Structural Properties and Charge Redistribution in Cocrystallized Pharmaceutical Ingredients: A Comparative Experimental and Theoretical Charge Density Analysis

The cocrystallization of active pharmaceutical ingredients (APIs) is known to be a technique suitable for overcoming certain physicochemical issues concerning the solid forms of drugs. In the case of the cocrystal of 5-fluorocytosine and isoniazid, two widely used active pharmaceutical ingredients, for example, the cocrystallization improved the phase stability of the latter against moisture, thus increasing its shelf life. The room-temperature crystal structure was already reported in the literature, but no charge density study has been published so far. To further evaluate the structural properties of this potential codrug, which is stabilized by a supramolecular synthon containing N-HN-type hydrogen bonds, here we performed the experimental and theoretical charge density analyses of the drug-drug cocrystal formed by the antimetabolite prodrug 5-fluorocytosine and the tuberculostatic drug isoniazid. Topological analyses were also performed for all models and compared, indicating a good agreement between experiment and theory. The comparison with gas-phase calculations enabled the evaluation of the charge redistribution upon cocrystallization as well as the effect of the intermolecular interactions. In this manner, it was possible to evaluate the variations in bond distances and electron densities at the bonds involved in the intermolecular heterosynthon. Through the total charge of each molecule in the cocrystal, it was also possible to have insights into the charge redistribution when both molecules crystallize together. Electrostatic potential maps were also calculated for the experimental data and compared with the gas-phase calculations.