drops as a solution or suspension in Purified Water doesnot preclude the inclusion of suitable additional substances where necessary for the purposesreferred to above under the requirements of the European Pharmacopoeia. However if bufferingagents are used in preparations intended for use in surgical procedures great care should be takento ensure that the nature and concentration of the chosen agent are suitable.

Where the active ingredient is susceptible to oxidative degradation appropriate precautions suchas the addition of a suitable antioxidant should be taken. If an antioxidant is added care should betaken to ensure compatibility between the antioxidant and the antimicrobial preservative.

Production Methods of sterilisation that may be used in the manufacture of Eye Drops aredescribed in Appendix XVIII.

Storage Eye Drops are supplied in tamper-evident containers. The compatibility of plastic or rubbercomponents should be confirmed before use.

Containers for multidose Eye Drops are fitted with an integral dropper or with a sterile screw cap ofsuitable materials incorporating a dropper and rubber or plastic teat. Alternatively such a capassembly is supplied, sterilised, separately.

Labelling The label states (1) the names and percentages of the active ingredients; (2) the date afterwhich the Eye Drops are not intended to be used; (3) the conditions under which the Eye Dropsshould be stored.

For multidose containers the label states that care should be taken to avoid contamination of thecontents during use.

Single-dose containers that because of their size bear only an indication of the active ingredient andthe strength of the preparation do so by use of an approved code, Appendix XIX D, together with anexpression of the percentage present. When a code is used on the container, the code is also stated onthe package.

EYE OINTMENTS

Definition Eye Ointments of the British Pharmacopoeia that are intended to be used solely orprimarily as a suitable eye-ointment basis contain no active ingredient.

Production Methods of sterilisation that may be used in the manufacture of Eye Ointments aredescribed in Appendix XVIII.

In preparing Eye Ointments in tropical or subtropical countries where the prevailing hightemperatures otherwise make the basis too soft for convenient use, the proportions of Yellow SoftParaffin and Liquid Paraffin specified in the individual monograph may be varied, or Hard Paraffinmay be added but the proportions of active ingredients must not be changed.

Storage Single-dose containers for Eye Ointments, or the nozzles of tubes, are of such a shape as tofacilitate administration without contamination. The former type of container is individuallywrapped. Tubes are tamper-evident.

Unless otherwise indicated Eye Ointments should be stored at a temperature not exceeding 25°.

Labelling The label states (1) the names and percentages of the active ingredients; (2) the date afterwhich the Eye Ointment is not intended to be used; (3) the conditions under which the EyeOintment should be stored.

The following eye preparations are the subject of an individual monograph in the British Pharmacopoeia.

Eye DropsAdrenaline Eye Drops/Epinephrine Eye DropsAtropine Eye DropsBetamethasone Eye DropsBetaxolol Eye Drops, SolutionBetaxolol Eye Drops, SuspensionCarteolol Eye DropsChloramphenicol Eye DropsCyclopentolate Eye DropsDipivefrine Eye DropsFluorescein Eye DropsFluoromethalone Eye DropsFlurbiprofen Eye DropsFusidic Acid Eye DropsGentamicin Eye DropsHomatropine Eye DropsHydrocortisone Acetate and Neomycin Eye DropsHyoscine Eye DropsHypromellose Eye Drops

45-22

Idoxuridine Eye DropsLevobunolol Eye DropsMetipranolol Eye DropsNeomycin Eye DropsNorfloxacin Eye DropsOxybuprocaine Eye DropsParaffin Eye Drops, Light LiquidPhenylephrine Eye DropsPilocarpine Hydrochloride Eye DropsPilocarpine Nitrate Eye DropsPrednisolone Sodium Phosphate Eye DropsProxymetacaine Eye DropsSodium Chloride Eye DropsSodium Citrate Eye DropsSodium Cromoglicate Eye DropsTetracaine Eye Drops/Amethocaine Eye DropsTimolol Eye DropsTropicamide Eye DropsZinc Sulphate Eye Drops

Eye Lotions

Sodium Bicarbonate Eye LotionSodium Chloride Eye Lotion

Eye Ointments

Aciclovir Eye OintmentAtropine Eye OintmentChloramphenicol Eye OintmentChlortetracycline Eye OintmentHydrocortisone Acetate and Neomycin Eye OintmentNeomycin Eye OintmentOxyphenbutazone Eye OintmentPolymyxin and Bacitracin Eye OintmentSimple Eye Ointment

45-23

MEDICATED FOAMS

revised 1/01

Medicated Foams comply with the requirements of the 3rd edition of the European Pharmacopoeia [1105].These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Additional requirements for medicated foams may be found, where appropriate, in other general monographs,for example on Rectal preparations (1145), Vaginal preparations (1164) and Liquid preparations forcutaneous application (0927).

DEFINITION

Medicated foams are preparations consisting of large volumes of gas dispersed in a liquid generallycontaining one or more active substances, a surfactant ensuring their formation and various otherexcipients. Medicated foams are usually intended for application to the skin or mucous membranes.

Medicated foams are usually formed at the time of administration from a liquid preparation in apressurised container. The container is equipped with a device consisting of a valve and a pushbutton suitable for the delivery of the foam.

Medicated foams intended for use on severely injured skin and on large open wounds are sterile.Medicated foams supplied in pressurised containers comply with the requirements of the mono-

graph on Pressurised pharmaceutical preparations (0523).

PRODUCTION

Sterile medicated foams are prepared using materials and methods designed to ensure sterility and toavoid the introduction of contaminants and the growth of micro-organisms; recommendations on thisaspect are provided in the text on Methods of preparation of sterile products (5.1.1).

TESTS

Relative foam density Maintain the container at about 25°C for at least 24 h. Taking care not towarm the container, fit a rigid tube 70 mm to 100 mm long and about 1 mm in internal diameteronto the push button. Shake the container to homogenise the liquid phase of the contents anddispense 5 ml to 10 ml of foam to waste. Tare a flat-bottomed dish with a volume of about 60 ml andabout 35 mm high. Place the end of the rigid tube attached to the push button in the corner of thedish, press the push button and fill the dish uniformly, using a circular motion. After the foam hascompletely expanded, level off by removing the excess foam with a slide. Weigh. Determine the massof the same volume of water R by filling the same dish with water R.

The relative foam density is equivalent to the ratio:

em

m =mass of the test sample of foam, in grams,e =mass of same volume of water R, in grams.

Carry out three measurements. None of the individual values deviate by more than 20 per centfrom the mean value.

Duration of expansion The apparatus (Fig. 1105–1) consists of a 50 ml burette, 15 mm in internaldiameter, with 0.1 ml graduations and fitted with a 4 mm single bore stopcock. The graduationcorresponding to 30 ml is at least 210 mm from the axis of the stopcock. The lower part of theburette is connected by means of a plastic tube not longer than 50 mm and 4 mm in internaldiameter to the foam-generating container equipped with a push button fitted to this connection.Maintain the container at about 25°C for at least 24 h. Shake the container, taken care not to warmit, to homogenise the liquid phase of the contents and dispense 5 ml to 10 ml of the foam to waste.Connect the push button to the outlet of the burette. Press the button and introduce about 30 ml offoam in a single delivery. Close the stopcock and at the same time start the chronometer and read thevolume of foam in the burette. Every 10 s read the growing volume until the maximum volume isreached.

Carry out three measurements. None of the times needed to obtain the maximum volume is morethan 5 min.

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Fig. 1105–1 Apparatus for the determination of the duration of expansion

Sterility (2.6.1). When the label indicates that the preparation is sterile, it complies with the testfor sterility.

LABELLING

The label states, where applicable, that the preparation is sterile.__________________________________________________________________________________________________________ Ph Eur

Medicated Foams of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to anymedicated foam that is the subject of an individual monograph in the British Pharmacopoeia.

Labelling The label states (1) the name and concentration of the active ingredient; (2) that theMedicated Foam is intended for external use only; (3) the date after which the Medicated Foam isnot intended to be used; (4) the conditions under which the Medicated Foam should be stored; (5)the directions for using the Medicated Foam; (6) any special precautions associated with the use ofthe Medicated Foam.

The following medicated foam is the subject of an individual monograph in the British Pharmacopoeia.

Felbinac Cutaneous Foam

45-25

GRANULES

revised 1/01

Granules comply with the requirements of the 3rd edition of the European Pharmacopoeia [0499]. Theserequirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Requirements for granules to be used for the preparation of oral solutions or suspensions are given in themonograph on Liquid preparations for oral use (0672).

DEFINITION

Granules are preparations consisting of solid, dry aggregates of powder particles sufficiently resistantto withstand handling. They are intended for oral administration. Some are swallowed as such, someare chewed and some are dissolved or dispersed in water or another suitable liquid before beingadministered.

Granules contain one or more active substances with or without excipients and, if necessary,colouring matter authorised by the competent authority and flavouring substances.

Granules are presented as single-dose or multidose preparations. Each dose of a multidose prepara-tion is administered by means of a device suitable for measuring the quantity prescribed. For single-dose granules, each dose is enclosed in an individual container, for example a sachet, a paper packetor a vial.

Where applicable, containers for granules comply with the requirements of Materials used for themanufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of granules may be distinguished:— effervescent granules,— coated granules,— gastro-resistant granules,— modified-release granules.

PRODUCTION

In the manufacture, packaging, storage and distribution of granules, suitable means are taken toensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosegranules with a content of active substance less than 2 mg or less than 2 per cent of the total masscomply with test B for uniformity of content of single-dose preparations. If the preparation has morethan one active substance, the requirement applies only to those substances which correspond to theabove conditions.

Uniformity of mass (2.9.5). Single-dose granules except for coated granules comply with the testfor uniformity of mass of single-dose preparations. If the test for uniformity of content is prescribedfor all the active substances, the test for uniformity of mass is not required.

STORAGE

Store in a well-closed container or, if the preparation contains volatile ingredients or the contentshave to be protected, store in an airtight container.

Effervescent Granules

DEFINITION

Effervescent granules are uncoated granules generally containing acid substances and carbonates orhydrogen carbonates which react rapidly in the presence of water to release carbon dioxide. They areintended to be dissolved or dispersed in water before administration.

TESTS

Disintegration Place one dose of the effervescent granules in a beaker containing 200 ml of water Rat 15°C to 25°C; numerous bubbles of gas are evolved. When the evolution of gas around theindividual grains ceases, the granules have disintegrated, being either dissolved or dispersed in thewater. Repeat the operation on five other doses. The preparation complies with the test if each of thesix doses used disintegrates within 5 min.

STORAGE

Store in an airtight container.

45-26

Coated Granules

DEFINITION

Coated granules are usually multidose preparations and consist of granules coated with one or morelayers of mixtures of various excipients.

PRODUCTION

The substances used as coatings are usually applied as a solution or suspension in conditions inwhich evaporation of the vehicle occurs.

TESTS

Dissolution A suitable test may be carried out to demonstrate the appropriate release of the activesubstance(s), for example one of the tests described in Dissolution test for solid dosage forms (2.9.3).

Modified-Release Granules

DEFINITION

Modified-release granules are coated or uncoated granules containing special excipients or which areprepared by special procedures, separately or together, designed to modify the rate, the place or thetime at which the active substance or substances are released.

Modified-release granules include prolonged-release granules and delayed-release granules.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Gastro-resistant Granules

DEFINITION

Gastro-resistant granules are delayed-release granules that are intended to resist the gastric fluid andto release the active substance(s) in the intestinal fluid. These properties are achieved by covering thegranules with a gastro-resistant material (enteric-coated granules) or by other suitable means.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s) oringredients.

TESTS

Dissolution Carry out a suitable test to demonstrate the appropriate release of the activesubstance(s), for example the test described in Dissolution test for solid dosage forms (2.9.3).

__________________________________________________________________________________________________________ Ph Eur

Granules of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply tothose granules that are the subject of an individual monograph in the British Pharmacopoeia.

Labelling For single-dose containers the label states the name and amount of active ingredient percontainer and for multidose containers the label states the name and amount of active ingredient in asuitable quantity by weight.

The label also states (1) the date after which the Granules are not intended to be used; (2) theconditions under which the Granules should be stored; (3) the instructions for using the Granules.

The following granules are the subject of an individual monograph in the British Pharmacopoeia.

Colestipol GranulesIspaghula Husk GranulesIspaghula Husk Effervescent GranulesMethylcellulose GranulesPancreatin GranulesSenna Granules, StandardisedSterculia Granules

45-27

HERBAL DRUG PREPARATIONS

revised 1/01

Herbal Drug Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia[1434]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Herbal drug preparations are obtained by subjecting herbal drugs to treatments such as extraction,distillation, expression, fractionation, purification, concentration or fermentation. These includecomminuted or powdered herbal drugs, tinctures, extracts, essential oils, expressed juices andprocessed exudates.

Extracts obtained from herbal drugs comply with the monograph on Extracts (0765).Tinctures obtained from herbal drugs comply with the monograph on Tinctures (0792).Herbal teas comply with the monograph on Herbal teas (1435).Instant herbal teas consist of powder or granules of one or more herbal drug preparation(s)

intended for the preparation of an oral solution immediately before use.__________________________________________________________________________________________________________ Ph Eur

45-28

HERBAL TEAS

1/00

Herbal Teas comply with the requirements of the 3rd edition of the European Pharmacopoeia [1435]. Theserequirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Herbal teas consist exclusively of one or more herbal drugs intended for oral aqueous preparations bymeans of decoction, infusion or maceration. The preparation is prepared immediately before use.

Herbal teas are usually supplied in bulk form or in sachets.

The herbal drugs used comply with the appropriate individual European Pharmacopoeia monographsor in their absence to the general monograph on Herbal drugs (1433).

Recommendations on the microbiological quality of herbal teas (5.1.4–Category 4) take into accountthe prescribed preparation method (use of boiling or non-boiling water).

IDENTIFICATION

The identity of herbal drugs present in herbal teas is checked by botanical examinations.

TESTS

The proportion of herbal drugs present in herbal teas is checked by appropriate methods.

Herbal teas in sachets comply with the following test:

Uniformity of mass Determine the average mass of twenty randomly chosen units as follows: weigha single full sachet of herbal tea, open it without losing any fragments. Empty it completely using abrush. Weigh the empty sachet and calculate the mass of the contents by subtraction. Repeat theoperation on the nineteen remaining sachets. Unless otherwise justified not more than two of thetwenty individual masses of the contents deviate from the average mass of the contents by more thanthe percentage deviation shown in the table below and none deviates by more than twicethat percentage.

Average mass Percentage deviation

less than 1.5 g 15 per cent1.5 g to 2.0 g included 10 per centmore than 2.0 g 7.5 per cent

STORAGE

Store in a well-closed container, protected from light.__________________________________________________________________________________________________________ Ph Eur

45-29

INFUSIONS

Definition Infusions are dilute solutions containing the readily-soluble constituents of crude drugs.They are usually prepared by diluting one volume of a concentrated Infusion to ten volumes withWater.

For dispensing purposes, Infusions should be used within 12 hours of their preparation.

Storage Infusions should be kept in well-closed containers.

Labelling The label states (1) the time after which the Infusion is not intended to be used; (2) theconditions under which the Infusion should be stored.

The following infusions are the subject of an individual monograph in the British Pharmacopoeia.

Gentian Infusion, CompoundOrange Peel Infusion

45-30

PREPARATIONS FOR INHALATION

revised 1/01

Preparations for Inhalation comply with the requirements of the 3rd edition of the European Pharmacopoeia[0671]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Preparations for inhalation are liquid or solid preparations intended for administration as vapours oraerosols to the lung in order to obtain a local or systemic effect. They contain one or more activesubstances which may be dissolved or dispersed in a suitable vehicle.

Preparations for inhalation may, depending on the type of preparation, contain propellants, co-solvents, diluents, antimicrobial preservatives, solubilising and stabilising agents, etc. Theseexcipients do not adversely affect the functions of the mucosa of the respiratory tract or its cilia.

Preparations for inhalation are supplied in multidose or single-dose containers. When supplied inpressurised containers, they comply with the requirements of the monograph on Pressurisedpharmaceutical preparations (0523).

Preparations intended to be administered as aerosols (dispersions of solid or liquid particles in a gas)are administered by one of the following devices:— nebuliser,— pressurised metered-dose inhaler,— dry-powder inhaler.

PRODUCTION

During the development of a preparation for inhalation which contains an antimicrobial preservative,the effectiveness of the chosen preservative shall be demonstrated to the satisfaction of the competentauthority. A suitable test method together with the criteria for judging the preservative properties ofthe formulation are described in the text on Efficacy of antimicrobial preservation (5.1.3).

The size of aerosol particles to be inhaled is controlled so that a significant fraction is deposited inthe lung. The fine-particle characteristics of preparations for inhalation are determined by themethod for Aerodynamic assessment of fine particles (2.9.18- apparatus C or D).

In assessing the uniformity of delivered dose, manufacturers may substitute alternative procedures,embracing more than one inhaler. Such procedures should assure conformity of all inhalers to therequirements of the Pharmacopoeia.

Pressurised metered-dose inhalers are tested for leakage. All inhalers are tested for extraneousparticulate contamination.

LABELLING

For metered-dose preparations the label states:— the delivered-dose, except for preparations for which the dose has been established as a metered-

dose or as a predispensed-dose,— where applicable, the number of deliveries from the inhaler to provide the minimum

recommended dose,— the number of deliveries per inhaler.

The label states, where applicable, the name of any added antimicrobial preservative.

Liquid Preparations for InhalationThree categories of liquid preparations for inhalation may be distinguished:

A. preparations intended to be converted into vapour,

B. liquid preparations for nebulisation,

C. pressurised metered-dose preparations for inhalation.

Liquid preparations for inhalation are solutions or dispersions.Dispersions are readily dispersible on shaking and they remain sufficiently stable to enable the

correct dose to be delivered. Suitable excipients may be used.

A. Preparations intended to be converted into vapour

DEFINITION

Preparations intended to be converted into vapour are solutions, dispersions or solid preparations.They are usually added to hot water and the vapour generated is inhaled.

B. Liquid Preparations for Nebulisation

45-31

DEFINITION

Liquid preparations for inhalation intended to be converted into aerosols by continuouslyoperating nebulisers or metered-dose nebulisers are solutions, suspensions or emulsions. Suitableco-solvents or solubilisers may be used to increase the solubility of the active substances.

