EXTEMPORANEOUS PREPARATIONS

BY

SANA GHAYAS

LEARNING OBJECTIVES:At the end of this lecture, students will be able to: Know about extemporaneous dispensing. Define different dosage forms Classify different dosage forms on the basis of their

use with examples (solutions, suspensions, creams, emulsions, ointments, paste, gels, suppositories, pessaries, powders, granules, oral unit dosage forms)

Contrast different dosage forms Dispense different dosage forms extemporaneously

with labels. Evaluate dispensed dosage forms and their labels. Provide special labels and advice for patients.

Dispensed products grouped into Solution Suspension Emulsion Creams Powders and oral unit-dosage forms Ointments Pastes & jellies Suppositories & pessaries

SOLUTIONS: Homogenous liquid preparations Containing one or more dissolved ingredients Designed for internal & external use.

FORMULATION OF SOLUTION:Following should be determined before formulating a

solution:1. Vehicles2. Solubility3. additives

VEHICLES:Medium in which ingredients of medicine are dissolved

or dispersed. Water Syrup Ethanol Glycerol Propylene glycol Acetone Solvent ether

SOLUBILITY: “The no. of parts of solvent (by volume) that will

dissolve one part (by weight of a solid or volume of a liquid )of the substance.

For oral solutions, ethanol, glycerol and propylene glycol may be used in various combinations with water as cosolvent.

Surfactant can be used for solubilization of poorly water soluble medicaments. E.g. polysorbates.

ADDITIVES GIT can tolerate solutions with a wide range of pH

values. Hypertonic solutions (potassium citrate mixture BP)

should be well diluted before taking orally. Solutions prepared for mucosal surfaces (nasal drops)

usually include sodium chloride to increase tonicity to that of body fluids.

Stabilizers preservative Colours Flavours

SOLUTIONS AS ORAL DOSAGE FORMS: Elixirs, mixtures & oral solutions contain one or

more ingredients dissolved in a suitable vehicle. If dose less than 5 ml prescribed, oral liquid usually

diluted. Choice of diluent is critical as their inclusion can

adversely affect flavour, stability or appearance. Extemporaneously dispensed products usually diluted

with water or syrup, appears as last line in the formula.

SHELF LIFE: SUPPLY OF PRODUCT WITH

SHORT HALF LIFE: Quantity of product supplied to patient

must not exceed that which would be expected to be used with in the shelf life.

CONTAINERS, LABELS AND ADVICE FOR PATIENTS:

MOUTHWASHES AND GARGLES: These are usually diluted with warm water before

use Most are not intended to be swallowed in significant

amounts. Long shelf life Stable products Prepared from stock. Extemporaneously prepared or poured preparations

are supplied in amber colored fluted bottles or medicine bottles for products intended to be swallowed.

SOLUTIONS INSTILLED INTO BODY CAVITIES: Nasal drops and sprays formulated as iso osmotic with

nasal secretions. Buffered Shelf life of extemporaneous products Dispensing: extemporaneous nasal drops supplied in hexagonal, amber

fluted glass bottles with a rubber teat and dropper closure. Nasal sprays packed in flexible plastic bottles or

pressurized containers. For decongestant drops, patient should “AVOID

EXCESSIVE USE” and “AVOID USE IN VERY YOUNG BABIES UNLESS UNDER MEDICAL ADVICE”

EAR DROPS: Water, glycerol and propylene glycol may be used as

vehicles. They are supplied in glass bottles with a teat and

dropper closure or plastic squeeze bottles.ENEMAS: Used for cleansing, therapeutic or diagnostic

purposes. shelf life Amber fluted glass bottles used for enemas and

disposable bags sealed to a rectal nozzle are for commercial use.

Label is marked as “FOR RECTAL USE ONLY”

SOLUTIONS FOR EXTERNAL USE: Liniments, lotions and paints are usually stable. Shelf-life of liniments, lotions and paints Containers for liniments, lotions and paints Special labels and advice for patients . Antiseptic and disinfectant solutions Shelf-life of antiseptic and disinfectant solutions Containers for antiseptic and disinfectant

solutions Special labels and advice for patients

PHARMACEUTICAL SUSPENSION: Suspensions are classified as:1. Coarse suspensions.2. Colloidal suspensions.FORMULATION OF SUSPENSION: Water is usually vehicle of choice. Non aqueous vehicle like fractionated coconut oil

are occasionally used. Other additives are buffers, stabilizers,

preservatives, colors and flavors.PROPERTIES OF A GOOD PHARMACEUTICAL

SUSPENSION

FACTORS AFFECTING PROPERTIES OF A PHARMACEUTICAL SUSPENSION:

