By Susan Elrod, BS, PharmD, PhD

Out of necessity, many drugs used in veterinary medicine are available in multiple formulations. The sheer quantity of species treated in this profession requires a wide range of doses and formulations be available for our patients.

In order to accommodate the vast diversity of treatment options for veterinary patients, various products are used. Commercial products may be either formulated specifically for veterinary patients or human products re-purposed for veterinary use.

Additionally, many drugs are compounded into formulations appropriate for veterinary doses. This compounding may involve the preparation of liquid at a drug concentration so the volume administered to a patient is not prohibitively large, or formulated into a delivery system more tolerable to a patient, such as a topical administration.

This flexibility in dosing concentrations and formulations introduces unique responsibilities to the veterinary pharmacist and dispenser; any medication dispensed to a patient must be proven to maintain stability for a reasonable amount of time. Indeed, if a commercial product is not used, the pharmacy compounding the medication must provide information on how long the drug is stable and what circumstances may be required for the medication to remain safe and effective.

What follows are details on how such stability is determined and how veterinarians can help educate clients on the specific storage requirements for their pets' medications.

Definition of 'stability'

Drug stability is defined as the extent to which a preparation maintains the same properties it had at the time of formulation.

This is a normal part of commercial drug development, and demonstration of such stability is required as part of the approval process.

In order to be determined stable, the drug product must maintain the same physical and chemical properties as at formulation, the therapeutic levels must remain appropriate, and microbial sterility must be preserved.

This stability must apply to the product as a whole, not just the active drug ingredient. This is essential for compounded medications, because inactive ingredients may interact with the active drug to cause degradation or may allow contamination to occur.

The prevention of such degradation and contamination relates directly to storage requirements of formulations. Below, we will discuss mechanisms of degradation, appropriate storage methods to prevent such degradation, and guidelines for maintaining sterility.

Mechanisms of drug degradation

Hydrolysis: An extremely common mechanism of drug degradation is hydrolysis,¹ or the reaction of water molecules with specific functional groups on the drug molecule. Ester and amide groups are part of many drug compounds and are especially susceptible to hydrolysis.

When water is introduced to the drug environment, a reaction occurs: a portion of the ester or amide leaves the parent compound and a carboxylic acid group is formed in its place. Esters form alcohol groups as a result of hydrolysis; amides form amine groups.

Ester drugs include ACE inhibitors, aspirin, and NSAIDs. Amide drugs include penicillins and cephalosporins. While amide drugs are less susceptible to hydrolysis than esters, it still limits drug stability.

This is the reason why these antibiotics are supplied as powders to be reconstituted prior to administration; once water is introduced, there is a finite period (10 to 14 days, depending on the product) before enough of the drug is hydrolyzed and drug levels drop below the acceptable range. Other drugs susceptible to hydrolysis include benzodiazepine, digoxin, heparin, and corticosteroids.

Ironically, the medicine cabinet is one of the worst places to keep medications. Heat can increase the rate of hydrolysis, which means steam (containing both heat and water) can accelerate the degradation of drugs kept in the bathroom medicine cabinet. This is why most drug packages contain the instruction to store in a cool, dry location.

Counsel clients to follow these instructions for any medication, not just their pets. It is also important they understand the appropriate amount of time to keep using reconstituted Clavamox and other antibiotic suspensions.

Photodegradation: In addition to keeping drugs cool and dry, many should also be protected from sunlight.

Certain drug molecules absorb UV light, and the molecule enters an excited state, becoming more chemically reactive. Free radicals are generated in this process, leading to photodegradation2 or oxidation, in the drug itself, which will cause drug instability.

Oxidative species in the drug may also interact with lipids, proteins, or DNA in patients who ingest the drug, potentially causing irritation or toxicity. Some drugs such as NSAIDs, fluoroquinolones, tetracycline, furosemide, vitamins, corticosteroids, and phenothiazines (chlorpromazine, etc.), are susceptible to photodegradation, along with far too many to list here. You can find more comprehensive lists in the references below.^3,4

This is why most prescription medications are dispensed in amber bottles. The amber color filters out UV light and prevents photodegradation. Although not all medications are subject to this process, most pharmacy professionals dispense all medications in amber bottles out of convenience. If the pharmacy does not use amber vials for all medications, they should still dispense photosensitive drugs in appropriate containers. It is best to counsel clients to keep the medication stored in the original dispensing container to avoid the possibility of photodegradation.

Oxidationt: Drugs are also subject to reaction with oxygen itself. A chain process may occur in which reactive species are generated, react with molecules, and generate further reactive species. As with hydrolysis, oxidation is a part of endogenous metabolism, and this type of drug degradation must be inhibited prior to administration.

