DDS LAB DISCUSSION.pdf

DDS LAB DISCUSSION (PRELIM) Particle Size POWDERS CAN INFLUENCE A VARIETY OF IMPORTANT FACTORS: Are intima...

DDS LAB DISCUSSION (PRELIM) Particle Size POWDERS CAN INFLUENCE A VARIETY OF IMPORTANT FACTORS: Are intimate mixtures of dry, finely divided drugs and/or chemicals 1. Dissolution Rate that may be intended for internal or external use (USP). 2. Suspendability o A dosage form composed of a solid or mixture of solids 3. Uniform distribution reduce to a finely divided state and intended for internal 4. Penetrability or external use (Ansel). 5. Lack of grittiness o Powders and granules are themselves dosage forms USES: POWDERS o They can be an intermediary for drugs normally administered as a solution or suspension in an aqueous vehicle. These are reconstituted just prior to use to avoid chemical degradation (e.g. antibiotic powders for syrups and powders for injection). o They are also, more commonly, intermediate products in the manufacture of other dosage forms. It may be Comminution of Drugs: Methods blended with powdered fillers and other ingredients (e.g. 1.Trituration or comminution tablets and capsule dosage forms) o grinding a drug in a mortar to reduce particle size; may be o Powders are also used for inhalation (pulmonary or nasal) both employed to comminute and to mix powders. and for external use (dusting powders) 2. Mills/pulverizers o It may be incorporated into semisolid bases: ointments and o rapidly moving blades in the comminuting chamber and creams passed through a screen of desired dimension. 3. Levigation Methods for the determination of particle size o commonly used in small-scale preparation of ointments 1. Sieving and suspensions to reduce the particle size and grittiness of 2. Microscopy added powders. 3. Sedimentation Rate paste is formed by combining the powder 4. Light energy diffraction and a small amount of liquid (levigating 5. Laser holography agent, ex: mineral oil and glycerin) 6. Cascade impaction Blending of Powders Particle Size and Analysis 1. Spatulation - blending small amounts of powders by movement of o United States of Pharmacopeia (USP) uses these descriptive a spatula through a sheet of paper or an ointment tile. terms to characterize particle size: o Not suitable for large quantities of powders o Very Coarse a. Eutectic mixtures - a mixture of two or more o Coarse components that produces a change of phase to o Moderately Coarse liquid at a certain temperature. o Fine b. Eutectic Temperature - the temperature at which such o Very Fine a system exists in the liquid phase. Above this temperature, the components are liquids and below this temperature they are solids. o Examples: phenol, camphor, menthol, thymol and other similar chemicals 2. Geometric Dilution - is used when a small amount of a potent substance is to be mixed with a large amount of diluent to ensure uniform distribution of the potent drug. Procedure in Geometric Dilution Steps: Potent drug and diluent (approx. equal volume) is mixed thoroughly 1. by trituration. 2. A second portion of diluent equal in volume to the mixture is added and the trituration repeated. 3. Repeat the whole process until all of the diluent is incorporated Blending of Powders - large scale manufacturing Sifting Tumbling Special Considerations when blending Particle Size and Analysis o Some powders may become sticky or pasty, or they may Very coarse (No. 8) All particles pass through a No. 8 sieve and liquefy when mixed together (eutectics) not more than 20% pass through No. 60 sieve o To keep the powders dry Coarse (No. 20) All particles pass through a No. 20 sieve and add magnesium oxide or magnesium carbonate not more than 40% pass through a No. 60 (powder adsorbent) sieve o Hygroscopic and Deliquescent Powders Moderately coarse (No. 40) All particles pass through a No. 40 sieve and o Efflorescent Powders not more than 40% pass through a No. 80 contains water of hydration or crystallization sieve Fine (No. 60 All particles pass through a No. 60 sieve and not more than 40% pass through a No. 100 Medicated Powders - classification of Powders sieve Very fine (No. 80) All particles pass through a No. 80 sieve MEDICATED POWDERS AEROSOL administered by inhalation (e.g. MDI) POWDERS Purpose of Particle Size Analysis? BULK POWDERS limited to non-potent substances (e.g. antacids o To obtain quantitative data on the size, distribution, and and laxatives) shapes of the drug, and other components to be used in DIVIDED packed in a small piece of paper (e.g. pharmaceutical formulations. POWDERS analgesic powders)  INSUFFLATIONS these powders are usually applied with an a. Particles are placed in a conical piece of equipment applicator known as insufflators; introduced b. Vigorously dispersed and suspended into different body cavities such as nose, ear, c. Liquid excipient is sprayed on the particles and the vagina, tooth sockets etc. product dried, forming granules or pellets of defined EFFERVESCENT these powders when mixed with water show particle size. POWDERS effervescence with the liberation of carbon dioxide 3. Dry Method o (e.g. citric acid, tartaric acid) Steps: DUSTING are used externally for local application, not a. Dry powder is passed through a roll compactor and POWDERS intended for systemic action then through a granulating machine. o (e.g. talc, kaolin, starch, zinc oxide). DENTRIFICES are bulk powders for external use to clean b. A roll compactor processes a fine powder into dense teeth; mainly contain an abrasive agent. It also sheets by forcing it through two mechanically rotating contains a surfactant, mild soap/detergent metal rolls and sweetening agents. c. The compacted powder is granulated to uniform particle DOUCHE commonly used for vaginal use and intended size