Stabilization of Oxidation Prone Ingredients

Sarah Taylor, PharmD
Academy Director
August 17, 2022

One of the constant struggles compounding pharmacists face is the stabilization of ingredients and formulations that are subject to change depending on a patient’s specific needs and conditions. Compatibility of different individual ingredients and combinations of ingredients at a wide potential range of concentrations can be difficult to ascertain without trial, error, and observation in the lab.

In this newsletter, we will discuss a few active pharmaceutical ingredients (APIs) that often cause issues and review stabilizers that can be added that have demonstrated efficacy for reducing oxidation.

Some ingredients commonly used for hyperpigmentation or other cosmetic conditions, such as aging skin are prone to oxidative degradation. Common examples include hydroquinone, kojic acid, and tretinoin.1 The degradation of hydroquinone and kojic acid is associated with a darkening of color usually to a yellowish or brownish hue that is easily visually detectable.2,3 Tretinoin is also susceptible to degradation by oxidation.4 The bulk powder itself is already a yellow color, and unlike with kojic acid and hydroquinone, significant color change may not be observed in association with degradation of tretinoin.

Interventions such as preventing prolonged exposure to light can help to prevent oxidation and degradation of these APIs.4 We should also consider the addition of chemicals called antioxidants to help prevent degradation of these APIs. Antioxidants work to prevent free radicals, which are atoms, molecules, or ions with unpaired electrons, from causing oxidation that, in the context of pharmaceuticals, can result in rapid drug degradation or generation of unwanted metabolites.5

Common antioxidants include vitamin E, ascorbic acid, ascorbyl palmitate, buylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, sodium metabisulfite, and sodium bisulfite among others. Choosing an antioxidant or a series of antioxidants can be challenging. Properties to consider when choosing an antioxidant include route of administration, solubility of antioxidant and characteristics of the compounded preparation, as well as APIs in question.

Some antioxidants such as BHA, BHT, and vitamin E have solubility in organic solvents such as ethanol, and propylene glycol or solubility in oils. These antioxidants are part of a group of antioxidants referred to as phenolic antioxidants and are commonly used in anhydrous preparations consisting of organic solvents or oils.6 Ascorbyl palmitate, a partially lipid soluble form of ascorbic acid, also has solubility in organic solvents.

Bisulfites including sodium metabisulfite and sodium bisulfite, in addition to citric acid, and ascorbic acid are all soluble in aqueous environments and are commonly used as antioxidants in aqueous based preparations such as creams, gels, or solutions.6 In aqueous environments, pH can play a factor in activity of a given antioxidant, for example, sodium metabisulfite has greater activity at pH in the acidic range and can undergo autoxidation if exposed to elevated pH, whereas BHA is stable up to a pH of 9.7

In addition to solubility and pH, another factor to consider is how your antioxidants work together, for example, vitamin E and ascorbyl palmitate are often used together due to a synergistic effect improving their antioxidant capabilities. Oftentimes, a combination of antioxidants are used together in compounded topical preparations to stabilize our oxidation prone ingredients.

There are many factors that affect which antioxidant is best for a given preparation including route of administration, API we intend to stabilize, and chemical and physical characteristics of the vehicle. To help you organize this material, Fagron Academy has put together a chart you can click here to view that offers a summary of a few common antioxidants, which routes they are typically used for, the concentration typically used, as well as information on solubility and temperature stability.


1. Bandyopadhyay D. Topical treatment of melasma. Indian J Dermatol. 2009;54(4):303-9. doi: 10.4103/0019-5154.57602.

2. Enguita FJ, Leitão AL. Hydroquinone: environmental pollution, toxicity, and microbial answers. Biomed Res Int. 2013;2013:542168. doi: 10.1155/2013/542168.

3. Draelos Z, Yatskayer M, Bhushan P, Pillai S, Oresaho C. Evaluation of kojic acid, emblica extract, and glycolic acid formulation compared with hydroquinone 4% for skin lightening. Therapeutics for the Clinician. 2010; 86: 153-158.

4. Del Rosso JQ, Pillai R, Moore R. Absence of Degradation of Tretinoin When Benzoyl Peroxide is Combined with an Optimized Formulation of Tretinoin Gel (0.05%). J Clin Aesthet Dermatol. 2010;3(10):26-28.

5. Lü JM, Lin PH, Yao Q, Chen C. Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems. J Cell Mol Med. 2010;14(4):840-860. doi:10.1111/j.1582-4934.2009.00897.x

6. Musakhanian, J., Rodier, JD. & Dave, M. Oxidative Stability in Lipid Formulations: a Review of the Mechanisms, Drivers, and Inhibitors of Oxidation. AAPS PharmSciTech 23, 151 (2022).

7. Rowe R, Sheskey P, Cook W, Fenton M. Handbook of Pharmaceutical Excipients. Philadelphia, PA: Pharmaceutical Press.

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Sarah Taylor, PharmD
Academy Director

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