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Abstract

Ritonavir was found to exhibit conformational polymorphism with two unique crystal lattices having significantly different solubility properties. Although the polymorph (form II) corresponding to the "cis" conformation is a more stable packing arrangement, nucleation, even in the presence of form II seeds, is energetically unfavored except in highly supersaturated solutions. The coincidence of a highly supersaturated solution and a probable heterogeneous nucleation by a degradation product resulted in the sudden appearance of the more stable form II polymorph.

Supramolecular gel phase crystallization: orthogonal self-assembly under non-equilibrium conditions

“…The reasons for the change were unknown but were thought to be due to some subtle alteration in manufacturing conditions, particularly impurity profile, and seeding by microscopic particles of the second 35 polymorph. 46 The new form proved to be thermodynamically more stable than the original polymorph. In this regard it obeys the classic Ostwald's step rule which states that in general it is not the most stable, but the least stable polymorph that crystallizes first with increasingly more stable forms crystallising out in 40 stages.…”

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

“…In the case of ritanovir, there is evidence that an impurity crystallized from a solution of the API and acted as a seed on which the previously unknown form II grew. 13 Both the impurity, a product of ritanovir degradation, and form II have the same conformation in a critical part of the molecule in the crystalline state. If material used in initial screening was not synthesized by the same procedure ultimately chosen for GMP production, it will likely have a different impurity profile than does GMP material.…”

Nucleation of crystals that are mixed composites of all three polymorphs in the Gaussian core model

“…2 Controlling which polymorph forms is often of crucial importance, especially in the pharmaceutical industry. 3 Failure to control the polymorph that forms can be disastrous, as illustrated by the problems experienced in the late 1990s with the anti-HIV (human immunodeficiency virus) drug ritonavir. While already in production, an additional and highly stable second polymorph appeared and the carefully formulated drug started to recrystallize in this new form.…”