Dosage Form & Drug Delivery System PDF

MODULE 5 PHARMACEUTICS 1 DOSAGE FORM & DRUG DELIVERY SYSTEM DOSAGE FORM & DRUG DELIVERY SYSTEMS USP Classification of Powders I. INTRODUCTION TO DOSAGE FORMS Sieve number no. of square openings per linear inch A. DEFINITION Descriptive Term very coarse coarse moderately coarse fine very fine Dosage...

MODULE 5 PHARMACEUTICS 1 DOSAGE FORM & DRUG DELIVERY SYSTEM DOSAGE FORM & DRUG DELIVERY SYSTEMS USP Classification of Powders I. INTRODUCTION TO DOSAGE FORMS Sieve number no. of square openings per linear inch A. DEFINITION Descriptive Term very coarse coarse moderately coarse fine very fine Dosage Forms Drug products/preparations containing: Active Pharmaceutical Ingredient (API)/ Drug Excipients/ Additives/Adjuncts Drug Delivery System Drug products that allow the uniform release and targeting of drugs into body Drug --> Ron Compounding of Powders ELMUNAE an agent intended for use in diagnosis, cure, treatment, mitigation or prophylaxis in man and other animals affects the structure or any function of the body -> 1. Comminution CNR c. Pulverization by Intervention addition of volatile substance to a gummy material (ex. camphor + alcohol; I2crystals + ether) Cosmetics any substance/preparation intended to be placed in contact with external parts of human body or with teeth and mucous membranes of oral cavity with a view exclusively or mainly to cleaning them, perfuming them, correcting body odors, changing their appearance, protecting them and/or keeping them in good condition 2. Mixing/ Blending a. Trituration mortar and pestle Types of mortar and pestle Glass smooth non-porous surface; for simple admixture; for chemicals that stain Porcelain rough inner surface; for comminution Wedgewood rougher surface; for crystalline substances Food Supplement processed food products that help supplement the diet may contain dietary ingredients such as vitamins, minerals, herbs, amino acids, and other dietary substances make take various forms including those of liquids, capsules, powders, etc., except parenteral b. Spatulation Blending of powders with a spatula on a tile or paper Use: small quantities, non-potent drugs, eutectic mixtures Compounding process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient. c. Sifting Powders are passed through sifters Results in light, fluffy product Not for potent substances B. LOCAL & SYSTEMIC EFFECTS d. Geometric Dilution addition of an equal volume of diluent to a potent substance placed in a mortar Local effects felt in general area of administration common route: topical Step 1: 100mg of potent drug + 100mg of diluent = 200mg of mixture Step 2: 200mg of mixture + 200mg of diluent = 400mg of mixture Step 3: 400mg of mixture + 400mg of diluent = 800mg of mixture Step 4: 800mg of mixture + remaining diluent = 1000mg of mixture Systemic effects occur in tissues distant from the site of contact between the body and the drug drug must enter the bloodstream common route: oral and parenteral e. Tumbling large containers rotated by a motorized process Types of Powders II. SOLID DOSAGE FORMS 1. Bulk Powders A. POWDERS dispensed in large quantities a. Oral Powders dissolved in water prior to use mixtures of finely divided drugs and/ or chemicals in a dry form which may be intended for internal or external use Advantages: rapid dispersion of ingredients flexibility in compounding good chemical stability Disadvantages: inaccuracy of dose not suitable for unpleasant-tasting, deliquescent and hygroscopic drugs Dosage form & Drug Delivery System a. Trituration mortar and pestle b. Levigation forming a paste by the addition of a levigating agent (ex. mineral oil, glycerin) Excipients (aka adjuncts or additives) nontherapeutic ingredients which improve the physical characteristics and efficacy of a drug in a dosage form Role: drugs more appealing and efficacious Use: solubilize, suspend, emulsify, dilute, stabilize, preservatives, color, flavor, etc. Module 5 Sieve Number no. 8 no. 20 no. 40 no. 60 no. 80 b. Dentifrices used to clean and polish teeth contain a soap, mild abrasive and anticariogenic agent c. Dusting Powders locally applied non-toxic powders that have no systemic action d. Douche Powders dissolve in warm water prior to introduction into a body cavity Page 1 of 9 RJAV 2022 e. Insufflations blown into body cavities using an insufflator a. Compressed Tablets formed by compression some are scored f. Trituration dilutions of potent powdered drugs (10% API) b. Multiple Compressed Tablets Layered tablets formed by compressing 2 or 3 layers of formulation against each other (ex. Neozep tablet) Compression coated tablets formed by compressing an outer shell around a tablet core 2. Divided Powders/Chartulae dispensed in individual doses usually in folded papers; block-and-divide method Types of Powder Paper c. Coated Tablets Sugar Coated Tablets coated with sucrose-based solution Film Coated Tablets coated with a thin layer of polymer material Enteric-Coated Tablets remain intact in the stomach but disintegrate in the small intestine a. White Bond Paper opaque paper with no moisture resistance b. Vegetable Parchment thin, semi-opaque, moisture resistant paper 2. Tablets Used in the Oral Cavity c. Glassine Paper glazed transparent moisture-resistant paper a. Chewable Tablets chewed first before swallowing diluent: mannitol and xylitol (ex. Multivitamins, antacids) d. Waxed Paper transparent waterproof paper; suitable for deliquescent and hygroscopic drugs b. Rapidly/ Orally Disintegrating Tablets liquefy on the tongue and then the patients swallow the liquid (ex. Risperidone, Ondansetron) B. GRANULES dry aggregates of powder particles Normal sieve no. 4 to 12 Tablet formulation: