EXTEMPORANEOUS PREPARATIONS BY SANA GHAYAS LEARNING OBJECTIVES At

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. Vehicles 2. Solubility 3. 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 p. H 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 solids THICKENING 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 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 test 2. Microscopic examination after staining with a oil soluble dye 3. Microscopic observation under UV radiation 4. 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 AGENTS 1. Synthetic or semi synthetic substances 2. Natural products 3. Finely divided solids � Many of the substances described as thickening agents also act as amulgents. �

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 1.

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 ADDITIVES Antioxidants: e. g. butylated hydroxyanisole (BHA) or butylated hydroxytoluene (BHT). Ethyl, propyl or dodecyl gallate may also used. Preservatives Desirable 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 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. Weighing 2. Measuring of liquids 3. 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 gels BASES FOR OINTMENTS AND OINTMENT TYPE PASTES They 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 GELS CELLULOSE 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 GELS LIFE OF OINTMENTS, PASTES AND � CONTAINERS GELS FOR OINTMENTS, PASTES AND � 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. (a) � � � � � FATTY BASES: 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 p. H 3. 2. � Type B which behaves as a anionic agent and most effective at p. H 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.

q CHOICE OF SUPPOSITORY OR PESSARY BASE q 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. q

q 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 = ag Prepare base containing 30% medicament, fill six moulds and weigh six suppositories = bg Calculate the amount of base, cg and medicament d g in the six suppositories c = 70% b and d = 30% b Therefore the amount of base displaced by displacement value = __d______ a c For 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. 25 Drug = 30% of 7. 5 = 2. 25 Base displaced by 2. 25 g = 6 5. 25 = 0. 75 g Therefore the displacement value of the drug = 2. 25/0. 75 =3 Method 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 g This will displace 2. 4/3= 0. 8 g of base Therefore amount of base required = 8 0. 8 = 7. 2 g

MOULD LUBRICATION Preparation of suppositories with a fatty base 1. 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 glycerogelatin 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 ADVICE 1. 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. ü Divided oral powders. ü Granules for oral administration. ü Dusting powders for external use. � FORMULATION OF POWDERS AND GRANULES: ü � COMPOUNDING: � Basic ü ü 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. Ø ADVANTAGES AND DISADVANTAGES OF UNDIVIDED POWDERS: Ø SHELF LIFE OF UNDIVIDED POWDERS: � Undivided powder are suitably packaged and stored. � Remain stable over a long period. Ø CONTAINERS OF UNDIVIDED POWDERS: � Plain glass jars with close fitting closures and a 5 ml measuring spoon should be supplied for undivided powders. Ø SPECIAL LABEL AND ADVICE FOR PATIENTS: 2. DIVIDED POWDERS AS ORAL DOSAGE FORMS: Ø SHELF LIFE OF DIVIDED POWDERS: Ø CONTAINERS OF DIVIDED POWDERS: Ø 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. Ø SHELF LIFE OF GRANULES Ø CONTAINERS OF GRANULES Ø SPECIAL LABEL AND ADVICE FOR PATIENTS: Ø 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 Ø SHELF LIFE OF DUSTING POWDERS Ø CONTAINERS OF DUSTING POWDERS Ø 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 carry DISADVANTAGES 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 tablets SUPPLY 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 TABLETS SPECIAL 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 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 950 650 450 300 250 200 150 100 ADVANTAGES 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 12 TH 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