Drug compounding: issues affecting safety and efficacy (Proceedings)
The use of compounded products in veterinary medicine is a common practice due to the lack of approved veterinary drugs and convenient, palatable administration forms. There is no regulation of pharmacies that compound drugs for veterinary use. There are no standard formulas available to pharmacies to guide them on the optimum methods for ensuring a quality product. Variation in product potency and stability is rarely, if ever tested. Additionally, the effect of storage conditions on the stability of these drugs in aqueous vehicles or in syrups has not been reported. An understanding of the rules and regulations, as well as the pharmacologic principles surrounding compounding practices, is necessary in order to ensure that the safest, most effective method of treatment is being used.
Why do we worry about compounded preparations?
Compounded drugs have not been evaluated by the FDA approval process for safety, efficacy, stability, potency and consistency of manufacturing. Therefore, you should not assume compounded drugs are consistent from one batch to another, contain the stated amount of drug substance, or are safe and efficacious for the intended use.Some compounded drug formulations can present problems if the safety and potency of the compounded product have not been considered. Tablets that must be crushed or broken to deliver a smaller dose size to dogs or cats may be unpalatable for oral use in animals. When drugs are administered to cats, either a portion of a tablet must be given, or the drug is reformulated into a capsule. Because ill cats are usually anorectic and because cats generally do not drink water frequently, solid dose forms have become trapped in the esophagus of cats. The latter problem was documented in two studies in which capsules were orally administered to cats. The location of the entrapment of capsules is particularly disturbing because some medications given to cats such as doxycycline, tetracycline, propranolol, iron supplements, and bromide are known to cause esophageal lesions in experimental cats.
The vehicle used for compounding may affect the drug in several ways. In some instances, the only change is a slight alteration of pH. But, according to the USP-NF, "... a pH change of only one unit could decrease drug stability by a factor of ten or greater." This change in stability may be secondary to stearic rearrangement or oxidation of the compound. Compounding often involves tablets being crushed, or capsules being reformulated, to make a more convenient and palatable oral dosage form. During this process, protective coatings are disrupted, which exposes the drug to the pH of the vehicle.
Storage temperature also can affect drug stability in compounded formulations. Package inserts for drug products contain strict recommendations for storage conditions, and the labels for compounded formulations often state specific storage temperatures. Accelerated degradation can be seen when drugs are exposed for short periods of time to temperatures of 40-60°C. These are similar to temperatures that the drugs can be exposed to if they are improperly stored in barns or inside vehicles. Both metronidazole and chloramphenical have shown an accelerated degradation at high temperatures when dissolved in aqueous vehicles. Other drugs, are degraded at lower temperatures (<5°C) or during the process of freezing and thawing. Compounded products stored in barns during the winter months may experience freezing temperatures and undergo daily freeze-thaw cycles during the course of treatment which may also adversely affect the stability of the drugs. Ora-Sweet may precipitate in cold temperatures, which will adversely affect drug solubility.
Drugs formulated as acids—such as the hydrochloride form of basic drugs—are designed to maintain their solubility in aqueous solutions. However, when these formulations are mixed with drugs that are basic, or are added to basic vehicles, drug precipitation may occur.
Several drugs are not soluble in aqueous vehicles. Therefore they are dissolved in organic solvents (propylene or ethylene glycol for example), or alcohols. These are notoriously unpalatable to some animals, particularly cats. However, if these formulations are diluted in aqueous fluids, or aqueous flavorings added, precipitation may occur. When these are stored at home by the pet owner, precipitation of the drug to the bottom of the container results in the dosing of a dilute mixture when the container is sampled from the top and a highly concentrated mixture when the container is sampled from the bottom (assuming that the precipitate at the bottom can be re-suspended). This also may be observed when mixing some drugs in aqueous fluids. For example if diazepam solution (which contains propylene glycol and alcohols) is diluted in saline solution or lactated Ringer's solution, precipitation occurs.