Dosage Foem chp 3 4

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Dosage Form Design:

Pharmaceutical andFormulation Considerations

Asso. Prof. Ma. Cristina C.Doria

Faculty of Pharmacy



Dosage Form Design

• Pharmaceutics- study on the: formulation, manufacture,

stability,and eectiveness of pharmaceutical dosage

forms

• Pharmaceutical ingredients or excipients

-elective use of these non medicinal agents

- Uses solubili!e thic"en stabili!e #avor

suspend dilute preserve e$cacious

suspend emulsify color appealing closure forms.



%e&uirements of a properdesign ' formulation of dosage

formConsideration of drug substances:

• Physical, chemical ' biological characteristics

(compatible )ith one another * stable, e$cacious,

attractive, easy to administer ' safe(manufactured under appropriate measures of

&uality control ' pac"aged in containers to ma"eproduct stable

(labeled to promote correct use ' stored underconditions to ma+imi!e shell life



he -eed for Dosage Forms

• To protect the drug substance from thedestructive influences of atmosphericoxygen or humidity.(Coated tablets)

• To protect the drug substance from thedestructive influence of gastric acid after

oral administration.(Enteric-coated)




• To conceal the bitter, salty or offensivetaste or odor of a drug substance.(Capsules, Flavored syrups)

• To provide liquid preparations ofsubstances that are either insoluble orunstable in the desired vehicle.(Suspension




• To provide clear liquid dosage forms ofsubstances.(Syrups, Solutions)

• To provide rate-controlled drug action.(Controlled-release tablets)

• To provide optimal drug action from topicaladministration sites.(Ointments,Creams,Transdermal patches)




• To provide for insertion of a drug into one of thebodys orifices(Suppositories)

• To provide placement of drugs directly in thebloodstream or body tissues(Injections)

• To provide for optimal drug action through inhalationtherapy(Inhalants, Inhalation aerosols)



/eneral Considerations in Dosage Form Design

Determine desired product type * frame)or" for

product development.

develop and e+amine initial formulations of the

product:

* desired features: drug release pro0lebioavailability

clinical eectiveness

* pilot plant studies and production scale*up.



• master formula

* formulation that best meets the goals of the

product

• Factors to consider before formulation of amedicinal agent in one or more dosage forms

• herapeutic matters 1nature of theillness2

• manner it is treated 1locally or through

systemic action2• age and anticipated condition of the

patient.



Preformulation tudies

• drug be chemically and physicallycharacteri!ed

• de0ne the nature of the drug

substance.



hree )ays li&uid drug begiven in solid form

3i&uid substance:

• ealed in soft gelatin capsule

• Developed into a solid ester or salt formsuitable for tablets or drug capsules

• Mi+ed )ith a solid or melted semisolidmaterial

* melted mi+true is poured into hardgelatin capsules to harden ' capsulessealed



Preformulation tudies4. Physical Description

* physical description particle si!e

crystalline structure melting pointsolubility.

• Chemical properties: structure form

reactivity

* purity of the chemical substance for:

identi0cation and for evaluation of itschemical, physical, and biologic

properties



Preformulation tudies 5. Microscopic 6+amination

• indication of: particle size and size rangeof the ra) material along )ith the crystal

structure.

• information in formulation processingattributable to changes in particle or crystalcharacteristics of the drug.



Preformulation tudies7. Melting Point Depression

• Determines the: purity of the substance

compatibility of various subsbefore

inclusion in the dosage form * pure subs: sharp melting point

* impure subs: depressed melting point



Preformulation tudies 8. Phase %ule

• Phase diagrams constructed determines:

* e+istence ' e+tent of the presence of solid andli&uid phases in binary, ternary ' other mi+tures

Particle i!e * aects : physical9chemical properties of drug subss:

(dissolution rate bioavailability contentuniformity

stability taste te+ture #o) properties absorption sedimentation rate



Preformulation tudiesPolymorphism

* substances can e+ist in more than one crystallineform

• Polymorphic forms 9 di. physical*chemical

properties 1incl. melting pt. ' solubility2• 6valuation of:

(crystal structure 1microscopy,

% spectroscopy, thermal analysis, +*ray

diraction2(polymorphism ' (solvate form



Preformulation tudiesolubility

• Determined by e&ulibrium solubility method

* e+cess amount of drug ; solvent < sha"en atconstant temp. over a prolonged period of timeuntil e&uilibrium is obtained

• Drug possess aqueous solubility * fortherapeutic e$cacy.