sieve no. 12 to 20 c. Buccal Tablets placed in the lining of the cheeks disintegrate slowly (4 hours) (ex. Progesterone) Advantages of Granules over Powder Flow well compared to powders Less tendency to cake or harden More stable to humidity More easily wetted by liquids d. Sublingual Tablets placed under the tongue for systemic absorption disintegrate rapidly (2-3 minutes) (ex. Nitroglycerin, ISDN) Compounding of Granules e. Lozenges solid dosage forms in a hard candy or sugar base that dissolve slowly in mouth for local effect (ex. Strepsils® - dicholorobenzyl alcohol + amylmetacresol) Types: Troches compressed lozenges Pastilles molded lozenges Lollipops lozenges on sticks 1. Wet Granulation addition of granulating fluid or liquid binder most common; 2. Dry Granulation for moisture-sensitive and heat labile materials use compaction/ compression forces 3. Tablets Used to Prepare Solutions 3. Effervescent Granules dissolved in water before use in which CO2 gas is released to mask the unpleasant taste of drug Components: Sodium bicarbonate Citric acid sticky Tartaric acid crumble Preparation: Dry/Fusion Method binder is 1 molecule of water in citric acid Wet Method binder is water + alcohol a. Effervescent Tablets Release CO2 upon dissolution in water ex. Berocca®, Alka-Seltzer® - antacid + pain reliever b. Compounding/ Dispensing Tablets contain a large amount of API used by pharmacists in compounding multiple dosage units no longer use c. Hypodermic Tablets used by physicians to prepare parenteral solutions no longer use C. TABLETS solid dosage forms which are prepared mainly by compression or molding Advantages: uniform content less manufacturing cost easy to package and ship simple to identify most stable of all oral dosage form tamperproof Disadvantages: some drugs resist compression some drugs that require encapsulation prior to compression d. Molded Tablets/ Tablet Triturates prepared by moistening powders and then putting on a triturate mold (may be compressed) results to cylindrical tablets which are very soluble in water D. CAPSULES solid dosage forms in which the drug is enclosed within in either a hard or soft, soluble shell, usually made of gelatin Gelatin partial hydrolysis of collagen from the skin/bones of animals Types: Type A mainly from pork skin; acid processing Type B from bones and animal skins; alkaline processing Vegetable Capsules alternative hydroxypropyl methylcellulose (HPMC) or hard starch Types of Tablets 1. Tablets for Oral Ingestion Module 5 Dosage form & Drug Delivery System Page 2 of 9 RJAV 2022 Plasma concentration 1. Hard Gelatin Capsules dry-filled or two-piece capsules (cap and body) main components: gelatin, sugar and water additives: colorant, opacifying agent (TiO2) + SO2 [0.15%] (to prevent decomposition of gel) moisture content: 12-16% stored at 21-25°C/30-35% RH capsule sizes: (increase capsule size = decrease capacity) Human No. 5 (smallest) No. 000 (largest) Veterinary No 10. No. 12 Other designs: Pulvule tapered at one end Spansule tapered at both ends Controlled Sustained Sustained Time Release Release 3. Repeat Actions contains 2 single doses of a medication (1st dose immediate; 2nd dose delayed) 4. Targeted Release drug release is isolated in a specific body region/ tissue absorption and action Colonic Tablets deliver the drug into the colon without dilution in other regions of GIT Gastro Retentive Tablets remain in the stomach for long period (floating tablets) E. ORAL MODIFIED-RELEASE SOLID DOSAGE FORMS drug release features are based on time, course and locations Advantages: Economic savings Avoid patient compliance problems Reduce fluctuation in drug level (to prolong therapeutic effect to reduce dosing frequency) Minimize or eliminate side effects F. PHARMACEUTICAL INSERTS 1. Suppositories Solid or semisolid masses intended to be inserted into a body orifice for local or systemic effect; they will melt at body temperature or dissolve into aqueous secretions of body cavity Used when oral route is inadvisable Disadvantages Inconvenient Erratic absorption Mechanism of Immediate-Release Formulation MTC Plasma concentration Time Immediate 2. Delayed-Release drug release is other than the time of prompt administration Ex: enteric-coated 2. Soft Gelatin Capsules one-piece capsules used to contains non-aqueous liquids (vitamin e, cod liver oil, digoxin), suspensions, pastes, and dry materials main components: gelatin, plasticizer (glycerin, sorbitol) and preservatives against fungi moisture content: 6-10% no specific sizes Types of suppositories Rectal bullet, torpedo, little finger 2 g (adult) 1 g (children) 32 mm (adult) 16 mm (children) MEC Duration onset Plasma concentration Plasma concentration Types of Capsules: Time AUC 5g 4 g (male) 2 g (female) 140 mm (male) 70 mm (female) varies Time b. Vaginal Indicated for bacterial or fungal infections and HRT May be in the form of tablet, suppository, and semisolids Buffered to pH of 4.5 Types of Modified-Release Dosage Forms 1. Extended-Release provides a prompt desired effect followed by a gradual release of remaining amount Problem: dose dumping Types: Controlled Release zero order Sustained Release first order Module 5 Urethral (Bougies) pencil-like a. Rectal Advantages Low cost and lack of technical difficulties compared to parenteral therapy Partially avoid the first-pass-effect Ex. Bisacodyl Disadvantages Surface area for absorption is smaller Defecation may interrupt absorption Fluid content is less More expensive compared to oral dosage forms cmax tmax Vaginal (Pessaries) globular, ovoid, cone Dosage form & Drug Delivery System c. Urethral Inserted into the urethra after urination Ex: Alprostadil micro suppository Suppository Bases