in a mechanical granulator POWDERS for the action of cleansing agents or used as an antiseptic. DIFFERENCE BETWEEN POWDER AND GRANULES POWDERS GRANULES 1. Divided Powders FINE PARTICLES SMALL GRAIN a) Simple bond paper CAN APPLIED TO THE BODY CANNOT BE APPLIED TO THE b) Vegetable parchment BODY a thin semiopaque paper with limited SMOOTH TO TOUCH ROUGH moisture resistance POOR FLOW PROPERTIES FLOW WELL c) Glassine LESS STABLE (PHYSICALLY MORE STABLE (PHYSICALLY AND glazed, transparent paper, also with AND CHEMICALLY) CHEMICALLY) limited moisture resistance PRODUCE MORE DUST PRODUCE LESS DUST d) Waxed Paper transparent, water-proof paper Effervescent Salts - the selection of the type of paper is based primarily on the nature of the powder. o Are granules or coarse to very coarse powders containing a medicinal agent in a dry mixture usually composed of POWDERS sodium bicarbonate, citric acid, and tartaric acid ADVANTAGES DISADVANTAGES o When added to water, the acids and the base react to Can be administered easily to Patient may misunderstand the liberate carbon dioxide, resulting in effervescence. infants/young children who correct method of use (without o Using a combination of citric and tartaric acid rather than cannot swallow tablets/capsules clear instruction, patients may either acid alone avoids certain difficulties. inhale through the nose a drug intended for oral administration). o When tartaric acid is used alone: the resulting granules Drug will have a rapid onset of Bitter or unpleasant taste readily lose their firmness and crumble. action since disintegration is not o When citric acid is used alone: will result in a sticky mixture required difficult to granulate, Can be made into many It is difficult to protect powders different dosage formulations containing hygroscopic, Method of Preparation: deliquescent (tending to melt or 1. Dry or Fusion Method dissolve in humid environment), a. The water of hydration present in citric acid act as binder or aromatic materials from b. Mix together with the medicament, tartaric acid, sodium decomposition bicarbonate Individually wrapped doses of c. Place in an oven powders may increase manufacturing expense Granulated mass is formed; pass through a suitable size sieve Inaccuracy of dose o No. 4 sieve = large granules o No. 8 sieve = medium sized granules GRANULES o No. 10 sieve = small granules o Are prepared agglomerates of smaller particles of powder. 2. Wet Method o Are defined as a dosage form composed of dry a. Mixed ingredients are moistened with non-aqueous liquid aggregates of powder particles that may contain one (alcohol) or more active pharmaceutical ingredients (APls), with b. Place in an oven or without other ingredients c. Granulated mass is formed; pass through a suitable size o They are irregularly shaped but may be prepared to sieve be spherical. o They are usually in the 4 -12 mesh sieve size range, although granules of various mesh sizes may be prepared depending upon their application. CHARTULA OR CHARTULAE o They are prepared by: Wet and Dry Methods METHOD OF PREPARATION: 1. Wet Method Steps: a. Moisten the powder —> paste is formed b. Pass the resulting paste through a screen of the mesh size to produce the desired size of granules c. Granules are placed on drying trays d. Dried by air or under heat. e. The granules are periodically moved on the drying trays to prevent adhesion into a large mass 2. Fluid Bed Processing Steps:  SUPPOSITORIES SHAPE cylindrical SIZE 32 mm (1.5 inch) long WEIGHT depending on the density of the base and the medicaments in the suppository, the weight may vary. ADULT weight about 2 grams when cocoa butter (theobroma oil) is employed as the base INFANT AND half the weight and size of adult suppositories CHILDREN and assume a more pencil-like shape TYPE OF INSERTS: SUPPOSITORIES INSERTS VAGINA (PESSARIES) SHAPE: globular, oviform, or cone shaped WEIGHT: 5 grams when cocoa butter is the base. CHAPTER 2: SUPPOSITORIES AND INSERT, STICKS REMINDER: However, depending on the base and the manufacturer’s product, the weights of vaginal inserts SUPPOSITORIES: GENERAL OVERVIEW may vary widely. Have not gained the level of acceptability, respect and URETHRAL (BOUGIES) usage as most other dosage forms. MALE FEMALE There is a tendency away from rectal delivery for routine SHAPE 3-6 mm in diameter half the administration of drugs. approximately 140 mm long length Suppositories generally have been employed for three WEIGHT when cocoa butter is used as the base, reasons: these suppositories weigh about 4 1. Promote defecation grams. 2. Introduce drugs into the body (CONTINUE VERSION SA FEMALE) weight of the male urethral 3. Treat anorectal diseases suppository being about 70 mm long and weighing about 2 g Not often the first route of choice; but it becomes a good when made of cocoa butter. alternative when the oral route is inadvisable. Relatively low cost and lack of technical difficulties make MEDICATION STICKS rectal drug administration attractive when compared to Shape: CYLINDRICAL parenteral therapy. Downside includes: ADVANTAGES DISADVANTAGES 1. Esthetics and stigma of violating the patient’s dignity A perceived lack of flexibility Defecation may interrupt the 2. Potential rectal irritation regarding dosage of absorption process of the drug; this 3. Difficulty in titrating a correct dose due to limited commercially available may especially occur if the drug is strengths of commercial properties suppositories resulting in underuse irritating. In treating hospice patients, rectally administered and a lack of availability. Absorbing surface area of the medications are essential in palliative medicine. If suppositories are made on rectum is much smaller than that of demand, they may be the small