• nsoluble compounds: incomplete=erraticabsorption



• olubility ' particle si!e

• olubility ' p>

* drug formulated to li&uid product:

ad?ustment of p> of solvent )here drugis dissolved to ad?ust solubility

* @ea" acidic or basic drugs * re&uire

extremes in pH outside or acceptedphysiologic limits or that may causestability problems )ith formulationingredients.



Preformulation tudiesDissolution %ate

• time for the drug to dissolve in the #uids atthe absorption site 1rate*limiting step inabsorption2.

• Dissolution rate of drugs * increased bydecreasing

the particle si!e.

• for higher dissolution rate

* use a highly )ater soluble salt of the parentsubstance.



2 methods in determining dissolution

rates of chemical compounds

1.Constant surface method - intrinsic dissolution rate of the agent

* Characteristic of compound ' solvent under0+ed e+perimental conditions* mg dissolved=min=cm s&uare

5.Particulate dissolution- eighed amount of po!dered sample ;

dissolution medium in constant agitationsystem

* to study the in#uence of particle si!e,surface area, and e+cipients upon the activeagent



"ic#$s la! %la! of di&usion'

- describes the:

( relationship of diusion ' dissolution

of the active drug in the dosage form ')hen administered in the body

* 4st la)

(relates to a steady state #o)

* 5nd

la) (relates to a change in conc. of drug

)ith time, at any distance, or anonsteady state of #o)



Preformulation tudiesMembrane Permeability

• 6verted intestinal sac

* determines degree ' rate of passage of drug throughthe membrane sac by passive ' active transport

• early assessment of passage of drug molecules acrossbiologic membranes

• o produce a biologic response * drug molecule must0rst cross a biologic membrane

• he biologic membrane 1lipid barrier2 * permits

absorption of lipid soluble substance by passivediusion

• Molecules lipophilic character 9 measured by the oil*)ater coe$cient



asis of p>*partitioncoe$cient

nterrelationship at the absorption site ' absorptioncharacteristics of various drugs:

• Dissociation constant

• lipid solubility• p>

ndication of absorption e+pectations:

• Data from basic physicochemical studies: pBa,solubility ' dissolution rate



Preformulation tudiesPartition Coe$cient

• selection of appropriate e+tractionsolvents, drug stability, use ofsalting*out additives and

environmental concerns.



Preformulation tudiespBa = Dissociation Constants

• e+tent of ioni!ation of drug * strong eecton formulation ' pharmaco"ineticparameters of the drug

• determined by potentiometric titration * for the pharmacist important:

(predicting precipitation in admi+tures

(calculating solubility of drugs atcertain p> values



tability

*extent a product retains )ithinspeci0ed limits and through itsperiod of storage and use

(tability studies conducted in thepreformulation phase:

• Solid-state of the drug alone• Solution phase

• with the expected excipients



Drug and Drug Producttability

• 6valuation of:* physical and chemical stability of puredrug

substances *important forpreformulation.

Drug tability : Mechanisms of Degradation

*Chemically drug substances )ith dierentsusceptibilities to)ard chemical instability:

alcohols, phenols, aldehydes, "etones,esters, ethers, acids, salts, al"aloids,glycosides and others.



most frequently encountered destructiveprocess:

• Hydrolysis 1solvolysis process2

* 1drug2 molecules interact )ith )atermolecule to yield brea"do)n product.

* susceptible to the hydrolytic

process: esters, substituted amides,lactones, and lactams



most frequently encountereddestructive process:

• OXIDATION

-loss of electrons from an atom or molecule;

- involvesfree radicals (molecules or atomscontaining one or more unpaired electrons).

- destructive to: aldehydes, alcohols, phenols,sugars, alkaloids & unsaturated fats & oils



Drug and Drug Product tability:A. Binetics and helf 3ife

Five types of stability4. Chemical 9active ingredient retains chemical

integrity and labeled potency )ithin thespeci0ed limits.

* important for selecting: (storage conditions 1temp., light, humidity2 (proper container for dispensing

(anticipating interactions )hen mi+ing drugs 'dosage forms

* must "no) reaction order ' rate



5. Physical * original physical properties,appearance,

palatability, uniformity, dissolution andsuspendability are retained.