Criteria: Inert, non-irritating, and non-sensitizing Firm and does not melt at RT Dissolves rapidly in the cavity fluid Page 3 of 9 RJAV 2022 a. Oleaginous Base Cocoa Butter most common and good base for rectal suppository; solid at 32°C, melts at 34-35°C; exhibits - least stable [18° most stable [34.5°C] Wecobee from coconut oil Witepsol lauric acid is the major component; saturated fatty acids (C12-C18) Example: Polyethylene Glycol (PEG) Ointment MW < 600 liquids MW 600-1000 semisolids MW > 1000 white, wax-like solids B. CREAMS semi-solid preparations containing 1 or more APIs dissolved or dispersed in either w/o or o/w emulsion soft, spreadable consistency Examples: Vanishing Creams o/w base; large % water (ex. glycerin, propylene glycol + stearic acid) Cold Creams/ Petrolatum Rose Water Ointment w/o base; mineral oil less rancid; white wax; spermaceti (cetyl esters wax) + Na borate Components Aqueous solution Oleaginous portion Emulsifying agent Humectant Preservatives b. Water-Soluble/Miscible Base Glycerinated Gelatin most common base for vaginal suppositories Polyethylene Glycol (PEG) 1. Vaginal Tablets/Inserts Ovoid or bullet-shaped tablets inserted into the vagina using a plastic inserter for local effects contains antimicrobial agents 2. Implants/Pellets long-acting dosage forms that provide continuous release of the drug to the body administered parenterally or subcutaneously Pellet implants small, sterile, cylindrical masses Levonorgestrel (Norplant ®) 5 years Leuprolide acetate (Viadur®) prostate cancer 1 year C. GELS clear, transparent, and non-greasy semisolids, containing API(s) dissolved in aqueous liquid, rendered jelly-like by the addition of gelling agent III. SEMISOLID DOSAGE FORMS A. OINTMENTS semisolid dosage forms intended for external use Uses: emollient occlusive vehicle Phenomena in Gels 1. Thixotropy reversible gel-sol formation 2. Imbibition taking up of liquid without an increase in size 3. Swelling taking up of liquid with increase in size 4. Syneresis liquid is squeezed out and the gel shrinks, forming a Xerogel Ointment Bases: 1. Oleaginous/ Hydrocarbon Base have emollient, occlusive greasy, anhydrous, non-water washable Examples: Petrolatum, USP (Yellow Petrolatum, Petroleum Jelly or Vaseline®) purified mixture of semisolid hydrocarbon from petroleum White Petrolatum, USP bleached or decolorized Yellow Wax (Beeswax) wax obtained from the honeycomb of Apis mellifera White Wax bleached or decolorized Yellow Ointment, USP (Simple Ointment) yellow petrolatum + yellow wax White Ointment, USP white petrolatum + white wax D. PASTES semisolid preparations containing a large proportion of solid Use: to prolong contact of drug Zinc Oxide Paste (ZnO) treatment of diaper rash E. PLASTERS solid or semisolid adhesive masses spread on a backing material (paper, fabric, moleskin or plastic) Use: Protection and mechanical support Provide prolonged and close contact with the skin Salicylic Acid Plaster keratolytic (10-40% salicylic acid) 2. Absorption Base without emulsion greasy and non-water-washable less emollient and occlusive effects can absorb small amounts of water Examples: Hydrophilic Petrolatum, (Aquaphor) white petrolatum + white wax + cholesterol + stearyl alcohol Lanolin, USP (Anhydrous lanolin) wax-like substance from the wool of sheep Ovis aries containing 0.25% moisture Hydrous Lanolin 25% moisture Modified Lanolin without free lanolin alcohols and excess detergents F. POULTICES/ CATAPLASM soft, moist masses of meal, herbs, seeds, etc.; applied hot in a cloth that consists of gruel-like consistency Use: to localize infectious materials and counterirritant Kaolin Poultice treatment for boils and anti-inflammatory G. PLEDGETS Small compress or tuft, usually of cotton or cotton wool, used to apply disinfectant or medicament to the skin H. GLYCEROGELATIN 3. Water-Removable Base o/w emulsions or creams easily washed off with water may be diluted with large amounts of water Example: Hydrophilic Ointment plastic masses applied on skin with a fine brush components: 40% glycerin 35% water 15% gelatin 10% API Zinc Gelatin Boot treatment of varicose ulcers 4. Water-Soluble Base lipid-free greaseless and water-washable used for incorporation of solid materials Module 5 Dosage form & Drug Delivery System Page 4 of 9 RJAV 2022 IV. TRANSDERMAL DRUG DELIVERY SYSTEMS V. LIQUID DOSAGE FORMS controlled release DDS or patches that allow the passage of drugs from the skin to the systemic circulation Advantages: Constant dosage can be maintained Avoids first pass effect Reduced need for active administration Noninvasive compared to parenteral therapy Can be promptly interrupted by removal Disadvantages: Skin structure poses a barrier on the MW of the drug Usually reserved for extremely potent drugs Drug should have adequate solubility in both lipophilic and aqueous environments Development of contact dermatitis A. SINGLE PHASE SYSTEMS SOLUTIONS liquid preparations containing one or more substances dissolved in a suitable solvent Advantages homogenous dose immediate availability for absorption flexibility Disadvantages bulky difficult to mask unpleasant taste and odor less stable than solid dosage forms degrade more rapidly interact with another component Types of TDDS 1. Monolithic Systems Incorporate matrix layer (polymer with dispersed drug) beneath the backing layer Solubility 2. Membrane-controlled Systems Contain a drug reservoir or pouch (liquid or gel) and a ratecontrolling membrane Descriptive Term Very Soluble Freely Soluble Soluble Sparingly Soluble Slightly Soluble Very Slightly Soluble Insoluble Parts of TDDS 1. Occlusive Backing Layer protects the patch from outer environment prevents drug loss and water loss