Understanding drug-excipient compatibility: Oxidation of compound A in a solid dosage form

Abstract

Drug-excipient compatibility studies lay the foundation for designing a chemically stable formulation for clinical and commercial development. This article describes the investigation of oxidative degradation encountered with compound A (a phenylalanine-drug complex) in a capsule dosage form. Two wet- granulation capsule formulations (2.5-mg and 25-mg strengths) were developed using excipients that showed satisfactory stability from initial drug-excipient compatibility studies. Both capsule strengths were chemically stable at 50°C (closed) for at least 18 weeks, but they showed discoloration. The 2.5-mg capsule exhibited degradation after four weeks at 40°C/75%RH (open) besides discoloration. LC/MS analysis indicated that the degradants were oxidation products of the parent compound. Oxidation of compound A was investigated by forced degradation with peroxide, use of isotopically labeled water (H₂¹⁸O) to study the source of oxygen, and use of different antioxidants to mitigate oxidation. Excipient(s) responsible for oxidation and discoloration were identified through extended and modified excipient compatibility studies. The discoloration was indicative of Maillard reaction occurring between a reducing sugar impurity from microcrystalline cellulose and L-phenylalanine in the drug complex. Reactive oxidative species generated by this reaction is postulated to cause oxidation of compound A.

Keywords::

• Drug-excipient compatibility
• oxidation
• solid dosage form
• degradants
• antioxidants
• discoloration
• maillard reaction
• reactive oxidative species
• free radicals
• microcrystalline cellulose

Acknowledgements

The authors would like to thank Drs Frank Hu and Ken Ray for performing UPLC/MS analysis for the degradants. We would also like to acknowledge Drs Ajit Thakur and Munir Hussain for helpful discussions during the course of the study and preparation of this manuscript.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.