Dealing with the impact of ritonavir polymorphs on the late stages of bulkdrug process development

Ritonavir (Kempf, D, J,; Marsh, K, C,, Denissen, J. F,; McDonald, E,; Vasav anonda, S,; Flentge, C, A.; Green, B, E,; Fine, L,; Park, C, H,; Kong, X, P ,; Wideburg, N, E.; Saldivar, A.; Ruitz, L,; Kati, W. M.; Sham, H, L,; Robi ns, T,; Stewart, K, D,; Hsu, A.; Plattner, J, J,; Leonard, J, hi,; Norbeck, D, W, Proc. Natl. Acad. Sci, U.S.A. 1995, 92, 2484) is Abbott's novel prot ease inhibitor, for human immunodeficiency virus (HIV), the causative organ ism of acquired immunodeficiency syndrome (AIDS), It is marketed as Norvir. From the discovery of ritonavir until the new drug application (NDA) filin g, only one crystalline form was known to exist. Attempts to identify other possible crystal forms were unsuccessful. Two years after the launch of No rvir to the market, some lots of Norvir capsules failed a dissolution speci fication. Investigation of this phenomena revealed the existence of a cryst al form of ritonavir other than the one already known (Form I), This new cr ystal form was designated as Form II. The two crystal forms are polymorphs and differ substantially in their physical properties such as solubility. I n this article, we will discuss the challenges these polymorphs created for the bulk drug substance as well as for the formulation, and how we dealt w ith these challenges.