Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization

Abstract

Pharmaceutical compounds are molecular solids that frequently exhibit polymorphism of crystal form. One high profile case of polymorphism was ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996. In 1998, a lower energy, more stable polymorph (form II) appeared, causing slowed dissolution of the marketed dosage form and compromising the oral bioavailability of the drug. This event forced the removal of the oral capsule formulation from the market. We have carried out high-throughput crystallization experiments to comprehensively explore ritonavir form diversity. A total of five forms were found: both known forms and three previously unknown forms. The novel forms include a metastable polymorph, a hydrate phase, and a formamide solvate. The solvate was converted to form I via the hydrate phase by using a simple washing procedure, providing an unusual route to prepare the form I ''disappearing polymorph'' Crystals of form I prepared by using this method retained the small needle morphology of the solvate and thus offer a potential strategy for particle size and morphology control. C rystalline polymorphism, or the ability of a compound to exist in multiple solid-state structures (1, 2), has significant impact on the physical properties, performance, and safety of an active pharmaceutical ingredient (API) and its formulated product(s). Hence, control of drug substance polymorphism is of major importance in drug discovery and development and is monitored carefully by the regulatory agencies. Thorough understanding of the relationship between the physical form and the physicochemical and͞or functional properties of an API is critical in selecting the most suitable form for development into a drug product. However, standard industry methods of solid form discovery rely on manual processes that are time consuming and often limited in scope because of the small amounts of material available at early stages of development. To overcome these challenges, high-throughput crystallization systems have been developed (3-5) permitting rapid and more comprehensive exploration of solid form diversity with only small amounts (Ͻ1 mg per trial) of API. Such systems also facilitate evaluation of the utility of all possible physical forms of a drug substance, enable rapid selection of the optimal solid form, and, thus, can accelerate the development process while minimizing the risk of downstream form-related manufacturing and performance issues (2).Ritonavir [Norvir, Abbott Laboratories, North Chicago, IL (5S,8S,10S,11S)-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester] is an important AIDS drug (6, 7) that garnered much attention when a previously unknown, thermodynamically more stable polymorph appeared unexpectedly, having serious implications for the marketed product and the patients taking the drug. During development and initial manufacture of ritonavir, only one monoclinic cryst...

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Polymorph Impact on the Bioavailability and Stability of Poorly Soluble Drugs

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

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