(730f) Polymorphism in the Development and Scale-up of Reactive-Crystallization of an Active Pharmaceutical Ingredient

Polymorphism in the Development and Scale-up of Reactive-crystallization of an Active Pharmaceutical Ingredient

Haitao Zhang, Kostas Saranteas

Chemical Process Research & Development, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, Massachusetts 01752, U.S.A.

Abstract

Polymorphism is widely observed in pharmaceutical compounds and continues to be an important issue in drug development because of its impact on the physicochemical properties of drugs. It is well recognized that polymorphism and solvate formation affect the various pharmaceutically important physicochemical properties, such as stability, solubility, dissolution rate, crystal habit (shape), tableting behavior. Crystallization is a crucial step in the pharmaceutical industry in terms of the understanding and further control over the polymorphism during the manufacturing of active pharmaceutical ingredients (APIs).

Herein is described the observed polymorphic behavior of the API SEP-363856-01 in the reactive-crystallization process. This API is crystallized out from isopropanol (IPA) as the HCl salt through the addition of HCl/IPA to an IPA solution of the SEP-363856 freebase. As the API crystallizes it displays two distinct morphologies, the first a block like crystal (Form A) and the second a needle like crystal (Form B). Single crystal x-ray diffraction has shown Form A has a monoclinic crystal system while Form B has an orthorhombic crystal system. The experimental results indicate that the supersaturation control during the addition of HCl/IPA is critical in terms of the polymorphism control. Polymorphism transformation of kinetically preferred Form B to thermodynamically stable Form A is observed during a solvent-mediated phase transition in isopropanol. It has been shown that the transformation of Form B needles to Form A blocks is influenced by the quantity of Form B present and is accelerated with increasing temperature. A controlled HCl/IPA addition strategy has been proposed and successfully implemented in the lab development and scale-up manufacturing campaign. With this, the generation of unstable form B crystal can be avoided in the first place.

Solid phase polymorphism transformation is observed as well. The isolated samples of Form B needles held in the laboratory for a period of time yield a more rod like morphology, however XRPD analysis shows this morphology is consistent with the Form A blocks.  Single crystal x-ray diffraction has shown Form A has a monoclinic crystal system while Form B has an orthorhombic crystal system.