Enabling Enantiopurity: Combining Racemization and Dual-Drug Co-crystal Resolution

A new process methodology to obtain enantiopure (<i>S</i>)-Ibuprofen has been designed. Starting from racemic Ibuprofen, co-crystallization with Levetiracetam is used as a resolution tool to obtain only the target enantiomer, (<i>S</i>)-Ibuprofen, in the solid state. The resulting mother liquor, enriched in (<i>R</i>)-Ibuprofen, is recovered and submitted to a racemization cycle, after which another co-crystallization step is introduced. Levetiracetam can be recovered from the co-crystal phase and reused, resulting in an economical use of the resolution agent. Overall, a novel approach to transform a racemic compound into enantiopure material has been developed

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

Crystallizing Ionic Cocrystals: Structural Characteristics, Thermal Behavior, and Crystallization Development of a Piracetam-CaCl₂ Cocrystallization Process

In this study, we aim to develop a robust crystallization process for the ionic cocrystal between piracetam and CaCl₂. We discuss the structural characteristics of the piracetam-CaCl₂ cocrystal and its thermal behavior; furthermore, we develop a robust crystallization process by construction of appropriate phase diagrams. CaCl₂ and piracetam form an ionic dihydrate cocrystal with formula piracetam₂·CaCl₂·2H₂O, in which the Ca²⁺ cation adopts an octahedral coordination with the oxygens of four different molecules of piracetam and of two water molecules. According to the TGA, DSC, and VT-XRPD, the cocrystal exhibits improved thermal stability compared to the parent drug compound. In this article we show how one can develop a robust, water-based cocrystallization process for ionic cocrystals, a relatively underexplored part of the cocrystal landscape. We also discuss the common ion effect on cocrystallization, and show how a common ion can strongly impact on the solubility of the cocrystal, as well as its constituting components. In addition, a common ion will also strongly impact the size of the cocrystal region in the ternary phase diagram

Structural Study of Prolinium/Fumaric Acid Zwitterionic Cocrystals: Focus on Hydrogen-Bonding Pattern Involving Zwitterionic (Ionic) Heterosynthons

Pharmaceutical compounds are mostly developed as solid dosage forms containing a single crystal form. This implies that the selection of a particular crystal state for a given molecule is an important step for further clinical outlooks. Different methods can be used in the case of polymorphism issues at the time of optimal phase selection. One of the promising techniques developed these last few years is cocrystallization. In this context, proline (pyrrolidine-2-carboxylic acid) is considered in the present work. Cocrystals of proline and fumaric acid (<i>E</i>-butenedioic acid) are mainly analyzed by powder and single-crystal X-ray diffraction (PXRD and SCXRD, respectively). At first, the cocrystallization conditions are optimized by grinding (dry grinding), a green method for cocrystals screening and synthesis. Under specific conditions, single crystals of a 2:1 l-proline–fumaric acid racemic zwitterionic cocrystal have been obtained, an outcome confirmed by crystallographic analysis. Enantiomeric cocrystal form was obtained starting from d-proline. With the racemic compound (dl-proline), a three-component cocrystal is formed, the 1:1:1 l-proline–d-proline–fumaric acid cocrystal. Interestingly, this latter seems to be obtained using two distinct synthetic ways. Calorimetric measurements have been performed in order to establish the binary-phase diagram of the l-proline–fumaric acid cocrystal. Structural comparison with related structures from the Cambridge Structural Database revealed similarities in the crystalline network and introduced a systematic and detailed analysis of hydrogen bond interactions in zwitterionic cocrystalline structures involving proline

Magnetic Levitation as a Tool for Separation: Separating Cocrystals from Crystalline Phases of Individual Compounds

In this contribution, we extend the phase separation abilities of magnetic levitation (MagLev), applying it to cocrystal systems. Most of these systems show incongruent solubility in solution. Crystallization from an equimolar mixture often leads to the crystallization of both cocrystal and coformer (one of the individual cocrystal formers). Using carbamazepine/salicylic acid and carbamazepine/camphoric acid systems, we demonstrated that MagLev is an efficient and straightforward tool for phase separation in these systems

Structural Investigation of Substituent Effect on Hydrogen Bonding in (<i>S</i>)‑Phenylglycine Amide Benzaldimines

A detailed structural analysis of 23 new crystal structures of (<i>S</i>)-phenylglycine amide benzaldimines with various substituents (CH₃, Ph, OCH₃, F, Cl, Br, NO₂) on the benzylidene is performed in this contribution. These compounds belong to the highly studied family of Schiff bases. Etter’s nomenclature and Hirshfeld surfaces are used to describe respectively the strong hydrogen bonds and the secondary interactions existing in these compounds. Surprisingly, all 23 obtained structures can be sorted into five types according to their hydrogen bonding motifs. The potential interplay of steric and electronic effects of the substituents on the resulting bonding patterns, conformational features and packing was investigated. Our analysis revealed that neither mesomeric/inductive factors of halogens nor π–π stacking, C–H···π, and other hydrophobic interactions affect the structural outcome. The type affiliation is rather due to the interplay of three parameters: (1) the number of strong hydrogen bonds forming the motif (thermodynamic factor), (2) the ease with which the motif is formed (kinetic factor), and (3) the capacity of the motif to accommodate substituents on the different positions (steric factor). It was thus possible to suggest a stability ranking of the five structural types and to identify stable forms when polymorphism was encountered

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

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

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

Predicting Keto–Enol Equilibrium from Combining UV/Visible Absorption Spectroscopy with Quantum Chemical Calculations of Vibronic Structures for Many Excited States. A Case Study on Salicylideneanilines

Salicylideneanilines are characterized by a tautomer equilibrium, between an enol and a keto form of different colors, at the origin of their remarkable thermochromic, solvatochromic, and photochromic properties. The enol form is usually the most stable but appropriate choice of substituents and conditions (solvent, crystal, host compound) can displace the equilibrium toward the keto form so that there is a need for fast prediction of the keto:enol abundance ratio. Here we demonstrate the reliability of a combined theoretical–experimental method, based on comparing simulated and measured UV/visible absorption spectra, to determine this keto/enol ratio. The calculations of the excitation energies, oscillator strengths, and vibronic structures of both enol and keto forms are performed for all excited states absorbing in the relevant (visible and near-UV) wavelength range at the time-dependent density functional theory level by accounting for solvent effects using the polarizable continuum model. This approach is illustrated for two salicylideneaniline derivatives, which are present, in solution, under the form of keto–enol mixtures. The results are compared to those of chemometric analysis as well as <i>ab initio</i> predictions of the reaction free enthalpies