Solvation and Aggregation of Meta-Aminobenzoic Acid in Water: Density Functional Theory and Molecular Dynamics Study

Meta-aminobenzoic acid, an important model system in the study of polymorphism and crystallization of active pharmaceutical ingredients, exist in water in both the nonionic (mABA) and zwitterionic (mABA(±)) forms. However, the constituent molecules of the polymorph that crystallizes from aqueous solutions are zwitterionic. This study reports atomistic simulations of the events surrounding the early stage of crystal nucleation of meta-aminobenzoic acid from aqueous solutions. Ab initio molecular dynamics was used to simulate the hydration of mABA(±) and mABA and to quantify the interaction of these molecules with the surrounding water molecules. Density functional theory calculations were conducted to determine the low-lying energy conformers of meta-aminobenzoic acid dimers and to compute the Gibbs free energies in water of nonionic, (mABA)(2), zwitterionic, (mABA(±))(2), and nonionic-zwitterionic, (mABA)(mABA(±)), species. Classical molecular dynamics simulations of mixed mABA–mABA(±) aqueous solutions were carried out to examine the aggregation of meta-aminobenzoic acid. According to these simulations, the selective crystallization of the polymorphs whose constituent molecules are zwitterionic is driven by the formation of zwitterionic dimers in solution, which are thermodynamically more stable than (mABA)(2) and (mABA)(mABA(±)) pairs. This work represents a paradigm of the role of molecular processes during the early stages of crystal nucleation in affecting polymorph selection during crystallization from solution.