7. Microbiologic 9sterility=resistance to

microbial gro)th

8. herapeutic 9therapeutic eect remains

unchanged

. o+icologic * no signi0cant increase in

to+icity occurs.



Drug and Drug Product tability:

B. RATE REACTIONS

- description of thedrug concentrationwith respect to time.

C. Q10 METHOD

-estimate the shelf lifeof a product that

has been stored or to be stored under adifferent set of conditions.



ENHANCING STABILITY

• drugs subjected to hydrolysis*water reduced or eliminated from the system.*water-liable drugs - waterproof protective coating

applied in the tablet.*in liquid formulation - water replaced by substitute liquids.

*suspending them in nonaqueous vehicle*for injectable products – anhydrous vegetable oils may be usedas solvent



ENHANCING STABILITY

• For unstable antibiotic drugs 1a&. prepn desired2

* supplied in dry form for reconstitution beforedispensing

• For unstable prepns: storage under refrigeration

• p> 9 ma?or determinant in stability

* optimum stability: p> '

* buering agents increases stability



ENHANCING STABILITY

• oxygen sensitive drugs

* prepared in dry state

*packaged in sealed containers with air replaced by inert

gas (Nitrogen, carbon dioxide). * add antioxidants (for stability):

- in aq. Prepns:

Na2SO3, NaHSO3, H3PO2, ascorbic acid

- in oleaginous/unctous prepns: alpha tocopherol, butylhydroxyanisole & ascorbylparmitate



ENHANCING STABILITY

• trace metals in drug, solvent, container orstopper

* source of di$culty in preparing stable solns of o+idi!able drugs * eliminated by:

(puri0cation of source of contaminant (comple+ing or binding metal by using

speciali!ed agents 1chelating agents* Ca disod edetate ' 6DA2 *



ENHANCING STABILITY

• 3ight

* catalyst to o+idation reactions

* prepns pac"aged in light resistantor opa&ue containers



n summary : easily o+idi!abledrugsmay be stabili!ed in formulation

by:• selective e+clusion from the system of:

o+ygen o+idi!ing agents trace metals

light heat other

chemicalcatalysis

• add to create and maintain a favorable p>:

antio+idants chelating agents buering agents



Other destructive process inpharmaceutical preparations

• Polymeri!ation

* reaction bet)een t)o or more identicalmolecules )ith resultant formation of ne) 'generally larger molecule 1formaldhyde2

Process )here one or more active chemical groupsremoved:

•Chemical decarbo+ylation• deamination



• Decarbo+ylation

* decomposition of %CEE> ' releaseof CE5

• Deamination

* removal of nitrogen containinggroup from organic amine 1e+.nsulin2



mportance of Drug tability

• in preclin. testing and in clinical1human2 trials

* for a true and accurate assessment

of the drug=drug prod evaluated

• mar"eted drug product

* for the safety and eectiveness

)hen distributed and during the entirecourse of its shelf*life and use



Product stability assessedbefore mar"eting:

• Formulation

• n#uence of:

* pharmaceutic ingredients present

* container ' closure• Manufacturing ' processing conditions

• Pac"aging components ' conditions of)arehousing=storage

• Conditions of shipping, temp., light ' humidity• helf life ' patient utili!ation



stability testing considerations

• product containers, closures, andother pac"aging features

• parenteral and other sterile prodsmust meet sterility test stds

* to ensure protection againstmicrobial contamination



Drug instability detected

• Change in:

physical appearance, color, odor,taste or te+ture of the formulation



cienti0c data pertaining to the stabilityof a formulation• leads to:

(prediction of the e+pected shelf*life ofthe

proposed product (redesign of the drug 1to more stable

salt or

ester form2(reformulation of the dosage form.

•



Accelerated stability testing

• Gse of e+aggerated conditions of temp., humidity,light ' others

• accelerated temp

* mons study at 8H o C )ith IJ relative humidity

• (hort tem accelerated studies

• Determines most stable of the proposedformulations for a drug product

• lesser temp and humidity* 7HoC and HJ humidity



• tress testing

* temp. elevations in 4Ho incrementshigher than used in acceleratedstudies

* employed until chem.. or phy.Degradation



3ong term stability studies

• product is sub?ected to dierentclimatic !ones 1temp. 'humidity2nationally ' internationally

