W0081

Pharmaceutical Applications for Crystalline Proteins, Example: Interferon alfa-2b. Paul Reichert and Patricia C. Weber, Department of Structural Chemistry, Schering Plough Research Institute, Kenilworth, NJ 07033-0539 USA.

Several potential applications for protein crystals exist within the pharmaceutical industry. These include the delivery of insulin. Crystallization features prominently in the production of interferon alpha which is the only approved therapeutic for hepatitis C. Interferon alfa-2b (IFN) crystallization methods exist for purification, structure determination, controlled release therapeutics and pulmonary delivery. Details of the methods and their utility will be discussed.

Examples of protein crystallization processes for purification are rare although organic and inorganic compounds are routinely purified using crystallization. A crystallization step suitable for the purification of IFN and of its utility will be described. Kilogram quantities of human interferon alphas have been available since the early 1980’s and several crystal morphologies have been discovered. None were suitable for structure determination however until very recently. Using a metal ion additive screen, a crystal morphology suitable for structure determination was identified and optimized for the X-ray structure of human interferon alfa-2b which has been reported.

Most protein crystallization studies identify and optimize conditions to produce large single crystals suitable for X-ray structural studies. We will describe methods to produce crystalline suspensions where the goal is to produce uniform particles in size and quality suitable for controlled release applications. We will describe processes to prepare sub-micron crystalline suspensions suitable for pulmonary delivery.

Based on these results future experiments are envisioned to investigate alternative applications for biologically active protein crystals.