Compounding II: Equipment, Stability & Excipients PDF

I CO MP O UNDIN G 16 II : EQ UIP M ENT, STAB ILIT Y & EXC IPI ENT S Which Compounds are Likely to Become Hydrolyzed? The most common functional groups susceptible to hydrolysis are esters, amides and lactams. The carbonyl group is subject to hydrolysis. - --Ester "}~rnon~ Carbonyl group bonded...

I CO MP O UNDIN G 16 II : EQ UIP M ENT, STAB ILIT Y & EXC IPI ENT S Which Compounds are Likely to Become Hydrolyzed? The most common functional groups susceptible to hydrolysis are esters, amides and lactams. The carbonyl group is subject to hydrolysis. - --Ester "}~rnon~ Carbonyl group bonded to an OR group group C R-?' "-OR' ---- Amide 0 Carbonyl group bonded to a Nitrogen R AR' N/ I - I R' ---- Lactam, a cyclic amide This is a beta-lactam ring, present in penicillins, carbapenems, cephalosporins and monobactams. . I (')===o N H Example: Hydrolysis of the ester group on acetylsalicylic acid (aspirin) to form acetic acid and salicylic acid. In this case, hydrolysis is beneficial. The analgesic is salicylic acid, which is formed by hydrolysis of the prod rug acetylsalicylic acid. &o-L,. (r . COOH o COOH '"•'°°" Asprln - acetylsallcyllc acid sallcyllc acid acettc acid How Can Hydrolysis be Prevented? To reduce hydrolysis, the compound should be protected from moisture (water) exposure and other factors that favor degradation, including light exposure, metal ions and changes in temperature and pH. 1 Light protection See Oxidotion toble . I - Msorbents (desiccants)~ Lyophilized powders -- Chelating agents Drugs can be stored as a lyophill zed (freeze-dried) powder instead of in solution. I See Oxidatio'n table. Hygroscopic salt -- -- - - ---- - Hygroscopic means wat er-absorbing. In some cases, a salt form of the drug can be chosen that is less hygroscopic, will absorb less water and will be less likely to degrade from hydrolysis. I -- Prodrug formulation ---- Control temperature Control pH adsorb any moisture that enters the container. Prodrugs that releas; the active drug by a hydrolysis reaction can be formulated [e.g., acetylsallcylic ac id (aspiri n) is hydrolyzed to salicylic acid (the analgesic) and acetic acid]. ,- --- - Control the temperature in which the product is stored; hydrolysis occurs more rapidly at higher temperatures. I Maintain pH with a buffer; see pH discussion that follows. - PHOTOLYSIS Many drugs are sensitive to UV light exposure, which causes photolysis (breakage) of covalent bonds and drug degradation. Photolysis can be prevented with light protection. Which Compounds are Likely to Become Degraded by Light Exposure? Compounds that are sensitive to light include ascorbic acid, folic acid, nitroprusside and phytonadione injection. Intravenous drugs that require light protection are discussed in the Intravenous Medications Principles chapter. 264 Rx PREP 2 022 COURSE BOOK I RxP RE P ©2021, ©2022 ADDITIONAL PROCESSES THAT DEGRADE DRUGS Other reactions that degrade drugs include: Isomerization, when a compound changes into a form with the same atoms but an inactive structure. Epimerization, when a compound changes into an isomer that differs only in the configuration of the atoms. The two compounds are stereoisomers. Epimerization creates a chiral counterpart. The epimer can be inactive, or active (e.g., doxorubicin is active, and epirubicin, the epimer, is also active) . Decarboxylation can happen to compounds with dissolved carboxylic acids. When heated, the carbon dioxide is lost from the carboxyl group. Drugs at risk of decarboxylation can be kept refrigerated. The compounder uses methods that limit drug degradation and help the product remain stable, including: Excipients, such as buffers to retain the pH in an adequate range and preservatives to prevent the growth of microorganisms. Bennlkonlum Light Protection, to block degradation from UV light exposure, causing photolysis. Packages, that seal tightly to keep out light and moisture. Proper storage, including refrigeration when a product is subject to damage from heat; heat causes molecules to vibrate (move), which speeds up chemical reactions. Some products must be kept at room temperature. They can crystallize or precipitate in the refrigerator (as in the image of the IV bag below). r fffi © RxPrep 265 16 I CO MPOUNDIN G II : EQU IP M ENT, STA BILIT Y & EXCIPI EN TS EXCIPIENTS MAJOR EXCIPIENTS MAJOR EXCIPIENTS PURPOSE AND NOTES EXAMPLES Binders Binders allow the contents of a tablet to stick together while permitting the contents to be released once ingested. Acacia They can provide stability and strength. Compressible sugar (e.g., Nu-Tab) :lt ahaso/! 