COURSE: PHARMACEUTICS-IIA (Dosage Forms Science) COURSE CODE: PD201 REFERENCE BOOKS: LV, Popovich NG. Ansel’s Pharmaceutical dosage forms and drug delivery systems.INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS Drug substances are seldom administered alone; rather they are given as part of a formulation in combination with one or more nonmedicinal agents that serve varied and specialized pharmaceutical functions. these nonmedicinal agents, referred to as pharmaceutical ingredients or excipients. Selective use of these nonmedicinal agents produces dosage forms of various types. The pharmaceutical ingredients, solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, color, * flavor, and * fashion medicinal agents * into efficacious and appealing dosage forms.Each type of dosage form is unique in: its physical and pharmaceutical characteristics. These varied preparations provide the manufacturing and compounding pharmacist with the challenges of formulation and the physician with the choice of drug and delivery system to prescribe. The general area of study concerned with: the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms is termed pharmaceutics.The proper design and formulation of a dosage form requires consideration of: the physical, chemical, and biologic characteristics of all of the drug substances and pharmaceutical ingredients to be used in fabricating the product. The drug and pharmaceutical materials must be compatible with one another to produce a drug product that is stable, efficacious, attractive, easy to administer, and safe.* The product should be manufactured with: * appropriate measures of quality control * and packaged in containers that keep the product stable. * The product should be labeled: * to promote correct use * and be stored under conditions that contribute to maximum shelf life. THE NEED FOR DOSAGE FORMS * The potent nature and low dosage of most of the drugs in use today * precludes any expectation * that the general public could safely obtain * the appropriate dose of a drug from the bulk material.Most drug substances are administered in milligram quantities, much too small to be weighed on anything but a sensitive prescription or electronic analytical balance. For instance, how could the lay person accurately obtain from a bulk supply the 325 mg of aspirin found in the common tablet? Not possible. Yet compared with many other drugs, the dose of aspirin is formidable. For example, the dose of ethinyl estradiol, 0.05 mg, is 1/6,500 the amount of aspirin in an aspirin tablet. To put it another way, 6,500 ethinyl estradiol tablets, each containing 0.05 mg of drug, could be made from an amount of ethinyl estradiol equal to the amount of aspirin in just one standard tablet.When the dose of the drug is minute, as with ethinyl estradiol, solid dosage forms such as tablets and capsules must be prepared with fillers or diluents so that the dosage unit is large enough to pick up with the fingertips. Besides providing the mechanism for the safe and convenient delivery of accurate dosage, dosage forms are needed for additional reasons: To protect the drug substance from the destructive influences of atmospheric oxygen or humidity. e.g. coated tablets, sealed ampules To protect the drug substance from the destructive influence of gastric acid after oral administration e.g. enteric-coated tablets. To conceal the bitter, salty, or offensive taste or odor of a drug substance e.g. capsules, coated tablets, flavored syrups. To provide liquid preparations of substances that are either insoluble or unstable in the desired vehicle e.g. suspensions. To provide clear liquid dosage forms of substances e.g. syrups, solutions.6. To provide rate-controlled drug action e.g. various controlled- release tablets, capsules, and suspensions. 7. To provide optimal drug action from topical administration sites. e.g. ointments, creams, transdermal patches, and ophthalmic, ear, and nasal preparations. 8. To provide for insertion of a drug into one of the body’s orifices e.g. rectal or vaginal suppositories. 9. To provide for placement of drugs directly in the bloodstream or body tissues. e.g. injections. 