Pharmaceutical Solvents/ Diluting Agents 2. Drug Reservoir/ Matrix System stores and releases the drug at the skin site 1. Water most common 3. Rate controlling membrane controls drug release from the reservoir in membranecontrolled systems Official Types of Water a. Purified Water obtained by distillation, ion exchange, reverse osmosis used for aqueous dosage forms except parenteral and other sterile solutions b. Water for Injection c. Sterile Water for Injection d. Bacteriostatic Water for Injection e. Sterile Water for Inhalation f. Sterile Water for Irrigation 4.. Adhesive Layer ensures contact of the patch to the skin 5.. Release Liner protects the drug during storage and is removed prior to use Examples Drug Scopolamine (Transderm Scop®) Nitogylcerin (Deponit®) Clonidine (Catapres-TTS®) Nicotine (Nicoderm®) Fentanyl (Duragesic®) Methylphenidate (Daytrana®) Use Motion sickness (1st TDDS developed) Prophylactic treatment of angina 1st TDDS for HTN Smoking cessation Breakthrough pain ADHD Estradiol (Climar®) HRT Testosterone (Androderm®, Testoderm®) HRT Parts of Solvent Required for 1 Part of Solute 10,000 Application Behind the ear every 3 days Upper part of body once daily Upper part of body every 7 days Upper part of body once daily Upper part of body every 3 days Hip area 2 hours before an effect is needed Lower abdomen or upper buttocks twice daily Androderm® - upper part of body or thighs Testoderm® - scrotum 2. Alcohol aka ethyl alcohol/ ethanol/ C2H5OH can dissolve water-insoluble substances used with co-solvents such as glycols and glycerin Alcohol Content Limit proposed by FDA to manufacturers of OTC oral products Age 12 years old Limit 0.5% 5% 10% Types of Alcohol: a. Alcohol, USP 94.9% to 96.0% v/v ethanol b. Dehydrated alcohol NLT 99.5% v/v ethanol Application site of application should be rotated cur or dry-shave first the hair before pacing the patch it may be left on when showering, bathing or swimming use of skin lotion should be avoided at the application site c. Rubbing alcohol 70% v/v ethanol, the remainder consisting of water and denaturant Denaturant: 8 parts acetone, 1.5 parts methyl isobutyl ketone, 100 parts ethyl alcohol d. Isopropyl Rubbing Alcohol 70% v/v isopropyl alcohol, the remainder consisting of water Module 5 Dosage form & Drug Delivery System Page 5 of 9 RJAV 2022 3. Glycerin clear, syrupy liquid with a sweet taste miscible with both water and alcohol has humectant, emollient and preservative qualities Evacuation Enema to evacuate the bowel (ex. Fleet Enema) sodium phosphates enema Retention Enema retained in the intestine for systemic absorption (ex. Sulfasalazine Enema) ulcerative colitis 4. Propylene Glycol viscous liquid miscible with both water and alcohol can be used as substitute for glycerin f. Mouthwashes aqueous solutions used by swishing the liquid in the oral cavity to cleanse the mouth May contain alcohol Use: therapeutic, cosmetic 5. Fixed Oils usually of vegetable origin can also use mineral oil for stability Examples: Corn oil Cottonseed oil Peanut oil Sesame oil g. Gargles aqueous solutions used for treating pharynx and nasopharynx by forcing air from the lungs through the solution held in the throat 2. Sweet and Other Viscid Aqueous Solutions Viscous liquids or semisolids Contain sugars, polyols, and/ or polysaccharides Classifications of Solution a. Syrups Concentrated aqueous solutions of sugar or sugar substitute with or without flavoring agents and medicinal substances May contain alcohol as preservatives 1. Aqueous Solution Solvent or vehicle is mainly water a. Aromatic Water/Medicated Waters clear, saturated aqueous solutions of volatile oils or other aromatic substances Use: flavored /perfumed vehicles for water soluble drugs Examples: Peppermint Water, USP Stronger Rose Water, USP Preparations: Distillation universal but not practical/ economical Used for Preparing Stronger Rose Water, Orange Flower Water Simple Solution more economical and simpler Talc may be used as dispersant Instability: Salting out formation of insoluble layer at top Types of Syrups i. Simple Syrup/ Syrup NF 85% w/v or 65% w/w sp. gr. = 1.313 selflow solvent capacity for drugs ii. Flavored Syrups syrups containing flavoring agents but not medicinal substances Examples: Orange and Cherry syrup acidic medium Cocoa syrup bitter Raspberry syrup sour and salty Glycyrrhiza masks bitterness of the complex vitamins Acacia syrup masking bitter taste for urea Eriodictyon syrup masking bitter taste for alkaloids b. Diluted Acids prepared by diluting concentrated acids with purified water expressed on a %w/v basis most have strength of 10% w/v with the exception of diluted acetic acid Example: Diluted HCl treatment for achlorhydria; taken with straw iii. Medicated Syrups Simple or flavored syrups with API(s) Examples: Dextromethorphan + Guaifenesin Diphenhydramine Ipecac c. Topical Solutions Astringent locally applied solutions that precipitate proteins and cause constriction of the skin Aluminum Acetate (Burrow Solution) 5% aqueous solution; wet dressing in contact dermatitis Calcium Hydroxide (Limewater or Liquor calcis) 0.14% aqueous solution; more soluble in cold water Coal Tar (LCD) 20% alcoholic solution; for eczema Anti-infective agents Hydrogen peroxide (Agua oxinada) 3% aqueous or 10 volumes solution; anti-infective Povidone Iodine (Betadine) 10% aqueous solution; anti-infective Chlorhexidine gluconate 4% aqueous solution; 0.12% solution is used as antiplaque mouthwash Thimerosal (Merthiolate) 0.1% solution Preparations of Syrups Solution with Heat fastest methods problem: overheating may cause sucrose inversion/ caramelization Solution without Heat avoids sucrose inversion Percolation preferred water is