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

Abstract

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 novel protease inhibitor, for human immunodeficiency virus (HIV), the causative organism of acquired immunodeficiency syndrome (AIDS). It is marketed as Norvir. From the discovery of ritonavir until the new drug application (NDA) filing, only one crystalline form was known to exist. Attempts to identify other possible crystal forms were unsuccessful. Two years after the launch of Norvir to the market, some lots of Norvir capsules failed a dissolution specification. Investigation of this phenomena revealed the existence of a crystal form of ritonavir other than the one already known (Form I). This new crystal form was designated as Form II. The two crystal forms are polymorphs and differ substantially in their physical properties such as solubility. In 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 with these challenges.

Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals

“…A culminating event was the temporary removal from the market of the life-saving protease inhibitor Norvir in 1998, which occurred because of the appearance of a previously unknown polymorph of the active ingredient ritonavir. 10 The marketed dosage form of Norvir consisted of gel-caps filled with a solution containing ritonavir. The new crystalline form is more stable, and therefore less soluble, than the old form and crystallized out of solution inside the gel-caps, rendering the formulation unmanufacturable.…”

Probing Pseudopolymorphic Transitions in Pharmaceutical Solids using Raman Spectroscopy: Hydration and Dehydration of Theophylline

“…A well-known example of this problematic quality-activity relationship of a final dosage form is the case of Norvir 1 brand of ritonavir semisolid capsules. [1][2][3][4] Commercial start-up of the drug as a semisolid capsule formulation began in the early 1996, but 2 years later most of the final product lots started to fail in the dissolution tests. It was found that during storage, the drug converted to a new, until then unknown, thermodynamically more stable but less soluble polymorph of ritonavir, leading to a loss of bioactivity.…”

“…It was found that during storage, the drug converted to a new, until then unknown, thermodynamically more stable but less soluble polymorph of ritonavir, leading to a loss of bioactivity. [1][2][3][4] Another example of loss of activity has been reported for phenytoin (a drug used to control epilepsy), due to storage of the capsules in damp and cool conditions. 5 This has generated a demand to develop fast and flexible methods of measurement of polymorphic and pseudopolymorphic transformations inline during pharmaceutical processing and storage procedures.…”

Crystal Forms of Anti-HIV Drugs: Role of Recrystallization

“…The late emergence of a thermodynamically more stable form (Form II) which unexpectedly precipitated from the semisolid capsule formulation led to the removal of the product from the market. The new crystal form (form II) appeared after conversion of metastable crystalline form I (Chemburkar et al, 2000;Bauer et al, 2001;Desikan et al, 2005;Miller et al, 2005). Ritonavir polymorphism was investigated using solid state spectroscopy and microscopy techniques including solid state NMR, near infrared spectroscopy, powder Xray diffraction and single crystal X-ray analysis.…”