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Trimethoprim (TMP) is a bacterial dihydroreductase inhibitor with broad-spectrum antibacterial properties. However, its oral absorption is limited by its low water solubility. Salification is one of the effective methods to solve this problem. This work proposes an efficient method for screening TMP salts using the conductor-like screening model for real solvents (COSMO-RS) model. 200 common compounds were introduced as candidates for screening. As a result, 39 hit compounds were subjected to experimental liquid-assisted grinding (LAG) with TMP, then 25 new solid phases were confirmed by PXRD. The solvent evaporation method was further used to acquire eight single crystals of TMP salts, whose structures were elucidated by single-crystal X-ray diffraction. Power X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier-transform infrared spectroscopy were employed to characterize seven of the TMP salts. Then, atoms-in-molecules was used to analyze intermolecular hydrogen bonding interactions in salts. Finally, we tested the equilibrium solubility and dissolution rate of the salt, which exhibited an increase in solubility. In a word, it is an effective screening method to obtain TMP salts combined with the COSMO-RS model and LAG method, which can be widely applied to other systems for screening of the target salts. [ABSTRACT FROM AUTHOR]

Solvates are important forms of crystalline materials and their formation and desolvation would affect the quality of the final products. In this work, to better understand the desolvation mechanism of solvates and its effect on the properties of the final products, cefathiamidine was selected as the model compound to investigate the influence of intermolecular interactions and the crystal structure on the desolvation process. Three new solvates and one reported solvate of cefathiamidine, including acetonitrile solvate monohydrate S1, acetone solvate monohydrate S2, n-propanol solvate 1.5 hydrate S3 and isopropanol solvate S4, were obtained by solution crystallization and their structures were determined by single crystal X-ray diffraction. The results indicated that the cefathiamidine molecule is highly conformationally flexible and eight conformations were observed in these solvates. The different solvates exhibit different intermolecular interactions, packing patterns and crystal stabilities. Furthermore, the desolvation processes of the solvates were systematically investigated by various analytical techniques and were analyzed based on the intermolecular interactions, molecular networks, void types, proportion of voids and packing patterns. The results showed that the desolvation of solvates S1 and S2 followed a cooperative–reorganization mechanism while the desolvation of solvate S3 and solvate S4 followed a destruction–reconstruction mechanism and a destruction–collapse mechanism, respectively. Finally, the corresponding mechanisms of the different solvates were proposed. [ABSTRACT FROM AUTHOR]

To investigate the effect of positional isomerism on cocrystallization and reveal the role of weak interactions in the formation of cocrystals, experimental characterization complemented with theoretical computations was thoroughly conducted by using p-hydroxybenzoic acid (PHBA), o-hydroxybenzoic acid (OHBA), m-hydroxybenzoic acid (MHBA) and malonic acid (MA) as model compounds. Selective formation of a new cocrystal was discovered between PHBA and MA molecules via several methods, while no cocrystal was formed between OHBA/MHBA and MA molecules. The PHBA–MA cocrystal was thoroughly characterized and analyzed through several solid characterization techniques such as powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) analysis, Fourier transform infrared (FTIR) spectroscopy, single crystal X-ray diffraction (SCXRD), etc. Taking advantage of a myriad of computational modelling techniques, the molecular recognition mechanism which drove the formation of cocrystals was comprehensively investigated and understood at a molecular level. The structural change accompanied by the cocrystal formation could be rationalized by FTIR spectroscopy and electron density variation analysis. Hirshfeld surface (HS) analysis indicated that O–H⋯O hydrogen bonds played a critical role in the formation of this cocrystal. Molecular electrostatic potential (MESP) surface analysis was employed to predict the interaction sites for cocrystallization, which were in good accordance with the experimental results. Moreover, possible reasons for the selective cocrystallization were analyzed and proposed. [ABSTRACT FROM AUTHOR]

Crystal purity is of primary importance for pharmaceutical crystallization, and the inclusion of mother liquids inside the crystals poses a great challenge and threat to the product quality and purification efficiency. It is well recognized in industry that mother liquids can be included inside the crystals; however, the underlying formation mechanism remains poorly understood. Herein, we investigated the formation of liquid inclusions during crystallization of a model compound tetramethylpyrazine (TMP), which is a bioactive alkaloid drug, with an aim to better understand and hence control the liquid inclusions formed inside the crystals. The formation of mother liquid inclusions inside TMP crystals was fully characterized by optical polarizing microscopy, micro-Raman spectroscopy, and powder X-ray diffraction. Three types of fluid inclusions were observed in TMP crystals, and the single-phase liquid inclusions dominate. The effects of initial supersaturation and temperature on the formation of liquid inclusions were studied both qualitatively and quantitatively by optical microscopy and gas chromatography. It was found that high supersaturation and high temperature were favorable to the mother liquid inclusions in the resultant crystals. Moreover, the amounts of liquid inclusions inside the crystals are positively correlated with the growth rate of the TMP crystals. Solvent effects on the formation of liquid inclusions were also studied by choosing four types of solvents of distinct polarity. The results showed the solvent dependence of the formation of liquid inclusions, and the TMP crystals harvested from ethyl acetate displayed the most remarkable inclusions of mother liquids while the fewest liquid inclusions were found in isopropanol. Furthermore, the inclusion amounts of mother liquids can be correlated with the growth rates in different solvents but could not simply be correlated with only one type of property of the four solvents such as polarity, viscosity, dielectric constant, or surface tension. Finally, the inclusion of mother liquids inside TMP crystals was suggested to be effectively suppressed by crystallization at lower temperature and supersaturation, as well as in solvents with greater polarity and viscosity. [ABSTRACT FROM AUTHOR]

There has been much interest in the role of solution chemistry in determining the polymorphic formation of organic crystals. For convenience, the predominantly investigated systems are those that contain distinct building blocks among the polymorphs; in this work, an important drug excipient, D-mannitol (D-man), was selected as a case study, which represents a polymorphic system that only has the same building blocks. By employing the Hirshfeld surface analysis and molecular dynamics (MD) simulations, D-man's crystal packing and the solvation nature in different solvents were studied on the molecular level. The results suggest that there is a direct link between the solution speciation and crystal structure, and two distinct solvation modes were identified along with their impacts on nucleation. This study indicates the significant role of solvation in determining D-man's nucleation and offers new insights into the research on systems that do not have distinct building blocks among the polymorphs. [ABSTRACT FROM AUTHOR]

We report here a unique method for the preparation of aggregated crystals with well-defined shape and size using a solvent penetration-mediated phase transformation. An unusually fast phase transformation of sulfadiazine was observed. The aggregated sulfadiazine crystals are obtained through a water penetration mediated transformation of sulfadiazine N-methyl pyrrolidone solvate. The aggregated particles keep the same shape and size of the parent crystals. [ABSTRACT FROM AUTHOR]