passed through a bed of sucrose in a column slow rate (1mL/min) to prevent bubbles (oxidation) d. Douches aqueous solutions directed against a part into a cavity of the body Use: cleansing or antiseptic agent Examples: Eye Douche removes foreign particles and discharges Pharyngeal Douche throat Vaginal Douche maintain the acidic pH of the vagina (ex. pH Care® - chlorhexidine gluconate) Reconstitution addition of sugar to a medicated liquid addition of medicated liquid to syrup b. Linctuses viscous oral liquid that contains one or more active ingredients dissolved in a suitable base that generally contains a higher concentration of sugar or other sugars indicated for cough and colds e. Enemas aqueous solutions administered rectally for either local or systemic effect Types: Module 5 Dosage form & Drug Delivery System c. Honeys thick liquid preparations somewhat allied to syrups but using honey as a base Page 6 of 9 RJAV 2022 d. Mucilage thick, viscid, adhesive liquids Preparation: Dispersion of gum in water Extraction of mucilaginous principles with water Examples: Acacia Mucilage Tragacanth Mucilage a. Liniments (Embrocation) alcoholic or oleaginous solutions of various APIs intended to be rubbed on the skin Types: Alcoholic counterirritant, rubefacient and penetrating action Oleaginous massage; less irritating b. Collodions Liquid preparations composed of pyroxylin dissolved in a solvent mixture usually composed of 3:1 mixture of ether and alcohol e. Jellies Class of gels in which the structural coherent matrix contains a high portion of water Uses: Lubricant (ex: K-Y Jelly) Contraceptive (ex: Nonoxynol-9) Topical anesthetic (ex: Lidocaine) Pyroxylin cotton + HNO3 + H2SO4 (act as catalyst) aka nitrocellulose, collodion cotton, soluble guncotton harsh to touch and flammable Uses: Occlusive protective coating to the skin Applied using a hair brush Water repellant Types: Flexible Collodion +3% castor oil flexible +2% camphor waterproof Salicylic Acid Collodion 10% salicylic acid in flexible collodion Keratolytic 3. Alcoholic or Hydroalcoholic Solutions Solvent may be either pure alcohol or alcohol mixed with water a. Elixirs Clear, sweetened or flavored, hydroalcoholic solutions intended for oral use Alcohol content: 5-40% may contain glycerin and syrup self-preserving at >10% alcohol Elixirs vs. Syrups Less sweet Less viscous More stable and more easily prepared Less effective in masking unpleasant taste Preparations: Simple Solution Admixture of 2 Medicated Liquids Types: Medicated Elixir digoxin, phenobarbital, diphenhydramine, dexamethasone Non-Medicate Elixir aromatic elixirs, iso-alcoholic elixir better solvent; higher content c. Oleo vitamins Fish liver oils diluted with edible vegetable oil or solutions of vitamins in fish liver oil d. Extracts medicinally active portions of vegetable drugs which have been isolated using a solvent or solvent mixture Methods of Extraction: Maceration soaking Digestion maceration with gentle heat Infusion maceration in hot or cold water Decoction boiling in water Percolation passage of solvent through column of the drug Forms of Extracts: b. Tinctures alcoholic or hydroalcoholic solutions prepared from vegetable drugs or chemical substances Alcohol content varies Strength: 10% w/v Preparations: Process P percolation (ex. Belladonna Tincture) Process M maceration (ex. Sweet Orange Peel Tincture) Simple Solution Iodine Tincture (2% in 50% alcohol); Examples: Laudanum Opium Tincture Paregoric Camphorated Opium Tincture Green Soap Tincture topical detergent Iodine Tincture topical anti-infective Compound Benzoin Tincture topical protectant Semi-Liquid Extract syrupy consistency prepared without the intent of removal the menstruum Pilular/ Solid Extract plastic consistency prepared with nearly all of the menstruum Powdered Extract prepared to be dry by the removal of all menstruum B. DISPERSE SYSTEMS contain undissolved or immiscible drug distributed throughout a liquid vehicle Phases: Dispersed Phase Dispersed Medium Types: Colloidal Dispersion: 1 nm 0.5 Fine Dispersion: 0.5 10 Coarse Dispersion: 10 50 c. Spirits/ Essences hydroalcoholic solutions of volatile oils Alcohol content: 50-90% Preparations: Simple Solution (ex: aromatic ammonia spirit) Solution with Maceration (ex: peppermint spirit) Chemical Reaction (ex: ethyl nitrite spirit) Distillation (ex: brandy spiritus vinivitis; whisky spiritus frumenti) Disperse Systems 1. Suspensions liquid preparations containing insoluble, solid drug particles (suspensoid) dispersed throughout a liquid vehicle (suspending medium) Reasons Improved stability Enhanced palatability For drugs insoluble in a specific liquid Desired Features: Fine, uniform-sized particles Slow rate of sedimentation Ease of redispersion Pour readily and evenly from its container d. Fluidextracts hydroalcoholic solutions from vegetable drugs (ONLY) prepared by percolation - too potent and too bitter Preparation: Percolation Example: Cascara Sagrada Fluidextract cathartic 4. Other Non-Aqueous Solutions Solvent may be ethereal or oleaginous Module 5 Dosage form & Drug Delivery System Page 7 of 9 RJAV 2022 Types of Suspensions a. Gels Examples: Betamethasone Gel anti-inflammatory Tretinoin Gel keratolytic Aluminum Hydroxide Gel antacid Phenomena in Gels Imbibition no increase in size Swelling increase in size Syneresis gel shrinks Xerogel formed when only framework remains c. Interfacial Film Theory (Plastic Theory) the emulsifier forms an interface between the oil and water, surrounding the droplets of the internal phase as a thin layer of film adsorbed on the surface of the drops d. Viscosity Theory the viscosity of the medium aids in the emulsification by the mechanical hindrance to coalesce