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By Andrew Glasnapp, PharmD, PCCA Senior Clinical Compounding Pharmacist
Compounding pharmacists have always diligently worked to maintain the stability of the compounds they produce. In PCCA’s Clinical Services department, we see this every day as we take numerous inquiries involving the issue of stability. The questions come in all kinds of variations like, “Will an active ingredient be stable in heat?” “Is it stable in water?” “How can I add more viscosity to a compound?” “What kind of container should the preparation be dispensed in?” “What kind of storage condition should be required?” “What should this compound look like?”
Recently, we’ve noticed a new question among the varied world of stability inquiries. Many compounding pharmacists are asking how they can document the stability of their compounds. This may be because of the proposed USP Chapter 795 guidelines on nonsterile compounded products. Section 8 of the proposed guidelines is titled Release Inspections. This section directs the pharmacist to produce a more formal stability check of each compound produced. A visual inspection of each compound is required to be documented on the master formula. The proposed guidelines also require verification that the label matches the original prescription as well as a check of the container closure system prior to dispensing the compound. Very soon, we may be required to step up the monitoring and documentation of our compounds’ stability.
This may seem like another daunting task in the list of new requirements for compounders. However, if we review of some most common stability issues and seek out the key chapters in USP for help, we can make this requirement useful, simple and functional.
USP Chapter 1191, Stability Considerations in Dispensing Practice, is a great resource to help compounders understand and comply with the new proposed release-inspections requirements of USP 795. In this chapter, USP defines stability and shares the five components of the overall stability of a compound. USP also shares the major factors affecting the stability of compounds. Near the end of the chapter, USP discusses many different dosage forms and shares the key issues that should be reviewed. This information should be very helpful in documenting and producing appropriate information for release-inspections requirements. Let’s take a closer look at USP 1191 and see just how helpful it can be.
Also on The PCCA Blog: Proposed Changes to USP 795
USP defines stability as the extent to which a product retains the same properties and characteristics that it had when it was produced throughout its shelf life. We don’t want to see any changes in our compounded preparation over the extent of its beyond-use date. The general stability of a compound is made up of five different types of stability: chemical, physical, microbiological, therapeutic and toxicological. Chemical stability means each active pharmaceutical ingredient (API) maintains its chemical integrity and potency. Physical stability means that properties like appearance, solubility, suspendability and particle size are maintained. Microbiological stability means that resistance to microbial growth is maintained. Therapeutic stability means the therapeutic effect does not change. Toxicological stability means that there is no significant increase in toxicity. When appropriate, these five stability types would be good to consider during release inspections.
USP 1191 discuses 11 factors that affect the stability of products. Of those 11, four factors are the most critical and common for compounded preparations: heat, light, oxidation and hydrolysis.
Many commonly compounded dosage forms require heat during their preparation. This includes suppositories, troches, lollipops and rapid dissolve tablets (RDTs). However, some APIs like liothyronine sodium (T3) and oxytocin are very susceptible to degradation below or near the temperature required to make these dosage forms, so compounders need to use caution.
A frequent request is to make oxytocin troches. The bases for troches typically require a temperature of 50-65° C for melting. At PCCA, we studied the degradation of oxytocin by heating it to 55° C and maintaining that temperature for five minutes. The oxytocin had a potency loss of 10%. This illustrates that oxytocin should not be exposed to heat and that another dosage form like sublingual drops or sprays should be considered in place of a troche.
Seasonal changes in temperature should also be considered especially if the compound is being shipped. During those periods of weather, insulated shipping packaging may be needed. This should also be considered when receiving chemicals.
Heat also universally increases the speed of chemical reactions. When considering degradation reactions like hydrolysis and oxidation, each 10° increase in temperature may cause an exponential increase in the degradation rate of an API. In an extreme example described in USP Chapter 1191, for instance, a drug that is susceptible to hydrolysis and is exposed to a 20° increase in temperature may lose up to 96% of its shelf life. Not all hydrolizable chemicals would degrade this much in a case like this, but it does illustrate the need to be aware of how heat can affect a drug.
Below are the general temperature ranges required to compound various dosage forms that require heat for preparation, though the actual temperature may vary by the formula ingredients, including the base used, as well as the process. For example, RDTs are typically baked at 110° C for 15 minutes, but if using PCCA’s base RDT-Plus™, they can be baked at 80° C for 30 minutes. For lollipops, the temperature is commonly taken up to 160° C, but the compounder would not add the API until after it dropped back to 90° C.
Some APIs are sensitive to light. Light can cause photo-oxidation and photolysis. Light may also produce free radicals, which are chemical intermediates that can perpetuate chain reactions. Therefore, it’s always a good idea to dispense compounds in light-resistant containers if possible.