Diffusible solids Stokes law Control of particle size Flocculation poorly wettable solids In diffusible solidsTHICKENING AGENTS: Polysaccharides i.e. acacia gum, tragacanth, sodium alginate,

starch. Water soluble celluloses i.e. methyl cellulose, hydroxyethyl

cellulose, sodium carboxymethyl cellulose. Clays i.e. bentonite, aluminium magnesium silicate, hectorite. Synthetic thickeners i. e. carbomers, colloidal silicon dioxide.

BASIC TECHNIQUES FOR PREPARING PHARMACEUTICAL SUSPENSIONS

SUSPENSIONS AS ORAL DOSAGE FORMS MIXTURES: Advantages of suspensions as oral dosage forms Disadvantages of suspensions as oral dosage

forms Shelf life of oral suspensions Containers for oral suspensions Special labels and advice for patients

SUSPENSIONS FOR EXTERNAL USE LOTIONS:• containers for lotions• Special labels and advice for patients INHALATIONS• Containers for inhalations • Special labels and advice for patients OTHER TYPES OF DISPENSED PRODUCT SUSPENSIONS AS 'EMERGENCY'

FORMULATIONS

EMULSION: An emulsion is a disperse system consisting of two

immiscible liquids, one of which(disperse phase) is finely divided and distributed through the other (continuous phase).

DETERMINATION OF EMULSION TYPE To distinguish between O/W and W/O emulsions,

following tests may be used:1. Miscibility test2. Microscopic examination after staining with a oil

soluble dye3. Microscopic observation under UV radiation4. Conductivity measurements

FORMULATION Emulsifying agents facilitate the production of a dispersion

by reducing interfacial tension and maintain the separation of the droplets of the dispersed phase by forming a barrier at the interfaces.

For oral/parenteral administration, O/W emulsions are required

For external use both O/W and W/O systems may be used. TYPES OF EMULSIFYING AGENTS1. Synthetic or semi synthetic substances2. Natural products3. Finely divided solids Many of the substances described as thickening agents

also act as amulgents.

1. SYNTHETIC OR SEMI SYNTHETIC SUBSTANCES They are further classified depending on their ionization

in aqueous solution as follows:(a) Anionic surfactants e.g. alkali metal and ammonium

soaps, amine soaps, soaps of di valent & tri valent metals, alkyl phosphate and alkyl sulphates.

(b) Cationic surfactants e.g. quarternary ammonium compounds like cetrimide

(c) Non ionic surfactants e.g. glycol and glycerol esters, sorbitan esters, polysorbates, macrogol ethers and esters

(d) Ampholytic or amphoteric surfactants which are not widely used as emulsifiers in pharmacy.

NATURAL PRODUCTS FINELY DIVIDED SOLIDS

Choice of an emulsifying agent Selection of appropriate emulsification system

depends on active ingredients incorporated into product and on use of final product and based on theoretical con siderations and on experience.

Formulation by the HLB method emulgents with high numbers (8-18) produce o/w

emulsions and with low numbers (3—6) give w/o emulsions.

OTHER ADDITIVESAntioxidants: e.g. butylated hydroxyanisole (BHA) or butylated hydroxytoluene

(BHT). Ethyl, propyl or dodecyl gallate may also used.PreservativesDesirable properties of a preservative for emulsions Preservatives commonly used in emulsions Organic acids. Parahydroxybenzoic acid esters. Chlorocresol. Phenethyl alcohol. Quaternary ammonium compounds. Chloroform. Colour and flavor Additional color is rarely necessary. Flavors are used for oral emulsions.

STABILITY OF EMULSIONS : The main difficulties encountered in practice are listed here.Creaming This is separation of the emulsion into two regions, one

containing more of the disperse phase, e.g. cream on milk.Cracking This involves coalescence of dispersed globules and

separation of the disperse phase as a separate layer.Phase inversion The most stable range of disperse phase concentrations is 30-

60%. If amount of disperse phase increased until it approaches or

exceeds the theoretical maximum of 74% of the total volume then phase inversion may occur, i.e. from o/w to w/o, or from w/o to o/w.