the globules b. Magmas/ Milks Aqueous suspensions of large, insoluble inorganic drugs giving them a whitish color compared to gels Examples: Bentonite Magma suspending agent Milk of Magnesia [Mg(OH)2] antacid Methods of Emulsion Preparation Dry Gum (Continental) Method 4(oil): 2(water): 1(gum) oil + gum, then add water all at once w/o c. Lotions liquid suspensions or dispersions intended for external application to the body Examples: Calamine Lotion ZnO + ferric oxide; trituration; antipruritic; White Lotion ZnSO4 + sulfurated potash; astringent, protective and mild antibacterial action Wet Gum (English) Method 4(water): 2(oil): 1(gum) water + gum, then add oil gradually in small portions o/w Forbes Bottle Method for volatile oils or fixed oils of low viscosities the gum and oil are shaken in a bottle; then water is added in portions 3:2:1 or 2:2:1 d. Mixtures Contain API which are dissolved or suspended in a liquid vehicle Examples: Bordeaux Mixture (CuSO4 + CaO) algaecide in pools Kaopectate (Kaolin + Pectin) antidiarrheal Nascent Soap/ In Situ Soap Method formation of a soap by mixing equal volumes of oil and an aqueous alkali solution soap formed acts as an emulsifier 2. Emulsions Prepared by combining 2 immiscible liquids, one of which is dispersed throughout the other Components Internal Phase discontinuous/ dispersed phase External Phase continuous phase/ dispersion medium Emulsifying agent reduces interfacial tension VI. STERILE DOSAGE FORMS dosage forms that are required to have absence of living microorganisms including its spores Examples: Parenteral injectable Ophthalmic eyes Inhalations Irrigation solution Dialysis Solutions Implants Types of Emulsions a. Oil-in-water (o/w) oil id the dispersed phase & water is the dispersion medium b. Water-in-oil (w/o) water is the dispersed phase and oil is the dispersion medium A. PARENTERALS Injected through the skin or directly into the body Must conform to strict requirements for microbiological impurity, particulate matter, pyrogenicity and isotonicity c. Multiple Emulsions the dispersed phase contains smaller droplets that have the same composition as the external phase w/o/w or o/w/o Parenteral Routes d. Microemulsions clear, stable, liquid mixtures of oil, water, and solubilizer vs. Macro emulsions: clear, transparent liquid 10-200 nm diameter formed by simple mixing thermodynamically stable 1. Intravenous (IV) Directly into the systemic circulation (back of the hand or dorsal forearm Can be injected at all one (IV bolus) or gradually over a sustained period of time (IV infusions) 2. Intramuscular (IM) Deep into the skeletal muscles (gluteal or deltoid muscle) For greater volume (2 to 5 mL) Ex: vaccines, antipsychotics 3. Subcutaneous (SC/ SQ) Injected into loose connective and adipose tissue (lower abdomen, upper arm, anterior thigh) Small volumes (1.3 mL or less) Ex: Insulin 4. Intradermal (ID) Into the corium of the skin Minimal volume (0.1 mL) Ex: tuberculin skin tests 5. Intracardiac Heart chamber Theories of Emulsification a. Surface Tension Theory the internal forces in liquid droplet promote association of the molecule of the substance resisting distortion of the droplet into a less spherical form b. Oriented Wedge Theory the surfactant forms monomolecular layers around the droplets of the internal phase of the emulsion Module 5 Dosage form & Drug Delivery System Page 8 of 9 RJAV 2022 6. Intra-arterial Artery 7. Intraspinal Vertebral column 8. Intrathecal Cerebrospinal fluid 9. Intra-articular Joint space 10. Intrasynovial Joint fluid 11. Epidural Near the dura mater of the CNS C. INHALATIONS Administered directly into the lungs for local action on the bronchial tree or systemic action may be in form of dry powders or solutions Advantages: Large area for absorption Good blood supply Avoids first pass effect Example: Budesonide (Budecort®) D. IRRIGATION Components of Parenteral 1. Solvent/ Vehicle Used to wash, soak, or flush wounds, surgical openings, or body tissues Usually packaged in large volume containers Examples: Sodium Chloride Irrigation Acetic Acid Irrigation carrying agent a. Aqueous Water for Injection (WFI) pyrogen-free water obtained by distillation or reverse osmosis Sterile Water for Injection (SWFI) WFI that has been sterilized Bacteriostatic Water for Injection (BWFI) SWFI with antimicrobial agent (benzyl alcohol) Sodium Chloride Injection 0.9% NaCl in WFI b. Non-Aqueous Alcohol Glycerin Propylene Glycol Polyethylene Glycol Fixed vegetable oils (CoCoPeSe) Ethyl oleate Isopropyl myristate VII. AEROSOLS pressurized dosage forms designed to deliver drugs systematically or topically with aid of a liquefied or propelled gas fire (liquid/ solid drug in a gaseous medium) Advantages rapid onset of action prevents first pass effect greater drug stability fewer systemic side effects painless and relatively convenient Types of Aerosols 2. Solutes 1. Space Spray remain in the air for prolonged periods 2. Surface Spray carry the API to a surface 3. Foams formed when expansion of propellant within an emulsion result in production of small bubbles Formulation: a. Active Pharmaceutical Ingredient (API) b. Buffers maintain the required pH of the solution (ex: citrate, acetate, phosphate) c. Tonicity Adjusters dextrose) reduce the pain of injection (ex: NaCl, 1. Product Concentrate API combined with required adjuncts: Surfactant Antioxidant Solvents 2. Propellant Gas which develops the pressure within an aerosol and expels the product when the valve is opened Types: Liquefied Gas propane, butane, isobutene, hydrofluorocarbons, dimethyl ether Compressed Gases CO2, N2, N2O d. Preservatives maintain sterility (ex: thimerosal, benzyl alcohol, benzalkonium chloride) 3. Inert