A single crystal to single crystal solvatomorphic phase transition in cocrystals of pyrimethamine with 4-hydroxybenzoic acid. An experimental and theoretical study

Abstract

The phenomenon of solvatomorphism is common in molecular crystals and cocrystals alike. It has special significance for the pharmaceutical industry and in the area of crystal engineering due to various implications involved. Usually the solvatomorphs differ from each other by a slight energy difference. Crystal growth mechanism and stability analysis of a new salt hydrate (pyrimethamine : 4-hydroxybenzoic acid : water, I) were performed based on the thermal profile, electron density derived properties and computational insight (symmetry-adapted perturbation theory, SAPT). Information from the thermal profile was used to obtain the anhydrous form pyrimethamine : 4-hydroxybenzoic acid (II) via a single crystal to single solvatomorphic phase transition. The experimental results demonstrate that the water molecule contributes towards the stability of the crystal packing. This aspect was explored via in-depth analysis of intermolecular interactions through topological mapping based on electron density distribution, electrostatic potential, electrostatic interaction energies and atomic charges. Theoretical studies supported by SAPT0 and related binding energy analyses reveal that strong hydrogen bonding, particularly N–H⋯O interactions, is the primary stabilizing force in cocrystal formation.