SOLUTIONS-notes-10

SOLUTIONS-notes-10 - 10/11/2010 SOLUTIONS LIQUID DOSAGE...

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Unformatted text preview: 10/11/2010 SOLUTIONS LIQUID DOSAGE FORMS Solutions • USP 23: liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed in a suitable solvent or mixture of mutually miscible solvents. TEIXEIRA SOLUTIONS: classification • By route of administration – – – – – – – – – ORAL TOPICAL Vaginal = douches g Rectal = enemas OTIC NASAL OPHTHALMIC IRRIGATING PARENTERAL TEIXEIRA SOLUTIONS: classification • By type of solvent – AQUEOUS • Oral solutions • Syrups • Aromatic waters – NON-AQUEOUS • • • • Elixirs Tinctures Spirits Other: fluid-extract, collodion, liniment, oleaginous solutions TEIXEIRA 1 10/11/2010 SOLUTIONS • ADVANTAGES SOLUTIONS • DISADVANTAGES – Homogeneous doses – Immediate availability for absorption – Most routes of admin admin. – Pt. can’t swallow tablets/caps – Easy dose adjustment – Enteral feeding – Nursing home, psychiatric & incarcerated patients – Less stability than dry form – Solubility in acceptable solvents – Taste + smell: additives – Bulk and weight of package – Bulk containers: dosage measurement errors TEIXEIRA TEIXEIRA SOLUTIONS: compounding principles SOLUTIONS: preparation principles • Comminution • • • • • Solubility of chemical(s) in solvent(s) Time to dissolve Chemical(s) t in l ti Ch i l( ) stay i solution Stability of chemical(s) in solution Preservation – Trituration – Micronization • • • • Viscosity o so e (s) scos y of solvent(s) Solubilizing agent: levigation Agitation: stirrer, shaker, sonicator Temperature – Hot plate – Thermostatically-controlled mixing tanks TEIXEIRA TEIXEIRA 2 10/11/2010 Solubility: “like dissolves Solubility: “like dissolves like” like” • • SOLIDS MISCIBILITY OF LIQUIDS – Oil + water = immiscible – Miscibility not always easily predicted: consult references – Inorganic compounds: high water solubility – Organic compounds (weak acids or weak bases): solubility depends on pH of solvent – Salts of organic compounds: high water solubility – Heating of solvent: may cause precipitation – Cosolvent system – Volatile substances • Merck Index, Remington, USP DI, vol. III H2O + alcohol = OK Glycerin + H2O = OK Glycerin + alcohol = OK Alcohol + Mineral oil = no Alcohol + castor oil = OK (50/50) Cottonseed oil + mineral oil = OK Castor oil + mineral oil = no TEIXEIRA SOLUTIONS: components • • TEIXEIRA Solvents for liquid preparations Drug(s) Pharmaceutic ingredients (excipients): Ch.4 – – – – – – – Solvents (vehicles) Sweeteners Flavorants/Odorants (oral, topical) Colorants (oral) Preservatives Buffers Stabilizers TEIXEIRA • • • • • • • • • • • • Purified water, USP Water for injection, USP Sterile Water for Injection, USP Bacteriostatic water for injection, USP Alcohol, USP (Ethyl alcohol, Ethanol): 94.9-96% (v/v) Dehydrated alcohol, USP: 99.5% (v/v); 200 proof Diluted alcohol, NF: 49% (v/v) ethanol Rubbing alcohol: 70% (v/v) ethanol + denaturants Isopropyl rubbing alcohol: 70%(v/v) isopropanol Glycerin (Glycerol), USP Propylene glycol, USP Vegetable Oils, USP/NF TEIXEIRA 3 10/11/2010 Sweeteners (sweetening agents) • sweetness and viscosity • GRAS list (generally recognized as safe) x 1958 Food Additives Amendment • CLASSIFICATION • GLYCOGENETIC: nutritive sweeteners; converted to glucose in the body – Sugars • Sucrose: sugar (cane, beets, carrots); agave nectar ( glycemic index), fruits • Dextrose (D-glucose): L-glucose is salty • Fructose (levulose) – Non-sugars (polyols /sugar alcohols) • Sorbitol (sorbitol sol. = 64% (w/w) • Glycerin • Gropylene glycol • Mannitol • Xylitol: 30% fewer calories than sugar; anti-cavity (teeth) TEIXEIRA Sweeteners • NON-GLYCOGENETIC (cont.) – Artificial (cont.) • Acesulfame Potassium (Sunett®): approved in 1998, structurally similar to saccharin, 130 x sweeter than sucrose, unmetabolized; some heat sucrose stability. • Sucralose (Splenda®): approved in 1998-2000; modified sucrose; unmetabolized; 600 x sweeter than sucrose; heat-stable. • Neotame: 2002; aspartame analog; also flavor enhancer; 30-60x sweeter than aspartame; amounts of phenylalanine; not available in USA TEIXEIRA Sweeteners • NON-GLYCOGENETIC: non-nutritive, non-caloric sweeteners, sugar-substitutes. – Natural: not hydrolyzed and not absorbed • methylcellulose • hydroxyethyl cellulose • Stevia: natural, 30x sweeter than sucrose; heat stable – Artificial: 1950 s diet soft drinks 1950’s • Saccharin (Sweet’n Low®): restricted use since 1977 (cancer in animals); un-metabolized; heat stable. • Cyclamate: banned in 1969; metabolized; carcinogenicity & teratogenicity • Aspartame (Equal®, NutraSweet®): 1973 – 3 metabolites: phenylalanine, aspartic acid, methanol – PKU : hyperphenylalaninemia & phenoketonuria – heat-labile TEIXEIRA Flavorants / Flavorings • 10,000 taste buds (tongue, roof of the mouth, cheeks and throat) = 60-100 receptor cells each. • Taste: complex blend of flavor, smell, texture, temperature and color • Patients expect: – psychogenic balance with color – immediate flavor identification and development – acceptable mouth feel – brief aftertaste – no undesirable sensations • Age preferences: – Children: sweet, fruity (berries), candy-like – Adults: less sweet, tart, sour, citrus, cocoa TEIXEIRA 4 10/11/2010 Flavorants / Flavorings Tastes to mask & suggested flavorings • Synthetic (artificial) • Natural (e.g. volatile oils, vanillin) • Spice: aromatic vegetable substance (food seasoning) → • SWEET BITTER → → • • → → • METALLIC – Flavorants are water- soluble/oil-soluble liquids or dry powders diluted in carriers SALTY SOUR/ACID OILY • Prediction of a drug’s taste is speculative → • – Usual taste: • Low MW salts are salty • High MW salts are bitter • Organic compounds – more -OH = sweeter – esters, alcohols and aldehydes: pleasant (volatile = odor) • Addition of flavors – Rule of thumb: “always possible to add more and too late to remove it” • Cinnamon, raspberry, orange, maple, butterscotch. glycyrrhiza (licorice) Fruit, berry, vanilla Cocoa, chocolate, mint, menthol, cherry, walnut, raspberry, tutti frutti, glycyrrhiza (licorice) Fruit, citrus, cherry Wintergreen, peppermint oil, lemon, anise Mint, marshmallow TEIXEIRA TEIXEIRA Drug Classes and Suggested Flavorings COLORANTS (dyes, lakes) DRUG CLASS FLAVOR Antibiotics Cherry, maple, pineapple, orange, y coconut-custard, strawberry-vanilla, banana-pineapple Antihistamines Apricot, cherry, cinnamon, grape, honey, lime, peach-orange, root beer Barbiturates Banana-pineapple, banana-vanilla, cinnamon-peppermint, grenadinestrawberry, lime, root beer Decongestants and Expectorants Anise, apricot, butterscotch, cherry, grenadine-peach, strawberry, lemon, maple, orange, coriander, tangerine Electrolytes and geriatric solutions Cherry, grape, lemon-lime, raspberry, lime, TEIXEIRA root beer, strawberry • Enhance the appeal of a dosage form • Psychogenic balance with flavor: liquids • Agents with inherent color: – Sulfur and riboflavin = yellow – cupric sulfate = blue – cyanocobalamine = red b l i d • Natural: mineral (red ferric oxide + zinc oxide = calamine pink color) • Synthetic: 90% from aniline (derivative of benzene) • Permitted • Certified: FD&C, D&C, external D&C TEIXEIRA 5 10/11/2010 PRESERVATIVES COLORANTS (dyes, lakes) • Studied for toxicity, carcinogenesis, and safety • FD&C red #2, #4: external application • FD&C yellow #5: tartrazine = must be listed on labels of foods; allergies to aspirin • Liquid dyes and lakes • ANTIMICROBIAL/ANTIFUNGAL: – – – – Long-term stability of dosage forms containing water Refrigeration Sterility: ophthalmics and injectables Medicated syrups: 0 1-0 2% benzoic acid or sodium 0.1 0.2% benzoate; 0.1% mixture of parabens. – Syrup, NF (simple syrup): self-preserved (85% sucrose in 100 mL solution). – 15% alcohol in acid media and 18% in alkaline media – Flavoring oils (Thymol, Cresol) and Sweeteners (glycerin, propylene glycol): have inherent antimicrobial activity. – pigments adsorbed t or precipitated i aluminum i t d b d to i it t d in l i hydroxide medium • Selection must consider: – – – – – water or oil solubility pH of preparation stability of other formulative ingredients dye chemical stability photo-stability TEIXEIRA PRESERVATIVES – Mode of Action: interference with microbial growth, multiplication and/or metabolism. – Free water: • water in a preparation that is not bound to other molecules; l l • determines the effective concentration of a preservative required for a given liquid (waterbased) formulation. TEIXEIRA PRESERVATIVES: classification • ALCOHOLS AND GLYCOLS: used mostly for oral and topical dosage forms – Ethyl alcohol • • – Propylene glycol • – preserves an equivalent quantity of volume Benzyl alcohol • • • • TEIXEIRA similar properties to ethyl alcohol Glycerin (glycerol) • – Alcohol, USP, 95-96% v/v Used at 15-17.5% of the free water present in the preparation to be effective bactericidal at 1-2% of total solution sharp, burning taste: approved for oral topical and parenteral dosage forms effectiveness not affected by the pH of the solution TEIXEIRA 6 10/11/2010 PRESERVATIVES: classification PRESERVATIVES: classification • PARABENS • ORGANIC ACIDS • • • • – Benzoic acid, Na benzoate, K benzoate • • effective concentration is 0.1-0.3% topical (including ophthalmics) and parenteral dosage forms. – Sorbic acid, Potassium sorbate • • • • • effective concentration is 0.05-0.2% highly irritating to the skin used for oral dosage forms and ophthalmics. – Methyl-paraben, Methyl-paraben sodium – Propyl-paraben – Butyl-paraben TEIXEIRA TEIXEIRA PRESERVATIVES: classification • MERCURIAL DERIVATIVES • • PRESERVATIVES: classification • effective conc. for topical products = 0.002-0.01% 0.004% = maximum conc. for eye and parenteral – Thimerosal • • • Effective conc. 0.001-0.04% max for ophth. = 0.01% max for parenteral =0.04%. TEIXEIRA SALTS OF QUATERNARY AMMONIUM BASES • • • may be sensitizing and cause allergies used for topical products (nasal and ophthalmic) and parenterals – – Phenylmercuric nitrate (PMN) & Phenylmercuric acetate (PMA) • • esters and salts of p-hydroxybenzoic acid used individually or in mixtures, up to 0.1% most effective against fungi for all kinds of dosage forms , including ophthalmics irritating to broken skin. tend to partition in presence of some flavoring oils – – • may be sensitizing and cause allergies topical products (nasal and ophthalmic), parenterals; causes many chemical incompatibilities. Benzalkonium