Gas prevent oxidation of components (ex: Nitrogen Gas) Type of Parenteral Injections 1. Small-volume Injection 100 mL or less Packaged in ampoules, vials, prefilled syringes, or minibags 2. large-volume injection more than 100 mL Packaged in plastic infusion bags or glass bottes with or without an air vent tube Parts of an Aerosol a. Fluid and Electrolyte Replenisher Sodium Chloride Injection 0.9% NaCl NaCl + KCl + CaCl2 Sodium Lactate Injection systemic alkalinizer NaCl + KCl + CaCl2 + Na lactate 1. Pressurizable Container Glass prone to breakage Tin-Plated Steel most widely used Aluminum seamless and more inert b. Fluid and Nutrient Replenisher Dextrose Injection 5% (D5W) most common Invert Sugar Injection dextrose + fructose Amino Acid Injection for protein synthesis Mannitol Injection diagnostic aid in renal function 2. Valve Assembly regulates flow Actuator button pressed to activate valve for emission of the product Stern supports actuator and delivers formulation in the proper form Gasket prevents leakage of formulation when the valve is closed Spring the mechanism by which the actuator retracts Mounting Cup holds the valve in place Housing links the dip tube, stem, and actuator Dip Tube brings the formulation from the container valve B. OPHTHALMIC Designed to be instilled onto the external surface of the eye (topical) or administered inside the eye (intraocular) May be in the form of solutions, emulsions, suspensions, and ointments Problem: Low drug bioavailability Remedy: increase viscosity Example: Eye Mo Module 5 Dosage form & Drug Delivery System Disadvantages environmental concern poor inhaler technique risk of oropharyngeal deposition airway obstruction and bronchospasms Page 9 of 9 RJAV 2022 MODULE 5 PHARM 3 PHYSICAL PHARMACY PHYSICAL PHARMACY responsible for the solubility of non-polar molecules Ex. Iodine complex with salts Application of physical chemistry in pharmacy Study of physiochemical properties of substances used in drug formulation PHYSICAL PROPERTIES OF MATTER Additive depends on the total contribution of the atoms in the molecules Ex. MW, Mass FORCES OF ATTRACTION INTRAMOLECULAR FORCES Forces of attraction within the molecule Constitutive depends on the arrangement of the number & kind of atoms within a molecule Ex. Refractive Index, Optical Rotation Types: a. Ionic Bond Transfer of electrons between a non-metal & a metal observed in formation of salts Colligative function of the number of species or particles present in a given solution Ex. Osmotic pressure elevation, Vapor Pressure lowering, Freezing Point Depression, Boiling Point Elevation b. Covalent Bond sharing of electrons between two non-metals observed in organic compounds INTERMOLECULAR FORCES TYPES OF PROPERTIES forces of attraction between molecules Intensive independent of the amount of the substance in the system Ex. Temperature, Pressure, Density, Viscosity, Surface tension, Specific Gravity Types: a. Binding Forces Cohesion similar molecules Adhesion different molecules Repulsive prevent molecules from annihilating each other Extensive depends on the quantity of substance in the system Ex. Mass, Length, Volume b. Attractive Forces Van der Waals Hydrogen Bond Ion-Dipole Ion-induced Dipole STATES OF MATTER THE GASEOUS STATE Gas Laws refers to an ideal situation where no intermolecular interactions exist and collisions are perfectly elastic there is no energy exchanged upon collision Van der Waals Forces weak forces that involve the dispersion of charge across a molecule called a dipole 1. Keesom Forces (orientation effect) Dipole-dipole molecules are polar with permanent polar dipoles Ex. water, HCl, ethanol, acetone, phenol 2. Debye Forces (induction effect) Dipole-induced dipole transient dipole induced by a permanent dipole polar molecules produce temporary electric dipole in nonpolar molecules Ex. Ethyl acetate, methylene chloride, ether relates volume and pressure constant temperature PV = k 2. Gay- 3. states that the volume and absolute temperature of a gas at constant pressure are directly proportional V = kT 3. Ideal Gas Law PV = nRT R = 0.08205 liter.atm/mole.K or 8.314 joules/mole.K or 1.987 cal/mole deg n = number of moles London Forces (dispersion effect) Induced dipole- induced dipole induce polarity between non polar molecules responsible for liquefaction of gases Ex. Carbon disulfide, CCl2, hexane Kinetic Molecular Theory Gases are composed of particles called atoms or molecules, the total volume of which is so small as to be negligible in relation to the volume of the space in which the molecules are confined The particles of the gas do not attract one another, but instead move with complete independence The particles exhibit continuous random motion owing to their kinetic energy The molecules exhibit perfect elasticity Hydrogen Bond electrostatic interaction of H with highly electronegative atoms (S, N, Cl, F, O) accounts for unusual properties of water Ion-Dipole Interaction polar molecules are attracted to either positive or negative charges occurs when salt is dissolved in a polar solvent solubility if crystalline substances in H2O quaternary ammonium + tertiary amine THE LIQUID STATE Critical temperature temperature above which a liquid can no longer exist Ion-Induced Dipole induced by close proximity of a charged ion to a non-polar molecule Module 5 Physical Pharmacy Page 1 of 7 RJAV 2022 Critical Pressure pressure required to liquefy a gas a critical temperature highest vapor pressure of a liquid Supercritical Fluids properties intermediate between those of liquids and gases formed from the gaseous state where the gas is held under a combination of temperatures and pressures that exceed the critical point of a substance