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

摘要

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 degrees C (closed) for at least 18 weeks, but they showed discoloration. The 2.5-mg capsule exhibited degradation after four weeks at 40 degrees 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 (H2(18)O) 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.