intestine. Excellent dosage form for those patients to whom one expensive. Fluid content of the rectum is much does not want to administer numerous injections daily. Different formulations of a drug less than that of the small intestine; Can be administered to avoid nausea and vomiting with a narrow therapeutic which may caused by certain medications upon oral administration margin, such as affect the dissolution rate, etc. and it is a dosage form that can often result in a fast aminophylline. There is a possibility of degradation onset of action. Bullet shaped suppository after of some drugs by the microflora DEFINITION: insertion can leave the anorectal present in the rectum Is a solid dosage form in which one or more API (active site and Dose of a drug required for rectal pharmaceutical ingredients) are dispersed in a suitable ascend to the rectosigmoid and administration may be greater than base and molded or otherwise formed into a suitable descending colon. or less than the dose of the same shape for insertion into the rectum to provide a local or drug given orally. systemic effect. Weight: 5-25g Note: inserts - solid dosage form that is inserted into a naturally occuring body cavity other than the mouth or rectum, including the USES AND APPLICATIONS: SUPPOSITORIES AND STICKS, INSERT vagina and urethra. 1. LOCAL ACTION SHAPES: SUPPOSITORIES AND STICKS, INSERT o Once inserted, the suppository base melts, softens, or SUPPOSITORIES dissolves, distributing its medicaments to the tissues of the Various shapes and weights region. These medicaments may be intended for retention Shape and size of a suppository must be such that it can within the cavities for local effects, be easily inserted into the intended orifice without causing o Or they may be intended to be absorbed for systemic undue distention, and once inserted, it must be retained effects for the appropriate period. o Examples: ▪ Rectal and antihemorroidal suppositories RECTAL. intended for local action most frequently used to relieve constipation or pain, irritation, itching, and inflammation assoc.  with hemorrhoids or other EXAMPLES: anorectal conditions FATTY BASES WATER-SOLUBLE AND POLYETHYLENE ANTIHEMORROIDAL suppositories frequently contain a number MISCIBLE GLYCOL of components including local anesthetics, cocoa butter Fattibase glycerinated vasoconstrictors, astringents, analgesics, fat obtained from triglycerides gelatin and soothing emollients, and protective agents. the roasted seed from palm, polyethylene GLYCERIN promote laxation by local irritation of the of Theobroma kernel and glycols. mucous membranes cacao. coconut oil VAGINAL INSERT intended for local effects; employed yellowish-white mainly as contraceptives (nonoxynol 9), as solid Witepsol bases antiseptics in feminine hygiene faint, agreeable triglycerides Trichomonacides chocolate-like of saturated o combat vaginitis caused odor. Chemically, fatty acids by Trichomonas vaginalis it is a glyceride. URETHRAL antibacterial or a local anesthetic Wecobee bases preparative for a urethral examination. Melts at 30-36c, it is an ideal trigylcerides suppository base, melting derived from STICKS - commonly used for local effect and include just below body coconut oil hydration/emollient, antibacterial, temperature. antipruritic and other uses WATER SOLUBLE AND MISCIBLE BASES 2. SYSTEMIC ACTION In the preparation of vaginal suppositories, glycerinated PROCHLORPERAZINE AND nausea and vomiting and as gelatin is the most frequently used base, with which CHLORPROMAZINE tranquilizer prolonged local action of the medicinal agent is usually MORPHINE AND opioid analgesia desired. OXYMORPHONE Prepared by: dissolving granular gelatin (20%) in glycerin ERGOTAMINE TARTRATE relief of migraine (70%) and adding water or a solution/susp (10%). INDOMETHACIN nonsteroidal anti-inflammatory Note: glycerinated gelatin base is slower to soften and mix with the analgesic and antipyretic physiologic fluids than is cocoa butter and therefore provides a ONDANSETRON relief of nausea and vomiting slower release. SOME FACTORS OF DRUG ABSORPTION FROM RECTAL SUPPOSITORIES DRUG RELEASE RATES The dose of a drug administered rectally may be greater than or less General approximate drug release rates as they relate to the drug than the dose of the same drug given orally, depending on such and base characteristics are summarized as follows; factors: 1. Constitution of the patient DRUG BASE CHARACTERISTICS APPROXIMATE DRUG RELEASE 2. Physicochemical nature of the drug and its ability to OIL SOLUBLE DRUG; OILY BASE slow release; poor escaping traverse the physiologic barriers to absorption tendency 3. Nature of the suppository base WATER SOLUBLE DRUG; OILY rapid release 4. Capacity to release the drug and make it available for BASE absorption OIL SOLUBLE DRUG; WATER moderate release MISCIBLE BASE SUPPOSITORIES BASES WATER SOLUBLE DRUG; WATER moderate release; based on Nature of the Base MISCIBLE BASE diffusion; all water soluble The base must be capable of melting, softening or dissolving to release its drug for absorption. PREPARATION OF SUPPOSITORIES Should not irritate the mucous membranes of the rectum molding Should not inhibit the drug absorption of the active drug Hand rolling (doesn’t affect stability/bioavailability) Shaping CLASSIFICATION OF BASES: SUPPOSITORIES BASES 1. MOLDING FATTY OR most frequently employed suppository base. Steps in Molding OLEAGINOUS BASES Melting the base WATER- SOLUBLE Have a tendency to absorb moisture as a Incorporating any required medicaments AND MISCIBLE result of the hygroscopic nature of glycerin, Pouring the melt into molds BASES they must be protected from atmospheric Allowing the melt to cool and congeal into suppositories moisture Removing the formed