Section 2.11: Non-sterile Compounding & Product Formulation
Key Takeaways
- USP <795> governs non-sterile compounding, classifying preparations as simple, moderate, or complex based on formula complexity and stability.
- Trituration involves grinding dry powders in a mortar and pestle to reduce particle size, while geometric dilution ensures uniform distribution of potent ingredients.
- Levigation is the process of wetting a powder with a viscous liquid (levigating agent) to create a smooth paste before incorporation into a base.
- Beyond-Use Dates (BUDs) under USP <795> are based on the presence of water, with non-aqueous formulations capped at 180 days and aqueous oral suspensions capped at 14 days refrigerated.
- Quality control documentation requires a Master Formulation Record (the recipe) and a Compounding Record (the log of the specific batch prepared).
Non-sterile Compounding & Product Formulation
Non-sterile compounding is the process of preparing customized drug formulations that are not required to be sterile. Examples include oral solutions, suspensions, capsules, ointments, creams, and suppositories. The primary regulatory standard governing these practices is USP Chapter <795>, which ensures that products are compounded with appropriate strength, purity, and quality, and packaged in suitable containers.
USP <795> Compounding Categories
USP <795> divides non-sterile compounding into three categories based on complexity and risk:
- Simple: Compounding that involves following a manufacturer's reconstitution instructions or a peer-reviewed, established formula where all components are stable (e.g., reconstituting an oral antibiotic suspension, preparing a topical cream by mixing two commercial ointments).
- Moderate: Compounding that requires special calculations, preparations where stability data is unavailable, or mixing ingredients with specialized dosage forms (e.g., compounding a suspension from tablets, molding suppositories).
- Complex: Compounding that requires highly specialized equipment, facilities, training, or advanced procedures (e.g., modified-release tablets, transdermal patches).
Core Compounding Techniques and Terminology
To ensure uniformity and quality, compounding pharmacists use specific mechanical techniques:
1. Particle Size Reduction
- Trituration: Grinding a dry, solid drug substance in a mortar and pestle to reduce the particle size. This increases the surface area, promoting faster dissolution or smoother blending.
- Pulverization by Intervention: Used for crystalline substances (e.g., camphor) that do not easily grind. The substance is dissolved in a volatile solvent, triturated while the solvent evaporates, leaving behind a fine powder.
2. Incorporation and Wetting
- Levigation: The process of reducing the particle size and grittiness of an insoluble powder by compounding it with a small amount of a viscous liquid (the levigating agent). This forms a smooth paste. The levigating agent must be compatible with the final base:
- Mineral Oil: Used for hydrophobic bases (oleaginous, absorption, water-in-oil bases).
- Glycerin or Propylene Glycol: Used for hydrophilic bases (oil-in-water bases, water-soluble bases).
- Spatulation: Blending powders or semisolids on an ointment slab using a spatula. This technique is useful for eutectic mixtures (compounds that liquify when mixed, such as phenol and menthol).
3. Mixing
- Geometric Dilution: A fundamental technique used when mixing a small amount of potent drug with a large quantity of diluent/base. The active drug is mixed with an equal volume of the diluent. A volume of diluent equal to this new mixture is then added, and the process is repeated until all ingredients are fully blended. This ensures homogenous distribution of the drug.
Formulation Bases: Ointments and Semisolids
Ointment bases act as vehicles for topical drug delivery. They are classified into five groups based on physical properties:
- Oleaginous (Hydrocarbon): Insoluble in water, non-washable, emollient, occlusive, greasy; does not absorb water. Example: White Petrolatum.
- Absorption: Insoluble in water, non-washable, can absorb water; greasy, occlusive. Example: Aquaphor, Lanolin.
- Water-in-Oil (W/O) Emulsion: Insoluble in water, poorly washable, contains water; emollient, greasy. Example: Cold Cream, Hydrous Lanolin.
- Oil-in-Water (O/W) Emulsion: Soluble in water, washable; "water-washable" bases; non-greasy, cosmetically elegant. Example: Hydrophilic Ointment, Dermabase.
- Water-Soluble: Soluble in water, washable, greaseless; lipid-free, absorbs water. Example: Polyethylene Glycol (PEG) ointment.
Stability and Beyond-Use Dates (BUD)
A beyond-use date (BUD) is the date after which a compounded preparation must not be used. Under USP <795> guidelines, in the absence of specific stability testing, default BUDs are determined by the presence of water and water activity ($a_w$):
- Non-aqueous Formulations: Capped at a maximum of 180 days (6 months) or the earliest expiration date of any individual component. Stored at controlled room temperature.
- Water-containing Oral Formulations: (e.g., oral suspensions, solutions). Capped at a maximum of 14 days under refrigeration ($2^\circ\text{C to }8^\circ\text{C}$).
- Water-containing Topical/Dermal and Mucosal Liquid and Semisolid Formulations: (e.g., creams, gels, topical emulsions). Capped at a maximum of 30 days at room temperature. Important: Any ingredient's expiration date that is shorter than the default BUD will overwrite the BUD.
Compounding Documentation
USP <795> requires thorough documentation to track quality:
- Master Formulation Record (MFR): The "recipe" for compounding. It includes the official name, strength, dosage form, ingredients, quantities, equipment needed, and step-by-step instructions.
- Compounding Record (CR): The "log" of the specific batch prepared. It includes the MFR source, individual lot numbers of ingredients, expiration dates, actual weights measured, the name of the compounder, date of compounding, and a unique prescription number.
Step-by-Step Worked Formulation Example
A pediatrician prescribes a $1.5%\text{ w/v}$ Spironolactone oral suspension for an infant. The pharmacist must compound $100\text{ mL}$ of this suspension. The recipe requires using $25\text{ mg}$ commercial Spironolactone tablets, a vehicle containing equal parts of Ora-Sweet (a sweetening agent) and Ora-Plus (a suspending agent).
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Calculate the amount of Spironolactone needed:
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Determine the number of 25 mg tablets required:
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Compounding Procedure:
- Place the $60$ tablets in a glass mortar and grind (triturate) to a fine powder.
- Measure $50\text{ mL}$ of Ora-Plus and $50\text{ mL}$ of Ora-Sweet.
- Add a small amount of the Ora-Plus to the powder in the mortar and rub to form a smooth paste (levigation).
- Gradually add the remaining vehicle in small portions using geometric dilution, transferring the contents quantitatively to a calibrated amber bottle.
- Rinse the mortar with the remaining vehicle and add it to the bottle to reach exactly $100\text{ mL}$.
- Label the bottle with a BUD of 14 days, and instruct the parents to refrigerate and shake well before use.
Which compounding technique should be utilized when mixing a very small quantity of a potent drug powder into a much larger volume of ointment base to ensure uniform drug distribution?
Under USP <795>, what is the default maximum beyond-use date (BUD) for a water-containing oral formulation (e.g., reconstituted amoxicillin powder compounded into a suspension) in the absence of stability information?
A pharmacist is compounding a sulfur ointment. To reduce the particle size of the sulfur powder and prevent a gritty texture, she rubs the powder on an ointment slab with a small amount of glycerin. What is this process called?