Compounding: Goal remains to fulfill unmet need - DVM
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Compounding: Goal remains to fulfill unmet need


DVM360 MAGAZINE


Because many drugs are not in a form that is ideal for the species being treated (e.g., cats, exotic animals, pet birds), the tablets have been crushed, capsules reformulated and solutions altered to make a more convenient and palatable oral-dosage form. However, when protective coatings are disrupted and vehicles are altered, the stability of the product may be compromised. In some instances, the only change is a slight alteration of pH. Improper pH ranks with exposure to elevated temperature as a factor most likely to cause a clinically significant loss of drug. A drug solution or suspension may be stable for days, weeks or even years in its original formulation, but when mixed with another liquid that changes the pH, it degrades in minutes or days.

It is possible that a pH change of only one unit could decrease drug stability by a factor of 10 or greater. Addition of a water-based solution to a product to create a liquid solution or a suspension results in the hydrolysis of certain compounds (e.g., -lactams and esters). Some drugs undergo epimerization (steric rearrangement) when exposed to a pH range higher than what is optimum for the drug (for example this occurs to tetracycline when exposed to a pH higher than 3.0). Other drugs are oxidized, a reaction catalyzed by exposure to a high pH, rendering the drug inactive. Drugs most likely to be subject to oxidation are those with a hydroxyl group bonded to an aromatic ring structure.

Veterinarians and pharmacists are obligated to be cognizant of the potential for interactions and interference with stability. Oxidation is often visible through a color change (e.g., color change to pink or amber). Loss of solubility may be observed through precipitation. Some drugs are prone to hydrolysis from moisture. A rule-of-thumb for veterinarians is that if a drug is packaged in blister packs or in moisture-proof barrier, it is probably subject to loss of stability and potency if mixed with aqueous vehicles.

If compounded formulations of solid-dose forms show cracking, "caking" or swelling, the formulation has probably acquired moisture and may have lost potency. Another rule-of-thumb is that if the original packaging of a drug is in a light-protected or amber container, it is probably prone to inactivation by light. Vitamins, cardiovascular drugs and phenothiazines are labile to oxidation from light during compounding. Also, as a general rule, if an antibiotic is available in a powder that must be reconstituted in a vial or in an oral dispensing bottle prior to administration, it should not be mixed with other drugs.

In a commercial formulation, the active ingredients and the excipients added to drug formulations are tested and must meet FDA-approved specifications to ensure the stability of the drug and to ensure uniformity in product in vivo performance. However, the addition of other chemicals, flavorings and vehicles, or compromising the protective coatings of tablets may interfere with the stability of the drug, decreasing its potency, compromise its oral absorption and consequently reduce its efficacy. There are published recipes in compounding journals, magazines and handbooks, but few of these formulations have been tested for their stability, potency and purity.

Veterinarians have an obligation to question their compounding pharmacist about the stability and potency of formulations he/she prepares for their patients and to insist on some valid documentation. When veterinarians compound formulations in their own practices, they should be cognizant of potential interactions that may compromise product performance.

Well-documented problems

For some drugs, the problems with compounding are well-known. Fluoroquinolone antibiotics are frequently modified for administration to exotic animals and horses. This class of drugs is compatible with most mixtures and remarkably stable. A notable exception is the chelation of fluoroquinolones with aluminum-containing products (e.g., antacids, sucralfate), resulting in a significant portion of the medication becoming unavailable for absorption. If crushed orbifloxacin tablets are mixed with a vitamin and mineral supplement that is sometimes used as a flavored vehicle for oral drug administration, potency is reduced to half that seen with the original formulation. The decrease in potency is attributed to the high levels of iron contained within this flavorant. Other flavorings and vehicles (for example, corn syrup, molasses, fish sauce, and Syrpalta (thick grape syrup) had no affect on orbifloxacin stability.

Antifungal drugs also are subject to instability. Itraconazole is frequently compounded from bulk drugs or the proprietary capsules. However, during compounding, inactivation may occur. Itraconazole may adsorb to plastic and glassware, decreasing product drug concentrations — the concentrations of itraconazole are either one-half of the intended potency or undetectable from the compounded capsule. Powdered bulk itraconazole is practically insoluble in aqueous solutions and has poor solubility when administered orally.


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Source: DVM360 MAGAZINE,
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