18.3 Nonsterile Compounding

Nonsterile compounding under USP <795> produces preparations that do not require sterility — oral capsules, oral suspensions, topicals, ointments, creams, and suppositories. Although sterility is not required, the chapter enforces standards for ingredient quality, equipment, documentation, and beyond-use dating. The DHA Pharmacist blueprint emphasizes four areas: geometric dilution, suppository bases, creams versus ointments, and nonsterile BUDs.

Geometric Dilution

When a potent active ingredient must be distributed evenly through a large amount of excipient, geometric dilution ensures uniform potency. The procedure:

1. Place the active ingredient in a mortar.
2. Add approximately an equal volume of excipient and triturate thoroughly.
3. Double the total quantity by adding an amount of excipient equal to the current mixture, and triturate.
4. Continue doubling until all the excipient has been incorporated.

For example, to distribute 10 mg of a potent drug in 400 mg of lactose: mix 10 mg drug + 10 mg lactose (total 20 mg); add 20 mg lactose (total 40 mg); add 40 mg (total 80 mg); add 80 mg (total 160 mg); add 160 mg (total 320 mg); add 80 mg (total 400 mg). The doubling pattern ensures the potent drug is progressively diluted rather than dumped into the full excipient at once, which would leave uneven pockets of high concentration.

Exam trap: Geometric dilution is used when the active ingredient is potent and low-dose relative to the excipient. It is unnecessary for 1:1 or near-1:1 mixtures.

Suppository Bases

A suppository base must melt or dissolve at body temperature, release the drug, and be physically stable during storage. Three families appear on the exam:

Cocoa Butter (Theobroma Oil)

Cocoa butter is a natural triglyceride base that melts around 30–35 °C, just below body temperature. Its key problem is polymorphism: cocoa butter has at least four crystalline forms (α, β′, β, and γ) with different melting points (roughly 18 °C for γ up to 36 °C for β). Rapid overheating converts the stable β form to lower-melting forms, so a suppository prepared from overheated cocoa butter may melt at room temperature and never resolidify properly. The practical rule is to heat cocoa butter gently (no higher than about 36–37 °C) and cool slowly.

Synthetic Fatty Bases (Fattibase, Witepsol)

Synthetic bases are manufactured to a defined melting point and lack the polymorphism of cocoa butter. Fattibase and Witepsol are common examples. They melt reproducibly, require less careful heating, and generally produce more stable suppositories. Most modern compounding uses these instead of cocoa butter.

Water-Soluble Bases

Polyethylene glycol (PEG) bases and glycerinated gelatin are water-soluble. They dissolve rather than melt in the rectal vault, releasing drug by dissolution. They are useful when the drug is heat-sensitive (because the base can be prepared with minimal heating) or when an oleaginous base is undesirable. PEG bases can cause rectal irritation in some patients.

Exam trap: If a question describes a cocoa butter suppository that melted during storage after being overheated during preparation, the answer is polymorphic conversion from the stable β form to a lower-melting metastable form.

Creams Versus Ointments

The distinction rests on emulsion type and washability:

A cream is an oil-in-water emulsion — oil droplets dispersed in a continuous aqueous phase, so water is the external phase and the product feels non-greasy and rinses off. An ointment is either a water-in-oil emulsion or an oleaginous base (petrolatum) with no water; the external phase is oleaginous, so the product is occlusive and greasy.

Exam trap: Absorption ointments (hydrophilic petrolatum) are still o/w-absorbing bases that can take up water, but the final ointment applied to skin remains oleaginous externally. Do not confuse an absorption base with a cream.

Equipment for Nonsterile Compounding

• Mortar and pestle — manual trituration; glass mortar for stains/odors; Wedgwood or porcelain for coarse grinding.
• Electronic mortar and pestle — motorized trituration for uniform mixing.
• Ointment mill (three-roller mill) — reduces particle size for smooth topical preparations; used for ointments and creams requiring fine particle dispersion.
• Suppository molds — calibrated to a specific weight per cavity; the base must be calibrated to the mold so each suppository contains the intended dose.

Beyond-Use Dating for Nonsterile Preparations

Under the older USP <795>:

The revised USP <795> (effective November 2023) sets simpler default maximum BUDs:

• Non-aqueous formulations: default maximum 90 days
• Water-containing formulations: default maximum 14 days (refrigerated as appropriate)

A shorter BUD applies whenever stability data, the active ingredient's expiration, or specific formulation factors require it. A longer BUD is permissible only with supporting stability data.

The governing principle on the exam: choose the shorter of the USP default maximum and the ingredient stability limit; never assign a BUD longer than USP allows without specific stability evidence.

Documentation and Quality

USP <795> requires a master formulation record (the recipe) and a compounding record (what was actually made, including lot numbers, quantities, who compounded, who verified). Ingredients must have appropriate certificates of analysis, and equipment must be calibrated. Although nonsterile preparations do not require the environmental controls of sterile compounding, the compounding area must be clean, organized, and separated from dispensing activity.