• predicted from the data generatedfrom continuing stability studies

• 45 months minimum and conducted

at 5 o C ;=* 5oC and at a relativehumidity of HJ ;=* J



PACBA/-/ ' E%A/6 of

P>A%MAC6GCA3• labeling is essential for:

(prod. stability

(e$cacious use

• C)*+,*/(

* stds for pac"aging ofpharmaceuticals by manufacturersare contained in the C/MP



ests performed depending on theintended use and type of container:

• physicochem. tests

• light*transmission tests for glass or plastic

• drug compatibility

• leaching and or migration tests,

• vapor*transmission test for plastics, moisture barrier tests,to+icity studies for plastics,

• valve, actuator, metered*dose, partical si!e, spraycharacteristics, lea" testing for aerosols,

• sterility and permeation tests for parenteral containers

• drug stability for all pac"aging

A di t GP



According to GP:

• CE-A-6%

* holds the article and is or may be in direct

contact )ith the article• MM6DA6 CE-A-6%

* in direct contact )ith the article at all times

• Closure

* part of the container

• Closure ' container

* clean and dry prior to its being 0lled )ith thedrug

C3AFCAE- EF CE-A-6% K >6 GP



C3AFCAE- EF CE-A-6% K >6 GPaccording to their ability to protect their contents

from e+ternal conditions:

• )ell*closed container

* protects the contents from e+traneous solids and from:

(loss of the article under ordinary conditions of handling,shipment, storage ' distribution

• tight container* protects the contents from contamination by e+traneous

li&s., solids, or vapors, from:

( loss of the articles, and from eLorescence,

deli&uescence, or evaporation under the ordinary orcustomary conditions of handling, shipment, storage anddistribution and is capable of tight re*closure






• hermetic container* impervious=resistant to air or any other gas under the ordinary

or customary conditions of handling, shipment, storage, and

distribution * those sterile are generally used to hold prepns intended for

in?ection or parenteral adm

• single*dose container

* &uantity of drug contained is intended as a single dose and)hen opened cannot be resealed )ith assurance that sterility hasbeen maintained

* includes fusion*sealed ampules, pre*0lled syringes andcartridges






• single*dose container

* designed to hold a &uantity of drug intended for adm as a singledose promptly after the container is opened

* single*unit pac"age is termed a unit*dose pac"age )hendispensed to a patient

* may be performed on a large scale by a manufacturer ordistributor or on a smaller scale by the pharmacy dispensing themedication






• multiple*dose container

* hermetic container that permits )ithdra)al of successive

portions of the contents )ithout changing the strength orendangering the &uality or purity of the remaining portion

* referred as vials * contain more than a single unit or dose of the medication



• ablets, capsules ' oral li&uids

* pac"aged in single*unit or multiple*unit containers



ingle*unit pac"ages

• convenient ' sanitary means of maintaining and utili!ing themedication

• advantages:

(positive D of each dosage unit and reduction of medication

errors

(reduced contamination of the drug due to its protective

)rapping

(reduced dispensing time

(greater ease of inventory control in the pharmacy or nursing

station(elimination of )aste through better medication

management

)ith less discarded medication



• Pac"aging materials

* may be combinations of paper, foil,

plastics or cellophane

• Pac"aging of solid dosage forms in:

(clear plastic or aluminum blister )ells

* most popular method of single*unit

pac"aging



• Eral li&uids

* may be single*unit dispensed in:

(paper (plastic (foil cups

(pre*pac"aged and dispensed inglass

containers 1)ith threaded caps orcrimped

aluminum caps2



3ight resistant containers

• re&uired by many pharmaceutical prods to protectthem from photochem. deterioration

• amber glass or light resistant opa&ue plastic )illreduce light transmission su$ciently to protect alight*sensitive pharmaceutical

• G absorbers may be added to plastic to decreasethe transmission of short G rays

• must meet the GP stds )=c de0ne the acceptablelimits of light transmission at any )avelength oflight bet)een 5NH and 8H nm



Classi0cation of glass used in pac"aging pharmaceuticals dependingupon the chem.. constitution of the glass and its ability to resist

deterioration:

• ype highly resistant, borosilicate glass

• treated soda*lime glass

• soda*lime glass

• -P gen. purpose soda*lime glass

• ypes , ' for parenteral prods

• ype -P 9 for non*parenteral



-e)er plastic materials used:

