Polymorphism ritonavir

Zhang, G.G. Law, D. Schmitt, E.A. Qiu, Y. Bauer, M. Bauer, J. Spanton, S. Henry, R. Quick, J. Dziki, W. Porter, W. Morris, J. Highleyman, L. Phase transformation considerations during process development and manufacture of solid oral dosage forms [Crystallization and solid state properties of molecules of pharmaceutical interest] Ritonavir an extraordinary example of conformational polymorphism Ritonavir manufacturing problems. Adv. Drug. Deliv. Rev. 2004, 56 (3), 371-390. 

The case study of Ritonavir [19] is valuable in highlighting the potential consequence of a previously unknown polymorph appearing in a pharmaceutical product. It has made a far reaching impact on the industry and the thoroughness of polymorph screening. 

Ritonavir is a product of Abbott Laboratories Ltd. for the treatment of HIV and is marketed as Norvir , in liquid and semisolid capsule formulations. It received FDA approval for market launch in march 1996, at which time only one polymorphic form of Ritonavir (Form I) was known. Two years later in early 1998 a laboratory responsible for testing the formulated product in the US reported dissolution test failures of the semisolid capsules, and noted that drug product had precipitated out of solution. A new polymorphic form had been discovered that was thermodynamically more stable than the existing form and approximately 5 times less soluble in the formulation. Figure 7. 

Chemburkar, S. R., et. al., 2000, Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development, Organic Process R D, 4, 413-417. 

Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, Morris J. Ritonavir an extraordinary example of conformational polymorphism. Pharm Res 2001 18(6) 859—866. 

If Form I could no longer be prepared reproducibly, then Abbott needed to be able to develop a viable formulation of Form II. Both plans were fully executed. After considerable work, the process group discovered a number of contributing factors to the appearance of Form II. Ultimately, the solution to the problem was a simple one batches of ritonavir were seeded with Form I crystals to encourage precipitation of the desired polymorph. 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

Table 4. Results of stable polymorph screen of ritonavir. Data from Miller et al. (2005).

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