Degradation of a fluoropyridinyl drug in capsule formulation: Degradant identification, proposed degradation mechanism, and formulation optimization

被引：10

作者：

Chen, JG ^{[1
]}

Markovitz, DA ^{[1
]}

Yang, AY ^{[1
]}

Rabel, SR ^{[1
]}

Pang, J ^{[1
]}

Dolinsky, O ^{[1
]}

Wu, LS ^{[1
]}

Alasandro, M ^{[1
]}

机构：

[1] Dupont Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA

来源：

PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY | 2000年 / 5卷 / 04期

关键词：

degradation chemistry; DMP; 543; fluoropyridinyl drug; formulation development;

D O I：

10.1081/PDT-100102039

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The purpose of this paper was to investigate the degradation chemistry of a fluoropyridinyl drug candidate in capsule formulation and to optimize the formulation based on a proposed degradation mechanism. Small developmental batches of capsules were made by tituration of drug substance and excipients using a mortar and pestle, followed by manual encapsulation. Degradants were identified by LC-MS/MS and LC-photodiode away detector (PDA) and were monitored by LC-ultraviolet detector (UVD) during stability studies. It was found that the drug could undergo a nucleophilic substitution reaction in which hydroxyl groups replace the fluorine substituents on the pyridine rings. The initial degradation rate is independent of the drug concentration but dependent on the temperature, the pH of the microenvironment, and the excipient type. On the basis of these experimental results, a nucleophilic substitution reaction mechanism for the degradation was proposed and a successful capsule formulation was developed.

引用

页码：561 / 570

页数：10