Sherry L. Morissette

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

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” [Dunitz, J. D. & Bernstein, J. (1995) Acc. Chem. Res. 28, 193–200]. 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.

Application of high throughput technologies to drug substance and drug product development

Abstract This presentation describes the application of novel high throughput physical–chemical technologies to the pharmaceutical discovery and development process. The rationale for such platforms is described in light of the changes that have occurred in the biological and chemical processes leading to drug target evaluation and lead identification. Several high throughput platforms are described for identification and evaluation of solid forms and formulations of drug candidates including salt, hydrate and solvate selection and polymorph discovery and evaluation. The application to the development of oral and intravenous formulations for animal model and human clinical evaluation is also discussed. The importance of informatics to design experiments and capture and analyze data is highlighted. Examples are described showing the power of high throughput systems to discover knowledge that enables pharmaceutical scientists to make more informed and better decisions about product development choices.