Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development

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• 作者：Sanjay R. Chemburkar ; John Bauer ; Kris Deming ; Harry Spiwek ; Ketan Patel ; John Morris ; Rodger Henry ; Stephen Spanton ; Walter Dziki ; William Porter ; John Quick ; Phil Bauer ; John Donaubauer ; B. A. Naray
• 刊名：Organic Process Research & Development
• 出版年：2000
• 出版时间：September 2000
• 年：2000
• 卷：4
• 期：5
• 页码：413 - 417
• 全文大小：550K
• 年卷期：v.4,no.5(September 2000)
• ISSN：1520-586X

文摘

Ritonavir (Kempf, D. J.; Marsh, K. C., Denissen, J. F.;McDonald, E.; Vasavanonda, S.; Flentge, C. A.; Green, B. E.;Fino, L.; Park, C. H.; Kong, X. P.; Wideburg, N. E.; Saldivar,A.; Ruitz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart,K. D.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W.Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 2484) is Abbott's novelprotease inhibitor, for human immunodeficiency virus (HIV),the causative organism of acquired immunodeficiency syndrome(AIDS). It is marketed as Norvir. From the discovery ofritonavir until the new drug application (NDA) filing, only onecrystalline form was known to exist. Attempts to identify otherpossible crystal forms were unsuccessful. Two years after thelaunch of Norvir to the market, some lots of Norvir capsulesfailed a dissolution specification. Investigation of this phenomena revealed the existence of a crystal form of ritonavir otherthan the one already known (Form I). This new crystal formwas designated as Form II. The two crystal forms are polymorphs and differ substantially in their physical properties suchas solubility. In this article, we will discuss the challenges thesepolymorphs created for the bulk drug substance as well as forthe formulation, and how we dealt with these challenges.