Boiling Point the temp at which the vapor pressure of the liquid equals the external and atmospheric pressure THE SOLID STATE relates the effect of the least number of independent variables (T, P & C) among the various phases (S, L & G) that can exist in an equilibrium system containing a given number of components Where: F = no. of degrees of freedom C = no. chemical components P = no. of phases X = variable dependent upon considerations of the phase diagram F least number of intensive/independent variables that must be fixed to describe the system completely C smallest number of constituents by which the composition of each phase in the system at equilibrium can be expressed in the form of a chemical formula or equation P number of homogenous physically distinct portion of a system that is separated from other portions of the system by bounding surfaces 1 Phase F=2 Bivariant 2 Phases F=1 Univariant 3 Phases F=0 Invariant have fixed shapes nearly incompressible have strong intermolecular forces very little kinetic energy atoms vibrate fixed positions about an equilibrium position, & so there is very little transitional motion Crystalline Solids Solids whose structural units are arranged in a fixed geometric pattern or lattices definite shape orderly arrangement of units definite and sharp melting points 6 Distinct Critical Systems Based on Symmetry Cubic Sodium Chloride Tetragonal Urea Hexagonal Iodoform Monoclinic Sucrose Rhombic I2 Triclinic Boric Acid THERMODYNAMICS Amorphous Solids glasses or supercooled liquids molecules are arranged in a random manner no definite melting points faster dissolution rate deals with the quantitative relationships of interconversion of the various forms of energy System a well-defined part of the universe under study Surroundings the rest of the universe from which the observations are made Boundaries physical or virtual barriers that separate a system from the surroundings Polymorphism condition where substances can exist in more than 1 crystalline form polymorphs have different melting points, x-ray crystals and diffraction patterns and solubility Theobroma Oil Polymorphs (Melting Points) 18°C 22°C 28°C 34°C Types of Polymorphism Enantiotropic reversible Monotropic unidirectional transition TYPES OF SYSTEMS 1. Open energy and matter can be exchanged with the surroundings 2. Closed not matter energy can be exchange with the surroundings but 3. Isolated neither matter not energy can be exchanged with the surroundings FIRST LAW OF THERMODYNAMICS Freezing Point temperature at which liquid solid melting point of a pure crystalline compound Energy cannot be created nor destroyed, it can only be transformed into a different form Adiabatic constant heat Isothermic constant temperature Isochoric constant volume Isobaric constant pressure Latent Heat of Fusion Energy absorbed when 1g of a solid melt Heat liberated when it freezes LIQUID CRYSTALLINE STATE SECOND LAW OF THERMODYNAMICS liquid crystals intermediate between liquid and solid states may result from the heating of solids (thermotropic) or from the action of certain solvents on solids (lyotropic liquid crystals) Refers to the probability of the occurrence of a process based on the tendency of a system to approach a state of energy equilibrium Entropy Two Main Types of Liquid Crystals THIRD LAW OF THERMODYNAMICS 1. Smectic Soap like or grease like molecules are mobile in 2 directions rotates in 1 axis The entropy of a pure crystalline substance is zero at absolute zero because the crystal arrangement must show the greatest orderliness at this temperature CONDENSED SYSTEMS 2. Nematic threadlike molecules are mobile in 3 directions rotates in 1 axis Cholesteric special type of nematic Module 5 Physical Pharmacy S & L phases only the vapor state is disregarded with an assumption of working at a pressure at 1atm 2 Components liquid phases 2 Components S & L eutectic mixtures 3 Components Page 2 of 7 RJAV 2022 TWO COMPONENT SYSTEM CONTAINING TWO LIQUIDS Bulk Volume Void Volume Binodal Curve area within the curve which represent a 2-phase system total volume of the material difference between bulk and true volume Density True Density density of actual particle Granule Density volume of particles together with intraparticulate spaces Bulk Density mass of powder divided by the bulk volume USP Method 1 Graduated Cylinder USP Method 2 Scott Volumeter USP Method 3 Vessel Upper Consulate/Critical Solution Temperature maximum temperature at which two phase region in the phase diagram of a two-component system containing two liquids will exist Tie line line from which a system separates into phases of constant composition approximates proportion of components in a particular temperature Conjugate Phases phases of constant composition that separate when a mixture is prepared within the boundary of the 2-phase system Flow Properties Angle of Response maximum angle possible between the surface of a pile of power and the horizontal plane Where: TWO COMPONENT SYSTEM CONTAINING SOLID AND LIQUID h = height of cone r = radius of base cone Tapped Density measured using a tapped density tester by repeated tapping until a consistent tapped volume is achieved Eutectic Point minimum temp. where both exist in liquid form point where solid A, solid B & the liquid phase co-exist LIQUIDS THREE COMPONENT SYSTEM less kinetic energy than gases occupy definite volume take the shape of containers denser than gases not compressible Ternary system 2 liquids that are miscible + 3rd component (co-solvent) with affinity to both layers has 4 degrees of freedom MICROMERITICS SOLUTIONS OF ELECTROLYTES & NON-ELECTROLYTES study of small particles True Solutions molecular dispersions particle size =