Liquid preparations for nebulisation in concentrated form for use in continuously operatingnebulisers are diluted to the prescribed volume with the prescribed liquid before use. Liquids fornebulisation may also be prepared from powders.

The pH of the liquid preparations for use in continuously operating nebulisers is not lower than 3and not higher than 8.5.

Suspensions and emulsions are readily dispersible on shaking and they remain sufficiently stable toenable the correct dose to be delivered.

Aqueous preparations for nebulisation supplied in multidose containers may contain a suitableantimicrobial preservative at a suitable concentration except where the preparation itself has adequateantimicrobial properties.

Continuously operating nebulisers are devices that convert liquids into aerosols by high-pressuregases, ultrasonic vibration or other methods. They allow the dose to be inhaled at an appropriate rateand particle size which ensures deposition of the preparation in the lungs.

Metered-dose nebulisers are devices that convert liquids into aerosols by high-pressure gases,ultrasonic vibration or other methods. The volume of liquid to be nebulised is metered so that theaerosol dose can be inhaled with one breath.

C. Pressurised Metered-Dose Preparations for Inhalation

DEFINITION

Pressurised metered-dose preparations for inhalation are solutions, suspensions or emulsions suppliedin special containers equipped with a metering valve and which are held under pressure with suitablepropellants or suitable mixtures of liquefied propellants, which can act also as solvents. Suitable co-solvents, solubilisers and stabilisers may be added.

The delivered dose is the dose delivered from the inhaler to the patient. For some preparations, thedose has been established as a metered-dose. The metered-dose is determined by adding the amountdeposited within the device to the delivered dose. It may also be determined directly.

TESTS

Uniformity of delivered dose Containers usually operate in an inverted position. For containersthat operate in an upright position, an equivalent test is applied using methods that ensure thecomplete collection of the delivered dose. In all cases, prepare the inhaler as directed in the instru-ctions to the patient.

The dose collection apparatus must be capable of quantitatively capturing the delivered dose.

The following apparatus and procedure may be used:

The apparatus (Fig. 0671–1) consists of a filter-support base with an open-mesh filter-support, suchas a stainless steel screen, a collection tube that is clamped or screwed to the filter-support base, anda mouthpiece adapter to ensure an airtight seal between the collection tube and the mouthpiece. Usea mouthpiece adapter which ensures that the front face of the inhaler mouthpiece is flush with thefront face of the sample collection tube. The vacuum connector is connected to a system comprisinga vacuum source and a flow regulator. The source should be adjusted to pull air through thecomplete assembly, including the filter and the inhaler to be tested, at 28.3 ± 1.5 litres/min. Airshould be drawn continuously through the apparatus to avoid loss of the active substance into theatmosphere. The filter support base is designed to accommodate 25 mm diameter filter disks. Thefilter disk and other materials used in the construction of the apparatus must be compatible with theactive substance and solvents that are used to extract the active substance from the filter. One end ofthe collection tube is designed to hold the filter disk tightly against the filter-support base. Whenassembled, the joints between the components of the apparatus are airtight so that when a vacuum isapplied to the base of the filter, all of the air drawn through the collection tube passes through theinhaler.

Unless otherwise prescribed in the instructions to the patient, shake the inhaler for 5 s anddischarge one delivery to waste. Fire the inverted inhaler into the apparatus, depressing the valve for asufficient time to ensure complete discharge. Repeat the procedure until the number of deliveries thatconstitute the minimum recommended dose have been sampled. Quantitatively collect the contentsof the apparatus and determine the amount of active substance.

Repeat the procedure for a further two doses.Discharge the device to waste, waiting not less than 5 s between actuations until (n/2) + 1 deliveries

remain, where n is the number of deliveries stated on the label. Collect four doses using theprocedure described above.

Discharge the device to waste, waiting not less than 5 s between actuations until three doses remain.Collect these three doses using the procedure described above.

45-32

For preparations containing more than one active substance, carry out the test for uniformity ofdelivered dose for each active substance.

Unless otherwise justified and authorised, the preparation complies with the test if nine out of tenresults lie between 75 per cent and 125 per cent of the average value and all lie between 65 per centand 135 per cent. If two or three values lie outside the range of 75 per cent to 125 per cent, repeatthe test for two more inhalers. Not more than three of the thirty values lie outside the range 75 percent to 125 per cent and no value lies outside the range 65 per cent to 135 per cent.

Fine particle dose Using an apparatus and procedure described in Aerodynamic assessment of fineparticles (2.9.18- apparatus C or D), calculate the fine particle dose.

Number of deliveries per inhaler Take one inhaler and discharge the contents to waste, actuatingthe valve at intervals of not less than 5 s. The total number of deliveries so discharged from theinhaler is not less than the number stated on the label. (This test may be combined with the test foruniformity of delivered dose).

Powders for Inhalation

DEFINITION

Powders for inhalation are presented as single-dose powders or multidose powders. To facilitate theiruse, active substances may be combined with a suitable carrier. They are generally administered bydry-powder inhalers. In pre-metered systems, the inhaler is loaded with powders pre-dispensed incapsules or other suitable pharmaceutical forms. For devices using a powder reservoir, the dose iscreated by a metering mechanism within the inhaler.

The delivered dose is the dose delivered from the inhaler. For some preparations, the dose hasbeen established as a metered dose or as a predispensed dose. The metered dose is determined byadding the amount deposited within the device to the delivered dose. It may also be determineddirectly.

TESTS

Uniformity of delivered dose In all cases, prepare the inhaler as directed in the instructions to thepatient. The dose collection apparatus must be capable of quantitatively capturing the delivered dose.A dose collection apparatus similar to that described for the evaluation of pressurised metered-doseinhalers may be used provided that the dimensions of the tube and the filter can accommodate themeasured flow rate. A suitable tube is defined in Fig. 0671–1. Connect the tube to a flow systemaccording to the scheme specified in Fig. 0671–2 and Table 0671–1.

45-33

Fig. 0671–1 Dose collection apparatus for pressurised metered-dose preparations.Dimensions in mm

Fig. 0671–2 Apparatus suitable for measuring the uniformity of delivered dose for powder inhalers

45-34

Table 0671–1 Component Specification for Figure 0671–2.

Code Item Description

A Sample collection tube Capable of quantitatively capturing the delivered dose, e.g. Dose collection tubesimilar to that described in Fig. 671.-1 with dimensions of 34.85 mm ID × 12 cmlength (e.g. product number XX40 047 00, Millipore Corporation, Bedford, MA01732, USA, with modified exit tube, ID ≥8 mm, fitted with Gelman product number61631), or equivalent.

B Filter 47 mm filter, e.g. A/E glass fibre filter (Gelman Sciences, Ann Arbor, MI 48106,USA), or equivalent.

C Connector ID ≥8 mm, e.g., short metal coupling, with low-diameter branch to P3.

D Vacuum tubing 8±0.5 mm ID × 50±10 cm length, e.g., silicone tubing with an OD of 14 mm and anID of 8 mm.

E Two-way solenoid valve Minimum airflow resistance orifice having an ID of ≥8 mm and a maximum responsetime of 100 ms (e.g. type 256-A08, Bürkert GmbH, D7118, Germany), or equivalent.

F Vacuum pump Pump must be capable of drawing the required flow rate through the assembledapparatus with the dry powder inhaler in the mouthpiece adapter (e.g. product type1023, 1423 or 2565, Gast Manufacturing Inc., Benton Harbor, MI 49022, USA), orequivalent. Connect the pump to the solenoid valve using short and/or wide (≥10 mmID) vacuum tubing and connectors to minimise pump capacity requirements.

G Timer Timer capable of driving the solenoid valve for the required time period(e.g. typeG814, RS Components International, Corby, NN17 9RS, UK), or equivalent.

P1 Pressure tap 2.2 mm ID, 3.1 mm OD, flush with internal surface of the sample collection tube,centred and burr-free, 59 mm from its inlet.

P1, P2,P3

Pressure measurements Differential pressure to atmosphere (P1) or absolute pressure (P2 and P3).

H Flow control valve Adjustable regulating valve with maximum Cv ≥1, (e.g. type 8FV12LNSS, ParkerHannifin plc., Barnstaple, EX31 1NP, UK), or equivalent.

Unless otherwise stated, determine the test flow rate and duration using the dose collection tube,the associated flow system, a suitable differential pressure meter and a suitable volumetric flowmeter, calibrated for the flow leaving the meter, according to the following procedure:

Prepare the inhaler for use and connect it to the inlet of the apparatus using a mouthpieceadapter to ensure an airtight seal. Use a mouthpiece adapter which ensures that the front face ofthe inhaler mouthpiece is flush with the front face of the sample collection tube. Connect one portof a differential pressure meter to the pressure reading point, P1, in Fig. 0671–2 and let the otherbe open to the atmosphere. Switch on the pump, open the two way valve and adjust the flowcontrol valve until the pressure drop across the inhaler is 4.0 kPa (40.8 cm H2O) as indicated bythe differential pressure meter. Remove the inhaler from the mouthpiece adapter and withouttouching the flow control valve, connect a flow meter to the inlet of the sampling apparatus. If theflow rate is above 100 litres/min adjust the flow control valve to obtain a flow rate of 100 ± 5 litres/min. Note the volumetric airflow rate and define this as the test flow rate, Q, in litres per minute.Define the test flow duration, T, in seconds so that a volume of 4 litres of air is drawn through theinhaler.

Ensure that critical flow occurs in the flow control valve by the following procedure. With theinhaler in place and the test flow rate Q, measure the absolute pressure on both sides of the controlvalve (pressure reading points P2 and P3 in Fig. 0671–2). A ratio P3/P2 £ 0.5 indicates critical flow.Switch to a more powerful pump and re-measure the test flow rate if critical flow is not indicated.

Predispensed systems. Prepare the inhaler as directed in the instructions to the patient and connect it tothe apparatus using an adapter which ensures a good seal. Draw air through the inhaler using thepredetermined conditions. Repeat the procedure until the number of deliveries which constitute theminimum recommended dose have been sampled. Quantitatively collect the contents of theapparatus and determine the amount of active substance.

Repeat the procedure for a further nine doses.

Reservoir systems. Prepare the inhaler as directed in the instructions to the patient and connect it tothe apparatus using an adapter which ensures a good seal. Draw air through the inhaler under the

45-35

predetermined conditions. Repeat the procedure until the number of deliveries which constitutethe minimum recommended dose have been sampled. Quantitatively collect the contents of theapparatus and determine the amount of active substance.

Repeat the procedure for a further two doses.Discharge the device to waste until (n/2) + 1 deliveries remain, where n is the number of

deliveries stated on the label. If necessary, store the inhaler to discharge electrostatic charges.Collect four doses using the procedure described above.

Discharge the device to waste until three doses remain. If necessary, store the inhaler todischarge electrostatic charges. Collect three doses using the procedure described above.

For preparations containing more than one active substance, carry out the test for uniformity ofdelivered dose for each active substance.

The preparation complies with the test if nine out of ten results lie between 75 per cent and125 per cent of the average value and all lie between 65 per cent and 135 per cent. If two or threevalues lie outside the range of 75 per cent to 125 per cent, repeat the test for two more inhalers. Notmore than three of the thirty values lie outside the range 75 per cent to 125 per cent and no value liesoutside the range 65 per cent to 135 per cent.

In justified and authorised cases, these ranges may be extended but no value should be greater than150 per cent or less than 50 per cent of the average value.

Fine particle dose Using the apparatus and procedure described in Aerodynamic assessment of fineparticles (2.9.18- apparatus C or D), calculate the fine particle dose.

Number of deliveries per inhaler for multidose inhalers Discharge doses from the inhaler untilempty, at the predetermined flow rate. Record the deliveries discharged. The total number of dosesdelivered is not less than the number stated on the label (this test may be combined with the test foruniformity of delivered dose).

__________________________________________________________________________________________________________ Ph Eur

Preparations for Inhalation of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyinhalation, powder for inhalation, pressurised inhalation or solution for nebulisation that is the subject of anindividual monograph in the British Pharmacopoeia.

INHALATIONS

Definition Inhalations are solutions or dispersions of one or more active ingredients which maycontain an inert, suspended, diffusing agent. They are intended to release volatile constituents forinhalation either when placed on a pad or when added to hot, but not boiling, water.

Labelling The label on the container states (1) the names and concentrations of the activeingredients; (2) that the Inhalation is not to be taken by mouth; (3) the date after which theInhalation is not intended to be used; (4) the conditions under which the Inhalation should bestored.

POWDERS FOR INHALATION

Labelling The label on the container states (1) the date after which the Powder for Inhalation is notintended to be used; (2) the conditions under which the Powder for Inhalation should be stored.

Where the Powder for Inhalation is supplied in a capsule, the label also states (3) the quantity ofthe active ingredient contained in each capsule; (4) that the capsules are intended for use in aninhaler and are not to be swallowed.

PRESSURISED INHALATIONSDefinition Pressurised Inhalations are Pressurised Metered-dose Preparations for Inhalation. Theyare intended to be inhaled in controlled amounts.

Production The formulation of the inhalation and the components of the delivery device (that is thepressurised container with its integral metering valve and the actuator) should be designed and,where appropriate, the particle size of the active ingredient should be controlled so that, when thepressurised inhalation is used in accordance with the manufacturer’s recommendations, an adequateproportion of the active ingredient is made available for inhalation. A proportion of the activeingredient is deposited on the inner surface of the actuator; the amount available for inhalation istherefore less than the amount released by actuation of the valve.

Pressurised Inhalations should be manufactured in conditions designed to minimise microbial andparticulate contamination.

Content of active ingredient delivered by actuation of the valve Remove the pressurisedcontainer from the actuator and remove all labels and markings which may be present on the

45-36

container with a suitable solvent. Dry the container, replace in its actuator, shake for about 30seconds and prime the metering valve as follows. Discharge once to waste, wait for not less than 5seconds and discharge again to waste. Remove the pressurised container from its actuator, cleanthe valve stem (internally and externally) and the valve ferrule by washing with a suitable solvent.Dry the complete valve assembly using an air line fitted with an appropriate narrow jet to ensurethat all solvent is removed from the inside of the valve stem.

Place a stainless steel base plate that has three legs and a central circular indentation with a holeabout 1.5 mm in diameter in a samll vessel suitable for shaking and add the volume of solventspecified in the monograph. The size of the vessel is such that when the pressurised inhalation isdischarged into the specified volume of solvent as described below the discharge takes place not lessthan 25 mm below the surface of the solvent.

Shake the pressurised container for about 30 seconds and place it inverted in the vessel. Discharge10 deliveries below the surface of the solvent actuating the valve at intervals of not less than 5seconds, maintaining the pressurised container in the vertical plane and discharging the pressurisedinhalation through the hole in the centre of the base plate. (It may be necessary because of the natureof the formulation to shake the pressurised container between each actuation of the valve; where thisis the case shaking should be carried out without removing the pressurised container from its invertedposition in the vessel.) Remove the pressurised container, wash it with the specified solvent and dilutethe combined solution and washings to the volume specified in the monograph. Determine theamount of active ingredient by the method described under the Assay and calculate the amountdelivered from each actuation of the valve. The result lies within the range for the content of activeingredient stated in the monograph.

Storage Pressurised Inhalations are supplied in suitable containers fitted with an appropriatemetering valve that forms an integral part of the container. Metal containers comply with the relevantrequirements of British Standard 3914: Part 1:1974 (Non-returnable metal containers up to 1400cm3 and 85 mm diameter). The containers are usually supplied with an appropriate actuator.

Labelling The label states (1) the name of the active ingredient or ingredients; (2) the amount ofactive ingredient or ingredients delivered by each actuation of the valve and the number of deliveriesavailable from the container; (3) the instructions for using the Pressurised Inhalation; (4) the dateafter which the Pressurised Inhalation is not intended to be used; (5) the conditions under which thePressurised Inhalation should be stored; (6) any special precautions associated with the use of thePressurised Inhalation.

SOLUTIONS FOR NEBULISATION

Labelling The label states (1) the date after which the solution for nebulisation is not intended to beused; (2) the conditions under which the solution for nebulisation should be stored.

The following preparations for inhalation are the subject of an individual monograph in the BritishPharmacopoeia.

InhalationsBenzoin InhalationMenthol and Benzoin Inhalation

Powders for InhalationSodium Cromoglicate Powder for Inhalation

Pressurised InhalationsBeclometasone Pressurised InhalationFenoterol Pressurised InhalationIpratropium Pressurised InhalationSalbutamol Pressurised Inhalation

Nebuliser SolutionsRibavirin Nebuliser SolutionSalbutamol Nebuliser Solution

45-37

PREPARATIONS FOR IRRIGATION

revised 1/01

Preparations for Irrigation comply with the requirements of the 3rd edition of the European Pharmacopoeia[1116]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Preparations for irrigation are sterile, aqueous large volume preparations intended to be used forirrigation of body cavities, wounds and surfaces, for example during surgical procedures.

Preparations for irrigation are either solutions prepared by dissolving one or more activesubstances, electrolytes or osmotically active substances in water complying with the requirements forWater for injections (0169) or they consist of such water alone. In the latter case, the preparation maybe labelled as water for irrigation. Irrigation solutions are usually adjusted to be isotonic with blood.

Examined in suitable conditions of visibility, preparations for irrigation are clear and practically freefrom particles.

Preparations for irrigation are supplied in single-dose containers. The containers and closurescomply with the requirements for containers for preparations for parenteral use (3.2.1 and 3.2.2) butthe administration port of the container is incompatible with intravenous administration equipmentand does not allow the preparation for irrigation to be administered with such equipment.

PRODUCTION

Preparations for irrigation are prepared using materials and methods designed to ensure sterility andto avoid the introduction of contaminants and the growth of micro-organisms; recommendations onthis aspect are provided in the text on Methods of preparation of sterile products (5.1.1).

TESTS

Deliverable mass or volume (2.9.28). Preparations for irrigation supplied in single-dose containerscomply with the test.

Sterility (2.6.1). Preparations for irrigation comply with the test for sterility.

Bacterial endotoxins (2.6.14). Not more than 0.5 I.U. of endotoxin per millilitre.

Pyrogens (2.6.8). Preparations for which a validated test for bacterial endotoxins cannot be carriedout comply with the test for pyrogens. Inject per kilogram of the rabbits mass, 10 ml of the prepara-tion, unless otherwise justified and authorised.