COMPOUNDING OF EMULSIONS AND CREAMS Basic techniques are:1. Weighing2. Measuring of liquids3. Mixing On small scale mortar and pestle are used producing

globule size larger than 10 µm. Homogenizers are used for extemporaneously

prepared emulsions.EMULSIONS AS ORAL DOSAGE FORMS Shelf-life of oral emulsions Containers for oral emulsions Special labels and advice for patients

EMULSIONS FOR EXTERNAL USE: Liniments and lotions are liquid or semi

liquid emulsions designed for application to skin.

Shelf-life of applications, liniments and lotions

Containers for applications, liniments and lotions

Special labels and advice for patients

CREAMS: They are viscous semi solids for external use. They may be W/O or O/W emulsions.

GENERAL COMPOUNDING PROCEDURE FOR CREAMS

DILUTED CREAMS SHELF-LIFE OF CREAMS CONTAINERS FOR CREAMS SPECIAL LABELS AND ADVICE FOR

PATIENTS

OINTMENTS PASTES AND GELS: Ointments are greasy preparations. Gels are transparent or translucent, non greasy, aqueous

preparations. Pastes contain a higher proportion of finely powdered

medicament than ointments or gelsBASES FOR OINTMENTS AND OINTMENT TYPE

PASTESThey may be classified into four main groups: HYDROCARBON BASES ABSORPTION BASES WATER MISCIBLE BASES WATER SOLUBLE BASES

OTHER ADDITIVES FOR OINTMENTS AND PASTES

These include: Antioxidants like BHT, BHA, EDTA and

must be compatible with the medicaments incorporated into the base.

Preservatives, which may not be required in anhydrous ointments. Examples are sorbic acid, quaternary ammonium compounds etc.

FORMULATION OF GELS: Gelling agents are either organic hydrocolloids or

hydrophilic inorganic substances. Slightly viscous gels may be used as replacement

solutions for body secretions i.e. artificial saliva and tears.

More viscous gels may be used as lubricants for catheters, examination gloves and surgical instruments.

Those designed for surgical or ophthalmic use must be supplied sterile.

TRAGACANTH GELS: Concentration of tragacanth from 2%-5% produce

gels of increasing viscosity.SODIUM ALGINATE GELS: A concentration of 1.5% produces fluid gels and 5-

10% gels are suitable as dermatological vehicles.PECTIN GELSCELLULOSE DERIVATIVES:POLYVINYL ALCOHOLS: The required concentration is usually between 10%

and 20%, depending on the grade of PVA and the desired viscosity.

OTHER ADDITIVES FOR GELS:1. HUMECTANTS: Like glycerol, propylene

glycol or sorbitol solution may be added to retain water, otherwise skin formation may occur.

2. PRESERVATIVES: like methyl and propyl hydroxybenzoates either alone or in combination are suitable for gels containing pectin, carmellose sodium, sodium alginate, tragacanth, etc.

3. CHELATING AGENTS: like EDTA may be used for protection against heavy metals.

COMPOUNDING OF OINTMENTS AND PASTES

The basic techniques are weighing, measuring of liquids, size reduction, size separation and mixing.

MIXING BY FUSION PREPARATION OF MEDICATED OINTMENT

AND PASTES BY FUSION MIXING BY TRITURATION

SHELF LIFE OF OINTMENTS, PASTES AND GELS CONTAINERS FOR OINTMENTS, PASTES AND

GELS Extemporaneously prepared ointments and pastes are

usually packed in screw capped amber glass or plastic pots.

SPECIAL LABELS FOR OINTMENTS, PASTES AND GELS

Store in a cool place. Sterile. The labels for collapsible tubes should be fixed to the

upper(nozle) end of the tube.

SUPPOSITORIES: They are solid medicated preparations designed for

insertion into rectum. They melt, dissolve or disperse and exerts a local or

systemic effect. Pessaries similar solid medicated preparations designed

for insertion into the vagina. Usually used to provide local effect. FORMULATION OF SUPPOSITORIES AND

PESSARIES: There are two main classes of suppository base:1. Fatty bases designed to melt at body temperature.2. Water soluble or water miscible bases designed to

dissolve or disperse within the body.