suppositories from the mold May have a dehydrating effect and irritate Note: cocoa butter, glycerinated gelatin, polyethylene glycol are the tissues upon insertion (water in the suitable for preparation by molding formula minimizes this action); however, if necessary the suppositories may be TYPES OF MOLDS moistened with water prior to insertion. SUPPOSITORY Made from stainless steel, aluminum, brass or Urethral suppositories (different formula): plastic gelatin (60%), glycerin (20%), and aqueous Care must be exercised in cleaning the molds, portion (20%) as any scratches on the POLYETHYLENE Don’t melt at body temperature but rather molding surfaces will take away from the desired GLYCOL BASE dissolve slowly in the body’s fluids. smoothness of the Thus, it is possible, to prepare suppositories suppositories. Plastic molds are especially prone from polyethylene glycol mixtures having to scratching. melting points considerably higher than LUBRICATION base is cocoa butter/polyethylene glycol - body temperature. lubrication is  seldom necessary; as these materials contract sufficiently on cooling to separate from the inner surfaces and allow easy VAGINAL TABLETS removal. Commonly used base when preparing vaginal inserts: base is glycerinated gelatin - lubrication is polyethylene glycol base necessary; a thin o Surfactants and preservative agents are also coating of mineral oil applied to the molding frequently added surfaces They are buffered to an acid pH usually about 4.5, consistent with the normal vagina CALIBRATION OF MOLD Are usually ovoid and are accompanied in their package 1st step: to prepare molded suppositories from base material alone. with a plastic inserter, a device for easy placement of the 2nd step: After removal from the mold, the suppositories are tablet within the vagina. weighed and the total weight and average weight of each suppository are recorded They are prepared by tablet compression and are 3rd step: To determine the volume of the mold, the suppositories are commonly formulated to contain lactose as the base or carefully melted in a calibrated beaker, and the volume of the melt filler, a disintegrating agent such as starch, a dispersing is determined for the total number as well as for the average of 1 agent such as polyvinylpyrrolidone, and a tablet lubricant suppository. such as magnesium stearate. They are intended to disintegrate within the vagina, DETERMINATION OF THE AMOUNT BASE REQUIRED releasing their medication. Example: if 12 ml of cocoa butter is required to fill a Some vaginal inserts are capsules of gelatin-containing suppository mold, and if the medicament (active medication to be released intravaginally; capsules may ingredient) in the formula has a collective volume of 2.8 ml, also be used rectally. then 9.2 ml of cocoa butter will be required. Capsule insertion into the rectum can be facilitated by first lightly wetting the capsule with water. Holes may be PREPARING AND POURING MELT punched into these capsules prior to moistening. Using the least possible heat, the weighed suppository CHAPTER 3: SEMISOLID DOSAGE FORM base material is melted, generally over a water bath. MANUFACTURING SUPPOSITORIES DEFINITION OF TERMS OLEAGINOUS consisting of oil, oily or greasy Generally prepared by the melt fusion method EMOLLIENT having the quality of softening or soothing the Involves 5 distinct steps: skin 1. Forming OCCLUSIVE forming a protective layer on the surface of 2. Dosing the skin and creating a barrier to prevent 3. Cooling moisture loss. 4. Sealing EMULSIFIER/ agents that permit the mixing of two or more 5. Finishing EMULSIFYING immiscible substances. AGENTS PACKAGING AND STORAGE EMULSION a mixture of two or more liquids that are Individually wrapped or otherwise separated in normally immiscible (unmixable or compartmented boxes to prevent contact and adhesion unblendable) PERCUTANEOUS passing through the skin. Glass containers; tightly closed Metallic foil (suppositories containing light-sensitive drugs) Ointments, Creams and Gels Foil or plastic / continuous strip separated by tearing Are semisolid dosage forms intended for topical Necessary to maintain them in a cool place. applications High humidity: spongy // Extreme dryness: may lose Skin, placed on the surface of the eye, or use nasally, moisture & become brittle vaginally or rectally. Used for both local and systemic effects. URETHRAL SUPPOSITORIES Tend to be thinner and tapered, often about 5 mm in Ointments diameter. Intended for external application to the skin or mucous When compounding urethral suppositories: in addition to a membranes. urethral mold,a straw or thin glass tube can also be used; a May be medicated or not. 1-mL tuberculin syringe can also be used if the lower Unmedicated ointments are used for the physical effects portion of the barrel is cut off. they provide: Example of urethral suppository: MUSE (alprostadil) - male urethra. o protectants, emollients and lubricants. Ointment bases - may be used for their physical effects or VAGINAL INSERTS as vehicles for medicated ointments These preparations are employed principally to combat Ointment Bases: Classification infections in the female genitourinary tract, to restore the vaginal mucosa to its normal state, and for contraception. 