10. To provide for optimal drug action through inhalation therapy. e.g. inhalants and inhalation aerosols.GENERAL CONSIDERATIONS IN DOSAGE FORM DESIGN Before formulating a drug substance into a dosage form, the desired product type must be determined insofar as possible to establish the framework for product development. Then, various initial formulations of the product are developed and examined for desired features (e.g., drug release profile, bioavailability, clinical effectiveness) and for pilot plant studies and production scale-up. The formulation that best meets the goals for the product is selected to be its master formula. Each batch of product subsequently prepared must meet the specifications established in the master formula. There are many different forms into which a medicinal agent may be placed for the convenient and efficacious treatment of disease. Most commonly, a manufacturer prepares a drug substance in several dosage forms and strengths for the efficacious and convenient treatment of disease. Before a medicinal agent is formulated into one or more dosage forms, among the factors considered are such therapeutic matters as the nature of the illness, the manner in which it is treated (locally or through systemic action), and the age and anticipated condition of the patient.* If the medication is intended for systemic use and oral administration is desired, tablets and/or capsules are usually prepared because they are easily handled by the patient and are most convenient in the self- administration of medication. If a drug substance has application in an emergency in which the patient may be comatose or unable to take oral medication, an injectable form of the medication may also be prepared. Many other examples of therapeutic situations affecting dosage form design could be cited, including motion sickness, nausea, and vomiting, for which tablets and skin patches are used for prevention and suppositories and injections for treatment. The age of the intended patient also plays a role in dosage form design. For infants and children younger than 5 years of age, pharmaceutical liquids rather than solid forms are preferred for oral administration. These liquids, which are flavored aqueous solutions, syrups, or suspensions, are usually administered directly into the infant’s or child’s mouth by drop, spoon, or oral dispenser or incorporated into the child’s food. A single liquid pediatric preparation may be used for infants and children of all ages, with the dose of the drug varied by the volume administered.* When a young patient has a productive cough or is vomiting, gagging, or simply rebellious, there may be some question as to how much of the medicine administered is actually swallowed and how much is expectorated. In such instances, injections may be required. Infant-size rectal suppositories may also be employed, although drug absorption from the rectum is often erratic. During childhood and even adulthood, a person may have difficulty swallowing solid dosage forms, especially uncoated tablets. For this reason, some medications are formulated as chewable tablets. Many of these tablets are comparable in texture to an after-dinner mint and breakdown into a pleasant-tasting creamy material. Newly available tablets dissolve in the mouth in about 10 to 15 seconds. * This allows the patient to take a tablet but actually swallow a liquid.* Capsules have been found by many to be more easily swallowed than whole tablets. If a capsule is moistened in the mouth before it is swallowed, it becomes slippery and readily slides down the throat with water. Also, a teaspoonful of gelatin dessert, liquid candy, or syrup placed in the mouth and partially swallowed before placing the solid dosage form in the mouth aids in swallowing them. Also, if a person has difficulty swallowing a capsule, the contents may be emptied into a spoon, mixed with jam, honey, or other similar food to mask the taste of the medication and swallowed. Medications intended for the elderly are commonly formulated into oral liquids or may be extemporaneously prepared into an oral liquid by the pharmacist. However, certain tablets and capsules that are designed for controlled release should not be crushed or chewed, because that would interfere with their integrity and intended performance.* Many patients, particularly the elderly, take multiple medications daily. * The more distinctive the size, shape, and color of solid dosage forms, the easier is proper identification of the medications. * Errors in taking medications among the elderly occur frequently because of their multiple drug therapy and impaired eyesight. * Dosage forms that allow reduced frequency of administration without sacrifice of efficiency are particularly advantageous. * In dealing with the problem of formulating a drug substance into a proper dosage form, research pharmacists employ knowledge gained through experience with other chemically similar drugs and through the proper use of the physical, chemical, biologic, and pharmaceutical sciences. * The early stages of any new formulation include studies to collect basic information on the physical and chemical characteristics of the drug substance. * These basic studies are the reformulation work needed before actual product formulation begins. 