Dicarboxylic acids (DiAs) are probably among of the most popular cocrystal formers. Due to the high hydrophilicity and nontoxicity, they are promising solubilizers of active pharmaceutical ingredients (APIs). Although DiAs appear to be highly capable of forming multicomponent crystals with various compounds, some systems reported in the literature are physical mixtures of the solid state without forming stable intermolecular complex. In this study, an accurate cocrystal screening model was developed based on the MARSplines (Multivariate Adaptive Regression Splines) methodology and easily computable descriptors driven simply from the SMILES codes. Additionally, the data set was enriched with several new mixtures of sulfamethazine. As demonstrated, this sulfonamide can form new multicomponent crystals with oxalic, malonic, and maleic acids. In the case of the latter system, a significant 10-fold solubility advantage was observed. The whole data set comprised 608 cocrystals and 104 systems hardy miscible in the solid state, denoted as simple eutectics. The final 7-factor equation was subjected to external and internal validation procedures, which indicated its high predicting power. The reliability of the proposed approach can be illustrated by the proper classification probability of cocrystals reaching 91%. The classification quality of simple binary eutectics was found to be only slightly worse (TN% = 81%).

Applicability of phenolic acids as potential cocrystal formers for methylxanthine derivatives was analyzed both in terms of cocrystallization probabilities and solubility advantage. The cocrystal formation abilities were evaluated using mixing enthalpy estimated within the conductor like screening model for real solvents (COSMO-RS) framework. The solubility improvement of potential cocrystals was estimated by formulation of the model relating experimental values to predicted solubilities. This enabled for ranking of potential cocrystals formers according to their solubility enhancement potential. According to the calculation results, a highly linear relationship (R 2 = 0.989) was found between estimated theophylline and caffeine cocrystal solubility values. It has been found that many phenolic acids, especially ones with several hydroxyl groups attached to phenyl ring, are the most promising candidates for cocrystallization with caffeine or theophylline. Experimental verification of the proposed protocol for caffeine and theophylline resulted in eight new molecular complexes, which were synthesized via a mechanochemical approach. All new solids were characterized using powder X-ray diffractometry and Fourier transform infrared spectroscopy combined with a attenuated total reflection technique.

The cocrystallization landscape of benzamide and urea interacting with aliphatic and aromatic carboxylic acids was studied both experimentally and theoretically. Ten new cocrystals of benzamide were synthesized using an oriented samples approach via a fast dropped evaporation technique. Information about types of known bi-component cocrystals augmented with knowledge of simple binary eutectic mixtures was used for the analysis of virtual screening efficiency among 514 potential pairs involving aromatic carboxylic acids interacting with urea or benzamide. Quantification of intermolecular interaction was achieved by estimating the excess thermodynamic functions of binary liquid mixtures under supercooled conditions within a COSMO-RS framework. The smoothed histograms suggest that slightly more potential pairs of benzamide are characterized in the attractive region compared to urea. Finally, it is emphasized that prediction of cocrystals of urea is fairly direct, while it remains ambiguous for benzamide paired with carboxylic acids. The two known simple eutectics of urea are found within the first two quartiles defined by excess thermodynamic functions, and all known cocrystals are outside of this range belonging to the third or fourth quartile. On the contrary, such a simple separation of positive and negative cases of benzamide miscibility in the solid state is not observed. The difference in properties between urea and benzamide R2,2(8) heterosynthons is also documented by alterations of substituent effects. Intermolecular interactions of urea with para substituted benzoic acid analogues are stronger compared to those of benzamide. Also, the amount of charge transfer from amide to aromatic carboxylic acid and vice versa is more pronounced for urea. However, in both cases, the greater the electron withdrawing character of the substituent, the higher the binding energy, and the stronger the supermolecule polarization via the charge transfer mechanism.Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-016-2964-6) contains supplementary material, which is available to authorized users.

No abstract