(302c) A Novel Approach to Achieve Clarifying Filtration for Poorly Soluble Organic Compounds and to Improve Polymorphic Control during Reactive Crystallization

Derdour L.

GlaxoSmithKline,

Drug Substance Development, Material Sciences. lotfi.x.derdour@gsk.com

1250 S. Collegeville Road, Collegeville, PA 19426, USA.

Abstract

In recent years, a gradual decrease in drug solubility both in aqueous and in organic media has been noted (Derdour1). From a manufacturing perspective, low solubility creates challenges to achieve clarifying filtration in the final particle forming step, an operation required to ensure removal of all foreign particulates prior to API particle isolation. Low solubility also results in high supersaturation which favors the precipitation of metastable undesired solid forms. In this presentation, a novel approach that enables clarifying filtration for poorly soluble ionizable drugs is presented. In addition, the approach allows a significant control of the polymorphic purity compared to the previous process. The approach is based on the formation of a soluble intermediate soluble salt, on which the clarifying filtration is achieved. The intermediate salt is then crystallized, and the desired salt is recovered via a combined counter-ion swap and crystallization. This process provided the robustness needed for scale-up to commercial scale.

Keywords: Clarifying filtration, reactive crystallization, polymorphic control, Induction time.

1: Derdour L., A pathway to first crystals for substances prone to Liquid-Liquid phase separation, Chem. Eng. Technol., 44(3), 488–494, 2021