Important Non-Sterile Compounding Terms: Comminution: to reduce solids from an average particle size to a smaller particle size by crushing/grinding/etc. - Trituration: to grind powder into smaller, finer particles. This can be done with a mortar & pestle. - Levigation: same as trituration, except you add in liquid (wetting agent/levigating agent) to help with grinding process, which turns the solid into a uniform paste. o Oil-based products: common levigating agent is mineral oil o Aqueous products: common levigating agent is glycerin Spatulation: a spatula is used instead of a pestle to grind powder in a mortar Geometric dilution: once grittiness is gone, a small amount of the drug powder is mixed into an equal amount of other ingredients (ex. filler like lactose for capsules or delivery vehicle like petrolatum for topical ointments). After initial small amount is thoroughly mixed, another equal amount of the remaining ingredients is mixed in. This is repeated until all ingredients are mixed together. Emulsion: liquid dispersed in a liquid. It is a two-phase heterogenous mixture. Emulsions are o/w or w/o. - Dispersed/internal/continuous phase: droplets - Continuous/external phase: the suspension that contains the droplets (add flavoring/coloring agents here) Surfactant Types: 1) Emulsifier 2) Wetting/ levigating agent 3) Detergent Emulsifier: type of surfactant that is used to reduce the surface tension between oil (liquid) and water (liquid), thus allowing these normally immiscible phases to come together - The appropriate emulsifier needs to be chosen according to its HLB number Suspension: solid dispersed in a liquid. It is a two-phase heterogenous mixture. - Wetting/levigating agents are types of surfactants used to reduce the surface tension between an insoluble drug and a liquid, thus allowing the drug to be incorporated into the liquid, forming a suspension Solution: solute dissolved in a solvent. Solutions are homogenous (consistent, uniform throughout). - Solutions include elixirs, syrups, tinctures, and spirits Precipitation/Sedimentation: happens when the dispersed phase settles/clumps together. This can happen with heterogeneous mixtures (emulsions and suspensions). Sedimentation is the process of solids settling on the bottom of the container. Shake or gently roll to re-disperse back into emulsion/suspension. - Ppt/sedimentation happens less commonly with solutions, but with some (such as insulin), the solid can settle to the bottom and must be re-dispersed prior to use. Preparing Powders: Excipients: - Glidant/lubricant (improves flowability of powder): magnesium stearate - Surfactant (neutralizes static charge and keeps powder from floating away): sodium lauryl sulfate (SLS) - Adsorbent powder (keeps eutectic powders dry when components are mixed together and start to melt at a temp lower than the melting temp of the individual components): magnesium oxide, magnesium carbonate, kaolin 1. Reduce the size of the powder – break tabs down with a grinder, followed by trituration or levigation. 2. After powder has been ground, sift the powder through a sieve onto glassine powder. Stir the powder with a sieve brush or plastic spatula to force particles through the mesh. a. High mesh size has many wires making many holes; only a fine powder will get through the mesh. b. Sieve number: based on # holes/in. (eg. #100 sieve has 100 holes/inch) 3. If the amount of powder per dose is v. small, you need to add an inert filler (diluent – ex. lactose). Fillers are also used to provide a minimum weighable qty if using a torsion balance. Add the filler and other excipients using geometric dilution. Preparing Capsules: Excipients: - Shells: gelatin (animal product) or hypromellose (vegetable product) o Hard-shell capsules: filled with powders (most commonly used in compounding) o Soft-shell capsules: filled with oils - Plasticizers (make capsule less brittle and more flexible): glycerol, sorbitol 1. First, triturate dry ingredients and geometrically mix them with the fillers/other excipients. 2. Hand filling (aka “punch method”): place powder on powder paper or an ointment slab. Smooth the pile of powder with a spatula to a height about a third of the length of one capsule. Take the open end of the capsule and repeatedly “punch” it into the pile of powder until the capsule is filled. When the base is filled, fit it with the cap. 3. Manual capsule-filling machine: these are small devices that help quickly load 50, 100, or 300 capsules. Plates sort the capsule bodies to stand upright and hold them in place. The powder is put above the capsules onto a plastic sheet where a plastic spreader and comb is used to brush the powder into the capsules. The comb and spreader are used repeatedly until the powder is packed into the capsules. Then, the caps are put over the capsule bodies. Preparing Molded Tablets: Notes: - Along with the API, tablets include excipients such as diluents, binders, disintegrants, lubricants, coloring agents, and flavoring agents. - Most common tab type made in compounding: molded tablet - Most common tab type made in manufacturing: compressed tablet 1. Triturate the dry ingredients and mix by geometric dilution. 