(488e) Effect of Solvent and Functional Group Position of Co-Formers on Cocrystal Polymorphism/Stoichiomorphism: A Case Study

Recently, cocrystal polymorphism and stoichiomorphism have gradually attracted the attention of researchers, because these new phases can not only provide directions for the development of drugs and materials but also involve patent applications^[1,2]. However, the research on relevant influencing factors is insufficient. Picolinamide (PAM), nicotinamide (NAM), and isonicotinamide (INA) are selected as co-formers in this study to form cocrystals with 4-chloro-3-sulfamoylbenzoic acid (CSBA). Through a series of characterizations, including molecular electrostatic potential analysis, neat grinding, liquid-assisted grinding, and slow solvent evaporation method, a total of six new crystals were prepared successfully and solved by single-crystal X-ray diffraction. PAM and NAM are found can only form one cocrystal with CSBA, respectively. While INA can form up to four cocrystals with CSBA with 2:1, 1:1, and 1:2 mole ratios, and the cocrystal with 1:1 exists in two polymorphic forms.

Further analysis shows that the functional group position of PAM limits the diversity of synthons, and the lattice energy advantage limits the stacking diversity when PAM acts as a co-former. However, only INA as a co-former is not subject to these restrictions. For the synthon of CSBA-INA 2:1, the INA molecule seems to be inserted into a carboxylic acid dimer formed by two CSBA molecules which is also the synthon of the CSBA crystal to form a trimer synthon. In the structure of CSBA-INA 1:2, the dimer composed of two INA molecules plays a crucial role in the stack of this cocrystal. In general, the symmetry of INA molecules and their ability to form dimers are the main reason for cocrystal stoichiomorphism. For the two cocrystal polymorphs with the stoichiometric ratio of 1:1, it can be found that their lattice energies are very similar (-134.31 kcal/mol for form Ⅰ and -129.26 kcal/mol for form Ⅱ), which enables the diversity of synthons to be fully reflected and is considered to be an important reason for cocrystal polymorphism.

Finally, the influence of solvent on cocrystals is illustrated by ternary phase diagrams and suspension experiments. CSBA was proved to form only one cocrystal with PAM or NAM. CSBA-INA 1:1 form Ⅰ was found to be available only in the solvent ethyl acetate. Unlike CSBA-INA 1:1 form Ⅰ, the phase region of CSBA-INA 1:1 form Ⅱ was found in methanol, acetone, and tetrahydrofuran. As for CSBA-INA 2:1 and CSBA-INA 1:2, their phase regions were presented in all four solvents. There was an obvious transition process from CSBA-INA 1:1 form Ⅰ to form Ⅱ in the suspension experiment in acetone. And the transition process was studied by FTIR and molecular simulations. The results show that there are complex relationships between solvents and different synthons, which affects cocrystal polymorphisms. And the difference in interactions between the two tetramer synthons in different cocrystal forms and acetone is believed to be the reason for the transformation of form Ⅰ to form Ⅱ. The relevant cases and analysis in this paper can deepen the understanding of cocrystal polymorphism/stoichiomorphism and improve screening efficiency.

[1] S. Aitipamula, P.S. Chow and R.B.H. Tan (2014): Polymorphism in cocrystals: a review and assessment of its significance, CrystEngComm 16, 3451-3465.

[2] I. Nugrahani and R.D. Parwati (2021): Challenges and Progress in Nonsteroidal Anti-Inflammatory Drugs Co-Crystal Development, Molecules 26, 4185.