1. Oleaginous bases 2. Absorption bases o Usual pathogens: Trichomonas vaginalis, Candida 3. Water-removable bases albicans or other species, and Haemophilus 4. Water-soluble bases vaginalis. o Anti-infective agents in commerical vaginal supp/inserts used: Nystatin, Clotrimazole, Butoconazole nitrate, teconazole, and miconazole (antifungals), povidone iodine, clindamycin, oxytetracycline, metronidazole o Vaginal contraception: Nonoxynol-9 (spermicide) o Restore vaginal mucosa: Dienestrol (estrogenic substance)  Effect of the drug on the consistency or other features of the OLEAGINOUS Are also termed hydrocarbon bases ointment base They have an emollient effect (soothing) Desire for a base easily removed by washing with water Protect against the escape of moisture, are Characteristics of the surface to which it is applied effective as occlusive (protective coating on the surface of the skin), can Preparation of Ointments remain on the skin for long periods without drying out 2 Methods: Incorporation and Fusion Difficult to wash off because of their immiscibility with water Incorporation ABSORPTION 2 types: Small scale: A. Anhydrous bases that permit the makes use of a mortar and pestle, or a spatula may be incorporation of aqueous solutions, resulting in used to rub the ingredients together on an ointment the formation of water in oil (w/o) emulsions slab/porcelain plate or pill tile (e.g hydrophilic petrolatum) Ointment mill, electric mortar and pestle, or a device B. Those that are already water in oil (w/o) called an "unguator" emulsions, that permit the incorporation of Fusion additional quantities of aqueous solutions (e.g. All or some of the components of an ointment are lanolin) combined by being melted together and cooled with constant stirring until congealed. Note: absorption bases are not easily Heat-labile substances and volatile components are removed from the skin with water, because added last when the temperature of the mixture is low the external phase of the emulsion is enough not to cause decomposition or volatilization. oleaginous. Done in a porcelain dish or glass beaker (small scale), WATER- Are oil-in-water (o/w) emulsions commonly once congealed, rubbed with a spatula or in a mortar REMOVABLE called creams. Ointment mill (large scale) External phase of the emulsion is aqueous, Medicated ointments and ointment bases containing they are easily washed from the components such as beeswax, paraffin, stearyl alcohol, skin and are often called water-washable and high molecular polyethylene glycol (PEG) are bases. processed by Fusion. WATER-SOLUBLE Do not contain oleaginous components. General rule: materials with highest melting points are Completely washable and often referred to heated to the lowest required temperature. The additional as greaseless. materials are added with constant stirring during the Because they soften greatly with the cooling of the melt until the mixture is congealed addition of water, large amounts of aqueous Incorporation of Solids solutions are not effectively incorporated into these bases. Levigation and geometric dilution are employed in this method Mostly used for incorporation of solid Levigating agents used: substances. Mineral oil - for bases in which oils are the external phase Glycerin - for bases in which water is the external phase EXAMPLES Incorporation of a gummy material (e.g camphor) PETROLEUM Petrolatum Also called “yellow petrolatum Incorporation of Liquids and petroleum jelly” and Liquids are added only after due consideration of an ointment obtained from petroleum base's capacity to accept the volume required. White petrolatum Also called “white petroleum Only very small amounts of an aqueous solution may be jelly” and obtained from incorporated into an oleaginous ointment. petroleum; has been wholly or Whereas, hydrophilic ointment bases readily accept aqueous nearly decolorized; considered solutions. more aesthetically pleasing Alcoholic solutions of small volume may be added easily to due to its lighter color. oleaginous vehicles or emulsion bases. Yellow ointment Also called “simple ointment” and obtained from the Compendial Requirements for Ointments honeycomb of the bee Apis Compendial Requirements for Ointments mellifera. Has a slightly greater MICROBIAL with the exception of ophthalmic preparations, viscosity than plain CONTENT topical acceptable standards for microbial petrolatum. content they must, however meet acceptable White ointment Substitution of white wax standards for microbial content (bleached and purified yellow Must contain antimicrobial wax) preservatives (benzoic acid, phenols, ABSORPTION Hydrophilic (Aquaphor, Aquabase) parabens) petrolatum MINIMUM FILL determines the net weight of the contents of Lanolin obtained from the wool of filled containers to ensure proper contents sheep (Ovis Aries), is a purified compared with the labeled amount. waxlike substance that has PACKAGING, STORAGE AND LABELING been cleansed, deodorized, and decolorized. It contains not Creams more than 0.25% water Are semisolid preparations containing one or more medical WATER- Hydrophilic ointment agents dissolved or dispersed in either an oil in water (o/w) emulsion REMOVABLE or in a water in oil (w/o) emulsion or in another type of water- WATER- Polyethylene Glycol ointment washable base. SOLUBLE Creams find primary application in topical skin products and in products used rectally and vaginally. Selection of the Appropriate Base Many patients and physicians prefer creams to ointments because Factors to consider: they are easier to spread and remove Release rate of the drug substance from the ointment base Example: Cold cream (w/o), Hydrophilic ointment (o/w) Desirability of topical or percutaneous drug absorption Generally described as either nonwashable or washable Desirability of occlusion of moisture from the skin An aqueous external phase (o/w) creams are more easily Stability of the drug in the ointment base removed than one with a nonaqueous external phase (w/o).  