PROPERTIES OF IDEAL SUPPOSITORY BASE:

1. FATTY BASES:(a) Theobroma oil (cocoa butter): Advantages of theobroma oil include: Disadvantages of theobroma oil include: Polymorphism Adherence to the mould Softening point too low for hot climates Melting point reduced by soluble ingredients Rancidity on storage Poor water-absorbing ability Leakage from the body expense

(b) Synthetic hard fat: They include mixture of mono-, di- and tri-glycerides

of saturated fatty acids.Advantages of these bases over theobroma oil:Disadvantages of synthetic bases include:

(2)Water soluble and water miscible bases:(a) glycero-gelatin Mixture of glycerol and water gelled by the addition of

gelatin.(b)Gelatin Two type of gelatin are used in pharmaceutical

preparations: Type A which behaves as a cationic agent and most

effective at pH 3.2. Type B which behaves as a anionic agent and most

effective at pH 7-8.(c) Macrogols (polyethylene glycols) Mixtures of macrogols can be used as bases for

suppositories and pessaries.

OTHER ADDITIVES Antioxidants can be added to prevent oxidation

which must be compatible with the medicament. Water miscible or water soluble bases should

include preservative which must be challenged with appropriate micro organisms to test its efficacy.

Emulsifying agents (wool fat, macrogols) may be included to facilitate incorporation of aqueous solutions or polar liquids but with caution.

Hardening agents are added to the base to raise the melting point.

Viscosity modifiers reduce the sedimentation rate.

CHOICE OF SUPPOSITORY OR PESSARY BASE

COMPOUNDING OF SUPPOSITORY OR PESSARY BASE

SUPPOSITORY OR PESSARY MOULDS For small scale, metal moulds are used having 6

cavities usually. Normal capacities of commonly used moulds include

1, 2, 4 and 8 g.

DISPLACEMENT VALUES

Use of displacement values (Method for determining displacement value) Using a nominal 1 g mould, Prepare and weigh six suppositories of unmedicated base = agPrepare base containing 30% medicament, fill six moulds and weigh six suppositories = bgCalculate the amount of base, cg and medicament d g in the six suppositories c = 70% b and d = 30%

bTherefore the amount of base displaced bydisplacement value = __d______

a-cFor example: Weight of six unmedicated suppos. = 6.0 g

Weight of six suppos. Containing 30% drug = 7.5 g Base = 70% of 7.5 = 5.25Drug = 30% of 7.5 = 2.25Base displaced by 2.25 g = 6 - 5.25 = 0.75 gTherefore the displacement value of the drug = 2.25/0.75 =3Method for using displacement value Required: to prepare for 8 suppositories each containing 300 mg drug of displacement value 3 using a

nominal 1 g mould.Total amount of drugs required = 8 x 300 mg = 2.4 gThis will displace 2.4/3= 0.8 g of baseTherefore amount of base required = 8-0.8 = 7.2 g

MOULD LUBRICATIONPreparation of suppositories with a fatty base1. Calculate the quantities required. 2. Prepare the mould. 3. Prepare the base. 4. Prepare the medicament. 5. Melt the base.6. Incorporate the medicament. 7. Fill the mould. 8. Remove the excess.9. Open the mould. Preparation of suppositories with a macrogol base

Preparation of suppositories with a glycero-gelatin base

1. Calculate the quantities required. 2. Prepare the mould. 3. Prepare the medicament. 4. Prepare the base. 5. Heat treatment of the base.6. Adjustment of base to weight. 7. Incorporate any medicament. 8. Fill the mould.

SHELF LIFE: Stable preparations if the packaging provides adequate

protection and that the storage temperature is low.

CONTAINERS

LABEL AND ADVICE1. Store in a cool place.2. For rectal use only.3. For vaginal use only.

EXAMPLES Compound bismuth subgallate suppositories BP Dimenhydrinate suppositories Glycerol suppositories BP

POWDERS: Undivided oral powders. Divided oral powders. Granules for oral administration. Dusting powders for external use. FORMULATION OF POWDERS AND GRANULES: COMPOUNDING: Basic techniques of compounding of powders and

granules are: Weighing Size reduction Size separation Mixing

PREPARATION OF UNDIVIDED ORAL POWDERS:

PREPARATION OF DIVIDED ORAL POWDERS: WRAPPING DIVIDED POWDERS: PREPARATION OF GRANULES: On small scale, granules are made with a mortar

and pestle and suitable sieves. PREPARATION OF DUSTING POWDERS: They are prepared using method as for undivided

oral powders. Sieve size should be 180 µm.