20D0 •t· 123 RF.com Diluents and fillers Diluents (to make something more dilute) and fillers (to bulk up a small amount) add size to very small dosages. In liquids, the diluent helps suspend the drug and facilitates disintegration, which is required for absorption (see disintegrants below). rel iStock.com/An110 zabella Dlslntegrants Starch paste i Sucrose syrup Tablets/capsules: Liquids: Topicals: Sugars: Lactose Mannitol Sorbitol Water Petrolatum Glycerin Mineral oil Alcohol Lanolin Waxes Starches Calcium salts Cellulose powder (many uses) Facilitates the breakup of a tablet after oral Alginic acid administration. Oral products have to be . Cellulose products dissolved in order to be absorbed in the small intestine, where most drugs are absorbed. ' Pofacrllfn potass um (e.g., Amber/ite) r,j, Alginates and cellulose absorb water, causing the tablet to swell and release its contents. Starches Flavorings and coloring agents make the product look and taste better. Coloring agents: Sweeteners: D&C Red No. 3 Salty or sweet tastes mask a bitter flavor. Mint and spices mask poor flavor. Acids (such as citric acid) enhance fruit flavors. Yellow No. 6 Caramel Non-caloric, artificial: Aspartame Saccharin Sucralose Ferric oxide (red) Glycerin ah,isoft2000 (( 123RF:com Flavorings and coloring agents Dextrose Sugar alcohols (e.g., mannitol. sorbi tol. xyli to l) O/zas/Shu!terstock com ~ Lubricants -•Preservatives Can be called glidants or anti-adherents. Lubricants and anti-adherents prevent ingredients from sticking to each other and to equipment. This can be useful for tablet molds and punches, suppository molds and for capsule filling. Glidants Improve powder flowablllty by reducing interparticle friction . Preservatives slow or prevent microorganism growth. They are required in most preparations except if sterile and used immediately or if sealed in single-use preparations. Ophthalmic (eye) preparations in multi-dose containers need a preservative. Do not use preservatives in neonates. Alcohols and acids are often used as preservatives. Preservatives commonly have "benz," "cetyl,'' "phenyl/cl " and "parabens" in the name. fVlagnesium stearate, calcium stearate, stearic acid Colloidal silica PEG Glycerin Mineral oil Talc Chlorhexidine [also used as an antiseptic in surgical scrubs to eliminate or reduce microorganisms (Hibic/ens) and as a dental rinse (Peridex)] Povidone iodine (used as a topical antiseptic and as a preservative in some ophthalmics) Sodium benzoate/benzoic acid, benzalkonium chloride. benzyl alcohol Sorbic acid/potassium sorbate Methyl/ethyl/propyl parabens EDTA Thimerosal (contains mercury, used in some vaccines) Cetylpyridinium chloride 266 . monk fruit extract RxPREP 2022 COURS E BOOK MAJOR EXCIPIENTS PURPOSE AND NOTES EXAMPLES Buffers Buffers keep the pH within a certain range, which can improve stability and solubility and decrease irritation to sensitive tissues in the body. Hydrochloric acid Acetic acid/sodium acetate Citric acid/sodium citrate I RxPREP ©2021, ©2022 Buffers used to maintain acidic pH: Ionized compounds are more polar, which makes them more water-soluble. The pKa determines how much of a compound is ionized when placed into a solution with a set pH. The pH of a buffer system can be calculated with the Henderson-Hasselbalch equation (see the Calculations IV and Compounding Ill chapters). Buffers used to maintain alkaline pH: SOLVENTS PURPOSE AND NOTES EXAMPLES Water Water Is commonly used as a solvent, as a delivery vehicle and for cleaning equipment and tools. USP specifies that purified water must be used in compounding, unless otherwise specified. 111,11.,ott l :tr iStock com/ Cathol Stadler Sodium hydroxide Boric acid/sodium borate Sodium bicarbonate/sodium carbonate Buffers used to maintain neutral pH: Sodium biphosphate/sodium phosphate Potassium phosphate/metaphosphate SOLVENTS Hydrophilic Solvents _.;;==. , --11 - Purified water has been treated to remove chemicals and ----contaminants. Types of purification include distillation, As a delivery vehicle, water is used for oral liquid formulations (e.g., solutions, suspensions, emulsions), topicals (e.g., creams, lotions) and in all types of injectable medications. deionization, reverse osmosis and carbon filtration. Distilled water is used for reconstitution [i.e., adding water to lyophilized (freeze-dried) powder] to prepare£@! suspensions and in non-sterile compounding preparations. Potable water (drinking/tap water) is safe to drink and used for hand washing and initial eq uipment cleaning, Sterile Water For preparation and reconstitution of sterile drugs. Sterile water for injection (SWFI) must be free of bacterial endotoxins (pyrogens) produced by microorganisms that inhabit water. Sterile water must be free of microorganisms. Bacteriostatic water for injection: SWFI with antimicrobial preservatives. Sterile water for irrigation: sterile water packaged in large containers for washing, rinsing and dilution of products used for irrigating body cavities, wounds, urinary catheters or surgical drainage tubes. f<l1 Burlingham!Shutterstock.com Alcohols il:!' Mohd Syis Zulkipli!Shutterstock com Glycols Polyethylene glycol (PEG) is a long, synthetic polymer. PEGs are numbered based on the molecular weight (e.g., PEG 400 and PEG 3350). The size/ molecular weight depends on the number of times the structure inside the parentheses repeats: H-(0- CH2-CH2)n-OH ------------------ Alcohols have high miscibll!ty (mixes easlly) with water and can be used to dissolve solutes that would be insoluble in water alone. lsopropyl alcohols (IPAs) are used as disinfectants on equipment or on skin (e.g., on an alcohol swab for skin disinfection prior to a needle stick). They can be used as solvents when compounding topicals . Benz y I alcohol: used as a solvent, preservative and for the aroma (fragrance), Alcohol USP: ethanol (grain alcohol, ethyl alcohol or drinking alcohol). can be used as an alternative to fomepizole for methanol or ethylene glycol toxicity. Methanol (toxic): fuel, used to make many chemicals. I IPA 70%: preferred disinfectant in sterile compounding, I Glycols have a low freezing point (which makes antifreeze possible), a high boiling point and are water-soluble. PEG 400 is used commonly in compounding and PEG 3350 is used as a laxative. When PEG is linked to a protein drug (pegylated), such as PEG-filgrastim, it increases the half-life. PEG has low toxicity and low systemic absorption, making it a useful excipient. It is used as a surfactant, solvent, plasticizer, suppository base, ointment base, lubricant and troche base. It is water-soluble and water-miscible (mixes well with water into a homogenous mixture). Polybase is a PEG mixture used as a suppository base. It is a good delivery vehicle and slides out of molds without the need for a lubricant. It is also a good emulsifier. Methoxy-polyethylene glycol (MPEG) Glycerin Propylene glycol: used in small quantities as a solvent (large quantities are toxic) Ethylene glycol (toxic): antifreeze 267 16 I COMPOUNDING II: EQUIPMENT, STABILITY & EXCIPIENTS Hydrophobic Solvents SOLVENTS PURPOSE AND NOTES EXAMPLES Olis and Fats Oils are used as delivery vehicles, for therapeutic or nutritional use, and some are used as scents and flavorings. Mineral oil: derived from petroleum, and is the ingredient in Baby Oil Oils are hydrocarbon liquids derived from plants, animals or petroleum [i.e., petrolatum (Vaseline petroleum jelly)]. Oils are immiscible in water; they are hydrophobic, lipophilic compounds. Almond, borage, canola, castor, coconut Omega-3 (alpha-linolenic fatty acids, DHA/EPA) Omega-6 (gamma-linoleic fatty acids) EMOLLIENTS (MOISTURIZERS) Prior to reviewing the emollients below, it is helpful to note the differences between emollients. An emollient refers to a product that softens and soothes the skin. Occlusive ointments, including petroleum jelly (i.e., white pea:olatum), theobroma oil (i.e., cocoa butter), beeswax, paraffin and other waxes form a protective barrier to prevent the loss of water molecules from the top layer of the skin (epidermis). Humectants are put into many emollient formulations to pull in water from the atmosphere to moisturize the skin. They can be sticky-feeling, and are combined with other more soothing ingredients. Humectants include glycerin or glycerol, propylene glycol, PEG, urea and hyah1ronic acid. Ointments have 80 - 100% oil, 0 - 20% water, and are best for extremely dry skin and thick skin, such as on elbows and feet. Creams are usually about half oil, half water (minimally greater than 20% water and up to 50% oil) and are best for normal and dry skin. Lotions have the most water, and are best for oily skin. EMOLLIENT Ointments USP separates ointments into 4 groups. Some contain water and some do not, which is important in determining the BUD; see the Compounding Ill chapter. The four ointment groups are listed below. 