Impact of antioxidant addition on drug dissolution: Implications for NDSRI mitigation biowaivers

Abstract

Nitrosamine impurities have garnered recent attention due to their presence in pharmaceuticals and their mutagenic risks. Recent studies have emphasized controlling impurities and suggest ways to mitigate the further formation of nitrosamines by the addition of antioxidants to tablets and capsules. Recent Food and Drug Administration (FDA) guidance supports this, however, practical experience with this new guidance update remains limited.

This study investigates the impact of added antioxidants on dissolution of diclofenac potassium tablets. Six antioxidants were tested for their effect on in vitro dissolution. Two tablet formulation families of 50 mg diclofenac potassium were fabricated with and without antioxidant. Tablets were subjected to quality testing, including in vitro dissolution in United States Pharmacopeia Simulated Intestinal Fluid (USP SIF) and in sodium bicarbonate buffer. Dissolution profiles were compared using the similarity factor f₂.

All tablets using ascorbic acid, cysteine, or sodium bicarbonate did not impact dissolution in USF SIF and sodium bicarbonate buffer, per a liberal interpretation of f₂ calculation in the 1997 FDA dissolution guidance, except formulation B tablets with antioxidant sodium bicarbonate in sodium bicarbonate buffer.

Meanwhile, due to coning, all tablets using caffeic acid, fumaric acid, or sodium ascorbate slowed dissolution in USF SIF and sodium bicarbonate buffer, except formulation B tablets with antioxidant sodium ascorbate. Overall, results point towards the feasibility of added antioxidant to not impact dissolution.

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Materials

Diclofenac potassium was purchased from Chem Shuttle (Burlingame, CA). Microcrystalline cellulose, croscarmellose sodium and dibasic calcium phosphate were purchased from JRS Pharma (Patterson, NY). Anhydrous lactose (Supertab21) was purchased from DFE Pharma (Paramus, NJ). Pregelatinized starch was purchased from Colorcon (Westpoint, PA). Magnesium stearate was purchased from Spectrum (New Brunswick, NJ). All antioxidants (i.e., ascorbic acid, cysteine, sodium bicarbonate, caffeic acid, fumaric acid, and sodium ascorbate), potassium phosphate, sodium hydroxide, sodium chloride, sodium bicarbonate and all organic solvents were purchased from SigmaAldrich (St. Louis, MO). Marketed tablets of diclofenac potassium 50 mg (Advagen; Plainsboro, NJ) were commercially obtained.

Rutu R. Valapil, James E. Polli, Impact of antioxidant addition on drug dissolution: Implications for NDSRI mitigation biowaivers, International Journal of Pharmaceutics, 2025, 125806, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2025.125806.