Your browser doesn't support javascript.
loading
Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.
Adams, Monica L; Sharma, Vijayata; Gokhale, Madhushree; Huang, Yande; Stefanski, Kevin; Su, Ching; Hussain, Munir A.
Afiliação
  • Adams ML; Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903. Electronic address: monica.adams@bms.com.
  • Sharma V; Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
  • Gokhale M; Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
  • Huang Y; Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
  • Stefanski K; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, New Jersey 08648.
  • Su C; Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, New Jersey 08648.
  • Hussain MA; Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
J Pharm Sci ; 105(4): 1478-88, 2016 Apr.
Article em En | MEDLINE | ID: mdl-26921118
ABSTRACT
BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
Assuntos
Palavras-chave

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonas / Imidazóis Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sulfonas / Imidazóis Idioma: En Ano de publicação: 2016 Tipo de documento: Article