The polymorphic behavior of racemic and enantiopure diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization.

Cocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO 2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO 2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO 2 feed rate, while very fast introduction of CO 2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO 2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals. ABSTRACTCocrystallization of naproxen racemic mixture and nicotinamide was investigated in this work, using compressed CO 2 as antisolvent. A novel racemic cocrystal structure containing both enantiomers of naproxen linked to nicotinamide has been produced thanks to CO 2 antisolvent batch crystallization process. The structure of the molecular complex and the analysis of its intermolecular interactions were investigated by Single Crystal X-ray Diffraction (SCXRD) andAttenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR). The antisolvent feed rate was found to have a direct influence on the cocrystallization outcome. The racemic cocrystal was obtained at slow and moderate CO 2 feed rate, while very fast introduction of CO 2 resulted in the formation of a mixture of chiral cocrystals (conglomerate). Cross-seedings, thermal analysis and Temperature Resolved X-Ray Powder Diffraction (TR-XRPD) were used to probe the relationship between the different phases. In addition, all powders produced with CO 2 technology were obtained as cocrystal-pure, without significant excess of naproxen or nicotinamide homocrystals.

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A mixture of two enantiomers can crystallize according to three types of heterogeneous equilibria: a racemic compound (a 1:1 stoichiometric compound), a conglomerate (a physical mixture of particles with opposite chirality) or, more rarely, as a solid solution (a crystalline architecture exhibiting a lack of chiral discrimination with respect to the two enantiomers). Due to the scarce occurrence of solid solutions, only a few examples of such behavior are known, and even fewer systems have been investigated by means of single crystal X-ray diffraction. Yet, preliminary work performed in the 1970s by several research teams revealed that structural investigations of solid solutions could provide valuable insights into chiral discrimination mechanisms at the crystal lattice scale. In the present paper, our aim is to review published cases of enantiomeric solid solutions for which both melting phase diagrams and crystal structures are available in order to analyze the lack of chiral discrimination associated to these phases. Our methodology consists in considering both the molecular and crystallographic aspects of stereoselectivity with the final aim of identifying structural criteria responsible for the occurrence of solid solutions. The experimental conditions allowing access to solid solutions will also be considered in light of these structural criteria.