Chirality and cocrystal systems : from fundamental understanding to development of a novel industrial chiral resolution technique

The study of cocrystals is a research topic that is recently on the rise, particularly in the pharmaceutical field. The incorporation of active pharmaceutical ingredients as cocrystal in the formulation of a drug, allows modifying the physicochemical properties without altering its biological activity. However, the identification of coformers able to cocrystallize with the target molecule remains a tedious work usually performed using a trial-and-error approach. In this work, we propose a more rational approach, based on the structural similarity of two molecules, under the assumption that two molecules with similar molecular structures are more likely to cocrystallize with the same coformers. As a large number of active pharmaceutical ingredients (API) are chiral, we have studied the specificities of chiral compounds in cocrystallization. We highlighted that an enantiopure API seems to prefer forming a cocrystal with only one out of the two enantiomers of a chiral cocrystal former (or coformer). This enantiospecific behavior suggests that a racemic mixture of a given API can be resolved through cocrystallization in solution. In a study system, we not only validated our innovative resolution technique but also showed high efficiency. We also showed that the construction of ternary and quaternary phase diagrams is an effective tool in the pursuit of optimal conditions for chiral resolution. Finally, we looked for cocrystals between a racemate and an enantiopure coformer, as well as cocrystals between two racemates. We noticed that the tendency towards cocrystal formation strongly decreases when racemic compounds are involved.(FSA - Sciences de l) -- UCL, 201

Innovative chiral resolution using enantiospecific co-crystallization in solution

A large number of active pharmaceutical ingredients (API) are chiral. Most of them are synthesized as racemic mixtures, and a chiral resolution step is introduced somewhere along the production process. In this study, we have used the specific hydrogen bonding interactions present in co-crystals to develop a new resolution technique. As these interactions are strongly direction dependent, we highlighted that an enantiopure API only forms a co-crystal with one of two enantiomers of a chiral co-crystal former (or co-former). Unlike salts, a diastereomeric pair cannot be obtained. This enantiospecific behavior of co-crystal candidates suggests that a racemic mixture of this candidate can be resolved through a co-crystallization in solution, which hitherto has not been observed yet. As a study system, we chose (RS)-2-(2-oxopyrrolidin-1-yl) butanamide, as the S-enantiomer is an API and no viable salts of this compound have been identified. The only known resolution technique for this compound is, therefore, based on chiral chromatography. Because of enantiospecific interactions with an S-mandelic acid coformer, we were able to selectively co-crystallize the S-enantiomer in acetonitrile. This enantiospecific co-crystallization in solution has been thermodynamically verified, by construction of ternary phase diagrams at different temperatures. Initial results not only validate our innovative resolution technique through co-crystallization but also furthermore already showed high efficiency, as 70% of the S-enantiomer could be separated from the racemic mixture in a single co-crystallization step. © 2012 American Chemical Society

Ternary and quaternary phase diagrams: Key tools for chiral resolution through solution cocrystallization

The goal of this contribution is to guide the reader through the construction and the understanding of quaternary phase diagrams in the pursuit of optimal conditions for a chiral resolution through cocrystallization in solution. The overall description will be illustrated by experimental results on a system involving RS-2-(2-oxopyrrolidin-1-yl) butanamide as chiral API to be separated, and S-mandelic acid as chiral coformer. © 2013 The Royal Society of Chemistry

Cocrystal formation between chiral compounds: How cocrystals differ from salts

A cocrystal screening on a series of chiral target compounds was performed in order to investigate the propensity for two optically active compounds to cocrystallize in an enantiospecific manner. 13 novel cocrystal systems were identified, out of which 11 are enantiospecific and two present a diastereomeric cocrystal pair, yielding a total of 15 novel cocrystals. 6 out of these are structurally characterized in this study. A meticulous search in the Cambridge Structural Database (CSD) has allowed expanding this study. The results lead us to the conclusion that enantiospecific cocrystallization seems to be the common rule of thumb, as over 85% of cocrystal systems behave enantiospecifically. Directionality of the hydrogen bonding motifs is likely responsible for cocrystals predilection towards enantiospecificity, while salts are mainly stabilized by less directional electrostatic interactions, leading to the formation of diastereomeric pairs

Importance of solvent selection for stoichiometrically diverse cocrystal systems: Caffeine/maleic acid 1:1 and 2:1 cocrystals

Phase diagrams of cocrystals often show a highly unsymmetrical nature. The solvent has an important impact on the overall aspect of these diagrams. In this paper, we show how the solvent affects the composition of the stoichiometric solid phase nucleated. Suitable conditions for nucleation and growth of a single 2:1 caffeine/maleic acid cocrystal are obtained in ethyl acetate, showing comparable solubility toward both caffeine and maleic acid. Through a full kinetic screen, we were able to identify, for the first time, reproducible conditions for the spontaneous crystallization of the 2:1 phase in solution. Furthermore, during the screening experiments, a hithertho unknown form of the 1:1 cocrystal phase was encountered. Structural X-ray diffraction analyses of both the 2:1, as well as the 1:1 polymorphic phases, show an out of plane maleic acid compound. The carboxylic acid groups are oriented in such a manner to promote intermolecular formation of hydrogen bonded synthons. © 2012 American Chemical Society