• P6 9 polyethylene terephthalate

• amorphous P6 1AP62

• P6 glycol 1P6/2

• AP6 ' P6/

* e+cellent transparency, luster and

can be sterili!ed )ith gamma radiation



Problems encountered in the use ofplastics in pac"aging:

• permeability of the containers to atmospherico+ygen and to moisture vapor

• leaching of the constituents of the container tothe internal contents

• absorption of drugs from the contents to thecontainer

• transmission of light through the container

• alteration of the container upon storage

properties of plastics may be



properties of plastics may bealtered

• addition of:

* plastici!ers, stabili!ers, antio+idants, antistaticagts, antimold agts, colorants, and others

drug subss sub?ected to o+idativedegradation* may undergo a greater degree of degradation

)hen pac"aged in plastic as compared to glass



36AC>-/

• movement of components of a container into thecontents

• Cpds leached from the plastic containers:

polymer additives as the plastici!ers, stabili!ers orantio+idants

• occurs )hen li&. or semi*solid dosage forms arepac"aged in plastic

• little leaching occurs for tabs or caps pac"aged in plastic

• n#uenced by: (temp (e+cessive agitation of the 0lled container

(solubili!ing eect of li&. contents on one or more of thepolymer additives



• oft*)alled plastic containers of PC9 polyvinyl Cl

* used to pac"age solns and

blood for transfusion



E%PE-

• binding of molecules to polymer materials

• absorption and adsorption are considered

• occurs through chem. or phy. means due to:

(chem.. structure of the solute molecules

(phy. and chem. properties of the polymer• occurs )ith active pharmacologic agts or )ith pharmaceu.

e+cipients thus, ings must be e+amined in the proposedplastic pac"aging to determine its tendency



• Pharmacist should dispensemedication to patients in:

* same type ' &uality of container

used by the manufacturer of theproduct.

Child %esistant=Adult enior Gse Pac"aging



Child*%esistant=Adult*enior Gse Pac"aging

• Child-resistant container

- de0ned as:

(signi0cantly di$cult for children under years of age toopen

or to obtain a harmful amount of its contents )ithin areasonable time

(not di$cult for Onormal adults to use properly.

• Child*proof closures

* initial regulations called for its use for

(aspirin products (certain household chemical products

* sho)n to have a signi0cant potential for causing accidentalpoisoning in youngsters



Drugs intended for oral use

• dispensed by the pharmacist to the patient in containershaving child*resistant closures unless the prescriber or thepatient speci0cally re&uests other)ise, or unless theproduct is speci0cally e+empt from the re&uirement

• Adults, particularly the elderly or those )ith arthritis or)ea"ened hand*strength 1)ith di$culty opening child*resistant pac"ages2

* the regulations )ere amended and 14NNQ2 to re&uire thatchild*resistant containers be capable of being readilyopened by senior adults



E%A/6

• product must be stored under properconditions

* to ensure the stability of apharmaceutical prepn for the period ofits intended shelf life

• 3abeling of each product

* includes the desired conditions ofstorage

erms employed for the



p ydesired conditions as de0ned

by the GP:• Cold

* any temp not e+ceeding QoC 18oF2

* a refrigerator is a cold place )herethe temp. is maintained bet. 5o andQoC 17o and 8oF2

• Cool

* any temp bet. Qo and 4oC 18o and NoF2

erms employed for the



p ydesired conditions as de0ned

by the GP:• %oom emp.

* temp prevailing in a )or"ing area

* 5Ho to 5oC 1QoF to IIoF2 but also allo)s for tempvariations bet 4o and 7HoC 1No and QoF2 e+periencedin pharmacies, hospitals, and drug )arehouses

• @arm

* any temp bet 7Ho and 8HoC 1Qo and 4H8oF2

• 6+cessive >eat

* any temp above 8HoC 14H8oF2



Protection from Free!ing

• protects the product from:

(free!ing

(ris" of brea"age of the container

(loss of strength or potency

(destructive alteration of the dosage

form



tability esting

(igns of degradation of the speci0c dosageforms must be observed and reported.

ablets : Apperance 1crac"ing, chipping,mottling2, friability, hardness, color.

