Cocrystal Synthesis through Crystal Structure Prediction

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