Fortunately, this type of drug degradation is prevented during the manufacturing process. Medications are formulated with pharmaceutical antioxidants, such as ascorbic acid and propylgallate, to protect the active drug during storage. Compounded drugs may also have antioxidants added (see below for discussion of beyond-use dates).

Shelf-life

Most veterinarians probably recall the concept of half-life; in the context of pharmacokinetics, this is the time required for the plasma concentration of a drug in the body to decrease by half.

A similar concept can be applied to a pharmaceutic substance, with content of the active drug in the formulation being measured rather than plasma concentration.

However, for a drug product used medically, the time it will take for it to decrease by half is not clinically useful; no drug should be used if only half the original concentration is still present. This is why the shelf-life calculation is used instead of half-life.

Instead of measuring the amount of time it takes a drug to decrease by half in the body, the shelf-life measures the amount of time required for the drug to degrade by 10 percent. This, along with various other factors relating to integrity of the drug and formulation, is how commercial manufacturers typically calculate expiration date.

In some cases, it may be safe to use a drug for longer than the manufacturer expiration date. The drug may lose effectiveness, but is unlikely to be actively harmful. Of course, if the drug is required to maintain the patient's health, even a small decrease in effectiveness may still be harmful.

Another concern is drugs degrading to harmful products, such as tetracycline, which degrades to 4-epianhydrotetracycline;⁵ this compound can induce Fanconi-like syndrome,⁶ with nausea, vomiting, acidosis, proteinuria, and other ill effects. While recent evidence suggests these effects may be reversible, best practice dictates discouraging clients from using expired medication for their pets.

Compounded medicine guidelines

For compounded medications, United States Pharmacopeia guidelines⁷ regarding the beyond-use date (BUD) should be observed. The BUD is used for compounded medication that has not been subjected to the same rigorous tests as commercially available medications. In general, water-based products can be used for 14 days if prepared without preservatives, and 35 days if preservatives are included; this is due to another potential drug instability: microbial contamination.

Depending on how the formulation was prepared, these BUDs may be extended if the product is refrigerated or frozen. Formulations not incorporating water (i.e. compounded in simple syrup, etc.) can be used for 90 days. Solid dosage forms, such as compounded capsules, can be used for 180 days. These guidelines apply to products that have not been independently tested; certain compounded pharmacies and laboratories may have subjected their products to analysis justifying a later beyond-use date. 

Summary

With the disparate medications and formulations used for the wide range of patients seen in veterinary medicine, it is important to counsel clients on proper storage conditions for their medication. Unless explicitly stated otherwise, most medications should be stored in a cool, dry place away from sunlight (i.e. not in the bathroom), ideally in their original container.

Be especially mindful of compounded medications that may have shorter beyond-use dates and/or special storage recommendations, such as refrigeration. For specific concerns, a pharmacist should be able to give the client more information regarding proper drug storage.

Susan Elrod, BS, PharmD, PhD, received her PharmD in 2008 and her PhD in pharmaceutical and biomedical sciences in 2014, both from the University of Georgia, where much of her research was conducted at the College of Veterinary Medicine. She has taught pharmaceutics, pharmacokinetics, pharmacology, and other topics at the University of Georgia College of Pharmacy, South University School of Pharmacy, and Arizona State University. Dr. Elrod currently works as a clinical lecturer and pharmacist at Auburn University College of Veterinary Medicine. 

References

1. The Pharmaceutical Journal, October 2010;DOI:10.1211/PJ.2021.1.72642.
2. Janga, K.Y., King, T., Ji, N. et al. Photostability Issues in Pharmaceutical Dosage Forms and Photostabilization. AAPS PharmSciTech. 2018;19, 48–59. https://doi.org/10.1208/s12249-017-0869-z
3. University of Illinois at Chicago College of Pharmacy, Drug Information Group. Light-sensitive injectable prescription drugs. Hosp Pharm. 2014;49(2):136-163. doi:10.1310/hpj4902-136
4. Perkins S, Evans A, King A. Updated List of Light-Sensitive Oral Medications. Hospital Pharmacy. 2020;55(6):349-365. doi:10.1177/0018578719844699
5. Pena A, Carmona A, Barbosa A, et al. Determination of tetracycline and its major degradation products by liquid chromatography with fluorescence detection. J Pharm Biomed Anal. 1998 Dec;18(4-5):839-45. doi: 10.1016/s0731-7085(98)00268-4. PMID: 9919986.
6. Benitz K-F, Diermeier HF. Renal Toxicity of Tetracycline Degradation Products. Proceedings of the Society for Experimental Biology and Medicine. 1964;115(4):930-935. doi:10.3181/00379727-115-29082
7. https://www.usp.org/sites/default/files/usp/document/our-work/compounding/usp-bud-factsheet.pdf