1PHARMACEUTICAL INGREDIENTS 1. Acidifying agent: Used in liquid preparations to provide acidic medium for product stability. Examples: Citric acid Acetic acid Fumaric acid Hydrochloric acid Nitric acid . Alkal ing agent: Used in liquid preparations to provide alkaline medium for product stability. Examples: Ammonia solution Ammonium carbonate Diethanolamine Monoethanolamine Potassium hydroxide Sodium bicarbonate Sodium borate Sodium carbonate Sodium hydroxide Trolamine eNeeeeee3. Adsorbent: * An agent capable of holding other molecules onto its surface by physical or chemical (chemisorption) means. * Examples: * Powdered cellulose * Activated charcoal 4. Aerosol propellant: * Agent responsible for developing the pressure within an aerosol container and expelling the product when the valve is opened. * Examples: * Carbon dioxide * Dichlorodifluoromethane * Dichlorotetrafluoroethane * Trichloromonofluoromethane 5. Air displacement: * Agent employed to displace air in a hermetically sealed container to enhance product stability. * Examples: * Nitrogen * Carbon dioxide 16. Antifungal preservative: * Used in liquid and semisolid preparations to prevent growth of fungi. Effectiveness of parabens is usually enhanced by use in combination. Examples: Butylparaben Ethylparaben Methylparaben Benzoic acid Propylparaben * Sodium benzoate * Sodium propionate 7. Antimicrobial preservative: * Used in liquid and semisolid preparations to prevent growth of microorganisms. * Examples: * Benzalkonium chloride 18. Antioxidant: * Used to prevent deterioration of preparations by oxidation. * Examples: * Ascorbic acid * Ascorbyl palmitate * Butylated hydroxyanisole * Butylated hydroxytoluene * Hypophosphorous acid * Monothioglycerol * Propyl gallate * Sodium ascorbate * Sodium bisulfite * Sodium formaldehyde * Sulfoxylate * Sodium metabisulfite9. Buffering agent: * Used to resist change in pH upon dilution or addition of acid or alkali. ¢ Examples: * Potassium metaphosphate * Potassium phosphate, monobasic * Sodium acetate * Sodium citrate, anhydrous and dihydrate 10. Chelating agent: * Substance that forms stable water-soluble complexes (chelates) with metals; used in some liquid pharmaceuticals as stabilizers to complex heavy metals that might promote instability. * In such use, they are also called sequestering agents. * Examples: * Edetic acid * Edetate disodium11. Colorant Used to impart color to liquid and solid (e.g., tablets and capsules) preparations. Examples: FD&C Red No. 3 FD&C Red No. 20 FD&C Yellow No. 6 FD&C Blue No. 2 D&C Green No. 5 D&C Orange No. 5 D&C Red No. 8 Caramel Ferric oxide, red12. Clarifying agent * Used as a filtering aid for its adsorbent qualities. * Examples: * Bentonite 13. Emulsifying agent Used to promote and maintain dispersion of finely subdivided particles of liquid in a vehicle in which it is immiscible. End product may be a liquid emulsion or semisolid emulsion (e.g., a cream). Examples: Acacia Cetomacrogol Cetyl alcohol Glyceryl monostearate Sorbitan monooleate Polyoxyethylene 50 stearate14. Encapsulating agent * Used to form thin shells to enclose a drug for ease of administration. ¢ Examples: * Gelatin 15. Flavorant Used to impart a pleasant flavor and often odor to a preparation. In addition to the natural flavorants listed, many synthetic ones are used. Examples: Anise oil Cinnamon oil Cocoa Menthol Orange oil Peppermint oil * Vanillin16. Humectant * Used to prevent drying of preparations, particularly ointments and creams. * Examples: * Glycerin * Propylene glycol * Sorbitol 17. Levigating agent * Liquid used as an intervening agent to reduce the particle size of a powder by grinding, usually in a mortar. * Examples: * Mineral oil * Glycerin * Propylene glycol 18. Ointment base Semisolid vehicle for medicated ointments. Examples: Lanolin Hydrophilic ointment Polyethylene glycol ointment Petrolatum Hydrophilic petrolatum White ointment Yellow ointment Rose water ointment19. Plasticizer * Component of film-coating solutions to make film more pliable, enhance spread of coat over tablets, beads, and granules. + Examples: * Diethyl phthalate * Glycerin 20. Solvent Used to dissolve another substance in preparation of a solution; may be aqueous or not (e.g., oleaginous). Cosolvents, such as water and alcohol (hydroalcoholic) and water and glycerin, may be used when needed. Sterile solvents are used in certain preparations (e.g., injections). Examples: Alcohol Corn oil Cottonseed oil Glycerin Isopropyl alcohol Mineral oil Oleic acid Peanut oil Purified water Water for injection Sterile water for injection Sterile water for irrigation21. Stiffening agent * Used to increase thickness or hardness of a preparation, usually an ointment. Examples: Cetyl alcohol Cetyl esters wax Microcrystalline wax Paraffin * Stearyl alcohol * White wax * Yellow wax 22. Suppository base * Vehicle for suppositories. * Examples: * Cocoa butter * Polyethylene glycols (mixtures) * PEG 335023. Surfactant (surface active agent) * Substances that absorb to surfaces or interfaces to reduce surface or interfacial tension. May be used as wetting agents, detergents, or emulsifying agents. Examples: Benzalkonium chloride Nonoxynol 10 Octoxynol 9 Polysorbate 80 * Sodium lauryl sulfate * Sorbitan monopalmitate24. Suspending agent * Viscosity-increasing agent used to reduce sedimentation rate of particles in a vehicle in which they are not soluble. Suspension may be formulated for oral, parenteral, ophthalmic, topical, or other route. Examples: ° Agar Bentonite Carbomer (e.g., Carbopol) Carboxymethylcellulose sodium Hydroxyethyl cellulose Hydroxypropyl cellulose Hydroxypropyl methylcellulose Kaolin Methylcellulose * Tragacanth ° Veegum25. Sweetening agent * Used to impart sweetness to a preparation. * Examples: * Aspartame * Dextrose * Glycerin * Mannitol * Saccharin sodium * Sorbitol * Sucrose 26. Tablet antiadherents * Prevent tablet ingredients from sticking to punches and dies during production. * Examples: * Magnesium stearate27. Tablet binders Substances used to cause adhesion of powder particles in tablet granulations. Examples: Acacia Alginic acid Carboxymethylcellulose sodium Compressible sugar (e.g., Nu-Tab) Ethylcellulose Gelatin Liquid glucose Methylcellulose Povidone Pregelatinized starch 8. Tablet and capsule diluent Inert filler to create desired bulk, flow properties, and compression characteristics of tablets and capsules. Examples: Dibasic calcium phosphate Kaolin Lactose Mannitol Microcrystalline cellulose Powdered cellulose Precipitated calcium carbonate Sorbitol Starch eee ee ew eee ewe29. Tablet coating agent * Used to coat a tablet to protect against decomposition by atmospheric oxygen or humidity, to provide a desired release pattern, to mask taste or odor, or for aesthetic purposes. Coating may be sugar, film, or thick covering around a tablet. Sugar-coated tablets generally start to break up in the stomach. Film forms a thin cover around a formed tablet or bead. Unless it is enteric, film dissolves in the stomach. Enteric coating passes through the stomach to break up in the intestines. Some water-insoluble coatings (e.g., ethylcellulose) are used to slow the release of drug in the gastrointestinal tract. 30. Sugar coating * Examples: * Liquid glucose * Sucrose31. Film coating ¢ Examples: * Hydroxyethyl cellulose ¢ Hydroxypropyl cellulose * Hydroxypropyl methylcellulose * Methylcellulose * (e.g., Methocel) * Ethylcellulose (e.g., Ethocel) 32. Enteric coating * Examples: * Cellulose acetate phthalate * Shellac (35% in alcohol, pharmaceutical glaze)33. Tablet direct compression excipient * Used in direct compression tablet formulations. ¢ Examples: * Dibasic calcium phosphate (e.g., Ditab) 34. Tablet disintegrant * Used in solid forms to promote disruption of the mass into smaller particles more readily dispersed or dissolved. * Examples: * Alginic acid * Polacrilin potassium (e.g., Amberlite) * Sodium alginate * Sodium starch glycolate * Starch 35. Tablet glidant * Used in tablet and capsule formulations to improve flow properties of the powder mixture * Examples: * Colloidal silica * Cornstarch * Talc36. Tablet lubricant * Used in tablet formulations to reduce friction during tablet compression. * Examples: * Calcium stearate * Magnesium stearate * Mineral oil * Stearic acid * Zinc stearate 37. Tablet or capsule opaquant * Used to render a coating opaque. May be used alone or with a colorant. + Examples: * Titanium dioxide 38. Tablet polishing agent * Used to impart an attractive sheen to coated tablets. * Examples: * Carnauba wax * White wax39. Tonicity agent * Used to render solution similar in osmotic-dextrose characteristics to physiologic fluids, e.g., in ophthalmic, parenteral, and irrigation fluids. * Examples: * Sodium chloride 40. Vehicle * Carrying agent used in formulating a variety of liquids for oral and parenteral administration. * Generally, oral liquids are aqueous (e.g., syrups) or hydroalcoholic (e.g., elixirs). * Solutions for intravenous use are aqueous, whereas intramuscular injections may be aqueous or oleaginous. Flavored, sweetened * Examples: * Acacia syrup * Aromatic syrup * Aromatic elixir * Cherry syrup * Cocoa syrup * Orange syrup * SyrupOleaginous * Examples: * Corn oil * Mineral oil * Peanut oil * Sesame oil Sterile * Examples: * Bacteriostatic sodium chloride injection 40. Viscosity-increasing agent * Used to render preparations more resistant to flow. Used in suspensions to deter sedimentation, in ophthalmic solutions to enhance contact time (e.g., methylcellulose), to thicken topical creams, etc. Examples: Alginic acid Bentonite Carbomer Carboxymethylcellulose Sodium Methylcellulose Povidone Sodium alginate Tragacanth