chloride: effective conc.is 0.004-0.02%, max for ophth. = 0.013% Benzethonium chloride: effective conc.is 0 01-0 02% conc is 0.01-0.02%, max for ophth. = 0.01% Cetylpyridinium chloride: effective conc.is 0.01-0.02% CHLOROBUTANOL: • • • • ophthalmic and parenteral products stable only at acid pH effective conc. = 0.5% not used for oral products (camphor-like odor and taste) TEIXEIRA 7 10/11/2010 Free water: calculation Free water: calculation Considering that alcohol is used at 15-17.5% of the free water present in the preparation to be effective, check the preservation of Mineral Oil Emulsion, USP Mineral oil ------------------------ 500 mL Acacia ----------------------------- 125 g Syrup ------------------------------ 100 mL Vanillin ----------------------------- 40 mg Alcohol, Alcohol USP ---------------------- 60 mL Purified water------- ad q.s.---- 1000 mL SOLUTION: Add volumes of ingredients that contain no water or that are already preserved Mineral oil has no water = 500 mL Solids (acacia & vanillin) occupy = 40 mL (added to a cylinder) 100 mL syrup = 85g sucrose in 100 mL solution (sp.gr. = 1.313) 100 mL x 1.313 g/mL = 131.3 g (total sol.) 131.3 g – 85 g = 46.3 g = 46.3 mL of water • (Cont.) SOLUTION Mineral oil ----------------------------- 500 mL Acacia ----------------------------- 125 g Syrup ------------------------------ 100 mL Vanillin ----------------------------- 40 mg Alcohol, USP ---------------------- 60 mL Purified water------- ad q.s.---- 1000 mL Sucrose occupies a volume of: 100 mL – 46 3 mL = 53 7 mL 46.3 53.7 The quantity of ethanol (alcohol 95%) in this product is: 60 mL x 95% = 57 mL Volume taken care of so far: 500 + 40 + 46.3 + 53.7 + 57 = 697 mL Quantity of free water remaining: 1000 – 697 = 303 mL, to be preserved with alcohol 57 mL/303 mL x 100% = 18.8% Conclusion: This prescription is properly preserved. TEIXEIRA TEIXEIRA Dry Mixtures for Solution Topical solutions & tinctures • Insufficient stability in aqueous medium to meet extended shelf-life • Dry powder/granule for reconstitution –L Lyophilization or spray-drying hili ti d i – Reconstitution with appropriate diluent – Refrigeration after reconstitution:7-14 days – Discard remaining solution TEIXEIRA • Topical tincture – – – – – – Solution with hydroalcoholic or alcoholic vehicle Simple solution of chemicals or vegetable materials Maceration (or Percolation) May contain 15-80% alcohol: self-preserved y p May contain a dye Dispensed in small volumes • Glass or plastic bottles with applicator tip • Plastic squeeze bottles: drops – iodine tincture, thimerosal tincture (anti-infectives) – compound benzoin tincture [protectant for bedsores or inhalant (vaporizer) for bronchitis]. TEIXEIRA 8 10/11/2010 Sprays • Aqueous or oleaginous solutions – – – – Coarse droplets Finely divided solids Nasopharyngeal: halitosis, sore throat Skin: antiseptics, local anesthetics anti fungals etc antiseptics anesthetics, anti-fungals, • Mechanical devices – – – – – VAGINAL & RECTAL SOLUTIONS • DOUCHES – solutions prepared from powders – solutions – feminine hygiene or with anti-infective agents, for local action. l l ti • ENEMAS Break up solution into small particle Facilitate spraying of powders Spray bottles One-way pumps Atomizer TEIXEIRA – rectal liquid preparations – Retention: for local effect (e.g. hydrocortisone) or for systemic effect (e.g. aminophylline). – Evacuation: to cleanse the bowel (e.g. Fleet®) TEIXEIRA 9 ...
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