LABELLING

The label states:— that the preparation is not to be used for injection,— that the preparation is to be used for one occasion only and that any unused portion of prepara-

tion is to be discarded.__________________________________________________________________________________________________________ Ph Eur

Preparations for Irrigation of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to thoseirrigation solutions that are the subject of an individual monograph in the British Pharmacopoeia.

Water for Irrigation When the term ‘Water for Irrigation’ is used within the individualmonographs of the British Pharmacopoeia, it has the meaning defined in the requirements of theEuropean Pharmacopoeia above.

IRRIGATION SOLUTIONS

Labelling The label states (1) the names and concentrations of the active ingredients; (2) the dateafter which the Irrigation Solution is not intended to be used; (3) the conditions under which theirrigation solution should be stored.

The following irrigation solutions are the subject of an individual monograph in the British Pharmacopoeia.

Chlorhexidine Irrigation SolutionGlucose Irrigation SolutionGlycine Irrigation SolutionSodium Chloride Irrigation SolutionSodium Citrate Irrigation Solution

45-38

MOUTHWASHES

Definition Mouthwashes are aqueous solutions containing one or more active ingredients. They areintended for use in contact with the mucous membranes of the oral cavity, usually after dilution withwarm water. They may contain excipients such as suitable antimicrobial preservatives.

Storage Mouthwashes should be kept in well-closed containers.

Labelling The label states (1) directions for the dilution of the Mouthwash for use, if appropriate;(2) that large quantities of the Mouthwash should not be swallowed; (3) the date after which theMouthwash is not intended to be used; (4) the conditions under which the Mouthwash should bestored.

The following mouthwashes are the subject of an individual monograph in the British Pharmacopoeia.

Benzydamine MouthwashChlorhexidine MouthwashHydrogen Peroxide MouthwashPovidone–Iodine MouthwashSodium Chloride Mouthwash, CompoundSodium Fluoride Mouthwash

45-39

NASAL PREPARATIONS

revised 1/01

Nasal Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia [0676].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Nasal preparations are liquid, semi-solid or solid preparations intended for administration to thenasal cavities to obtain a systemic or local effect. They contain one or more active substances. Nasalpreparations are as far as possible non-irritating and do not adversely affect the functions of the nasalmucosa and its cilia. Aqueous nasal preparations are usually isotonic and may contain excipients, forexample, to adjust the viscosity of the preparation, to adjust or stabilise the pH, to increase thesolubility of the active substance, or to stabilise the preparation.

Nasal preparations are supplied in multidose or single-dose containers, provided, if necessary, witha suitable administration device which may be designed to avoid the introduction of contaminants.

Unless otherwise justified and authorised, aqueous nasal preparations supplied in multidosecontainers contain a suitable antimicrobial preservative in appropriate concentration, except wherethe preparation itself has adequate antimicrobial properties.

Where applicable, the containers comply with the requirements of Materials used for the manufactureof containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of nasal preparations may be distinguished:— nasal drops and liquid nasal sprays,— nasal powders,— semi-solid nasal preparations,— nasal washes,— nasal sticks.

PRODUCTION

During the development of a nasal preparation, the formulation for which contains an antimicrobialpreservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction ofthe competent authority. A suitable test method together with criteria for judging the preservativeproperties of the formulation are provided in the text on Efficacy of antimicrobial preservation (5.1.3).

In the manufacture, packaging, storage and distribution of nasal preparations, suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

Sterile nasal preparations are prepared using materials and methods designed to ensure sterility andto avoid the introduction of contaminants and the growth of micro-organisms; recommendations onthis aspect are provided in the text on Methods of preparation of sterile products (5.1.1).

In the manufacture of nasal preparations containing dispersed particles, measures are taken to ensurea suitable and controlled particle size with regard to the intended use.

TESTS

Sterility (2.6.1). Where the label states that the preparation is sterile, it complies with the test forsterility.

STORAGE

Store in a well-closed container. If the preparation is sterile, store in a sterile, airtight, tamper-proofcontainer.

LABELLING

The label states:— the name of any added antimicrobial preservative,— where applicable, that the preparation is sterile.

Nasal Drops and Liquid Nasal Sprays

DEFINITION

Nasal drops and liquid nasal sprays are solutions, emulsions or suspensions intended for instillationor spraying into the nasal cavities.

Emulsions may show evidence of phase separation but are easily redispersed on shaking.Suspensions may show a sediment which is readily dispersed on shaking to give a suspension whichremains sufficiently stable to enable the correct dose to be delivered.

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Nasal drops are usually supplied in multidose containers provided with a suitable applicator.Liquid nasal sprays are supplied in containers with atomising devices or in pressurised containers

fitted with a suitable adapter and with or without a metering dose valve, which comply with therequirements of the monograph on Pressurised pharmaceutical preparations (0523).

The size of droplets of the spray is such as to localise their deposition in the nasal cavity.

TESTS

Unless otherwise prescribed or justified and authorised, nasal drops supplied in single-dosecontainers and single doses of metered nasal sprays intended for systemic action, comply with thefollowing tests.

Uniformity of mass Nasal drops that are solutions comply with the following test: weighindividually the contents of ten containers emptied as completely as possible, and determine theaverage mass. Not more than two of the individual masses deviate by more than 10 per cent from theaverage mass and none deviates by more than 20 per cent.

Metered-dose nasal sprays that are solutions comply with the following test: discharge once towaste. Wait for not less than 5 s and discharge again to waste. Repeat this procedure for a furtherthree actuations. Weigh the mass of the container, discharge once to waste and weigh the remainingmass of the container. Calculate the difference between the two masses. Repeat the procedure for afurther nine containers. They comply with the test if not more than two of the individual valuesdeviate by more than 25 per cent from the average value and none deviates by more than 35 per cent.

Uniformity of content (2.9.6). Nasal drops that are suspensions or emulsions comply with thefollowing test: empty each container as completely as possible and carry out the test on the individualcontent. They comply with test B of uniformity of content.

Uniformity of delivered dose Metered-dose nasal sprays that are suspensions or emulsions complywith the following test. Use an apparatus capable of quantitatively retaining the dose leaving theactuator of the atomising device.

Shake a container for 5 s and discharge once to waste. Wait for not less than 5 s, shake for 5 s anddischarge again to waste. Repeat this procedure for a further three actuations. After 2 s, fire one doseof the metered-dose nasal spray into the collecting vessel by actuating the atomising device. Collectthe contents of the collecting vessel by successive rinses. Determine the content of active substance inthe combined rinses.

Repeat the procedure for a further nine containers.Unless otherwise justified and authorised, the preparation complies with the test if not more than

one of the individual contents is outside the limits of 75 per cent to 125 per cent and none is outsidethe limits of 65 per cent and 135 per cent of the average content.

If two or three individual contents are outside the limits of 75 per cent to 125 per cent but withinthe limits of 65 per cent to 135 per cent, repeat the test for twenty more containers. The preparationcomplies with the test if not more than three individual contents of the thirty individual contents areoutside the limits of 75 per cent to 125 per cent and none is outside the limits of 65 per cent to135 per cent of the average content.

Nasal Powders

DEFINITION

Nasal powders are powders intended for insufflation into the nasal cavity by means of a suitabledevice.

They comply with the requirements of the monograph on Powders for cutaneous application (1166).The size of the particles is such as to localise their deposition in the nasal cavity and verified by

adequate methods of particle-size determination.

Semi-Solid Nasal Preparations

DEFINITION

Semi-solid nasal preparations comply with the requirements of the monograph on Semi-solid prepara-tions for cutaneous application (0132).

The containers are adapted to deliver the product to the site of application.

Nasal Washes

DEFINITION

Nasal washes are generally aqueous isotonic solutions intended to cleanse the nasal cavities.Nasal washes intended for application to injured parts or prior to a surgical operation are sterile.

TESTS

Deliverable mass or volume (2.9.28). Nasal washes supplied in single-dose containers comply withthe test.

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Nasal Sticks

DEFINITION

Nasal sticks comply with the monograph on Sticks (1154).__________________________________________________________________________________________________________ Ph Eur

Nasal Preparations of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyintranasal solution, intranasal suspension, nasal drops or nasal spray that is the subject of an individualmonograph in the British Pharmacopoeia.

INTRANASAL SOLUTIONS AND INTRANASALSUSPENSIONS

Definition Intranasal Solutions and Intranasal Suspensions are intended for administration to thenostrils for local or systemic effects. When supplied in a container fitted with a spray mechanism,they may be entitled Nasal Spray.

Labelling The label states (1) the name and quantity of the active ingredient; (2) the name andquantity of any added substance; (3) that the preparation is for intranasal administration; (4) the dateafter which the preparation is not intended to be used; (5) the conditions under which thepreparation should be stored.

NASAL DROPS

Labelling The label states (1) the name and quantity of the active ingredient; (2) the instructions forusing the Nasal Drops; (3) the date after which the Nasal Drops are not intended to be used; (4) theconditions under which the Nasal Drops should be stored.

The following nasal preparations are the subject of an individual monograph in the British Pharmacopoeia.

Intranasal SolutionsDesmopressin Intranasal Solution

Nasal Drops

Ephedrine Nasal DropsXylometazoline Nasal Drops

Nasal Sprays

Beclometasone Nasal Spray

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ORAL LIQUIDS

LIQUID PREPARATIONS FOR ORAL USE revised 1/01

Oral Liquids comply with the requirements of the 3rd edition of the European Pharmacopoeia for LiquidPreparations for Oral Use [0672]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Liquid preparations for oral use are usually solutions, emulsions or suspensions containing one ormore active substances in a suitable vehicle; they may, however, consist of liquid active substancesused as such (oral liquids).

Some preparations for oral use are prepared by dilution of concentrated liquid preparations, orfrom powders or granules for the preparation of oral solutions or suspensions, for oral drops or forsyrups, using a suitable vehicle.

The vehicle for any preparations for oral use is chosen having regard to the nature of the activesubstance(s) and to provide organoleptic characteristics appropriate to the intended use of thepreparation.

Liquid preparations for oral use may contain suitable antimicrobial preservatives, antioxidants andother excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting,solubilising, stabilising, flavouring and sweetening agents and colouring matter, authorised by thecompetent authority.

Emulsions may show evidence of phase separation but are readily redispersed on shaking.Suspensions may show a sediment which is readily dispersed on shaking to give a suspension whichremains sufficiently stable to enable the correct dose to be delivered.

Where applicable, containers for liquid preparations for oral use comply with the requirements ofMaterials used for the manufacture of containers (3.1 and subsections) and Containers (3.2 andsubsections).

Several categories of preparations may be distinguished:— oral solutions, emulsions and suspensions,— powders and granules for oral solutions and suspensions,— oral drops,— powders for oral drops,— syrups,— powders and granules for syrups.

PRODUCTION

During the development of a preparation for oral use, the formulation for which contains anantimicrobial preservative, the effectiveness of the chosen preservative shall be demonstrated to thesatisfaction of the competent authority. A suitable test method together with criteria for judging thepreservative properties of the formulation are provided in the text on Efficacy of antimicrobialpreservation (5.1.3).

In the manufacturing, packaging, storage and distribution of liquid preparations for oral use,suitable means are taken to ensure their microbial quality; recommendations on this aspect areprovided in the text on Microbiological quality of pharmaceutical preparations (5.1.4).

In the manufacture of liquid preparations for oral use containing dispersed particles, measures aretaken to ensure a suitable and controlled particle size with regard to the intended use.

TESTS

Uniformity of content (2.9.6).Unless otherwise prescribed or justified and authorised, single-dosepreparations that are suspensions comply with the following test. After shaking, empty each containeras completely as possible and carry out the test on the individual contents. They comply with test Bfor uniformity of content of single-dose preparations.

Uniformity of mass Single-dose preparations that are solutions or emulsions comply with thefollowing test: weigh individually the contents of 20 containers, emptied as completely as possible,and determine the average mass. Not more than two of the individual masses deviate by more than10 per cent from the average mass and none deviates by more than 20 per cent.

Dose and uniformity of dose of oral drops Into a suitable, graduated cylinder, introduce bymeans of the dropping device the number of drops usually prescribed for one dose or introduce bymeans of the measuring device, the usually prescribed quantity. The dropping speed does not exceed2 drops per second. Weigh the liquid, repeat the addition, weigh again and carry on repeating theaddition and weighing until a total of 10 masses are obtained. No single mass deviates by more than10 per cent from the average mass. The total of ten masses does not differ by more than 15 per cent

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from the nominal mass of ten doses. If necessary, measure the total volume of ten doses. Thevolume does not differ by more than 15 per cent from the nominal volume of ten doses.

Deliverable mass or volume (2.9.28). Liquid preparations for oral use supplied in single-dosecontainers comply with the test.

STORAGE

Store in a well-closed container.

LABELLING

The label states the name of any added antimicrobial preservative.

Oral Solutions, Emulsions and Suspensions

DEFINITION

Oral solutions, emulsions and suspensions are supplied in single-dose or multi-dose containers. Eachdose from a multi-dose container is administered by means of a device suitable for measuring theprescribed volume. The device is usually a spoon or a cup for volumes of 5 ml or multiples thereof oran oral syringe for other volumes.

Powders and Granules for Oral Solutions and Suspensions

DEFINITION

Powders and granules for the preparation of oral solutions or suspensions generally conform to thedefinitions in the monographs on Oral powders (1165) or Granules (0499) as appropriate. They maycontain excipients in particular to facilitate dispersion or dissolution and to prevent caking.

After dissolution or suspension, they comply with the requirements for oral solutions or oralsuspensions, as appropriate.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosepowders and single-dose granules with a content of active substance less than 2 mg or less than 2 percent of the total mass comply with the test B for uniformity of content of single-dose preparations(2.9.6). If the preparation has more than one active substance, the requirement applies only to thosesubstances that correspond to the above conditions.

Uniformity of mass (2.9.5). Single-dose powders and single-dose granules comply with the test foruniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed forall the active substances, the test for uniformity of mass is not required.

STORAGE

Store in a well-closed container.

LABELLING

The label states:— the method of preparation of the solution or suspension,— the conditions and the duration of storage after constitution.

Oral Drops

DEFINITION

Oral drops are solutions, emulsions or suspensions which are administered in small volumes such asdrops by the means of a suitable device.

LABELLING

The label states the number of drops per millilitre of preparation or per gram of preparation if thedose is measured in drops.

Powders for Oral Drops

DEFINITION

Powders for the preparation of oral drops generally conform to the definition of Oral powders (1165).They may contain excipients to facilitate dissolution or suspension in the prescribed liquid or toprevent caking.

After dissolution or suspension, they comply with the requirements for oral drops.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosepowders for oral drops with a content of active substance less than 2 mg or less than 2 per cent of thetotal mass comply with the test B for uniformity of content of single-dose preparations. If the prepa-

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ration has more than one active substance, the requirement applies only to those substances thatcorrespond to the above conditions.

Uniformity of mass (2.9.5). Single-dose powders for oral drops comply with the test for uniformityof mass of single-dose preparations. If the test for uniformity of content is prescribed for all the activesubstances, the test for uniformity of mass is not required.

Syrups

DEFINITION

Syrups are aqueous preparations characterised by sweet taste and a viscous consistency. They maycontain sucrose at a concentration of at least 45 per cent m/m. The sweet taste can also be obtainedby using other polyols or sweetening agents. Syrups usually contain aromatic or other flavouringagents. Each dose from a multi-dose container is administered by means of a device suitable formeasuring the prescribed volume. The device is usually a spoon or a cup for volumes of 5 ml ormultiples thereof.

LABELLING

The label states the name and concentration of the polyol or sweetening agent.

Powders and Granules for Syrups

DEFINITION

Powders and granules for syrups generally conform to the definitions in the monograph on Oralpowders (1165) or Granules (0499). They may contain excipients to facilitate dissolution.

After dissolution, they comply with the requirements for syrups.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosepowders and granules for syrups with a content of active substance less than 2 mg or less than 2 percent of the total mass comply with the test B for uniformity of content of single-dose preparations. Ifthe preparation has more than one active substance, the requirement applies only to those substancesthat correspond to the above conditions.

Uniformity of mass (2.9.5). Single-dose powders and granules for syrups comply with the test foruniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed forall the active substances, the test for uniformity of mass is not required.

__________________________________________________________________________________________________________ Ph Eur

Oral Liquids of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyelixir, linctus, mixture, oral drops, oral emulsion, oral solution, oral suspension or syrup that is the subject ofan individual monograph in the British Pharmacopoeia.

Definition The vehicle for any particular Oral Liquid should be chosen having regard to the natureof the active ingredient or ingredients and to provide organoleptic characteristics appropriate to theintended use of the preparation.

Oral Liquids other than Oral Emulsions may be supplied as liquids or prepared just before issue foruse by dissolving or dispersing granules or powder in the liquid stated on the label.

Storage Oral Liquids should be kept in well-closed containers.

Labelling The label states (1) the date after which the Oral Liquid is not intended to be used; (2)the conditions under which the Oral Liquid should be stored; (3) for Oral Emulsions, OralSuspensions and, where appropriate, for Mixtures, that the bottle should be shaken before use.

If the Oral Liquid is supplied as granules or powder to be constituted just before issue for use thelabel states (1) that the contents of the container are granules or powder for the preparation of anOral Liquid; (2) the strength as the amount of the active ingredient in a suitable dose-volume of theconstituted preparation; (3) the directions for preparing the Oral Liquid including the nature andquantity of liquid to be used.

ELIXIRS

Definition Elixirs are clear, flavoured Oral Liquids containing one or more active ingredientsdissolved in a vehicle that usually contains a high proportion of Sucrose or a suitable polyhydricalcohol or alcohols and may also contain Ethanol (96 per cent) or a Dilute Ethanol.

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LINCTUSES

Definition Linctuses are viscous Oral Liquids that may contain one or more active ingredients insolution. The vehicle usually contains a high proportion of Sucrose, other sugars or a suitablepolyhydric alcohol or alcohols. Linctuses are intended for use in the treatment or relief of cough, andare sipped and swallowed slowly without the addition of water.

MIXTURES

Definition Mixtures are Oral Liquids containing one or more active ingredients dissolved,suspended or dispersed in a suitable vehicle. Suspended solids may separate slowly on standing butare easily redispersed on shaking.