Capsules: Moisture tac"iness, color appearance,shape, brittleness and dissolution

Eral olutions and uspensions: Appearance,precipitation, p>, color, odor, dispersibility1suspension2 and clarity 1solutions2



• Eral Po)ders: Appearance, color, odor,moisture

• Metered9dose inhalation aerosols delivereddose per activation, number of metereddoses, color, particle si!e distribution, loss ofpropellant, pressure, valve corrosion, spraypattern, absence of pathogenicmicroorganism

• opical creams: ointments, lotions, solutions,and gels. Appearance, color, homogeneity,odor, p>, resuspendability 1lotions2,consistency, particle si!e, distribution

strength, )eight loss.



• Epthalmic and -asal and Eralinhalation preparations:

Appearance, color consistency, p>,clarity 1solutions2, particle si!e, andresuspendability 1suspensions,

ointments2, strength and sterility.• mall olume Parenterals:

Appearnace, color, clarity,particulate matter, p> volumes ande+tractables 1)hen plasticcontainers are used2, sterility,pyrogenicity and closure integrity.



• uppositories: oftening rangeRappearance and melting.

• 6mulsions: Appearance 1such as phaseseparation2 color, odor, p>, and viscosity.

• Controlled release membrane drugdelivery systems: seal strength of thr

drug reservoir, decomposition products,membrane integrity, drug strength anddrug release rate.

FDA guidelines on stability for



FDA guidelines on stability fore+temporaneous compounding

• -ona&ueous li&uids ' solid formulations

1source of active ingredient2s

* not later than 5J of the time remaining untilthe products e+piration date or months,

)hichever is earlier

• -ona&ueous li&s ' solid formulations in )=c GPor -F substance 1source of ing2

* beyond*use not later than 48 days in storage at

cold temperatures

FDA guidelines on stability for



FDA guidelines on stability fore+temporaneous compounding

• Ether formulations beyond*use date of theintended duration of therapy or 7H days

)hichever is earlier



P>A%MAC:

• oral a&. li& prepns made from e+isting tab or cap formulation

* pharmacist should ma"e up only at most a 48 days supplyand must be stored in a ref.

• must dispense the medication in a container conducive tostability and use

* advise the patient of the proper method of use andconditions of storage of the medication

• )hen compounding on the basis of e+trapolated or less thanconcrete information

* should "eep the formulation simple and not to shortcutbut use the necessary pharmaceutical ad?uvants to preparethe prescription

•

t bilit t ti



tability testing

• manufactured products * shelf life of5 or more years to ensure stability atthe time of consumption.

• e+piration date * limits the timeduring )hich the product may bedispensed by the pharmacist or used

by the patient.

P>A%MAC6GC -/%6D6-



P>A%MAC6GC -/%6D6-

• re&uired in preparing the drug subs. intoa 0nal dosage form

• for each dosage form:

(establish the primary features of theprod

(contribute to the physical form,

te+ture,stability, taste and over all

appearance

Pharmaceutical ngredients and



Pharmaceutical ngredients and6+cipients

De0nition of terms

• olvents are used to dissolve thedrug substance.

• Flavors and s)eeteners are used toma"e the product more palatable

• Colorants are added to enhance

appeal• Preservatives may be added to

prevent microbial gro)th





• tabili!ers 1antio+idants and chelating2 * toprevent decomposition.

• Diluents or 0llers * to increase the bul" of theformulation.

• inders 9 to cause adhesion of the po)dered drugand pharmaceutical substances.

• Antiadherents or lubricants to assist smoothtablet information.





• Disintegrating agents * promotetablet brea" up after administrationand coatings to improve stability,

control disintegration or enhanceappearance.

)eetening



)eeteningPharmaceuticals

• used in foods and pharmaceuticals:

(sucrose

(arti0cial s)eetening agents• (+** PH,/,C3+C,4(

* mas" un)anted taste

* commonly used * sucrose

*5elaney Clause6 no ne) food additives may be

used if animal studies=appropriate tests sho)edthat

it caused cancer



• accharin ' cyclamate * used in foods

*Ogenerally recogni!ed as safe 1before the

amendments passage2 * use on rats: developed incidence of bladder

tumors 1cancer2

* continued availability but )arning labels be used

*cyclamates %banned2 * possible carcinogenicity,

genetic damage, testicular atrophy

)eetening



gPharmaceuticals

• Aspartame 9

* 4st arti0cial s)eetener 14NQ amendment2

)= re&uirement for pre*mar"eting proof of safety.

