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 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.

Reactive Impurities in Excipients: Profiling, Identification and Mitigation of Drug–Excipient Incompatibility

“…Products of the Maillard reaction between the primary amine drug, Vigabatrin, and the monosaccharide component of MCC, i.e., glucose, were implicated in the browning of Vigabatrin tablets on aging. In another study, MCC was found to be responsible for granulation discoloration in a capsule formulation of BMS compound A (9). Approximately 40 ppm of glucose was detected in the particular lot of MCC used in the formulation.…”

Formation of Reactive Impurities in Aqueous and Neat Polyethylene Glycol 400 and Effects of Antioxidants and Oxidation Inducers

“…Reactive impurities such as metal ions, peroxides, low‐molecular‐weight aldehydes and organic acids have been found in trace levels in many pharmaceutical excipients 1–3. These and other excipient impurities have been shown to lead to degradation of the active ingredients in a variety of pharmaceutical formulations 4–9. Trace levels of peroxides, aldehydes, and organic acids in polyethylene glycols (PEG) have often been linked to drug–excipient interactions that lead to instability of the active compound in drug product formulations 2,5,8–11.…”

“…[1][2][3] These and other excipient impurities have been shown to lead to degradation of the active ingredients in a variety of pharmaceutical formulations. [4][5][6][7][8][9] Trace levels of peroxides, aldehydes, and organic acids in polyethylene glycols (PEG) have often been linked to drug-excipient interactions that lead to instability of the active compound in drug product formulations. 2,5,[8][9][10][11] (UV) activity and as a result are difficult to detect.…”

Совместимость Лекарственных И Вспомогательных Веществ При Разработке Лекарственных Форм

“…Çàìåòèì, ÷òî îáðàçóþùèåñÿ îñíîâàíèÿ Øèôôà (ïðèìåñè) èíîãäà ïðèâîäÿò ê ñòîëü èíòåíñèâíîé îêðàñêå ïðåïàðàòîâ, ÷òî îíà ïðîÿâëÿåòñÿ äàaeå ïðè î÷åíü íèçêîì ñîäåðaeàíèè ïðèìåñåé -íà óðîâíå ñîòûõ äîëåé ïðîöåíòà è ìåíüøå. Èìåþòñÿ òàêaeå äàííûå, ÷òî íà íà÷àëüíîì ýòàïå ðåàêöèè Ìàéëàðà ìåaeäó ëàêòîçîé è  ìîaeåò çàïóñêàòüñÿ ðàäèêàëüíàÿ ðåàêöèÿ: â [30] îêèñëåíèå Ë îáúÿñíåíî ðàäèêàëüíûì ïðîöåññîì, çàïóñêàåìûì ïðèìåñüþ â ëàêòîçå.…”