2. To moisten the powder, add alcohol and/or water. The powder mixture should have a pasty consistency, which can be molded into tablets (using tablet molds) and allowed to dry. 3. If the tab is a lozenge, flavoring, coloring, and coating may be added. Preparing Lozenges (aka Troches): Excipients: - Hard lozenge base: API is contained in a base of sucrose or syrup - Soft lozenge base: API is contained in a base of PEG - Chewable lozenge base: API is contained in a base of glycerin or gelatin - Flavoring agents and coloring agents can be added 1. Base is melted, mixed with API and excipients, placed into a mold, and allowed to cool back into a solid. Lotions, Creams, and Ointments: 5 Ointments Types, Classified by Base: 1) 2) 3) 4) 5) Oleaginous bases (oily/greasy) Absorption bases Water-in-oil (w/o) emulsion bases Oil-in-water (o/w) emulsion bases Water-soluble bases Preparing Ointments: 1. Triturate powders well using a levigating agent. The levigating agent must be miscible with the base. Mix powder into ointment base using geometric dilution. 2. Fusion method: some ointments will require heat to mix components together well. Always use lowest temp possible. First, melt the ingredients with the highest melting point, then add the others in according to their decreasing melting points. Otherwise, undesired chemical reactions could occur. A water bath used to heat ointment components helps prevent over-heating. Pastes: thickest ointments, used as protective barriers Gels: semisolids interpenetrated by a liquid. Pluronic lecithin organogel (PLO gel – lipophilic base in water & alcohol vehicle) is commonly used for transdermal drug delivery. Drugs are dissolved/suspended in the gel. Preparing Suppositories: Excipients: - Suppository bases are either oil-soluble (oleaginous) or water-soluble o Oleaginous bases: cocoa butter (aka Theobroma oil) & hydrogenated vegetable oils (palm, palm kernel, coconut oils) o Water-soluble bases: PEG & glycerinated gelatin - Density factor of drug: the API will displace part of the base. If drug has same density as base, it will displace an equal amt of volume. If drug’s density is greater, it will displace less. If drug’s density is lower, it will displace more. To calculate the amount of base displaced, the density factor of the drug is needed. - Lubricants (applied to mold to make suppositories easier to remove): o Oleaginous bases: glycerin, propylene glycol o Water-soluble bases: mineral oil, vegetable oil spray - Note: suppositories bypass oral route, thereby avoiding first-pass metabolism Vaginal Suppositories Candida infections, dryness/vaginal pain, menopausal sx, contraception (ex. OTC spermicides), hormone replacement suppositories Rectal Suppositories Local condition: hemorrhoids, local infection, rectal pain, distal UC Systemic infection: pain and fever in an NPO pt (ex. APAP suppository) Three Methods of Suppository Preparation: 1. Hand molding: o uses unmelted cocoa butter base. Cocoa butter is not melted; it is grated and then mixed with drug in a mortar & pestle or on a pill tile with a spatula. The mass is rolled into a cylinder, which is cut into suppository-size pieces. A tip is formed on one end to insertion into butt easier. 2. Fusion molding: o Base is gently heated, ingredients are added, and the mixing is poured into room temp molds, then left to congeal. If base is poured into a cold mold, suppositories can crack. If suppository does not congeal, the molds can be refrigerated. Disposable plastic molds can be used for molding. Often, the suppositories are dispensed in the mold because suppositories are soft and easily damaged, so they are stored in the mold (pt takes them home) until needed 3. (Cold) Compression molding: v. different from Fusion Molding, which does not like cold o Pharmacist needs to know the weight of each mold and the drug’s density factor. The amount of base required to fill each mold is calculated, the base is grated, mixed with the drug, and put into a cold compression mold. Preparing Emulsions (must utilize HLB #): HLB #: used to describe how hydrophilic or lipophilic a surfactant is used to choose the right surfactant (range: 0-20) Agents with low HLB # (<10): more oil-soluble used for w/o emulsions (bc oil would be the prominent phase, the continuous/external phase) - Pretend fat has an HLB of 0 Agents with high HLB # (>10): more water-soluble used for o/w emulsions (bc water is the continuous/external phase, aka there’s way more water in an o/w emulsion than there is oil) - Pretend pure water has an HLB of 20 Two Methods of Emulsion Preparation: Continental Gum Method (aka Dry Gum Method): 4 parts oil, 2 parts water, 1 part emulsifier (4 o: 2 w: 1 e) 1. Levigate the gum with oil, then add water all at once. a. Emulsifier used: acacia or another gum-type emulsifier 2. Then shake the mixture to triturate until a cracking sound is heard and the mixture looks creamy white. 3. Add other ingredients by dissolving them first in solution, and QS with water to make the final volume. 4. Homogenize to make the emulsion uniform. English Gum Method (aka Wet Gum Method): also 4 o: 2 w: 1 e with different preparation steps 1. Triturate the gum and water to form a mucilage, then add the oil slowly, while triturating to form the emulsion. 2. Finish the same way as in Dry Gum Method.