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 (<i>RS</i>)-2-(2-oxopyrrolidin-1-yl)­butanamide, as the <i>S</i>-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 <i>S</i>-mandelic acid coformer, we were able to selectively co-crystallize the <i>S</i>-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 <i>S</i>-enantiomer could be separated from the racemic mixture in a single co-crystallization step

Advances in Pharmaceutical Co-crystal Screening: Effective Co-crystal Screening through Structural Resemblance

Co-crystal screening was applied under the assumption that two molecules having relatively similar chemical structures are likely to form co-crystals with identical coformers, in an attempt to improve co-crystal screening efficiency. Piracetam and Levetiracetam were used as model compounds. Both molecules are racetam compounds and have a relatively similar molecular structure. Eleven co-crystals of Piracetam have been described in the literature using ten different acids. These ten acids were selected as potential coformer candidates for the preparation of Levetiracetam co-crystals. Four co-crystals of Levetiracetam were successfully identified by solvent drop and neat grinding: Levetiracetam–d-tartaric acid 1:1 (LDTA), Levetiracetam–<i>R</i>/<i>S</i>-mandelic acid 1:1 (L­(RS)­MA), Levetiracetam–<i>S</i>-mandelic acid 1:1 (LSMA), and Levetiracetam–2,4-dihyroxybenzoic acid 1:1 (L2,4DHBA). The overall success rate of 40% shows the usefulness of the presented approach. Structural investigation shows the increased success rate to most likely be due to the proficiency of two similar molecules to share the same driving force for assembling multicomponent systems with similar coformers

Advances in Pharmaceutical Co-crystal Screening: Effective Co-crystal Screening through Structural Resemblance

Co-crystal screening was applied under the assumption that two molecules having relatively similar chemical structures are likely to form co-crystals with identical coformers, in an attempt to improve co-crystal screening efficiency. Piracetam and Levetiracetam were used as model compounds. Both molecules are racetam compounds and have a relatively similar molecular structure. Eleven co-crystals of Piracetam have been described in the literature using ten different acids. These ten acids were selected as potential coformer candidates for the preparation of Levetiracetam co-crystals. Four co-crystals of Levetiracetam were successfully identified by solvent drop and neat grinding: Levetiracetam–d-tartaric acid 1:1 (LDTA), Levetiracetam–<i>R</i>/<i>S</i>-mandelic acid 1:1 (L­(RS)­MA), Levetiracetam–<i>S</i>-mandelic acid 1:1 (LSMA), and Levetiracetam–2,4-dihyroxybenzoic acid 1:1 (L2,4DHBA). The overall success rate of 40% shows the usefulness of the presented approach. Structural investigation shows the increased success rate to most likely be due to the proficiency of two similar molecules to share the same driving force for assembling multicomponent systems with similar coformers

How Cocrystallization Affects Solid-State Tautomerism: Stanozolol Case Study

Three original cocrystals of stanozolol with monoacidic and diacidic coformers are presented and fully characterized in this study. Powder X-ray diffraction (PXRD) permits cocrystal formation to be highlighted, with the help of liquid-assisted grinding (LAG) from the two starting coformers. Single-crystal X-ray diffraction (SCXRD) gives a detailed structural characterization, which allows comparison with existing structures coming from the Cambridge Structural Database (essentially stanozolol solvates) and determination of structural similarities between the new cocrystal structures and the existing ones. As stanozolol can exist under two tautomeric forms (on its pyrazole moiety), statistical and theoretical studies have been performed in order to better apprehend the potential appearance of one of its tautomers at the cost of the other in crystal structures, and the eventuality of “freezing” the molecule in one of these forms by cocrystallization

Advances in Pharmaceutical Co-crystal Screening: Effective Co-crystal Screening through Structural Resemblance

Co-crystal screening was applied under the assumption that two molecules having relatively similar chemical structures are likely to form co-crystals with identical coformers, in an attempt to improve co-crystal screening efficiency. Piracetam and Levetiracetam were used as model compounds. Both molecules are racetam compounds and have a relatively similar molecular structure. Eleven co-crystals of Piracetam have been described in the literature using ten different acids. These ten acids were selected as potential coformer candidates for the preparation of Levetiracetam co-crystals. Four co-crystals of Levetiracetam were successfully identified by solvent drop and neat grinding: Levetiracetam–d-tartaric acid 1:1 (LDTA), Levetiracetam–<i>R</i>/<i>S</i>-mandelic acid 1:1 (L­(RS)­MA), Levetiracetam–<i>S</i>-mandelic acid 1:1 (LSMA), and Levetiracetam–2,4-dihyroxybenzoic acid 1:1 (L2,4DHBA). The overall success rate of 40% shows the usefulness of the presented approach. Structural investigation shows the increased success rate to most likely be due to the proficiency of two similar molecules to share the same driving force for assembling multicomponent systems with similar coformers