(503a) Selection and Crystallization Development of a Practical Salt Form for a Pharmaceutical Compound

This paper presents a fully integrated solid form screen and crystallization development workflow for the development of an active pharmaceutical ingredient (API) at BI. Salt I of an in-licensed compound was initially used in the Phase I and Phase IIa studies. However, Salt I was later characterized as an ethanolate/hydrate and had several development issues, including the high and variable moisture content and unstable physical/chemical properties under various conditions (heat, humidity, mechanical and light). As a result, a new salt form that can provide better developability was required that triggered extensive salt/polymorph screen and selection activities, in order to select a new salt form to be used for Phase IIb and beyond.

After a thorough solid form screen and selection process, Salt II, with its superior physicochemical properties to the other crystalline salts identified, was chosen as the new development form. In the initial development, a workable process (Process I) was developed in EtOH/Heptane that was able to produce multiple kilo scale of Salt II to supply for the formulation development. The particle size was controlled by dry milling initially. Later, a more comprehensive crystallization development was conducted to address several development challenges, including the purification of the major impurity from the synthesis, hydrolysis of the compound in the crystallization system, color removal and powder property control, etc. A new modified process (Process II) was successfully developed, enabled by the selection of appropriate solvent system and design of crystallization condition that can inhibit the hydrolysis of the compound during crystallization. Process II used milled seeds and controlled crystallization to directly produce the desired particle size distribution without milling. Process II was successfully scaled up to multiple 30 kg batches in the Pilot Plant.