Analysis of Enantiospecific and Diastereomeric Cocrystal Systems by Crystal Structure Prediction

Cocrystals offer two novel variants on the classic salt formation method of chiral resolution. Diastereomeric cocrystal pairs are directly analogous to salts but without the requirement for proton transfer. Conversely, a coformer that cocrystallizes with one enantiomer but not the other (enantiospecific cocrystallization) has recently been shown to give high enantiomeric yield. For either variant an understanding of intermolecular interactions is vital. In this study computational crystal structure prediction (CSP) is applied to three recently reported examples: levetiracetam with mandelic acid and with tartaric acid, which display enantiospecific cocrystallization, and tartaric acid with malic acid, which forms a diastereorneric cocrystal pair. The ability of CSP techniques to predict the experimental cocrystal structures is demonstrated. The chirally selective interactions are determined using the unique capabilities of CSP, with reference to alternative structures for each cocrystal system, including the hypothetical diastereorneric twins of the levetiracetam cocrystals. In each case, chiral selectivity can be described in terms of the dominant R-2(2)(8) dimer's response to the change in enantiomer. It is concluded that when designing a cofornier for chiral resolution a predilection toward a single, orientationally restrictive intermolecular motif, with minimal ability to form alternative motifs, is the best strategy.