ORAL POWDERS AS DOSAGE FORMS:1. UNDIVIDED POWDERS AS ORAL DOSAGE FORMS: Relatively few medicaments are formulated as undivided/divided powders. ADVANTAGES AND DISADVANTAGES OF UNDIVIDED

POWDERS: SHELF LIFE OF UNDIVIDED POWDERS: Undivided powder are suitably packaged and stored. Remain stable over a long period. CONTAINERS OF UNDIVIDED POWDERS: Plain glass jars with close fitting closures and a 5 ml measuring spoon

should be supplied for undivided powders. SPECIAL LABEL AND ADVICE FOR PATIENTS:

2. DIVIDED POWDERS AS ORAL DOSAGE FORMS: SHELF LIFE OF DIVIDED POWDERS: CONTAINERS OF DIVIDED POWDERS: SPECIAL LABEL AND ADVICE FOR PATIENTS:

3. GRANULES AS ORAL DOSAGE FORMS: Bulk granules can be used to deliver medicaments of low potency. Granules packed in individual sachets. SHELF LIFE OF GRANULES CONTAINERS OF GRANULES SPECIAL LABEL AND ADVICE FOR PATIENTS: GRANULES FOR MIXTURES: Some antibiotics are unstable in solution or suspension, which are

formulated by manufacturers as dry granules containing medicaments and various adjuncts.

4. BULK POWDERS FOR EXTERNAL USE SHELF LIFE OF DUSTING POWDERS CONTAINERS OF DUSTING POWDERS SPECIAL LABEL AND ADVICE FOR PATIENTS

ORAL UNIT DOSAGE FORMS have accurately measured amount of medicaments in a single dosage unit

Easily handled by the patient. Major oral unit dosage forms are tablets and capsules.ADVANTAGES OF ORAL UNIT DOSAGE FORMS: Accurate release Release characteristics of drug can be controlled Uniform product Stable & attractive product Easy to administer Unpleasant tastes can be masked Simple to pack, Convenient to carryDISADVANTAGES OF ORAL UNIT DOSAGE FORMS: Difficult to swallow Unsuitable for the young Excipients may produce unwanted effects Release characteristics may not be ideal

DISPENSING OF TABLETS: Mostly packaged by manufacturer into unit packs suitable

to issue to the patient with out re-packing by the pharmacist.

Role of pharmacist in dispensing of these tabletsSUPPLY OF TABLETS FROM BULK PACK: Required number of tablets must be counted from the bulk

container. Tablets must remain untouched by hands. Cross contamination of different tablets must not occur. Counting devices must be cleaned after each usage.CONTAINERS FOR TABLETSSPECIAL LABELS FOR TABLETS AND ADVICE FOR

PATIENTS:

CAPSULES: These are dosage forms in which the medicaments are enclosed

within a hard or soft gelatin shell. Soft gelatin capsules Hard gelatin capsules Hard gelatin capsules are available in a range of sizes. Approximate capacities of hard gelatin capsule shells, based on

lactose: Cap. 000 00 0 1 2 3 4 5 Content 950 650 450 300 250 200 150 100ADVANTAGES OF HARD GELATIN CAPSULE: Mask unpleasant taste. Easy to swallow. Require fewer excipients and can be made light resistant. Give rapid & uniform release of medicaments.

FORMULATION OF CAPSULES: COMPOUNDING OF CAPSULES: Hand filling of hard gelatin capsules is rarely carried

out in a community pharmacy but can be done in hospital pharmacy.

Two methods are suggested: (a)filling from a powder mass (b)filling with weighed aliquots SHELF LIFE OF CAPSULES CONTAINERS FOR CAPSULES AND ADVICE

FOR PATIENTS

OTHER PRODUCTS IN CAPSULE SHELLS:1. INSUFFLATIONS: They are fine powders prepared for inhalation from

a suitable insufflators. EYE OINTMENTS AND RECTAL OR VAGINAL

DOSAGE FORMS:

REFERENCES: Pharmaceutical Practice by D M Collett and M E

Aulton. Solutions - Pg: 87 Suspensions - Pg: 99 Emulsions/Creams - Pg: 109 Ointments, pastes, gels - Pg: 125 Suppositories and pessaries - Pg: 135 Powders and granules - Pg: 145 oral unit dosage forms - Pg: 151

EXTRA REFERENCES: COOPER & GUNN’S, DISPENSING FOR

PHARM. STUDENTS BY S. J. CARTER-12TH EDITION.

Dispensed preparations - Pg: 8 Solutions - Pg: 67 Suspensions - Pg: 100 Emulsions/Creams - Pg: 120 Powders and oral unit dosage forms - Pg: 168 Ointments, pastes, jellies - Pg: 192 Suppositories and pessaries - Pg: 232