Cocrystal Synthesis through Crystal Structure Prediction

• DOI: 10.1021/acs.molpharmaceut.2c01098
• Publication Date: 2023-06-07T02:38:09Z
• Authors: Yuriy A. Abramov; Luca Iuzzolino; Yingdi Jin; Gregory York; Chien-Hung Chen; C. Scott Shultz; Zhuocen Yang; Chao Chang; Baimei Shi; Tian Zhou; Chandler Greenwell; Sivakumar Sekharan; Alfred Y. Lee
• Keywords: Cocrystal

Crystal structure prediction (CSP) is an invaluable tool in the pharmaceutical industry because it allows to predict all possible crystalline solid forms of small-molecule active ingredients. We have used a CSP-based cocrystal method rank ten potential coformers by energy cocrystallization reaction with antiviral drug candidate, MK-8876, and triol process intermediate, 2-ethynylglyclerol. For was performed retrospectively successfully predicted maleic acid as most likely be observed. The known form two different cocrystals 1,4-diazabicyclo[2.2.2]octane (DABCO), but larger landscape desired. screening triol-DABCO one, while triol-l-proline two. Computational finite-temperature corrections enabled determination relative crystallization propensities stoichiometries polymorphs free-energy landscape. obtained during subsequent targeted experiments found exhibit improved melting point deliquescence behavior over triol-free acid, which could considered alternative synthesis islatravir.