Tretinoin is an example of a drug that is sensitive to UV light. In a study, Del Rosso et al. (2012) showed that when exposed to UV light for eight hours, there was 9% degradation of micronized tretinoin in one type of gel and 72% degradation of tretinoin in another gel. While the difference in chemical degradation was significant between the two products, even the one with 9% degradation is cause for concern.
Methylcobalamin is very light sensitive when in water. However, its appearance will not change when exposed to light. When compounding with methylcobalamin, beakers and vessels should be wrapped in aluminum foil to minimize exposure to light. It should always be stored in a light-resistant container as well.
Apomorphine, by contrast, does change color when exposed to water and light. It changes from a grayish-white appearance to a dark greenish-black appearance, and compounders should take proper precautions to limit its exposure to light.
Hydroquinone has a molecular structure with two hydroxyl groups directly bonded to an aromatic ring. That structure makes hydroquinone very likely to oxidize. Other chemical structures susceptible to oxidation include conjugated dienes (free fatty acids) and heterocyclic aromatic rings (nitroso derivatives).
The chemical structure of hydroquinone (pictured above), with its two hydroxyl groups bonded to an aromatic ring, makes it very likely to oxidize.
When hydroquinone oxidizes, it turns brown and loses activity as a therapeutic ingredient. Epinephrine is another common agent used in compounding that turns brown when oxidized, accompanied with loss of therapeutic activity.
Amides and esters are the chemical bonds that are most likely to hydrolyze in the presence of water. Aspirin, for instance, is hydrolyzed to acetic acid and salicylic acid in the presence of water, but in a dry environment, the hydrolysis of aspirin is insignificant. It’s helpful to recognize molecules that contain amide and/or ester functional groups to identify potential hydrolysis and design formulations that are anhydrous when necessary.
An amide functional group (pictured above) is a chemical structure within a molecule that, among other things, makes that molecule more likely to decompose in the presence of water.
An ester functional group (pictured above) is a chemical structure that gives molecules various properties, including the tendency to break down in the presence of water.
Below are common signs that various compounded dosage forms have stability issues. Pharmacies that observe such evidence should take the proper steps to ensure that their selection and storage of ingredients as well as their compounding and storage of medications prevent these stability issues.
Many solid dosage forms are designed for storage in low-moisture conditions. They require protection from environmental water and should be stored in airtight containers. The appearance of condensation, liquid drops or clumping of the product signifies improper conditions. A change in the physical appearance or consistency, including hardening or softening of the capsule shell, is evidence of instability.
As an example, betahistine dihydrochloride is very hygroscopic and often compounded into capsules. Pharmacies must take care to avoid exposure to environmental moisture during the compounding process and to avoid exposure during storage. Pharmacists should visually check that capsules are not softened and stuck together prior to dispensing.
Precipitation and evidence of excessive microbial growth (such as dark areas or streaks, or a change in odor) are signs of instability in solutions, elixirs and syrups.
The breaking of an emulsion (separation of the oil phase that is not easily redispersed) is a sign of instability.
A caked solid phase that cannot be resuspended by a quick shaking and/or the presence of large particles may mean that excessive crystal growth has occurred. Both are signs of instability in suspensions.
Creams are emulsions containing water and oil. Emulsion breakage, crystal growth, shrinking due to water evaporation and evidence of microbial growth (such as dark areas or streaks, or a change in odor) are signs of instability.
Changes in consistency, excessive “leaking” (separation of liquid) and formation of particles (grittiness) are signs of instability in ointments.
Excessive softening, brittleness and changes in melting point are all signs of instability in suppositories.
On your journey to step up the monitoring of your compounds’ stability, we hope this information helps you perform and document appropriate release inspections. This is just a start, though, and compounding pharmacies should familiarize themselves with the appropriate USP chapters, including USP 1191, to ensure that they are maintaining the stability of the medications they compound. PCCA Members with Clinical Services support can contact our team of clinical compounding pharmacists for any questions they have about monitoring and documenting the stability of their compounds.
Also on The PCCA Blog: Choosing the Appropriate Antimicrobial Preservative for Compounded Medication
Andrew Glasnapp, PharmD, FAPC, PCCA Senior Clinical Compounding Pharmacist, has been a registered pharmacist since 1990 and has worked for PCCA since 1993. He has served as a clinical instructor in drug information for both the University of Houston and the University of Arizona colleges of pharmacy. Andrew is also a past member of the compounding task force of the Iowa Pharmacists Association and the compounding section of the Texas Pharmacy Association’s executive committee.