1. Hydrocarbon Bases 1 PURPOSE AND NOTES EXAMPLES Ointments are defined as semisolids, with 0 - 20% water hydrocarbons, waxes and/ or polyols (compounds with multiple OH groups). Common emollients: Petrolatum, lanolin, mineral oil, dimethicone Provide a barrier to water loss from the skin and are used as vehicles for topical drug delivery. In some products the emollient components are mixed with humectants, which draw w ater into t he skin, and make t he prod uct less greasy. Called "oleaginous" ointments (oil-containing, no water); good for drug delivery and forming a protective barrier, hard to wash off/greasy. ------------------~Can be used to form water-in-oil emulsions, 2. Absorption Bases Common combination products: , Polybase: PEG 400, PEG 8000, polysorbate 80; water-soluble, water-miscible Aquaphor (OTC): 41% petrolatum, with mineral oil, lanolin, glycerin + other ' ingredients. Semi-occlusive barrier, less greasy than petrolatum. , Aquabase (OTC): similar to Aquaphor White ointment, white petrolatum (e.g., Vaseline petroleum jelly) Hydrophilic petrolatum, lanolin useful as emollients. 3. Water-Removable Bases Hydrophilic, oil-in-water emulsions. Per USP, more correctly called creams; more easily diluted, and easier to wash off the skin. Hydrophilic ointment 4. Water-Soluble Bases Do not contain petrolatum; per USP, are more correctly called gels. Polyethylene glycol ointment Creams Creams are semi-solid preparations that have a soft, spreadable consistency. Most creams are water-in-oil or oil-in-water emulsions. Water-in-oil creams feel more greasy. Lipoderm cream More water than ointments. Eucerin: water, petrolatum, mineral oil, ceresin, lanolin + other ingredients Cetaphi/: water, glycerin, petrolatum, dimethicone, benzyl alcohol, PEG + other ingredients Lotions More water than creams, which makes them more fluid. Lotions are sometimes poured from a container. which is not feasible with creams. 268 Lotions can be aqueous or hydroalcoholic, : with a small amount of alcohol added I t o ~ ingredients, or to hasten evaporation of the solvent from the skin. , Versabase lotion RxPREP 2 0 22 CO U RSE BOO K Gels Gels are semisolid preparations of small inorganic particles or large organic molecules interpenetrated by a liquid, If the gel has small discrete particles in it, is classified as a two-phase system. If the particles are distributed uniformly so that the gel does not appear to have any discrete particles, it is a single-phase system. I Rx PREP ©2021, © 2 0 22 Polyethylene+ mineral oil (Plastibase, Jelene) Gels can be used to administer medications by various routes, including topical, oral, intranasal, vaginal and rectal. Poloxamer 407NF Poloxamer (Pluronic) Lecithin Organogel (PLO) gel Aqueous solutions of poloxamers are liquid when refrigerated and form a gel at room temperature, in a reversible process. PLO gel is used often because of this property; compounds are easily mixed into the liquid (when taken from the refrigerator), which then forms a gel when stored at room temperature (see comic below). Poloxamers contain a hydrophobic chain of polyoxypropylene with two hydrophilic chains of polyoxyethylene. This means poloxamer gel can be used for hydrophobic or hydrophilic drug delivery. Pastes Pastes contain powder in an ointment base. Zinc oxide paste, used for diaper rash; zinc oxide is a desiccant (draws water from the baby's bottom). Suppository bases, made of various fats and glycols Suppository bases have to stay intact for insertion, and melt once inserted. Theobroma oil (cocoa butter) used to be a common base for suppositories, but it melts easily. Newer bases are now more popular. Polybase, cocoa butter (theobroma oil), hydrogenated vegetable oils (palm, palm kernel, and coconut oils), PEG polymers, glycerinated gelatin What is this PLO gel? It's a liquid in the refrigerator, too! But it turned into a gel when I left it out. I don't get it! This was a gel when I left It on the counter (at room temperature) but when I took it from the refrigerator, It had turned ,~ d . Usually the cold makes liquids thicker! r.