ORAL DROPS

Definition Oral Drops are Oral Liquids that are intended to be administered in small volumes withthe aid of a suitable measuring device.

ORAL EMULSIONS

Definition Oral Emulsions are Oral Liquids containing one or more active ingredients. They arestabilised oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solidsmay also be suspended in Oral Emulsions.

When issued for use, Oral Emulsions should be supplied in wide-mouthed bottles.

Extemporaneous preparation In Oral Emulsions prepared according to the formula and directionsgiven for Extemporaneous preparation, the quantity of emulsifying agent specified in individualmonographs may be reduced to yield a preparation of suitable consistency provided that by so doingthe stability of the preparation is not adversely affected.

ORAL SOLUTIONS

Definition Oral Solutions are Oral Liquids containing one or more active ingredients dissolved in asuitable vehicle.

ORAL SUSPENSIONS

Definition Oral Suspensions are Oral Liquids containing one or more active ingredients suspendedin a suitable vehicle. Suspended solids may slowly separate on standing but are easily redispersed.

SYRUPS

Definition Syrups do not contain active ingredients. They are not intended to be administered assuch but are used as vehicle ingrredients for their flavouring and sweetening properties.

Production They should be recently prepared unless they contain suitable antimicrobialpreservatives.

Storage Syrups should be kept in well-closed containers and stored at temperatures not exceeding30°.

Labelling The label states (1) the date after which the Syrup is not intended to be used; (2) theconditions under which the Syrup should be stored.

The following oral liquids are the subject of an individual monograph in the British Pharmacopoeia.

ElixirsEphedrine ElixirPhenobarbital ElixirPiperazine Citrate Elixir

LinctusesCodeine LinctusCodeine Linctus, PaediatricMethadone LinctusPholcodine LinctusPholcodine Linctus, StrongSimple LinctusSimple Linctus, PaediatricSquill Linctus, OpiateSquill Linctus, Paediatric OpiateTolu Linctus, Paediatric Compound

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MixturesAmmonium Chloride MixtureGentian Mixture, AcidGentian Mixture, AlkalineIpecacuanha Emetic Mixture, PaediatricKaolin and Morphine MixtureKaolin MixtureMagnesium Carbonate Mixture, AromaticMagnesium Hydroxide MixtureMagnesium Sulphate MixtureMagnesium Trisilicate MixturePotassium Citrate Mixture

Oral DropsSodium Fluoride Oral Drops

Oral EmulsionsLiquid Paraffin Oral EmulsionLiquid Paraffin and Magnesium Hydroxide Oral Emulsion

Oral SolutionsAlimemazine Oral Solution, Paediatric/Trimeprazine Oral Solution, PaediatricAlimemazine Oral Solution, Strong Paediatric/Trimeprazine Oral Solution, Strong PaediatricAmantadine Oral SolutionAtenolol Oral SolutionBaclofen Oral SolutionBumetanide Oral SolutionChlorphenamine Oral Solution/Chlorpheniramine Oral SolutionChlorpromazine Oral SolutionCimetidine Oral SolutionClemastine Oral SolutionClomethiazole Oral SolutionCloxacillin Oral SolutionCo-amilozide Oral SolutionCodeine Phosphate Oral SolutionDiazepam Oral SolutionDicycloverine Oral Solution/Dicyclomine Oral SolutionDigoxin Oral Solution, PaediatricDihydrocodeine Oral SolutionDiphenhydramine Oral SolutionDocusate Oral SolutionDocusate Oral Solution, PaediatricEthosuximide Oral SolutionFerrous Sulphate Oral Solution, PaediatricFlucloxacillin Oral SolutionFluoxetine Oral SolutionHaloperidol Oral SolutionHaloperidol Oral Solution, StrongIodine Oral Solution, AqueousLithium Citrate Oral SolutionMethadone Oral Solution (1 mg per ml)Metoclopramide Oral SolutionNeomycin Oral SolutionOrciprenaline Oral SolutionParacetamol Oral Solution, PaediatricPhenoxymethylpenicillin Oral SolutionProchlorperazine Oral SolutionPromethazine Oral SolutionRanitidine Oral SolutionSelegiline Oral SolutionSodium Feredetate Oral SolutionSodium Valproate Oral SolutionTemazepam Oral SolutionThioridazine Oral SolutionTriclofos Oral Solution

Oral SuspensionsAciclovir Oral Suspension

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Aluminium Hydroxide Oral SuspensionAmoxicillin Oral SuspensionAmphotericin Oral SuspensionAmpicillin Oral SuspensionBarium Sulphate Oral SuspensionBenorilate Oral SuspensionCefaclor Oral SuspensionCefadroxil Oral SuspensionCefalexin Oral SuspensionCimetidine Oral SuspensionCo-fluampicil Oral SuspensionCo-magaldrox Oral SuspensionCo-trimoxazole Oral SuspensionCo-trimoxazole Oral Suspension, PaediatricErythromycin Ethyl Succinate Oral SuspensionFerrous Fumarate Oral SuspensionFlucloxacillin Oral SuspensionFusidic Acid Oral SuspensionIbuprofen Oral SuspensionMagaldrate Oral SuspensionNabumetone Oral SuspensionNalidixic Acid Oral SuspensionNaproxen Oral SuspensionNitrazepam Oral SuspensionNitrofurantoin Oral SuspensionNystatin Oral SuspensionParacetamol Oral SuspensionPhenytoin Oral SuspensionPrimidone Oral SuspensionPromazine Oral SuspensionRifampicin Oral SuspensionTerfenadine Oral SuspensionThioridazine Oral Suspension

SyrupsBlack Currant SyrupInvert SyrupLemon SyrupOrange SyrupSyrupTolu Syrup

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ORAL POWDERS

revised 1/01

Oral Powders comply with the requirements of the 3rd edition of the European Pharmacopoeia [1165]. Theserequirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Requirements for powders to be used for the preparation of oral solutions or suspensions are given in themonograph for Liquid preparations for oral use (0672).

DEFINITION

Oral powders are preparations consisting of solid, loose, dry particles of varying degrees of fineness.They contain one or more active substances, with or without excipients and, if necessary, colouringmatter authorised by the competent authority and flavouring substances. They are generallyadministered in or with water or another suitable liquid. They may also be swallowed directly. Theyare presented as single-dose or multidose powders.

Where applicable, containers for oral powders comply with the requirements of Materials used forthe manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Multi-dose oral powders require the provision of a measuring device capable of delivering thequantity prescribed. Each dose of a single-dose powder is enclosed in an individual container, forexample a sachet, a paper packet or a vial.

PRODUCTION

In the manufacture of oral powders, means are taken to ensure a suitable particle size with regard tothe intended use.

In the manufacture, packaging, storage and distribution of oral powders, suitable means are taken toensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-doseoral powders with a content of active substance less than 2 mg or less than 2 per cent of the totalmass comply with test B for uniformity of content of single-dose preparations. If the preparation hasmore than one active substance, the requirement applies only to those substances which correspondto the above conditions.

Uniformity of mass (2.9.5). Single-dose oral powders comply with the test for uniformity of massof single-dose preparations. If the test for uniformity of content is prescribed for all the activesubstances, the test for uniformity of mass is not required.

STORAGE

Store in a well-closed container or, if the preparation contains volatile ingredients, store in an airtightcontainer.

Effervescent PowdersEffervescent powders are presented as single-dose or multidose powders and generally contain acidsubstances and carbonates or hydrogen carbonates which react rapidly in the presence of water torelease carbon dioxide. They are intended to be dissolved or dispersed in water before administration.

STORAGE

Store in an airtight container.__________________________________________________________________________________________________________ Ph Eur

Oral Powders of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to thoseoral powders that are the subject of an individual monograph in the British Pharmacopoeia.

Labelling For single dose containers the label states the name and quantity of active ingredient percontainer. For multidose containers the label states the name and quantity of active ingredient in asuitable amount by weight.

The label also states (1) the name and proportions of any antimicrobial preservative; (2) thedirections for use of the Oral Powder; (3) the date after which the Oral Powder is not intended to beused; (4) the conditions under which the Oral Powder should be stored.

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The following oral powders are the subject of an individual monograph in the British Pharmacopoeia.

Colestyramine Oral PowderIspaghula Husk Oral PowderLactulose Oral PowderMagnesium Trisilicate Oral Powder, CompoundOral Rehydration SaltsSodium Picosulfate Oral PowderVigabatrin Oral Powder

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PARENTERAL PREPARATIONS

revised 1/01

Parenteral Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia[0520]. These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

The requirements of this monograph do not necessarily apply to products derived from human blood, toimmunological preparations, or radiopharmaceutical preparations.

DEFINITION

Parenteral preparations are sterile preparations intended for administration by injection, infusion orimplantation into the human or animal body.

Parenteral preparations may require the use of excipients, for example to make the preparationisotonic with blood, to adjust the pH, to increase solubility, to prevent deterioration of the activesubstances or to provide adequate antimicrobial properties but not to adversely affect the intendedmedicinal action of the preparation or, at the concentrations used, to cause toxicity or undue localirritation.

Containers for parenteral preparations are made as far as possible from materials that aresufficiently transparent to permit the visual inspection of the contents, except for implants and inother justified and authorised cases.

Where applicable, the containers for parenteral preparations comply with the requirements forMaterials used for the manufacture of containers (3.1 and subsections) and Containers (3.2 andsubsections).

Parenteral preparations are supplied in glass containers (3.2.1) or in other containers such as plasticcontainers (3.2.2, 3.2.2.1 and 3.2.9) and prefilled syringes. The tightness of the container is ensuredby suitable means. Closures ensure a good seal, prevent the access of micro-organisms and othercontaminants and usually permit the withdrawal of a part or the whole of the contents withoutremoval of the closure. The plastic materials or elastomers (3.2.9) of which the closure is composedare sufficiently firm and elastic to allow the passage of a needle with the least possible shedding ofparticles. Closures for multidose containers are sufficiently elastic to ensure that the puncture isresealed when the needle is withdrawn.

Several categories of parenteral preparations may be distinguished:— injections,— infusions,— concentrates for injections or infusions,— powders for injections or infusions,— implants.

PRODUCTION

During the development of a parenteral preparation, the formulation for which contains anantimicrobial preservative, the effectiveness of the chosen preservative shall be demonstrated to thesatisfaction of the competent authority. A suitable test method together with criteria for judging thepreservative properties of the formulation are provided under Efficacy of antimicrobial preservation(5.1.3).

Parenteral preparations are prepared using materials and methods designed to ensure sterility andto avoid the introduction of contaminants and the growth of micro-organisms; recommendations onthis aspect are provided in the text on Methods of preparation of sterile products (5.1.1).

Water used in the manufacture of parenteral preparations complies with the requirements of waterfor injections in bulk stated in the monograph on Water for injections (0169).

TESTS

Particulate contamination: sub-visible particles (2.9.19). For preparations for human use,solutions for infusion or solutions for injection supplied in containers with a nominal content of morethan 100 ml comply with the test.

Products for which the label states that the product is to be used with a final filter are exempt fromthese requirements.

Sterility (2.6.1). Parenteral preparations comply with the test for sterility.

STORAGE

Store in a sterile, airtight, tamper-proof container.

LABELLING

The label states:

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— the name and concentration of any added antimicrobial preservative,— where applicable, that the solution is to be used in conjunction with a final filter.

Injections

DEFINITIONInjections are sterile solutions, emulsions or suspensions. They are prepared by dissolving,

emulsifying or suspending the active substance(s) and any added excipients in water for injections R, ina suitable, sterile non-aqueous liquid or in a mixture of these vehicles.

Solutions for injection, examined under suitable conditions of visibility, are clear and practicallyfree from particles.

Emulsions for injection do not show any evidence of phase separation. Suspensions for injectionmay show a sediment which is readily dispersed on shaking to give a suspension which remainssufficiently stable to enable the correct dose to be withdrawn.

Multidose preparations. Multidose aqueous injections contain a suitable antimicrobial preservative atan appropriate concentration except when the preparation itself has adequate antimicrobialproperties. When it is necessary to present a preparation for parenteral use in a multidose container,the precautions to be taken for its administration and more particularly for its storage betweensuccessive withdrawals are given.

Antimicrobial preservatives. Aqueous preparations which are prepared using aseptic precautions andwhich cannot be terminally sterilised may contain a suitable antimicrobial preservative in anappropriate concentration.

No antimicrobial preservative is added when:— the volume to be injected in a single dose exceeds 15 ml, unless otherwise justified,— the preparation is intended for administration by routes where, for medical reasons, an

antimicrobial preservative is not acceptable, such as intracisternally, epidurally, intrathecally orby any route giving access to the cerebrospinal fluid, or intra- or retro-ocularly.

Such preparations are presented in single-dose containers.

PRODUCTION

In the manufacture of injections containing dispersed particles, measures are taken to ensure asuitable and controlled particles size with regard to the intended use.

Single-dose preparations. The volume of the injection in a single-dose container is sufficient to permitthe withdrawal and administration of the nominal dose using a normal technique.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosesuspensions for injection with a content of active substance less than 2 mg or less than 2 per cent ofthe total mass comply with test A for uniformity of content of single-dose preparations. If the prepa-ration contains more than one active substance, the requirement applies only to those substances thatcorrespond to the above conditions.

Bacterial endotoxins - pyrogens A test for bacterial endotoxins (2.6.14) is carried out or, wherejustified and authorised, the test for pyrogens (2.6.8).

When the volume to be injected in a single dose is 15 ml or more, the preparation complies with atest for bacterial endotoxins (2.6.14) or with the test for pyrogens (2.6.8).

Where the label states that the preparation is free from bacterial endotoxins (or apyrogenic,respectively), the preparation complies with a test for bacterial endotoxins (2.6.14) or with the testfor pyrogens (2.6.8), respectively.

Infusions

DEFINITION

Infusions are sterile, aqueous solutions or emulsions with water as the continuous phase; they areusually made isotonic with blood. They are principally intended for administration in large volume.Infusions do not contain any added antimicrobial preservative.

Solutions for infusion, examined under suitable conditions of visibility, are clear and practically freefrom particles.

Emulsions for infusion do not show any evidence of phase separation.

PRODUCTION

In the manufacture of infusions containing dispersed particles measures are taken to ensure a suitableand controlled particle size with regard to the intended use.

The volume of the infusion in the container is sufficient to permit the withdrawal andadministration of the nominal dose using a normal technique (2.9.17).

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TESTS

Bacterial endotoxins - pyrogens They comply with a test for bacterial endotoxins (2.6.14) or,where justified and authorised, with the test for pyrogens (2.6.8). For the latter test, inject 10 ml perkilogram of body mass into each rabbit, unless otherwise justified and authorised.

Concentrates for Injections or Infusions

DEFINITION

Concentrates for injections or infusions are sterile solutions intended for injection or infusion afterdilution. They are diluted to a prescribed volume with a prescribed liquid before administration.After dilution, they comply with the requirements for injections or for infusions.

TESTS

Bacterial endotoxins - pyrogens They comply with the requirements prescribed for injections orinfusions, after dilution to a suitable volume.

Powders for Injections or Infusions

DEFINITION

Powders for injections or infusions are solid, sterile substances distributed in their final containersand which, when shaken with the prescribed volume of a prescribed sterile liquid, rapidly form eitherclear and practically particle-free solutions or uniform suspensions. After dissolution or suspension,they comply with the requirements for injections or for infusions.

Freeze-dried products for parenteral use are considered as powders for injections or infusions.

PRODUCTION

The uniformity of content and uniformity of mass of freeze-dried products for parenteral use areensured by the in-process control of the amount of the solution prior to freeze-drying.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, powders forinjections or infusions with a content of active substance less than 2 mg or less than 2 per cent of thetotal mass or with a unit mass equal to or less than 40 mg comply with test A for uniformity ofcontent of single-dose preparations. If the preparation contains more than one active substance, therequirement applies only to those substances that correspond to the above conditions.

Uniformity of mass (2.9.5). Powders for injections or infusions comply with the test for uniformityof mass of single-dose preparations. If the test for uniformity of content is prescribed for all the activesubstances, the test for uniformity of mass is not required.

Bacterial endotoxins - pyrogens They comply with the requirements prescribed for injections orinfusions, after dissolution or suspension in a suitable volume of liquid.

LABELLING

The label states the instructions for the preparation of injections and infusions.

ImplantsDEFINITION

Implants are sterile, solid preparations of a size and shape suitable for parenteral implantation andrelease the active substance(s) over an extended period of time. Each dose is provided in a sterilecontainer.

__________________________________________________________________________________________________________ Ph Eur

Parenteral Preparations of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyinjection, intravenous infusion or implant that is the subject of an individual monograph in the BritishPharmacopoeia.

Definition Definition of a particular Parenteral Preparation as a solution, emulsion or suspension inWater for Injections does not preclude the inclusion of suitable excipients where necessary for thepurposes referred to in the requirements of the European Pharmacopoeia above. In particular,aqueous Parenteral Preparations for administration by the subcutaneous, intradermal, intramuscular,or, in the case of larger volumes, intravenous route, should if possible be made isotonic with blood bythe addition of Sodium Chloride or other suitable substances. However if buffering agents are used inpreparations intended for intra-ocular or intracardiac injection, or in preparations that may gainaccess to the cerebrospinal fluid, great care should be taken to ensure that the nature andconcentration of the chosen agent are suitable for the intended route of administration.

45-53

Where the active ingredient is susceptible to oxidative degradation appropriate precautions, suchas the addition of a suitable antioxidant or storage under oxygen-free nitrogen or other suitableinert gas, should be taken.

Production Methods of sterilisation that may be used in the manufacture of ParenteralPreparations are described in Appendix XVIII.

Where a direction is given to use Water for Injections in the manufacture of a ParenteralPreparation, Water for Injections in bulk is used. Where the use of Water for Injections free fromdissolved air or Water for Injections free from dissolved carbon dioxide is specified, water freshlyprepared by the process described under Water for Injections is boiled for at least 10 minutes with aslittle exposure to air as possible, cooled with precautions to exclude air and carbon dioxide, andsterilised by heating in an autoclave.

Storage Closures used for containers of oily parenteral preparations should be made of oil-resistantmaterials.

Labelling Where appropriate the label states the strength of the parenteral preparation in terms ofthe amount of active ingredient in a suitable dose-volume.

The label also states (1) the name of any added substance; (2) the date after which the ParenteralPreparation is not intended to be used; (3) the conditions under which the Parenteral Preparationshould be stored.