* ,cesulfame potassium %nonnutritive s!eetener'

- structurally similar to saccharin 1GP approved2

*47H times as s)eet as sucrose, e+cretedunchanged in

the urineR

* more stable than aspartame

* (tevia 1tevia rebaudiana ertoni2

9 ne) s)eetening agent: natural, nonto+ic, safe,

7H+ s)eeter than cane sugar=sucrose

Sucrose Saccharin aspartame



Source Sugar cane;sugar beet

Chemicalsynthesis;phthalic

anhydride

Methyl esterdipeptide ofphenylalanineand asparticacid

Relativesweetness

1 300 180!00

"itterness #one Moderate to

strong none

$fter taste #one Moderate to

strong metallic

to bitter

none

Calories acidstability

%&g 0 %&g

$cid stability good '(cellent fair

Coloring Pharmaceuticals




• for esthetics.

• Coal tar 1pi+ carbonis2

* thic" blac" viscid li&uid

* by product of destructive distillation of coal. * source of synthetic coloring agents in pharm.

products in the middle of the 4Nth century

• Dyes 9 added to pharmaceutical prens in the

form of diluted solutions• 3a"es * commonly used in the form of 0ne

dispersions or suspensions.





• NHJ of the dyes used in the products * synthesi!ed from

derivative of ben!ene 1aniline'

• FDA * regulates use color additives in foods, drugs, and

cosmetics 1Federal Food, Drug, and Cosmetic Act of 4N7Q2

* "57C color additives * foods, drugs, and cosmetics

* 57C color additives - drugs, some in cosmetics '

medical devices

* external 57C color additives - restricted to e+ternal

parts

of the body 1not including the lips and other parts that

are covered by mucous membrane2

Factors in selecting dyes



Factors in selecting dyes

• olubility of prospective dye

• p> ' p> stability of the preparationto be colored

• Dyes must be photostable

Preservatives



Preservatives

• li&uid and semisolid preparations

* must be preserved againstmicrobial

contamination.

terili!ation and



Preservation

• some types of pharmaceutical products

1e+. Ephthalmic and in?ectable

preparations2

* sterilized by physical methods :

(autoclaving 15Hmin at 4 lb. press. '

454SC, dry heat at 4QHSC for 4 hr2

(bacterial 0ltration.

terili!ation and



Preservation• Preparations that provide e+cellent gro)th media

for microbes

* aqueous preparations: syrups, emulsions,

suspensions

* semi solid preparations particularly creams.

* hydro-alcoholic 7 most alcoholicpreparation

(may not re&uire addition of chemical

preservative

terili!ation and



Preservation

• prevent microbial gro)th:

(4J alcohol in acid media

(4QJ alcohol in al"aline media.

• Alcohol*containing pharmaceuticals1eli+irs, spirits, and tinctures2 * selfsterilizing and do not re&uireadditional preservation.

Preservative election




• Considerations in selecting preservative inpharmaceutical

preparations6

4. prevents the gro!th of the type of microorganisms

1 contaminants of the preparations2

5. soluble enough in !ater to achieve ade&uateconcentrations in a&ueous phase )ith t)o or more

phase

systems

7. proportion of preservative remaining undissociated at the

p> of preparation 1can penetrate the microorganism '

destroy its integrity2.





8. concentration of the preservative does not a&ect the

safety=comfort of the patient

. )ith ade&uate stability and not reduced in concentration by chemical

decomposition=volatili!ation

. compatible )ith all other formulative ingredients and

does not interfere )ith them

I. does not adversely a&ect the preparations container

or closure.

Mode of action



Mode of actionMechanisms preservative interfere )ith microbial

gro)th, multiplications, and metabolism:

4. Modi0cations of cell membrane permeability andlea"age of cell constituents 1partial lysis2

5. 3ysis and cytoplasmic lea"age

7. rreversible coagulation of cytoplasmic constituents

8. nhibition of cellular metabolism by interfering )ithen!yme systems=inhibition of cell )all synthesis

. E+idation of cellular constituents

. >ydrolysis

P%66%A6 G3TAE-



P%66%A6:* suitable substances added to enhance its permanency

or usefulness

* e+amples: commonly employed:

ben!oic acid alcohol sodium ben!oate phenylmercuric nitrate andacetate

phenol ben!al"onium chloride



• prepns in large volumes as bloodreplenishers=nutrients

* no bacteriostatic additives

• n?ectable prepns in small volumes

* can be preserved )ith suitablepreservatives

Documents

Dosage Foem chp 3 4