Gels (Jellies) Ocular drug penetration is limited (due to short residence time) Are semisolid systems consisting of dispersions of small or large Rapid removal by tearing and other natural mechanisms molecules in an aqueous liquid vehicle rendered jellylike by the Small surface area for drug absorption addition of a gelling agent. The cornea's natural resistance to drug penetration Gelling agents: Ointment base selection Carbomer 934, cellulose derivatives such as Non irritating to the eye carboxymethylcellulose or hydroxypropy|methylcellulose Must permit the diffusion of the medicinal substance throughout Gels may form a thixotrope the secretions Thixotrope/thixotropy Should have a softening point close to body temperature Is a time-dependent shear thinning property o It is when certain gels or fluids that are thick or Bases used: viscous under static conditions will flow (become Mixtures of white petrolatum and liquid petrolatum thinner, less viscous) over time when shaken, Lanolin agitated, or stressed. Polyethylene glycol o Takes a fixed time to return to a more viscous Mineral oil state. Contain antimicrobial preservatives, such as methylparaben and TEST propylparaben or chlorhexidine gluconate, and stabilizers such as STERILITY strict aseptic technique edetate disodium. METAL PARTICLSES microscopic examination of a Medicated gels may be prepared for administration by various heat-melted routes: skin, eye, nose, vagina, and the rectum Can be administered by the topical oromucosal routes (relating to More than one tube contains more than ten particle larger from ten the oral cavity). product tubes does not exceed 50, and if not more than one tube TYPE OF GELS contains more than 8 such particles SINGLE-PHASE are gels in which the macromolecules are GELS uniformly distributed throughout a liquid Miscellaneous Semisolid Preparations: Features and Use of Vaginal with no apparent boundaries between the Preparations dispersed macromolecules and the liquid. TWO-PHASE a gel mass consisting of floccules of small Topical application to the perianal area and for insertion (SYSTEM GELS) distinct particles, often referred to as a within the anal canal. magma. They are largely used to treat local conditions Example: Milk of Magnesia Anorectal pruritis Miscellaneous Semisolid Preparations Inflammation Pastes The pain and discomfort associated with hemorrhoids The vaginal surface is lined with squamous epithelium cells Application: skin and mucous produce from various underlying glands They generally contain a larger proportion of solid material Topical products are used to treat: than ointments and therefore are stiffer. o Vulvovaginal infections Prepared in the same manner as ointments o Vaginitis Because of the stiffness of pastes, they remain in place o Conditions of endometrial atrophy after application and are effectively employed to absorb o Examples: Nystatin, clotrimazole, miconazole, serous secretions clindamycin, sulfonamides Not suitable for application to hairy parts of the body Plasters CAPSULES Are solid or semisolid adhesive masses spread upon a Are solid dosage forms in which medicinal agents and/or inert backing material of paper, fabric, moleskin or plastic substances are enclosed in a small shell of gelatin. Are applied to the skin to provide prolonged contact at Gelatin capsule shells may be hard or soft, depending on their the site. composition. Example: Salicylic acid (keratolytic) plaster used on the Intended to be swallowed whole; however, it is fairly common in toes for the removal of corns. hospitals/ extended care facilities for a caregiver to open capsules Glycerogelatins or crush tablets to mix with food or drink especially for children or Are plastic masses containing gelatin (15%), glycerin (40%), other patients unable to swallow solid dosage forms. water (35%), and an added medical substance (10%) such HARD GELATIN CAPSULES as zinc oxide. used in most commercial medicated capsules. Following application, the glycerogelatin hardens, is usually commonly employed in clinical drug trials to compare the effects covered with a bandage and is allowed to remain in of an investigational drug with those of another drug product or place for weeks. placebo. o Example: Zinc gelatin - treatment of varicose Used in extemporaneous compounding of prescriptions. ulcers Empty capsule shells are made of gelatin, sugar and water. Gelatin is obtained by the partial hydrolysis of collagen obtained Miscellaneous Semisolid Preparations from the skin, white connective tissue, and bones of animals Hydroxypropy|methy/cellulose (HPMC) - gelatin coming from OPHTHALMIC OINTMENTS AND GELS vegetable origin Opth. Oinment using an eyepiece micrometer disk May be colored with various FD&C and D&C dyes MAJOR ROUTE cornea of the eye via simple diffusion Made opaque by adding agents such as titanium dioxide ALTERNATE ROUTE the conjuctive, and sclera Contain 13%-16% moisture LIPOPHILIC DRUGS are more capable of penetration than If stored in high humidity, additional moisture is absorbed by the hydrophilic compounds capsules and they may become distorted. 3 layers of the cornea Extreme dryness: Capsules may become brittle and crumble Lipophilic epithelial layer Many capsules are packaged along with a small packet of Hydrophilic stromal layer dessicant material to protect against the absorption of atmospheric Less lipophilic endothelial layer moisture Dessicant most often used: Dried silica gel, clay and activated Note: drug penetration depends on a drug's ability to traverse these charcoal three layers  Hard gelatin capsule shells are manufactured in two sections: the Micronization - produces particles 1-20 microns. capsule body and a shorter cap. LUBRICANT The shells are produced industrially by the mechanical dipping of makes powders free-flowing to allow steady passage of pins or pegs of the desired shape and diameter into a temperature- the capsule fill from the hopper through the encapsulating controlled reservoir of melted gelatin mixture (fig. 7.3) equipment and into the capsule shells The pegs, made of manganese bronze, affixed to plates, each Enhances flow properties capable of holding up to about 500 pegs. o Examples: Fumed silicon dioxide, magnesium CAPSULE SHELLS stearate, calcium stearate,, stearic acid, or talc Each plate is lowered into the gelatin bath (about 0.25% to 1%) Submerged to the desired depth and maintained for the desired period to achieve the proper length and thickness of coating. Developing the formulation and selecting the capsule size Then the plate and pegs are slowly lifted from the bath and the gelatin is dried by a gentle flow of temperature and humidity- MAGNESIUM (water-insoluble/has waterproofing controlled air STEARATE characteristics) is used as a lubricant, it can retard THE MANUFACTURE OF HARD GELATIN CAPSULE SHELLS penetration by the gastrointestinal fluids and When dried, each capsule part is trimmed mechanically to the delay drug dissolution and absorption proper length and removed from the pegs, and the capsule bodies SURFACE such as sodium lauryl sulfate (SLS) is used to ACTIVE facilitate wetting by the gastrointestinal fluids to and caps are joined together. AGENT overcome the problem Important: The thickness of the gelatin walls must be strictly controlled so that the capsule's body and cap fit snugly to prevent Capsules are use for filling different materials like disengagement. 1. Powder There is a continuous dipping, drying, removing and joining of 2. Granules capsules as the peg-containing plates rotate in and out of the 3. Beads gelatin bath. 4. Tablets A manufacturer also may prepare distinctive-looking capsules by 5. Caplets altering the usual rounded shape of the capsule-making pegs. // by 6. Pastes tapering Considerations in selecting the capsule size: The Manufacture of Hard Gelatin: Capsule Shells 1. Dose of the active ingredient Coni-snap 2. Density of powder Coni-snap Supro 3. Compaction characteristics (capsule-filling machine) Snap-fit 4. Hard gelatin capsules are used to encapsulate about 65 Spansule capsule mg to 1 gram of powdered material. Selecting the capsule size *capsules and tablets also may be imprinted with the names or Step 1: Weigh the ingredients for the required number of capsules to monograms of the manufacturer. be prepared Step 2: Place the powders in a graduated cylinder CAPSULE SIZES Step 3: Obtain the volume occupied by the powders Are manufactured in various lengths, diameters and capacities. Step 4: Divide the volume by the number of capsules to be The size selected for use is determined by the amount of fill prepared material to be encapsulated. Step 5: This provides the volume that will be occupied by the The density and compressibility of the fill will largely determine to powder for each capsule what extent it may be packed into a capsule shell (fig. 7.6) Step 6: Compare this volume (in mL) with the appropriate line Of For estimation, a comparison may be made with powders of well- table 7.1 known features (fig. 7.1) and an initial judgment is made as to the approximated capsule size needed to hold a specific amount of Capsule Sizes material. Example: However, the final determination may be largely the result of trial Ferrous Sulfate - 200 mg x 5 capsules = 1000 mg and error Lactose - 350 mg x 5 capsules = 1750 mg Preparation of Filled Hard Gelatin Capsules: Large-scale/small-scale Total weight: 2750 mg or 2.76 grams Step 1: Developing and preparing the formulation and selecting the 2 ml ÷ 5 capsules = 0.4 mL capsule size Filling hard capsule shells Step 2: Filling the capsule shells Step 3: Capsule sealing (optional) FILLING HARD CAPSULE SHELLS Step 4: Cleaning and polishing the filled capsules PUNCH The amount of powder packed into a capsule Developing the formulation and selecting the capsule size METHOD depends on the degree of compression, the Active and inactive components must be blended thoroughly to pharmacist should punch each capsule in the ensure a uniform powder mix for the fill same manner and weigh the product after DILUENT (FILLER) capping. may be added to produce the proper capsule volume. Capsules should be prepared and weighed o Examples: lactose, microcrystalline cellulose, starch periodically to check the uniformity of the process. o In addition to providing bulk, these materials often Such weighings protect against uneven filling of provide cohesion to the powders, which is beneficial capsules in the transfer of the powder blend into capsule shells. DISINTEGRANTS CAPSULE Hand-operated filling machine FILLING Have capacities ranging from 24-300 capsules are frequently included in a capsule formulation to assist MACHINE and when efficiently operated are capable of breakup and distribution of the capsule's contents in the (FETON) producing about 200-2000 capsules per hour stomach OSAKA Industrial use o Examples: pregelatinized starch, croscarmellose, and AUTOMATIC Automatically separate the caps from empty sodium starch glycolate CAPSULE capsules, fill the bodies, scrape off excess powder, o Note: to achieve uniform drug distribution, it is FILLER replace the caps, seal the capsules as desired advantageous if the density and particle size of the MODEL 165,000 capsules per hour drug and nondrug components are similar. Particle size may be reduced by milling to produce particles ranging from about 50 to 1000 microns.  