The label of a single-dose parenteral preparation states that any portion of the contents remainingshould be discarded.

INTRAVENOUS INFUSIONS

Labelling The label states the nominal volume of the contents.

POWDERS FOR INJECTIONS

Uniformity of weight When required for the Assay of a powder for injection, determine theweight of the contents of 10 containers as described in the test for uniformity of weight, Appendix XIIG.

Labelling The label states (1) that, when dissolved or suspended, the contents of the sealedcontainer are intended for parenteral use; (2) the amount of active ingredient contained in the sealedcontainer; (3) the directions for the preparation of the Injection or Intravenous Infusion.

If a container of the liquid for constituting the parenteral preparation is supplied with the powderfor injections, the label of this container states the composition of this liquid.

CONCENTRATED SOLUTIONS FOR INJECTIONS

Labelling The label states (1) the name of the concentrated solution; (2) that the solution must bediluted before use; (3) the directions for the preparation of the Injection or Intravenous Infusion.

The following parenteral preparations are the subject of an individual monograph in the BritishPharmacopoeia. Those distinguished by the symbol in ‘ ’ in the list below are monographs of the EuropeanPharmacopoeia.

ImplantsTestosterone Implants

InjectionsAcetylcysteine InjectionAdrenaline Injection/Epinephrine InjectionAdrenaline Injection 1 in 10,000, Dilute/Epinephrine Injection 1 in 10,000, DiluteAminophylline InjectionAmoxicillin InjectionAmpicillin InjectionAprotinin InjectionAscorbic Acid InjectionAtenolol InjectionAtropine InjectionBenzatropine InjectionBenzylpenicillin InjectionBetamethasone InjectionBleomycin InjectionBretylium InjectionBumetanide InjectionBupivacaine InjectionBupivacaine and Adrenaline Injection/Bupivacaine and Epinephrine Injection

45-54

Calcitonin (Salmon) Injection/Salcatonin InjectionCalcium Chloride InjectionCalcium Folinate InjectionCalcium Gluconate InjectionCapreomycin InjectionCarboplatin InjectionCefazolin InjectionCefotaxime InjectionCefoxitin InjectionCeftriaxone InjectionCefuroxime InjectionChloramphenicol Sodium Succinate InjectionChlormethine Injection/Mustine InjectionChloroquine Sulphate InjectionChlorphenamine Injection/Chlorpheniramine InjectionChlorpromazine InjectionChorionic Gonadotrophin InjectionCimetidine InjectionCisplatin InjectionClindamycin InjectionClonazepam InjectionClonidine InjectionCloxacillin InjectionColecalciferol InjectionColistimethate InjectionCyclizine InjectionCyclophosphamide InjectionCytarabine InjectionDacarbazine InjectionDesferrioxamine InjectionDesmopressin InjectionDiamorphine InjectionDiazepam InjectionDiazoxide InjectionDigoxin InjectionDigoxin Injection, PaediatricDihydrocodeine InjectionDimercaprol InjectionDinoprost InjectionDoxapram InjectionDoxorubicin InjectionDroperidol InjectionEdrophonium InjectionErgocalciferol InjectionErgometrine InjectionErgometrine and Oxytocin InjectionErythromycin Ethyl Succinate InjectionEstradiol InjectionEtamiphylline InjectionEthanolamine Oleate InjectionFentanyl InjectionFlecainide InjectionFlucloxacillin InjectionFluorescein InjectionFluorouracil InjectionFlupenthixol InjectionFluphenazine Decanoate InjectionFosfestrol InjectionFurosemide Injection/Frusemide InjectionGallamine InjectionGentamicin InjectionGlucagon InjectionGonadorelin InjectionHaloperidol InjectionHeparin Injection

45-55

Hyaluronidase InjectionHydralazine InjectionHydrocortisone Acetate InjectionHydrocortisone Sodium Phosphate InjectionHydrocortisone Sodium Succinate InjectionHydroxocobalamin InjectionHydroxyprogesterone InjectionHyoscine Butylbromide InjectionHyoscine InjectionInsulin Preparations Biphasic Insulin Injection Biphasic Isophane Insulin Injection Insulin Injection Insulin Zinc Suspension Insulin Zinc Suspension (Amorphous) Insulin Zinc Suspension (Crystalline) Isophane Insulin Injection Protamine Zinc Insulin InjectionInulin InjectionIodised Oil Fluid InjectionIophendylate InjectionIron Dextran InjectionIron Sorbitol InjectionIsoniazid InjectionIsoprenaline InjectionKetamine InjectionLabetalol InjectionLidocaine Injection/Lignocaine InjectionLidocaine and Adrenaline Injection/Lignocaine and Epinephrine InjectionLorazepam InjectionLypressin Injection Magnesium Chloride InjectionMagnesium Sulphate InjectionMeglumine Amidotrizoate InjectionMeglumine Iodipamide InjectionMeglumine Iotalamate InjectionMelphalan InjectionMenadiol Phosphate InjectionMenotrophin InjectionMeptazinol InjectionMetaraminol InjectionMethadone InjectionMethotrexate InjectionMethoxamine InjectionMethyldopate InjectionMethylprednisolone Acetate InjectionMetoclopramide InjectionMetoprolol InjectionMexiletine InjectionMidazolam InjectionMorphine Sulphate InjectionMorphine and Atropine InjectionNaloxone InjectionNaloxone Injection, NeonatalNandrolone Decanoate InjectionNandrolone Phenylpropionate InjectionNeostigmine InjectionNikethamide InjectionNoradrenaline Injection/Norepinephrine InjectionOxytocin InjectionPancuronium InjectionPapaveretum InjectionParaldehyde InjectionPentagastrin InjectionPentamidine Injection

45-56

Pentazocine InjectionPethidine InjectionPhenobarbital InjectionPhenol Injection, AqueousPhenol Injection, OilyPhenol and Glycerol InjectionPhentolamine InjectionPhenylephrine InjectionPhenytoin InjectionPhytomenadione InjectionPotassium Chloride Concentrate, SterilePrilocaine InjectionProcainamide InjectionProcaine Benzylpenicillin Injection/Procaine Penicillin InjectionProcaine Benzylpenicillin Injection, Fortified/Procaine Penicillin Injection, FortifiedProchlorperazine InjectionProcyclidine InjectionProgesterone InjectionPromazine InjectionPromethazine InjectionPropranolol InjectionProtamine Sulphate InjectionRanitidine InjectionRitodrine InjectionSalbutamol InjectionSodium Aurothiomalate InjectionSodium Amidotrizoate InjectionSodium Etacrynate InjectionSodium Iodide InjectionSodium Iotalamate InjectionSodium Stibogluconate InjectionSodium Tetradecyl Sulphate InjectionSodium Thiosulphate InjectionSomatropin Injection [incorporating Somatropin For Injection ]Sotalol InjectionSpectinomycin InjectionStreptokinase InjectionStreptomycin InjectionSulfadiazine InjectionSuxamethonium Chloride InjectionTenoxicam InjectionTestosterone Propionate InjectionTetracosactide InjectionTetracosactide Zinc InjectionThiamine InjectionThiopental InjectionThiotepa InjectionTobramycin InjectionTranexamic Acid InjectionTriamcinolone Acetonide InjectionTriamcinolone Hexacetonide InjectionUrofollitropin InjectionVancomycin InjectionVerapamil InjectionVinblastine InjectionVincristine InjectionVindesine InjectionVitamins B and C InjectionZuclopenthixol Acetate InjectionZuclopenthixol Decanoate Injection

Intravenous InfusionsAciclovir Intravenous InfusionAmiodarone Intravenous InfusionArginine Hydrochloride Intravenous InfusionCiprofloxacin Intravenous Infusion

45-57

Clomethiazole Intravenous InfusionCo-trimoxazole Intravenous InfusionDextran 40 Intravenous InfusionDextran 70 Intravenous InfusionDisodium Pamidronate Intravenous InfusionDobutamine Intravenous InfusionDopamine Intravenous InfusionErythromycin Lactobionate Intravenous InfusionEtoposide Intravenous InfusionFoscarnet Intravenous InfusionFructose Intravenous InfusionGlucose Intravenous InfusionMannitol Intravenous InfusionMetronidazole Intravenous InfusionMitoxantrone Intravenous Infusion/Mitozantrone Intravenous InfusionNimodipine Intravenous InfusionPiperacillin Intravenous InfusionPotassium Chloride and Glucose Intravenous InfusionPotassium Chloride and Sodium Chloride Intravenous InfusionPotassium Chloride, Sodium Chloride and Glucose Intravenous InfusionSodium Bicarbonate Intravenous InfusionSodium Calcium Edetate Intravenous InfusionSodium Chloride and Glucose Intravenous InfusionSodium Chloride Intravenous InfusionSodium Lactate Intravenous InfusionSodium Lactate Intravenous Infusion, CompoundSodium Nitroprusside Intravenous InfusionSorbitol Intravenous InfusionTrisodium Edetate Intravenous Infusion

45-58

PRESSURISED PHARMACEUTICAL PREPARATIONS

revised 1/01

Pressurised Pharmaceutical Preparations comply with the requirements of the 3rd edition of the EuropeanPharmacopoeia [0523]. These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Additional requirements for preparations presented in pressurised containers may be found, where appropriate,in other general monographs, for example Preparations for inhalation (0671), Liquid preparations forcutaneous application (0927), Powders for cutaneous application (1166), Nasal preparations (0676) andEar preparations (0652).

DEFINITION

Pressurised pharmaceutical preparations are presented in special containers under pressure of a gasand contain one or more active substances. The preparations are released from the container, uponactuation of an appropriate valve, in the form of an aerosol (dispersion of solid or liquid particles in agas, the size of the particles being adapted to the intended use) or of a liquid or semisolid jet such as afoam. The pressure for the release is generated by suitable propellants.

The preparations consist of a solution, an emulsion or a suspension and are intended for localapplication to the skin or to mucous membranes of various body orifices, or for inhalation. Suitableexcipients may also be used, for example solvents, solubilisers, emulsifying agents, suspending agentsand lubricants for the valve to prevent clogging.

Propellants. The propellants are either gases liquefied under pressure or compressed gases or low-boiling liquids. Liquefied gases are, for example, fluorinated hydrocarbons and low-molecular-masshydrocarbons (such as propane and butane). Compressed gases are, for example, carbon dioxide,nitrogen and nitrous oxide.

Mixtures of these propellants may be used to obtain optimal solution properties and desirablepressure, delivery and spray characteristics.

Containers. The containers are tight and resistant to the internal pressure and may be made of metal,glass, plastic or combinations of these materials. They are compatible with their contents. Glasscontainers are protected with a plastic coating.

Spraying device. The valve keeps the container tightly closed when not in use and regulates thedelivery of the contents during use. The spray characteristics are influenced by the type of sprayingdevice, in particular by the dimensions, number and location of orifices. Some valves provide acontinuous release, others (“metering dose valves”) deliver a defined quantity of product upon eachvalve actuation.

The various valve materials in contact with the contents are compatible with them.

Requirements for pressurised pharmaceutical preparations Pressurised preparations areprovided with a delivery device appropriate for the intended application.

Special requirements may be necessary for the selection of propellants, for particle size and thesingle-dose delivered by the metering valves.

LABELLING

The label states:— the method of use,— any precautions to be taken,— for a container with a metering dose valve, the amount of active substance in a unit-spray.

__________________________________________________________________________________________________________ Ph Eur

45-59

RECTAL PREPARATIONS

revised 1/01

Rectal preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia [1145].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Rectal preparations are intended for rectal use in order to obtain a systemic or local effect, or theymay be intended for diagnostic purposes.

Where applicable, containers for rectal preparations comply with the requirements for Materialsused for the manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of rectal preparations may be distinguished:— suppositories,— rectal capsules,— rectal solutions, emulsions and suspensions,— powders and tablets for rectal solutions and suspensions,— semi-solid rectal preparations,— rectal foams,— rectal tampons.

PRODUCTION

During the development of a rectal preparation, the formulation for which contains an antimicrobialpreservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction ofthe competent authority. A suitable test method together with criteria for judging the preservativeproperties of the formulation are provided in the text on Efficacy of antimicrobial preservation (5.1.3).

In the manufacture, packaging, storage and distribution of rectal preparations, suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

In the manufacture of semi-solid and liquid rectal preparations containing dispersed particlesmeasures are taken to ensure a suitable and controlled particle size with regard to the intended use.

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, solid single-dose preparations with a content of active substance less than 2 mg or less than 2 per cent of the totalmass comply with test A (tablets) or test B (suppositories, rectal capsules) for uniformity of contentof single-dose preparations. If the preparation contains more than one active substance, this require-ment applies only to those substances that correspond to the above conditions.

Uniformity of mass (2.9.5). Solid, single-dose preparations comply with the test for uniformity ofmass. If the test for uniformity of content is prescribed for all active substances, the test foruniformity of mass is not required.

Deliverable mass or volume (2.9.28). Liquid and semi-solid rectal preparations supplied in single-dose containers comply with the test.

Dissolution A suitable test may be required to demonstrate the appropriate release of the activesubstance(s) from solid, single-dose preparations, for example the dissolution test for suppositoriesand soft capsules (2.9.3).

Where a dissolution test is prescribed, a disintegration test may not be required.

LABELLING

The label states the name of any added antimicrobial preservative.

Suppositories

DEFINITION

Suppositories are solid, single-dose preparations. The shape, volume and consistency of suppositoriesare suitable for rectal administration.

They contain one or more active substances dispersed or dissolved in a suitable basis which may besoluble or dispersible in water or may melt at body temperature. Excipients such as diluents,adsorbents, surface-active agents, lubricants, antimicrobial preservatives and colouring matter,authorised by the competent authority, may be added if necessary.

PRODUCTION

Suppositories are prepared by compression or moulding. If necessary, the active substance(s) are

45-60

previously ground and sieved through a suitable sieve. When prepared by moulding, the medicatedmass, sufficiently liquified by heating, is poured into suitable moulds. The suppository solidifies oncooling. Various excipients are available for this process, such as hard fat, macrogols, cocoa butter,and various gelatinous mixtures consisting of, for example, gelatin, water and glycerol. Whereapplicable, the determination of the softening time of lipophilic suppositories (2.9.22) and/or thedetermination of the resistance to rupture of suppositories (2.9.24) are carried out.

A suitable test is carried out to demonstrate the appropriate release of the active substance(s) fromsuppositories intended for modified release or for prolonged local action.

In the manufacture of suppositories containing dispersed active substances, measures are taken toensure a suitable and controlled particle size.

TESTS

Disintegration Unless intended for modified release or for prolonged local action, they comply withthe test for disintegration of suppositories and pessaries (2.9.2). For suppositories with a fatty base,examine after 30 min and for suppositories with a water-soluble base after 60 min, unless otherwisejustified and authorised.

STORAGE

Store in a well-closed container.

Rectal Capsules

DEFINITION

Rectal capsules (shell suppositories) are solid, single-dose preparations generally similar to softcapsules as defined in the monograph on Capsules (0016) except that they may have lubricatingcoatings. They are of elongated shape, are smooth and have a uniform external appearance.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s) fromrectal capsules intended for modified release or for prolonged local action.

TESTS

Disintegration Unless intended for modified release or for prolonged local action, they comply withthe test for disintegration of suppositories and pessaries (2.9.2). Examine the state of the capsulesafter 30 min, unless otherwise justified and authorised.

Rectal Solutions, Emulsions and Suspensions

DEFINITION

Rectal solutions, emulsions and suspensions are liquid preparations intended for rectal use in order toobtain a systemic or local effect, or they may be intended for diagnostic purposes.

Rectal solutions, emulsions and suspensions are supplied in single-dose containers and they containone or more active substances dissolved or dispersed in water, glycerol or macrogols or other suitablesolvents. Emulsions may show evidence of phase separation but are readily redispersed on shaking.Suspensions may show a sediment which is readily dispersible on shaking to give a suspension whichremains sufficiently stable to enable the correct dose to be delivered.

Rectal solutions, emulsions and suspensions may contain excipients, for example to adjust theviscosity of the preparation, to adjust or stabilise the pH, to increase the solubility of the activesubstance(s) or to stabilise the preparation. These substances do not adversely affect the intendedmedical action or, at the concentrations used, cause undue local irritation.

Rectal solutions, emulsions and suspensions are supplied in containers containing a volume in therange of 2.5 ml to 2000 ml. The container is adapted to deliver the preparation to the rectum or it isaccompanied by a suitable applicator.

Powders and Tablets for Rectal Solutions and Suspensions

DEFINITION

Powders and tablets intended for the preparation of rectal solutions or suspensions are single-dosepreparations which are dissolved or dispersed in water at the time of administration. They maycontain excipients to facilitate dissolution or dispersion or to prevent aggregation of the particles.

After dissolution or suspension, they comply with the requirements for rectal solutions or rectalsuspensions, as appropriate.

TESTS

Disintegration Tablets for rectal solutions or suspensions disintegrate within 3 min when testedaccording to the test for disintegration of tablets and capsules (2.9.1) but using water R at 15°C to25°C.

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LABELLING

The label states:— the method of preparation of the rectal solution or suspension,— the conditions and duration of storage of the solution or suspension after constitution.

Semi-Solid Rectal Preparations

DEFINITION

Semi-solid rectal preparations are ointments, creams or gels.They are often supplied as single-dose preparations in containers provided with a suitable

applicator.Semi-solid rectal preparations comply with the requirements of the monograph on Semi-solid

preparations for cutaneous application (0132).

Rectal Foams

DEFINITION

Rectal foams comply with the requirements of the monograph on Medicated foams (1105).

Rectal Tampons

DEFINITION

Rectal tampons are solid, single-dose preparations intended to be inserted into the lower part of therectum for a limited time.

They comply with the requirements of the monograph on Medicated tampons (1155).__________________________________________________________________________________________________________ Ph Eur

Rectal Preparations of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to anyenema, rectal solution or suppositories that is the subject of an individual monograph in the BritishPharmacopoeia.

ENEMAS

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that thepreparation should not be swallowed; (3) the date after which the Enema is not intended to be used;(4) the conditions under which the Enema should be stored; (5) the directions for using the Enema.

RECTAL SOLUTIONS

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that thepreparation should not be swallowed; (3) the date after which the Rectal Solution is not intended tobe used; (4) the conditions under which the Rectal Solution should be stored; (5) the directions forusing the Rectal Solution.

