Characterization of a Unique Co-crystal of the BACE1 Inhibitor Verubecestat and a Reaction Intermediate: Implications for the Development of a Commercial Manufacturing Process

Laura Artino, Richard Varsolona, Andrew P. J. Brunskill, William J. Morris, David A. Thaisrivongs, Jacob H. Waldman, Thomas W. Lyons, Yanke Xu

Index: 10.1021/acs.oprd.8b00015

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Abstract

Verubecestat is an inhibitor of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) that is currently under clinical evaluation for the treatment of prodromal Alzheimer’s disease. This article describes the characterization of a co-crystal composed of a HBr salt of verubecestat and a HBr salt of a reaction intermediate as the components. This unique co-crystal was formed during production of a multikilogram batch of verubecestat. The impact of this observation is discussed, followed by the description of a modified procedure that served to prevent the formation of this highly unusual crystalline material.