Capsule sealing Do not impair the product's bioavailability, Manufacturers make distinctive-looking capsules by sealing therapeutic efficacy, or safety. them with a: Do not interfere with requisite compendial o Colored band of gelatin (Kapseals, Parke-Davis) assays and tests o Heat-welding process - fuses the capsule cap CONTAINERS Tight, well-closed, light resistant, and/or through the double wall thickness at their juncture FOR DISPENSING combination of these. o Usage of a liquid wetting agent that lowers the CAPSULES melting point in the contact areas of the DISSOLUTION Equipment used: capsule's cap and body and then thermally TEST Speed stirrer motor bonds the two parts using low temperatures. A cylindrical stainless steel basket on a stirrer shaft Finishing of capsules A 1 Liter vessel of glass fitted with a FINISHING OF CAPSULE cover CLOTH capsules are rubbed with cloth A water bath to maintain the DUSTING temperature of the dissolution POLISHING Accela-Cota pan is used to dust and polish using a medium in the vessel polyurethane cloth DISINTEGRATION Capsules are placed in a basket racket BRUSHING Capsules are feed under soft rotating brush. TEST assembly FIGURE 7.15 Cleaning and polishing hard-filled Immersed 30 times per minute in a capsules using the Accela-Cota apparatus. thermostatically controlled fluid (37c) (Courtesy of ElI Lilly and Company.) Observed over time The capsules should disintegrate completely Soft Gelatin Capsules into a mass having no palpably firm core Are made of gelatin to which glycerin or a polyhydric alcohol such as sorbitol has been added. WEIGHT Hard Capsules VARIATION Soft Capsules Contain more moisture than hard capsules, may have a preservative such as HARD CAPSULES 10 capsules are individually weighed and They may be single colored or two toned and may be imprinted their contents removed. Emptied shells are with identifying markings. individually weighed, and the net weight of They may be prepared with opacifiers the contents is calculated by subtraction. Are used to encapsulate and hermetically seal liquids, suspensions, SOFT CAPSULES Gross weight of 10 capsules is determined pasty materials, dry powders, and even preformed tablets. individually; then each capsule is cut open, Are pharmaceutically elegant and easily swallowed. and the contents are removed by washing with a suitable solvent. Soft Gelatin Capsules Preparation The solvent is allowed to evaporate at room 1. Plate process - using a set of molds to form the capsules temperature over about 30 minutes. Step 1: a warm sheet of plain or colored gelatin is placed on the The individual shells are weighed and the bottom plate of the mold and the medication containing liquid net contents calculated. evenly poured into it. CONTENT Unless otherwise stated in the USP Step 2: second sheet of gelatin is carefully placed on top plate of UNIFORMITY monograph, the amount of active ingredient, the medication, and top plate of the mold is put into place determined by assay, is within the range of Step 3: pressure is then applied to the mold to form, fill and seal the 85%-115% of the label claim for 9 of 10 dosage capsules simultaneously. units assayed, with no unit outside the range Step 4: the capsules are removed and washed with a solvent of 70% to 125% of the label claim harmless to the capsules. STABILITY Stability of the active drug under the 2. Rotary Die Process (Robert P. Scherer in 1933) TESTING influence of environmental factors such as Liquid gelatin flowing from an overhead tank is formed into two Temperature, humidity, light, continuous ribbons by the rotary die machine and brought together container, and closure system between two rotating dies where the capsule are simultaneously MOISTURE The degree and rate of moisture penetration filled, shaped, hermetically sealed and cut from the gelatin ribbon. PERMEATION are determined by: 3. Reciprocating Die Process TEST Packaging the dosage unit together with a Similar to rotary die process in that ribbons of gelatin are formed color-revealing desiccant pellet and used to encapsulate the fill, but it differs in the actual Exposing the packaged unit to known encapsulating process. relative humidity over a specified time The gelatin ribbons are fed between a set of vertical dies that Observing the desiccant pellet for color continually open and close to form rows of pockets in the gelatin change (indicating the absorption of ribbons. moisture) These pockets are filled with the medication and are sealed, Advantages vs. Disadvantages of Capsules Advantage: shaped and cut out of the film. ADVANTAGES DISADVANTAGES As the capsules are cut from the ribbons, they fall into refrigerated Ease of use (easy to swallow) It may not be suitable for high- tanks that prevent the capsules from adhering to one another. Suitable for substances dose drugs Use of Soft Gelatin Capsules having bitter taste and When compared to tablets, the Soft gelatin capsules are prepared to contain a variety of liquid, unpleasant odor production speed is slower paste, and dry fills. Fewer excipients are required Not appropriate for highly than tablets efflorescent substances Water-immiscible volatile and nonvolatile liquids: vegetable and A high degree of flexibility to More costly in production aromatic oils, aromatic and aliphatic hydrocarbons, chlorinated the formulation compared to tablets hydrocarbons, ethers, esters, alcohols, and organic acids Economical than other Materials reactive with gelatin Water-miscible nonvolatile liquids, such as polyethylene glycols, dosage forms cannot be dispensed and nonionic surface-active agents, such as polysorbate 80 The gelatin shell can give Large and crystal shape Water-miscible and relatively nonvolatile compounds such as protection of the drug from powders cannot be dispensed in propylene glycol and isopropyl alcohol, depending on factors light capsules such as concentration used and packaging conditions. A high degree of flexibility to COMPENDIAL REQUIREMENTS FOR CAPSULES the formulation ADDED Are harmless in the quantities used SUBSTANCES Do not exceed the minimum amounts OR EXCIPIENTS required to provide their intended effect