SUPPOSITORIES

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that thepreparation should not be swallowed; (3) the date after which the Suppositories are not intended tobe used; (4) the conditions under which the Suppositories should be stored.

The following rectal preparations are the subject of an individual monograph in the British Pharmacopoeia.

EnemasArachis Oil EnemaDocusate Enema, CompoundPhosphates EnemaPrednisolone Enema

Rectal SolutionsDiazepam Rectal Solution

SuppositoriesBisacodyl SuppositoriesChlorpromazine SuppositoriesEtamiphylline SuppositoriesFlurbiprofen SuppositoriesGlycerol Suppositories

45-62

Indometacin SuppositoriesMetronidazole SuppositoriesMorphine SuppositoriesNaproxen SuppositoriesParacetamol SuppositoriesPentazocine Suppositories

45-63

SPIRITSDefinition Spirits are solutions of one or more substances in Ethanol (96 per cent) or a DiluteEthanol. They may contain a proportion of Water.

Storage Spirits should be kept in well-closed containers of glass or other suitable materials andstored at temperatures not exceeding 25°.

Labelling The label states (1) the date after which the Spirit is not intended to be used; (2) theconditions under which the Spirit should be stored.

The following spirits are the subject of an individual monograph in the British Pharmacopoeia.

Ammonia Spirit, AromaticChloroform SpiritLemon SpiritOrange Spirit, CompoundPeppermint SpiritSoap SpiritSurgical Spirit

45-64

STICKS

revised 1/01

Sticks comply with the requirements of the 3rd edition of the European Pharmacopoeia [1154]. Theserequirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Additional requirements for sticks may be found, where appropriate, in other general monographs, for exampleNasal preparations (0676).

DEFINITION

Sticks are solid preparations intended for local application. They are rod-shaped or conical prepara-tions consisting of one or more active substances alone or which are dissolved or dispersed in asuitable basis which may dissolve or melt at body temperature.

Urethral sticks and sticks for insertion into wounds are sterile.

PRODUCTION

In the manufacture, packaging, storage and distribution of sticks, suitable means are taken to ensuretheir microbial quality; recommendations on this aspect are provided in the text on Microbiologicalquality of pharmaceutical preparations (5.1.4).

Urethral sticks and other sterile sticks are prepared using materials and methods designed to ensuresterility and to avoid the introduction of contaminants and the growth of micro-organisms;recommendations on this aspect are provided in the text on Methods of preparation of sterile products(5.1.1).

In the manufacture of sticks means are taken to ensure that the preparation complies with a test formass uniformity or, where appropriate, a test for uniformity of content.

TESTS

Sterility (2.6.1). Urethral sticks and sticks for insertion into wounds comply with the test forsterility.

LABELLING

The label states:— the quantity of active substance(s) per stick,— for urethral sticks and sticks to be inserted into wounds that they are sterile.

__________________________________________________________________________________________________________ Ph Eur

45-65

TABLETS

revised 1/01

Tablets comply with the requirements of the 3rd edition of the European Pharmacopoeia [0478]. Theserequirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

The requirements of this monograph do not necessarily apply to preparations that are presented as tabletsintended for use other than by oral administration. Requirements for such preparations may be found, whereappropriate, in other general monographs; for example Rectal preparations (1145) and Vaginal preparations(1164). This monograph does not apply to lozenges, oral lyophilisates, oral pastes and oral gums.

DEFINITION

Tablets are solid preparations each containing a single dose of one or more active substances andusually obtained by compressing uniform volumes of particles. Tablets are intended for oraladministration. Some are swallowed whole, some after being chewed, some are dissolved or dispersedin water before being administered and some are retained in the mouth where the active substance isliberated.

The particles consist of one or more active substances with or without excipients such as diluents,binders, disintegrating agents, glidants, lubricants, substances capable of modifying the behaviour ofthe preparation in the digestive tract, colouring matter authorised by the competent authority andflavouring substances.

Tablets are usually solid cylinders, the end surfaces of which are flat or convex and the edges ofwhich may be bevelled. They may have lines or break-marks and may bear a symbol or othermarkings. Tablets may be coated.

Where applicable, containers for tablets comply with the requirements for Materials used for themanufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of tablets for oral use may be distinguished:— uncoated tablets,— coated tablets,— effervescent tablets,— soluble tablets,— dispersible tablets,— gastro-resistant tablets,— modified-release tablets,— tablets for use in the mouth.

PRODUCTION

Tablets are usually prepared by compressing uniform volumes of particles or particle aggregatesproduced by granulation methods. In the manufacture of tablet cores, means are taken to ensure thatthey possess a suitable mechanical strength to resist handling without crumbling or breaking. Thismay be demonstrated by examining the Friability of uncoated tablets (2.9.7) and the Resistance tocrushing (2.9.8). Chewable tablets are prepared to ensure that they are easily crushed by chewing.Tablets with a break-line can be divided into uniform halves.

In the manufacture, packaging, storage and distribution of tablets, suitable means are taken toensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, tablets witha content of active substance less than 2 mg or less than 2 per cent of the total mass comply with testA for uniformity of content of single-dose preparations. If the preparation has more than one activesubstance, the requirement applies only to those substances which correspond to the aboveconditions.

Uniformity of mass (2.9.5). Uncoated tablets and, unless otherwise justified and authorised, film-coated tablets comply with the test for uniformity of mass of single-dose preparations. If the test foruniformity of content is prescribed for all the active substances, the test for uniformity of mass is notrequired.

Dissolution A suitable test may be carried out to demonstrate the appropriate release of the activesubstance(s), for example one of the tests described in Dissolution test for solid dosage forms (2.9.3).

Where a dissolution test is prescribed, a disintegration test may not be required.

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STORAGE

Store in well-closed container, protected from crushing and mechanical shock.

Uncoated Tablets

DEFINITION

Uncoated tablets include single-layer tablets resulting from a single compression of particles andmulti-layer tablets consisting of concentric or parallel layers obtained by successive compression ofparticles of different composition. The excipients used are not specifically intended to modify therelease of the active substance in the digestive fluids.

Uncoated tablets conform to the general definition of tablets. A broken section, when examinedunder a lens, shows either a relatively uniform texture (single-layer tablets) or a stratified texture(multi-layer tablets) but no signs of coating.

TESTS

Disintegration Uncoated tablets comply with the test for disintegration of tablets and capsules(2.9.1). Use water R as the liquid medium. Add a disc to each tube. Operate the apparatus for15 min, unless otherwise justified and authorised, and examine the state of the tablets. If the tabletsfail to comply because of adherence to the discs, repeat the test on a further six tablets omitting thediscs. The tablets comply with the test if all six have disintegrated.

Chewable tablets are not required to comply with the test.

Coated Tablets

DEFINITION

Coated tablets are tablets covered with one or more layers of mixtures of various substances such asnatural or synthetic resins, gums, gelatin, inactive and insoluble fillers, sugars, plasticisers, polyols,waxes, colouring matter authorised by the competent authority and sometimes flavouring substancesand active substances. The substances used as coatings are usually applied as a solution or suspensionin conditions in which evaporation of the vehicle occurs. When the coating is a very thin polymericcoating, the tablets are known as film-coated tablets.

Coated tablets have a smooth surface which is often coloured and may be polished; a brokensection, when examined under a lens, shows a core surrounded by one or more continuous layerswith a different texture.

TESTS

Disintegration Coated tablets other than film-coated tablets comply with the test for disintegrationof tablets and capsules (2.9.1). Use water R as the liquid medium. Add a disc to each tube. Operatethe apparatus for 60 min, unless otherwise justified and authorised, and examine the state of thetablets. If any of the tablets has not disintegrated, repeat the test on a further six tablets, replacingwater R with 0.1M hydrochloric acid. The tablets comply with the test if all six have disintegrated in theacid medium.

Film-coated tablets comply with the disintegration test prescribed above except that the apparatusis operated for 30 min, unless otherwise justified and authorised.

If coated tablets or film-coated tablets fail to comply because of adherence to the discs, repeat thetest on a further six tablets omitting the discs. The tablets comply with the test if all six havedisintegrated.

Chewable coated tablets are not required to comply with the test.

Effervescent Tablets

DEFINITION

Effervescent tablets are uncoated tablets generally containing acid substances and carbonates orhydrogen carbonates which react rapidly in the presence of water to release carbon dioxide. They areintended to be dissolved or dispersed in water before administration.

TESTS

Disintegration Place a tablet in a beaker containing 200 ml of water R at 15°C to 25°C; numerousbubbles of gas are evolved. When the evolution of gas around the tablet or its fragments ceases thetablet has disintegrated, being either dissolved or dispersed in the water so that no agglomerates ofparticles remain. Repeat the operation on five other tablets. The tablets comply with the test if eachof the six tablets used disintegrates in the manner prescribed within 5 min, unless otherwise justifiedand authorised.

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Soluble Tablets

DEFINITION

Soluble tablets are uncoated or film-coated tablets. They are intended to be dissolved in waterbefore administration. The solution produced may be slightly opalescent due to the addedexcipients used in the manufacture of the tablets.

TESTS

Disintegration Soluble tablets disintegrate within 3 min when examined by the test fordisintegration of tablets and capsules (2.9.1), but using water R at 15°C to 25°C.

Dispersible Tablets

DEFINITION

Dispersible tablets are uncoated or film-coated tablets intended to be dispersed in water beforeadministration giving a homogeneous dispersion.

TESTS

Disintegration Dispersible tablets disintegrate within 3 min when examined by the test fordisintegration of tablets and capsules (2.9.1), but using water R at 15°C to 25°C.

Fineness of dispersion Place two tablets in 100 ml of water R and stir until completely dispersed. Asmooth dispersion is produced, which passes through a sieve screen with a nominal mesh aperture of710 µm.

Modified-Release Tablets

DEFINITION

Modified-release tablets are coated or uncoated tablets which contain special excipients or which areprepared by special procedures, or both, designed to modify the rate, the place or the time at whichthe active substance(s) are released.

Modified-release tablets include prolonged-release tablets, delayed-release tablets, pulsatile-releasetablets and accelerated-release tablets.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Gastro-Resistant Tablets

DEFINITION

Gastro-resistant tablets are delayed-release tablets that are intended to resist the gastric fluid and torelease their active substance(s) in the intestinal fluid. Usually they are prepared from granules orparticles already covered with a gastro-resistant coating or in certain cases by covering tablets with agastro-resistant coating (enteric-coated tablets).

Tablets covered with a gastro-resistant coating conform to the definition of coated tablets.

PRODUCTION

For tablets prepared from granules or particles already covered with a gastro-resistant coating, asuitable test is carried out to demonstrate the appropriate release of the active substance(s).

TESTS

Disintegration For tablets covered with a gastro-resistant coating carry out the test fordisintegration (2.9.1) with the following modifications. Use 0.1M hydrochloric acid as the liquidmedium. Operate the apparatus for 2 h, or other such time as may be justified and authorised,without the discs and examine the state of the tablets. The time of resistance to the acid mediumvaries according to the formulation of the tablets to be examined. It is typically 2 h to 3 h but evenwith authorised deviations is not less than 1 h. No tablet shows signs of either disintegration (apartfrom fragments of coating) or cracks that would allow the escape of the contents. Replace the acid byphosphate buffer solution pH 6.8 R and add a disc to each tube. Operate the apparatus for 60 min andexamine the state of the tablets. If the tablets fail to comply because of adherence to the discs, repeatthe test on a further six tablets omitting the discs. The tablets comply with the test if all six havedisintegrated.

Dissolution For tablets prepared from granules or particles already covered with a gastro-resistantcoating, a suitable test is carried out to demonstrate the appropriate release of the active substance(s),for example the test described in Dissolution test for solid dosage forms (2.9.3).

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Tablets for Use in the Mouth

DEFINITION

Tablets for use in the mouth are usually uncoated tablets. They are formulated to effect a slowrelease and local action of the active substance(s) or the release and absorption of the activesubstance or substances at a defined part of the mouth. Some tablets for use in the mouth areformulated as:— sublingual tablets,— buccal tablets,— muco-adhesive tablets,— chewable tablets.

__________________________________________________________________________________________________________ Ph Eur

Tablets of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosetablets that are the subject of an individual monograph in the British Pharmacopoeia.

Definition Unless otherwise stated in the individual monograph, tablets of the British Pharmaco-poeia are solid, right circular cylinders the end surfaces of which are flat or convex and the edges ofwhich may be bevelled.

Tablets of the British Pharmacopoeia may contain flavouring only when indicated in the individualmonograph.

Tablets that are the subject of individual monographs in the British Pharmacopoeia may beuncoated, compression-coated, film-coated or sugar-coated unless otherwise indicated in themonograph. Tablets for which the monograph states ‘They are coated’ are compression-coated orfilm-coated or sugar-coated. Tablets may be made gastro-resistant by enteric-coating or by othermeans only where this is specifically indicated in the monograph. When presented as coatedformulations it may be necessary to remove the coating before performing the Assay and testsdescribed in the monograph.

In preparing Tablets for which Chocolate Basis is specified, the active ingredient may beincorporated with a mixture of 15 parts of non-alkalinised cocoa powder of commerce, 15 parts ofSucrose and 70 parts of Lactose.

Content of active ingredient of tablets The range for the content of active ingredient stated in themonograph is based on the requirement that 20 tablets, or such other number as may be indicated inthe monograph, are used in the Assay. In circumstances where 20 tablets cannot be obtained, asmaller number, which must not be less than five, may be used, but to allow for sampling errors thetolerances are widened in accordance with Table I.

The requirements of Table I apply when the stated limits are 90 to 110%. For limits other than 90to 110%, proportionately smaller or larger allowances should be made.

Table 1

Weight of active ingredientin each tablet

Subtract from the lowerlimit for samples of

Add to the upper limit forsamples of

15 10 5 15 10 5

0.12 g or less 0.2 0.7 1.6 0.3 0.8 1.8More than 0.12 and less than 0.3 g

0.2 0.5 1.2 0.3 0.6 1.5

0.3 g or more 0.1 0.2 0.8 0.2 0.4 1.0

Disintegration For those Uncoated or Coated Tablets for which a requirement for Dissolution isincluded in the individual monograph, the requirement for Disintegration does not apply.

Uniformity of content Details of the analytical method to be employed for determining the contentof active ingredient may be included in certain monographs. Unless otherwise stated in themonograph the limits are as given in test A for Uniformity of content, Appendix XII H.

Any tablets that when examined individually show a gross deviation from the prescribed or statedcontent are not official.

Labelling The label states (1) the quantity of the active ingredient contained in each tablet; (2)‘enteric-coated’ for tablets coated in this manner; (3) the date after which the Tablets are notintended to be used; (4) the conditions under which the Tablets should be stored.

The following tablets are the subject of an individual monograph in the British Pharmacopoeia.

Acebutolol TabletsAcenocoumarol Tablets/Nicoumalone Tablets

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Acetazolamide TabletsAciclovir TabletsAciclovir Tablets, DispersibleAlimemazine Tablets/Trimeprazine TabletsAllopurinol TabletsAloxiprin TabletsAluminium Hydroxide TabletsAmiloride TabletsAminoglutethimide TabletsAminophylline TabletsAmiodarone TabletsAmitriptyline TabletsAscorbic Acid TabletsAspirin and Caffeine TabletsAspirin TabletsAspirin Tablets, DispersibleAspirin Tablets, Effervescent SolubleAspirin Tablets, Enteric-coatedAtenolol TabletsAtropine TabletsAzapropazone TabletsAzathioprine TabletsBaclofen TabletsBendroflumethiazide Tablets/Bendrofluazide TabletsBenorilate TabletsBenzatropine TabletsBetamethasone Sodium Phosphate TabletsBetamethasone TabletsBisacodyl TabletsBromocriptine TabletsBrompheniramine TabletsBumetanide TabletsBumetanide and Slow Potassium TabletsBusulfan TabletsCalcium and Colecalciferol TabletsCalcium and Ergocalciferol TabletsCalcium Carbonate Tablets, ChewableCalcium Folinate TabletsCalcium Gluconate TabletsCalcium Gluconate Tablets, EffervescentCalcium Lactate TabletsCaptopril TabletsCarbamazepine TabletsCarbimazole TabletsCascara TabletsCefaclor Tablets, SlowCefalexin TabletsCefuroxime Axetil TabletsChlorambucil TabletsChlordiazepoxide Hydrochloride TabletsChloroquine Phosphate TabletsChloroquine Sulphate TabletsChlorphenamine Tablets/Chlorpheniramine TabletsChlorpromazine TabletsChlorpropamide TabletsChlortalidone TabletsCholine Theophyllinate TabletsCimetidine TabletsCiprofloxacin TabletsClemastine TabletsClomifene TabletsClonidine TabletsCo-amilofruse TabletsCo-amilozide TabletsCo-amoxiclav Tablets

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Co-beneldopa Tablets, DispersibleCo-careldopa TabletsCo-codamol TabletsCo-codaprin TabletsCo-codaprin Tablets, DispersibleCo-dergocrine TabletsCo-dydramol TabletsCo-magaldrox TabletsCo-proxamol TabletsCo-tenidone TabletsCo-triamterzide TabletsCo-trimoxazole TabletsCo-trimoxazole Tablets, DipersibleCo-trimoxazole Tablets, PaediatricCodeine Phosphate TabletsColchicine TabletsColecalciferol TabletsColistin TabletsCortisone TabletsCyanocobalamin TabletsCyclizine TabletsCyclopenthiazide TabletsCyclophosphamide TabletsCyproheptadine TabletsCyproterone TabletsDapsone TabletsDesipramine TabletsDexamethasone TabletsDexamfetamine TabletsDextromoramide TabletsDiazepam TabletsDiazoxide TabletsDichlorophen TabletsDiclofenac TabletsDiclofenac Tablets, SlowDicycloverine Tablets/Dicyclomine TabletsDiethylstilbestrol TabletsDiflunisal TabletsDigitoxin TabletsDigoxin TabletsDihydrocodeine TabletsDiloxanide TabletsDimenhydrinate TabletsDipipanone and Cyclizine TabletsDipyridamole TabletsDisulfiram TabletsDocusate TabletsDomperidone TabletsDosulepin Tablets/Dothiepin TabletsDoxycycline Tablets, DispersibleDroperidol TabletsDydrogesterone TabletsEphedrine Hydrochloride TabletsErgocalciferol TabletsErgometrine TabletsErgotamine Sublingual TabletsErythromycin Ethyl Succinate TabletsErythromycin Stearate TabletsErythromycin TabletsEstropipate TabletsEthambutol TabletsEthinylestradiol TabletsEtodolac TabletsFamotidine TabletsFenbufen TabletsFenoprofen Tablets

