Crystal form control and particle size control of RG3487, a nicotinic α7 receptor partial agonist

This paper describes solid form control and particle size control of RG3487, a nicotinic receptor partial agonist. Four crystal forms were identified by polymorph screen under ∼100 varying conditions. Form A and Form B are anhydrates, while Forms C and D are solvates. Forms A, which is enantiotropically related to Form B, is the more thermodynamically stable form under ambient conditions and the desired form selected for clinical development. The crystal form control of Form A was achieved by crystallization solvent selection which consistently produced the desired form. Several process parameters impacting particle size of Form A in the final crystallization step were identified and investigated through both online and offline particle size measurement. The investigation results were utilized to control crystallization processes which successfully produced Form A with different particle size in 500 g scale.

Graphical abstractThis paper describes the crystal form control and particle size control of a drug candidate, RG3487. Based on polymorph screen results and form stability investigation, the crystal form control was achieved by appropriate crystallization solvent selection which consistently produced the desired solid form. The particle size control was successfully accomplished by tuning key crystallization parameters, including HCl addition temperature, agitation rate, MTBE addition time and hold times. As a result, three batches of drug substances in 500 g scale with the right crystal form and intentionally different particle sizes were produced for downstream formulation development.Figure optionsDownload full-size imageDownload high-quality image (111 K)Download as PowerPoint slide