The pre-ordering of molecules in the solution state is not fully understood with respect to the formation of crystal nuclei. Here we investigate the importance of the conformational stability in nucleation and subsequent growth of the two polymorphic forms of para-amino benzoic acid (PABA) and further to the examination of molecular pre-ordering of clusters in the solution state. Additionally solvent continuum calculations have proven effective in predicting solute-solvent interactions without the need of computationally expensive resources.

PABA is an enantiotropic system which has two known forms, α stable above 13.8C and β stable below this transition temperature. However crystallization experiments above or below the transition temperature almost always yield the α polymorph. Conformational analysis was performed for the single molecule of PABA in the gas phase with respect to the conformational preference in the crystal structure based on a hierarchical selection scheme using electronic structure theory methods. The conformational analysis showed that the β monomer is the most stable conformer which is a result of the pyramidal formation of the amino functional group of the β monomer compared to the planar conformation of the amino group of the α. Thus a scan of the dihedral angle that defines the amino group of PABA was explored to probe a potential energy barrier between the two polymorphs.

We then model the crystallization process through fundamental building blocks of increasing complexity (monomers, dimers, tetramer, octamers etc) to probe the transition state nucleation pathway from solvated molecules to their directed assembly at the crystal/solution interface into the solid state. All the building blocks were optimized within the COSMO solvent continuum model and the statistical thermodynamics COSMO-RS method was applied.

In agreement with the conformational analysis, the COSMO calculations showed that the β monomer is the most favoured conformer in solution. Comparison of dimers suggests that different building blocks favour different polymorphs in solution. When carboxylic acid dimers are present (which are only present in the α structure) these clusters are always favoured in solution, whereas alternate building blocks favour β beta in some solvents. Comparison of small clusters (up to 8 molecules) showed favourability to the α polymorph reflecting experimental data.

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