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Ferrous Fumarate and Folic Acid TabletsFerrous Fumarate TabletsFerrous Gluconate TabletsFerrous Sulphate TabletsFerrous Sulphate Tablets, Prolonged-releaseFlavoxate TabletsFlecainide TabletsFlucytosine TabletsFludrocortisone TabletsFluphenazine TabletsFlurbiprofen TabletsFluvoxamine TabletsFolic Acid TabletsFosfestrol TabletsFurosemide Tablets/Frusemide TabletsGemfibrozil TabletsGlibenclamide TabletsGliclazide TabletsGlipizide TabletsGliquidone TabletsGlyceryl Trinitrate TabletsGriseofulvin TabletsGuanethidine TabletsHaloperidol TabletsHydralazine TabletsHydrochlorothiazide TabletsHydroflumethiazide TabletsHydrotalcite TabletsHydroxychloroquine TabletsHyoscine Butylbromide TabletsHyoscine TabletsIbuprofen TabletsImipramine TabletsIndoramin TabletsInositol Nicotinate TabletsIopanoic Acid TabletsIsoniazid TabletsIsosorbide Dinitrate TabletsIsosorbide Mononitrate TabletsIsradipine TabletsLabetalol TabletsLevodopa TabletsLevonorgestrel and Ethinylestradiol TabletsLevothyroxine Tablets/Thyroxine TabletsLiothyronine TabletsLisinopril TabletsLithium Carbonate TabletsLithium Carbonate Tablets, SlowLofepramine TabletsLoprazolam TabletsLorazepam TabletsLormetazepam TabletsMagnesium Trisilicate Tablets, CompoundMebeverine TabletsMegestrol TabletsMelphalan TabletsMenadiol Phosphate TabletsMeptazinol TabletsMepyramine TabletsMercaptopurine TabletsMetformin TabletsMethadone TabletsMethotrexate TabletsMethylcellulose TabletsMethyldopa Tablets

45-72

Methylphenobarbital TabletsMethylprednisolone TabletsMethysergide TabletsMetoclopramide TabletsMetoprolol Tartrate TabletsMetronidazole TabletsMianserin TabletsMinocycline TabletsMitobronitol TabletsMorphine TabletsMorphine Sulphate Tablets, Prolonged-releaseMoxisylyte Tablets/Thymoxamine TabletsNabumetone TabletsNalidixic Acid TabletsNaproxen TabletsNeomycin TabletsNeostigmine TabletsNiclosamide TabletsNicotinamide TabletsNicotinic Acid TabletsNicotinyl Alcohol TabletsNimodipine TabletsNitrazepam TabletsNitrofurantoin TabletsNorethisterone TabletsNorfloxacin TabletsNortriptyline TabletsNystatin TabletsOrciprenaline TabletsOrphenadrine Hydrochloride TabletsOxazepam TabletsOxprenolol TabletsOxybutynin TabletsOxymetholone TabletsOxytetracycline TabletsPancreatin TabletsParacetamol TabletsParacetamol Tablets, DispersibleParacetamol Tablets, SolublePenicillamine TabletsPentazocine TabletsPentobarbital TabletsPerphenazine TabletsPethidine TabletsPhenelzine TabletsPhenindione TabletsPhenobarbital Sodium TabletsPhenobarbital TabletsPhenoxymethylpenicillin TabletsPhenytoin TabletsPhytomenadione TabletsPimozide TabletsPindolol TabletsPiperazine Phosphate TabletsPizotifen TabletsPoldine TabletsPolythiazide TabletsPotassium Chloride Tablets, EffervescentPotassium Chloride Tablets, SlowPotassium Iodate TabletsPrazosin TabletsPrednisolone TabletsPrednisolone Tablets, Enteric-coatedPrimidone TabletsProbenecid Tablets

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Procainamide TabletsProchlorperazine Buccal TabletsProchlorperazine TabletsProcyclidine TabletsProguanil TabletsPromazine TabletsPromethazine Hydrochloride TabletsPromethazine Teoclate TabletsPropantheline TabletsPropranolol TabletsPropylthiouracil TabletsProtriptyline TabletsPseudoephedrine TabletsPyrazinamide TabletsPyridostigmine TabletsPyridoxine TabletsPyrimethamine TabletsQuinidine Sulphate TabletsQuinine Bisulphate TabletsQuinine Sulphate TabletsRanitidine TabletsRitodrine TabletsSalbutamol TabletsSelegiline TabletsSenna TabletsSodium Bicarbonate Tablets, CompoundSodium Chloride TabletsSodium Citrate TabletsSodium Fluoride TabletsSodium Valproate TabletsSodium Valproate Tablets, Enteric-coatedSotalol TabletsSpironolactone TabletsStanozolol TabletsSulindac TabletsSulfasalazine TabletsSulfinpyrazone TabletsSulpiride TabletsTamoxifen TabletsTemazepam TabletsTenoxicam TabletsTerbutaline TabletsTerfenadine TabletsTetracycline TabletsThiamine TabletsThioridazine TabletsTiabendazole TabletsTimolol TabletsTioguanine TabletsTocopheryl Succinate Tablets, AlphaTolazamide TabletsTolbutamide TabletsTranexamic Acid TabletsTranylcypromine TabletsTriamcinolone TabletsTrifluoperazine TabletsTrihexyphenidyl Tablets/Benzhexol TabletsTrimethoprim TabletsTrimipramine TabletsTriprolidine TabletsUrsodeoxycholic Acid TabletsVerapamil TabletsVerapamil Tablets, Prolonged-releaseVigabatrin TabletsWarfarin TabletsZuclopenthixol Tablets

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MEDICATED TAMPONS

revised 1/01

Medicated Tampons comply with the requirements of the 3rd edition of the European Pharmacopoeia [1155].These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

Additional requirements for medicated tampons may be found, where appropriate, in other general mono-graphs, for example Rectal preparations (1145), Vaginal preparations (1164) and Ear preparations (0652).

DEFINITION

Medicated tampons are solid, single-dose preparations intended to be inserted into the body cavitiesfor a limited period of time. They consist of a suitable material such as cellulose, collagen or siliconeimpregnated with one or more active substances.

PRODUCTION

In the manufacture, packaging, storage and distribution of medicated tampons, suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

LABELLING

The label states the quantity of active substance(s) per tampon.__________________________________________________________________________________________________________ Ph Eur

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TINCTURES

Tinctures comply with the requirements of the 3rd edition of the European Pharmacopoeia [0792]. Theserequirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Tinctures are liquid preparations usually obtained from dried vegetable or animal matter. For somepreparations, the matter to be extracted may undergo a preliminary treatment, for example,inactivation of enzymes, grinding or defatting.

Tinctures are prepared by maceration, percolation or other suitable, validated methods, usingalcohol of suitable concentration. Tinctures may also be obtained by dissolving or diluting extracts inalcohol of suitable concentration.

Tinctures are usually obtained using either 1 part of drug and 10 parts of extraction solvent or 1part of drug and 5 parts of extraction solvent. Tinctures are usually clear. A slight sediment may formon standing and that is acceptable as long as the composition is not changed significantly.

PRODUCTION

Production by percolation If necessary, reduce the matter to be extracted to pieces of suitable size.Mix thoroughly with a portion of the prescribed extraction solvent and allow to stand for anappropriate time. Transfer to a percolator and allow the percolate to flow slowly making sure that thematter to be extracted is always covered with the remaining extraction solvent. The residue may bepressed out and the expressed fluid combined with the percolate.

Production by maceration Unless otherwise prescribed, reduce the matter to be extracted topieces of suitable size, mix thoroughly with the prescribed extraction solvent and allow to stand in aclosed container for an appropriate time. The residue is separated from the extraction solvent and, ifnecessary, pressed out. In the latter case, the two liquids obtained are combined.

Production from extracts The tincture is prepared by dissolving or diluting an extract, usingalcohol of appropriate concentration. The content of alcohol and constituents or, where applicable,the content of alcohol and of dry residue correspond to that of tinctures obtained by macerationor percolation.

Adjustment of the constituents Adjustment of the content of constituents may be carried out, ifnecessary, either by adding the extraction solvent of suitable concentration or by adding anothertincture of the vegetable or animal matter used for the preparation.

TESTS

Relative density (2.2.5). Where applicable, the tincture complies with the limits prescribed in themonograph.

Ethanol content (2.9.10). The ethanol content complies with that prescribed.

Methanol and 2-propanol (2.9.11). Not more than 0.05 per cent V/V methanol and not more than0.05 per cent V/V of 2-propanol, unless otherwise prescribed.

Dry residue Where applicable, the tincture complies with the limits prescribed in the monograph. Ina flat-bottomed dish about 50 mm in diameter and about 30 mm in height, introduce rapidly 2.00 gor 2.0 ml of the tincture. Evaporate to dryness on a water-bath and dry in an oven at 100°C to 105°Cfor 3 h. Allow to cool in a desiccator over diphosphorus pentoxide R and weigh. Calculate the result as amass percentage or in grams per litre.

STORAGE

Store in a well-closed container, protected from light.

LABELLING

The label states:— the vegetable or animal matter used,— where applicable, that fresh vegetable or animal matter was used,— the concentration of alcohol used for the preparation,— the concentration of alcohol in the final tincture,— the content of active principle and/or the ratio of starting material to extraction fluid or of

starting material to final tincture.__________________________________________________________________________________________________________ Ph Eur

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Tinctures of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosetinctures that are the subject of an individual monograph in the British Pharmacopoeia. Those distinguishedby the symbol ‘ ’ in the list below are monographs of the European Pharmacopoeia.

Definition Certain preparations of the British Pharmacopoeia entitled Tinctures do not conformstrictly to the definition of the European Pharmacopoeia and consequently application of some of theabove requirements is inappropriate. Any necessary exceptions are stated in the relevant individualmonographs.

The following tinctures are the subject of an individual monograph in the British Pharmacopoeia.Belladonna TinctureBenzoin Tincture, CompoundCardamom Tincture, AromaticCardamom Tincture, CompoundChloroform and Morphine TinctureGinger Tincture, StrongGinger Tincture, WeakIpecacuanha Tincture, Standardised Opium TinctureOpium Tincture, CamphoratedOpium Tincture, Concentrated CamphoratedOrange TinctureQuillaia TinctureRhubarb Tincture, Compound

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TOPICAL POWDERS

POWDERS FOR CUTANEOUS APPLICATION revised 1/01

Topical Powders comply with the requirements of the 3rd edition of the European Pharmacopoeia for Powders forCutaneous Application [1166]. These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Powders for cutaneous application are preparations consisting of solid, loose, dry particles ofvarying degrees of fineness. They contain one or more active substances, with or withoutexcipients and, if necessary, colouring matter authorised by the competent authority.

Powders for cutaneous application are presented as single-dose powders or multidose powders.They are free from grittiness. Powders specifically intended for use on large open wounds or onseverely injured skin are sterile.

Multidose powders for cutaneous application may be dispensed in sifter-top containers, containersequipped with a mechanical spraying device or in pressurised containers.

Powders dispensed in pressurised containers comply with the requirements of Pressurisedpharmaceutical preparations (0523).

Where applicable, containers for powders comply with the requirements of Materials used for themanufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

PRODUCTION

In the manufacture of powders for cutaneous application, measures are taken to ensure a suitableparticle size with regard to the intended use.

In the manufacture, packaging, storage and distribution of powders for cutaneous application,suitable means are taken to ensure their microbial quality; recommendations on this aspect areprovided in the text on Microbiological quality of pharmaceutical preparations (5.1.4).

Sterile powders for cutaneous application are prepared using materials and methods designed toensure sterility and to avoid the introduction of contaminants and the growth of micro-organisms;recommendations on this aspect are provided in the text on Methods of preparation of sterile products(5.1.1).

TESTS

Fineness If prescribed, the fineness of a powder is determined by the sieve test (2.9.12) or anotherappropriate method.

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, single-dosepowders for cutaneous application with a content of active substance less than 2 mg or less than 2 percent of the total mass comply with test B for uniformity of content of single-dose preparations. If thepreparation has more than one active substance, the requirement applies only to those substanceswhich correspond to the above conditions.

Uniformity of mass (2.9.5). Single-dose powders for cutaneous application comply with the test foruniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed forall the active substances, the test for uniformity of mass is not required.

Sterility (2.6.1). Where the label indicates that the preparation is sterile, it complies with the test forsterility.

STORAGE

Store in a well-closed container.

LABELLING

The label states:— that the preparation is for external use,— where applicable, that the preparation is sterile.

__________________________________________________________________________________________________________ Ph Eur

Topical Powders of the British PharmacopoeiaIn addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosedusting powders that are the subject of an individual monograph in the British Pharmacopoeia.

DUSTING POWDERS

Definition Dusting Powders are finely divided powders that are intended to be applied to the skin

45-78

for therapeutic, prophylactic or lubricant purposes.

Storage Dusting Powders should be stored in a dry place.

Labelling The label states (1) the date after which the Dusting Powder is not intended to be used;(4) the conditions under which the Dusting Powder should be stored.

The following dusting powders are the subject of an individual monograph in the British Pharmacopoeia.

Hexachloraphene Dusting PowderTalc Dusting Powder

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TOPICAL SEMI-SOLID PREPARATIONS

SEMI-SOLID PREPARATIONS FOR CUTANEOUS APPLICATION revised 1/01

Topical semi-solid Preparations comply with the requirements of the 3rd edition of the European Pharmacopoeiafor Semi-solid Preparations for Cutaneous Application [0132]. These requirements are reproduced below.

Ph Eur ___________________________________________________________________________________________________________

The requirements of this monograph apply to all semi-solid preparations for cutaneous application. Whereappropriate, additional requirements specific to semi-solid preparations intended to be applied to particularsurfaces or mucous membranes may be found in other general monographs, for example Ear preparations(0652), Nasal preparations (0676), Rectal preparations (1145), Eye preparations (1163) and Vaginalpreparations (1164).

DEFINITION

Semi-solid preparations for cutaneous application are intended to be applied to the skin or to certainmucous surfaces for local action or transdermal activity of active substances, or for their emollient orprotective action. They are of homogeneous appearance.

Semi-solid preparations for cutaneous application consist of a simple or compound basis in which,usually, one or more active substances are dissolved or dispersed. According to its composition, thebasis may influence the action of the preparation and the release of the active substance(s).

The basis may consist of natural or synthetic substances and may be single-phase or multiphasesystems. According to the nature of the basis, the preparation may have hydrophilic or hydrophobic(lipophilic) properties; it may contain suitable excipients such as antimicrobial preservatives,antioxidants, stabilisers, emulsifiers and thickeners.

Semi-solid preparations for cutaneous application intended for use on large open wounds or onseverely injured skin are sterile.

Where applicable, containers for semi-solid preparations for cutaneous application comply with therequirements for Materials used for the manufacture of containers (3.1 and subsections) and Containers(3.2 and subsections).

Several categories of semi-solid preparations for cutaneous application may be distinguished:— ointments,— creams,— gels,— pastes,— poultices.

PRODUCTION

During the development of semi-solid preparations for cutaneous application, the formulation forwhich contains an antimicrobial preservative, the effectiveness of the chosen preservative shall bedemonstrated to the satisfaction of the competent authority. A suitable test method together withcriteria for judging the preservative properties of the formulation are provided in the text on Efficacyof antimicrobial preservation (5.1.3).

In the manufacture, packaging, storage and distribution of semi-solid preparations for cutaneousapplication, suitable means are taken to ensure their microbial quality; recommendations on thisaspect are provided in the text on Microbiological quality of pharmaceutical preparations (5.1.4).

Sterile preparations are prepared using materials and methods designed to ensure sterility and toavoid the introduction of contaminants and the growth of micro-organisms; recommendations on thisaspect are provided in the text on Methods of preparation of sterile products (5.1.1).

In the manufacture of semi-solid preparations for cutaneous application containing dispersedparticles, measures are taken to ensure a suitable and controlled particle size with regard to theintended use.

TESTS

Deliverable mass or volume (2.9.28). Semi-solid preparations for cutaneous application suppliedin single-dose containers comply with the test.

Sterility (2.6.1). Where the label indicates that the preparation is sterile, it complies with the test forsterility.

STORAGE

Store in a well-closed container or, if the preparation contains water or other volatile ingredients,store in an airtight container. The containers are preferably collapsible metal tubes from which thepreparation may be readily extruded. If the preparation is sterile, store in a sterile, airtight, tamper-proof container.

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LABELLING

The label states:— the name of any added antimicrobial preservative,— where applicable, that the preparation is sterile.

Ointments

DEFINITION

An ointment consists of a single-phase basis in which solids or liquids may be dispersed.

Hydrophobic Ointments

Hydrophobic (lipophilic) ointments can absorb only small amounts of water. Typical substances usedfor their formulation are hard, soft and liquid paraffins, vegetable oils, animal fats, syntheticglycerides, waxes and liquid polyalkylsiloxanes.

Water-Emulsifying Ointments

Water-emulsifying ointments can absorb larger amounts of water. Their bases are those ofhydrophobic ointments, incorporating water-in-oil emulsifying agents such as wool fat, wool alcohols,sorbitan esters, monoglycerides and fatty alcohols.

Hydrophilic Ointments

Hydrophilic ointments are preparations having bases that are miscible with water. The bases usuallyconsist of mixtures of liquid and solid macrogols (polyethylene glycols). They may containappropriate amounts of water.

Creams

DEFINITION

Creams are multiphase preparations consisting of a lipophilic phase and an aqueous phase.

Hydrophobic Creams

Hydrophobic creams have as the continuous phase the lipophilic phase. They contain water-in-oilemulsifying agents such as wool fat, sorbitan esters and monoglycerides.

Hydrophilic Creams

Hydrophilic creams have as the continuous phase the aqueous phase. They contain oil-in-wateremulsifying agents such as sodium or trolamine soaps, sulphated fatty alcohols and polysorbates,combined, if necessary, with water-in-oil emulsifying agents.