-:'. ~ • I • ' It Is a poloxamer gel, which is "thermo-reversible". It Is a liquid at cold temperatures, and a gel at room temperature. The gel is called pluronic, because it Is made of two joined polymer compounds (poly-oxy-ethylene and poly-oxy-propylene). - '8 _ ,,. , Why do we use a lot of the PLO gel? Well, It's easy to mix from the fridge, but at room temperature It thickens up and Is great for transdermal drug delivery! The gel has both a hydrophilic (water-loving) and hydrophobic (oil-loving) phase, so It's great for drugs or any exclplents that are llpophilic, hydrophilic or even amphoterlc (both water and oll-lovlng). The P Is for the pluronic, , . , poloxamer gel. That's In there, with 2 other ingredients: The Land O Is 11 for Lecithin (that's the L) and lsopropyl palmltate, which Is palm oil (0 for Oil). Do you love me? _,, '8 No, sorry. If you are making a topical preparation with PLO gel, the BUD should not be longer than 30 days; the gel contains water. ,r - 269 16 I COMPOUNDING II: EQUIPMENT, STABILITY & EXCIPIENTS OTHER EXCIPIENTS EXCIPIENTS PURPOSE AND NOTES EXAMPLES Adsorbents To keep pow ders dry, to prevent hydrolysis reactions. Magnesium oxide/ carbonate, kaolin Anti-foaming agent Breaks up and inhibits the formation of foams. Coatings (regular) Prevent degradation due to oxygen, light, moisture, mask unpalatable taste. Emulsifiers Reduce the surface tension between two liquids (e.g., oil and water), allowing the two phases to come closer together. Emulsifiers are a type of surfactant. Enteric-coating l Simethi~ n~ dimethicon_e _ _ _ _ _ _ _ _ __ Shellac. gelatin, gluten (food grade) - Acacia, agar, carbomers, glyceryl monostearate, pectin, PEG, sodium lauryl sulfate, sorbitan lipophilic esters (Ar/ace/, Span), sorbitan hydrophilic esters (Myrj, Tween) Most drugs dissolve in the stomach and are absorbed In the small intestine. Some drugs would be destroyed by stomach ' acid and require an acld·resistant (enterlc·coated) protective layer to prevent dissolution in the stomach. Cellulose acetate phthalate Shellac (a natural polymer resin, from insects) The coating can also be used to mask poor taste. ------------Gelling (thickening) agent, stabilizer Increases the viscosity of a substance; can stabilize the mixture. Gelatin, cellulose and bentonite are used commonly; they swell well when mixed with water. Agar, alginate s, various gun;s (guar, xanthao, acacia (a natural gum)], gelatins, bentonite (a type of clay), carbomer, cellulose, starches, tragacanth, acrylates, cetyl alcohol, magnesium aluminum silicate (Veegum), poloxamer (pluronic) gels, polyvinyl alcohol (eye lubricant), sorbitol Humectant Prevents preparations from becoming dry and brittle, when put into emollients, draws water into the skin to moisturize. Glycerin or glycerol, propylene glycol, PEG, lecithin, urea, hyaluronic acid Levigating (wetting) agent Liquid used in the process of reducing the particle size to reduce the surface tension. Mineral oil, glycerin, glycols, PEG, propylene glycol EXCIPIENT AVOID IN ALTERNATIVE Alcohol, used as a solvent. Children SeleGt alternative solvent; see excipient table. Aspartame (contains phenylalanlne), Phenylketonuria (PKU), not able to metabolize phenylalanine Select alternative sweeteners; see excipient table. Vegetarians and vegans, anyone who wishes to avoid pork Hypromellose capsule shells are made from cellulose and are vegan (no meat or dairy) and vegetarian (no meat). used as a sweetener. Gelatin, used to form capsule shells. i ------, Celiac disease, anyone who wishes to avoid gluten Starch can come from non-gluten sources (e.g., corn, potato, tapioca). Lactose intolerance or lactose allergy Lactose content may/may not cause symptoms (with intolerance) as the amount in compounded products can be small. Select an alternative (with lactose allergy, and possibly with lactose intolerance), depending on the purpose. Preservatives (e.g., benzyl alcohol). Neonates Use preservative-free formulations. Sorbltol, used as a sweetener. Irritable bowel syndrome (IBS); sorbitol can cause GI distress in IBS Sucrose (table sugar), used as a Diabetes The amount used may/may not cause the blood glucose to increase. Select alternative sweeteners; see excipient table. Do not use in dogs; it can cause xylitol toxicosis (hypoglycemia and liver damage). Select alternative sweeteners; see excipient table. Gluten, used as a starch (filler). Gluten is in wheat, barley and rye. Gluten as a starch in drugs is primarily from wheat. Lactose, used as a sweetener, to compress tablets and as a filler/diluent. sweetener and coating. Xylitol, used as a sweetener. Xylitol can cause GI upset in humans. 270 I Select alternative sweeteners; see excipient table.