The Structural Pathway from its Solvated Molecular State to the Solution Crystallisation of the α- and β-Polymorphic Forms of Para Amino Benzoic Acid

Para amino benzoic acid has two well-characterised polymorphic forms and, whilst both crystallise in the monoclinic space group, they have quite different crystal chemistry and crystallisability behaviour. The molecular conformation deformation energy in the crystalline state is higher for the β-form than for the α-form and the lattice energy for the former converges more slowly than for the latter. This suggests a higher barrier to crystallisation for the β-form and low solution supersaturations might be needed for it to preferentially nucleate. Solute cluster propensity and solute solvation energetic analysis highlights the importance of an aqueous solvation environment in inhibiting the α-form’s strong OH…O carboxylic acid hydrogen bond dimer. Despite this, the detailed molecular-scale pathway from solvated molecules to 3D crystallographic structure still remains unclear, most notably regarding how the nucleation process is activated to mediate the preferential formation of either of the two polymorphic forms. Molecular dynamics simulations coupled with FTIR studies and intermolecular synthon analysis addresses this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of these polymorphic forms within the solution state. Molecular trajectory analysis within organic solution simulations reveals a greater propensity for OH…O synthons (both single H-bonds and homodimers) typical of the α-form and NH…O synthons found in both the α- and β-forms when compared to aqueous solutions but much lower propensities for the β-form’s “fingerprinting” OH…N and π-π stacking synthons. In contrast, data from the aqueous solution environments reveals a much greater propensity for the β-form’s π-π interaction synthons. IR dilution studies in organic solvent in the carbonyl region reveal the presence of two C=O vibrational stretching bands, whose relative intensities vary as a function of solution dilution. These were assigned to the solvated PABA monomer and a COOH dimer of PABA. IR data is consistent with the organic solvent MD data, albeit IR aqueous solutions was precluded due to its strong OH vibrational mode which restricted validation in aqueous solutions.