Gels

DEFINITION

Gels consist of liquids gelled by means of suitable gelling agents.

Hydrophobic Gels

Hydrophobic gels (oleogels) are preparations whose bases usually consist of liquid paraffin withpolyethylene or fatty oils gelled with colloidal silica or aluminium or zinc soaps.

Hydrophilic Gels

Hydrophilic gels (hydrogels) are preparations whose bases usually consist of water, glycerol orpropylene glycol gelled with suitable gelling agents such as tragacanth, starch, cellulose derivatives,carboxyvinyl polymers and magnesium-aluminium silicates.

Pastes

DEFINITION

Pastes are semi-solid preparations for cutaneous application containing large proportions of solidsfinely dispersed in the basis.

Poultices

DEFINITION

Poultices consist of a hydrophilic, heat-retentive basis in which solid or liquid active substances aredispersed. They are usually spread thickly on a suitable dressing and heated before application to theskin.

__________________________________________________________________________________________________________ Ph Eur

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Topical Semi-solid Preparations of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to anycream, gel, ointment, paste or poultice that is the subject of an individual monograph in the British Pharma-copoeia. Eye ointments are described in the monograph on Eye Preparations.

CREAMS

Definition Creams are formulated to provide preparations that are essentially miscible with the skinsecretion. They are intended to be applied to the skin or certain mucous membranes for protective,therapeutic or prophylactic purposes especially where an occlusive effect is not necessary.

Creams should not normally be diluted. However, should dilution be necessary care should betaken, in particular, to prevent microbial contamination. The appropriate diluent should be used andheating should be avoided during mixing. Excessive dilution may affect the stability of some creams.If diluted, creams should normally be used within two weeks of their preparation.

Storage Creams should be stored at temperatures not exceeding 25° unless otherwise authorised.They should not be allowed to freeze.

Labelling The label states (1) the date after which the Cream is not intended to be used; (2) theconditions under which the Cream should be stored.

GELS

Storage Gels should be stored at temperatures not exceeding 25° unless otherwise prescribed. Theyshould not be allowed to freeze.

Labelling The label states (1) the date after which the Gel is not intended to be used; (2) theconditions under which the Gel should be stored.

OINTMENTS

Definition Ointments are formulated to provide preparations that are immiscible, miscible oremulsifiable with the skin secretion. Hydrophobic ointments and water-emulsifying ointments areintended to be applied to the skin or certain mucous membranes for emollient, protective,therapeutic or prophylactic purposes where a degree of occlusion is desired. Hydrophilic ointmentsare miscible with the skin secretion and are less emollient as a consequence.

In tropical and subtropical countries varying quantities of Arachis Oil, White Beeswax, Wool Fat,Hard Paraffin, White Soft Paraffin, Yellow Soft Paraffin or Liquid Paraffin may be used in thepreparation of the Ointments of the Pharmacopoeia when prevailing high temperatures otherwisemake them too soft for convenient use, but the specified proportions of the active ingredients must bemaintained.

Ointments should not normally be diluted. However, should dilution be necessary care should betaken in the selection of diluents to avoid risk of incompatibility or instability.

Storage Ointments should be stored at a temperature not exceeding 25° unless otherwise authorised.

Labelling The label states (1) the date after which the Ointment is not intended to be used; (2) theconditions under which the Ointment should be stored.

PASTES

Definition Pastes are usually intended to be applied to small, localised areas of the skin.

Storage Pastes should be stored at a temperature not exceeding 25° unless otherwise authorised.

Labelling The label states (1) the date after which the Paste is not intended to be used; (2) theconditions under which the Paste should be stored.

The following topical semi-solid preparations are the subject of an individual monograph in the BritishPharmacopoeia.

CreamsAciclovir CreamAqueous CreamBeclometasone CreamBenzoyl Peroxide CreamBenzydamine CreamBetamethasone Valerate CreamBetamethasone and Clioquinol CreamBuffered CreamCalamine Cream, AqueousCetrimide Cream

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Clobetasol CreamClobetasone CreamClotrimazole CreamCrotamiton CreamDiethylamine Salicylate CreamDiflucortolone CreamDiflucortolone Oily CreamDithranol CreamEconazole CreamFluocinolone CreamFluocinonide CreamFluocortolone CreamFluorouracil CreamFluticasone CreamFusidic Acid CreamGentamicin CreamHydrocortisone CreamHydrocortisone Acetate CreamHydrocortisone and Clioquinol CreamHydrocortisone and Neomycin CreamIbuprofen CreamMexenone CreamMiconazole CreamPotassium Hydroxyquinoline Sulphate and Benzoyl Peroxide CreamTioconazole CreamTriamcinolone CreamUrea CreamZinc CreamZinc and Ichthammol Cream

GelsBenzoyl Peroxide GelCholine Salicylate Dental GelDiclofenac GelFelbinac GelIbuprofen GelIsotretinoin GelKetoprofen GelLidocaine Gel/Lignocaine GelLidocaine and Chlorhexidine Gel/Lignocaine and Chlorhexidine GelMetronidazole GelPiroxicam GelTretinoin Gel

OintmentsBeclometasone OintmentBenzoic Acid Ointment, CompoundBetamethasone Valerate OintmentBetamethasone and Clioquinol OintmentCalamine OintmentCalamine and Coal Tar OintmentCetomacrogol Emulsifying OintmentCetrimide Emulsifying OintmentChlortetracycline OintmentClobetasol OintmentClobetasone OintmentDiflucortolone OintmentDithranol OintmentEmulsifying OintmentFluocinolone OintmentFluocinonide OintmentFluticasone OintmentGentamicin OintmentHydrocortisone OintmentHydrocortisone Acetate OintmentHydrocortisone and Clioquinol OintmentHydrous Ointment

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Macrogol OintmentMethyl Salicylate OintmentNystatin OintmentParaffin OintmentSalicylic Acid OintmentSimple OintmentSodium Fusidate OintmentTar and Salicylic Acid Ointment, CoalTar and Zinc Ointment, CoalTitanium OintmentTriamcinolone OintmentWool Alcohols OintmentZinc OintmentZinc and Castor Oil Ointment

PastesAluminium Paste, CompoundDithranol PasteMagnesium Sulphate PasteTar Paste, CoalTriamcinolone Dental PasteZinc Paste, CompoundZinc and Coal Tar PasteZinc and Salicylic Acid Paste

PoulticesKaolin Poultice

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TRANSDERMAL PATCHES

revised 1/01

Transdermal Patches comply with the requirements of the 3rd edition of the European Pharmacopoeia [1011].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Transdermal patches are flexible pharmaceutical preparations of varying sizes, containing one ormore active substances. They are intended to be applied to the unbroken skin in order to deliver theactive substance(s) to the systemic circulation after passing through the skin barrier.

Transdermal patches normally consist of an outer covering which supports a preparation whichcontains the active substance(s). The transdermal patches are covered on the site of the releasesurface of the preparation by a protective liner, which is removed before applying the patch to theskin.

The outer covering is a backing sheet impermeable to the active substance(s) and normallyimpermeable to water, designed to support and protect the preparation. The outer covering may havethe same dimensions as the preparation or it may be larger. In the latter case the overlapping borderof the outer covering is covered by pressure-sensitive adhesive substances which assure the adhesionof the patch to the skin.

The preparation contains the active substance(s) together with excipients such as stabilisers,solubilisers or substances intended to modify the release rate or to enhance transdermal absorption. Itmay be a single layer or multi-layer solid or semi-solid matrix, and in this case it is the compositionand structure of the matrix which determines the diffusion pattern of the active substance(s) to theskin. The matrix may contain pressure-sensitive adhesives which assure the adhesion of the prepara-tion to the skin. The preparation may exist as a semi-solid reservoir one side of which is a membranewhich may control the release and the diffusion of the active substance(s) from the preparation. Thepressure-sensitive adhesive substances may, in this case, be applied to some or all parts of themembrane, or only around the border of the membrane of the outer covering.

When applied to the dried, clean and unbroken skin, the transdermal patch adheres firmly to theskin by gentle pressure of the hand or the fingers and can be peeled off without causing appreciableinjury to the skin or detachment of the preparation from the outer covering. The patch must not beirritant or sensitising to the skin, even after repeated applications.

The protective liner generally consists of a sheet of plastic or metal material. When removed, theprotective liner does not detach the preparation (matrix or reservoir) or the adhesive from the patch.

Transdermal patches are normally individually enclosed in sealed sachets.

PRODUCTION

In the manufacture, packaging, storage and distribution of transdermal patches suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, transdermalpatches comply with test C for uniformity of content of single-dose preparations.

Dissolution A suitable test may be required to demonstrate the appropriate release of the activesubstance(s), for example one of the tests described in Dissolution test for transdermal patches (2.9.4).The disc assembly method, the cell method or the rotating cylinder method may be used, as suitable,according to the composition, dimensions and shape of the patch.

A membrane may be used. It can be of various materials, such as inert porous cellulose or silicones,and must not affect the release kinetics of the active substance(s) from the patch. Furthermore, itmust be free of substances that may interfere with its performance (for example grease). Themembrane may be suitably treated before the tests, for example, by maintaining it in the medium tobe used in the test for 24 h. Apply the membrane above the releasing surface of the patch, avoidingthe formation of air bubbles.

The test conditions and the requirements are to be authorised by the competent authority.

STORAGE

Store at room temperature, unless otherwise indicated.

LABELLING

The label states, where applicable, the total quantity of active substance(s) per patch, the dosereleased per unit time and the area of the releasing surface.

__________________________________________________________________________________________________________ Ph Eur

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Transdermal Patches of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosepreparations that are the subject of an individual monograph in the British Pharmacopoeia.

Labelling The label states (1) the date after which the Transdermal Patches are not intended to beused; (2) the conditions under which the Transdermal Patches should be stored; (3) the directionsfor using the Transdermal Patches.

The following transdermal patches are the subject of an individual monograph in the British Pharmacopoeia.

Glyceryl Trinitrate Transdermal Patches

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VAGINAL PREPARATIONS

revised 1/01

Vaginal preparations comply with the requirements of the 3rd edition of the European Pharmacopoeia [1164].These requirements are reproduced after the heading ‘Definition’ below.

Ph Eur ___________________________________________________________________________________________________________

DEFINITION

Vaginal preparations are liquid, semi-solid or solid preparations intended for administration to thevagina usually in order to obtain a local effect. They contain one or more active substances in asuitable basis.

Where appropriate, containers for vaginal preparations comply with the requirements for Materialsused for the manufacture of containers (3.1 and subsections) and Containers (3.2 and subsections).

Several categories of vaginal preparations may be distinguished:— pessaries,— vaginal tablets,— vaginal capsules,— vaginal solutions, emulsions and suspensions,— tablets for vaginal solutions and suspensions,— semi-solid vaginal preparations,— vaginal foams,— medicated vaginal tampons,— vaginal inserts.

PRODUCTION

In the manufacturing, packaging, storage and distribution of vaginal preparations, suitable means aretaken to ensure their microbial quality; recommendations on this aspect are provided in the text onMicrobiological quality of pharmaceutical preparations (5.1.4).

TESTS

Uniformity of content (2.9.6). Unless otherwise prescribed or justified and authorised, solid single-dose preparations with a content of active substance less than 2 mg or less than 2 per cent of the totalmass comply with test A (vaginal tablets) or test B (pessaries, vaginal capsules) for uniformity ofcontent of single-dose preparations. If the preparation has more than one active substance, therequirement applies only to those substances which correspond to the above conditions.

Uniformity of mass (2.9.5). Solid single-dose vaginal preparations comply with the test foruniformity of mass of single-dose preparations. If the test for uniformity of content is prescribed forall the active substances, the test for uniformity of mass is not required.

Deliverable mass or volume (2.9.28). Liquid and semi-solid vaginal preparations supplied insingle-dose containers comply with the test.

Dissolution A suitable test may be carried out to demonstrate the appropriate release of the activesubstance(s) from solid single-dose preparations, for example one of the tests described in Dissolutiontest for solid dosage forms (2.9.3).

When a dissolution test is prescribed, a disintegration test may not be required.

Pessaries

DEFINITION

Pessaries are solid, single-dose preparations. They have various shapes, usually ovoid, with a volumeand consistency suitable for insertion into the vagina. They contain one or more active substancesdispersed or dissolved in a suitable basis that may be soluble or dispersible in water or may melt atbody temperature. Excipients such as diluents, adsorbents, surface-active agents, lubricants,antimicrobial preservatives and colouring matter authorised by the competent authority may beadded, if necessary.

PRODUCTION

Pessaries are usually prepared by moulding. Where appropriate in the manufacture of pessaries,measures are taken to ensure a suitable and controlled particle size of the active substance(s). Ifnecessary, the active substance(s) are previously ground and sieved through a suitable sieve.

When prepared by moulding, the medicated mass, sufficiently liquified by heating, is poured intosuitable moulds. The pessary solidifies on cooling. Various excipients are available for this process,such as hard fat, macrogols, cocoa butter, and various gelatinous mixtures consisting, for example, of

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gelatin, water and glycerol.A suitable test is carried out to demonstrate the appropriate release of the active substance(s)

from pessaries intended for prolonged local action.Where appropriate, the determination of the resistance to rupture of pessaries (2.9.24) is carried

out.

TESTS

Disintegration Unless intended for prolonged local action, they comply with the test fordisintegration of suppositories and pessaries (2.9.2). Examine the state of the pessaries after 60 min,unless otherwise justified and authorised.

STORAGE

Store in a well-closed container.

Vaginal Tablets

DEFINITION

Vaginal tablets are solid, single-dose preparations. They generally conform to the definitions ofuncoated or film-coated tablets given in the monograph on Tablets (0478).

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s) fromvaginal tablets intended for prolonged local action.

TESTS

Disintegration Unless intended for prolonged local action, they comply with the test fordisintegration of suppositories and pessaries (special method for vaginal tablets, 2.9.2). Examine thestate of the tablets after 30 min, unless otherwise justified and authorised.

Vaginal Capsules

DEFINITION

Vaginal capsules (shell pessaries) are solid, single-dose preparations. They are generally similar to softcapsules, differing only in their shape and size. Vaginal capsules have various shapes, usually ovoid.They are smooth and have a uniform external appearance.

PRODUCTION

A suitable test is carried out to demonstrate the appropriate release of the active substance(s) fromvaginal capsules intended for prolonged local action.

TESTS

Disintegration Unless intended for prolonged local action, they comply with the test fordisintegration of suppositories and pessaries (2.9.2). Examine the state of the capsules after 30 min,unless otherwise justified and authorised.

Vaginal Solutions, Emulsions and Suspensions

DEFINITION

Vaginal solutions, emulsions and suspensions are liquid preparations intended for a local effect, forirrigation or for diagnostic purposes. They may contain excipients, for example to adjust the viscosityof the preparation, to adjust or stabilise the pH, to increase the solubility of the active substance(s) orto stabilise the preparation. The excipients do not adversely affect the intended medical action or, atthe concentrations used, cause undue local irritation.

Vaginal emulsions may show evidence of phase separation but are readily redispersed on shaking.Vaginal suspensions may show a sediment that is readily dispersed on shaking to give a suspensionwhich remains sufficiently stable to enable a homogeneous preparation to be delivered.

They are supplied in single-dose containers. The container is adapted to deliver the preparation tothe vagina or it is accompanied by a suitable applicator.

PRODUCTION

In the manufacture of vaginal suspensions measures are taken to ensure a suitable and controlledparticle size with regard to the intended use.

Tablets for Vaginal Solutions and Suspensions

DEFINITION

Tablets intended for the preparation of vaginal solutions and suspensions are single-dose preparationswhich are dissolved or dispersed in water at the time of administration. They may contain excipients

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to facilitate dissolution or dispersion or to prevent caking.Apart from the test for disintegration, tablets for vaginal solutions or suspensions conform with

the definition for Tablets (0478).After dissolution or dispersion, they comply with the requirements for vaginal solutions or

vaginal suspensions, as appropriate.

TESTS

Disintegration Tablets for vaginal solutions or suspensions disintegrate within 3 min when testedaccording to the test for disintegration of tablets and capsules (2.9.1), but using water R at 15°C to25°C.

LABELLING

The label states:— the method of preparation of the vaginal solution or suspension,— the conditions and duration of storage of the solution or suspension after constitution.

Semi-Solid Vaginal Preparations

DEFINITION

Semi-solid vaginal preparations are ointments, creams or gels.They are often supplied in single-dose containers. The container is provided with a suitable

applicator.Semi-solid vaginal preparations comply with the requirements of the monograph on Semi-solid

preparations for cutaneous application (0132).

Vaginal Foams

DEFINITION

Vaginal foams comply with the requirements of the monograph on Medicated foams (1105).

Medicated Vaginal Tampons

DEFINITION

Medicated vaginal tampons are solid, single-dose preparations intended to be inserted in the vaginafor a limited time.

They comply with the requirements of the monograph on Medicated tampons (1155).__________________________________________________________________________________________________________ Ph Eur

Vaginal Preparations of the British Pharmacopoeia

In addition to the above requirements of the European Pharmacopoeia, the following statements apply to thosepessaries that are the subject of an individual monograph in the British Pharmacopoeia.

PESSARIES

Labelling The label states (1) the names and concentrations of the active ingredients; (2) that thepreparation should not be swallowed; (3) the date after which the Pessaries are not intended to beused; (4) the conditions under which the Pessaries should be stored.

The following pessaries are the subject of an individual monograph in the British Pharmacopoeia.

Clotrimazole PessariesDiethylstilbestrol PessariesEconazole PessariesIsoconazole Nitrate PessariesLactic Acid PessariesNystatin Pessaries

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AROMATIC WATERS

Definition Aromatic Waters are saturated solutions of volatile oils or other aromatic substances inwater, usually employed for their flavouring rather than their medicinal properties. Aromatic Watersprepared as described below contain a small amount of Ethanol.

Production Aromatic Waters are normally prepared by diluting a concentrated, ethanolic solution ofthe aromatic substance with Water.

Labelling The label states (1) the date after which the Aromatic Water is not intended to be used;(2) the conditions under which the Aromatic Water should be stored.

The following aromatic waters are the subject of an individual monograph in the British Pharmacopoeia.

Anise Water, ConcentratedCamphor Water, ConcentratedChloroform WaterChloroform Water, Double-strengthCinnamon Water, Concentrated