Robert B. Hammond

Para amino benzoic acid (PABA) has two well-characterised α- and β-polymorphic forms and, whilst both crystallise in the monoclinic space group P2₁/n, they have quite different crystal chemistry and crystallisability behaviour. Previous work has shown that the molecular conformation deformation energy in the crystalline state is higher for the β-form than for the α-form and that the lattice energy for the former converges more slowly than for the latter overall. This suggests that not only is there a higher barrier to crystallisation for the β-form but also that low solution supersaturations might be needed for it to preferentially nucleate. Additionally, solute cluster propensity and solute solvation energetic analysis highlight the importance of an aqueous solvation environment in inhibiting the α-form’s strong OH⋯O carboxylic acid hydrogen bond (H-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 and how, as a result, this mediates the preferential formation of either of the two polymorphic forms. Molecular dynamics (MD) simulations coupled with FTIR studies and intermolecular synthon analysis address this issue through characterisation of the propensity of the incipient bulk synthons that are important in the crystallisation of the two polymorphic forms within the solution state. MD molecular trajectory analysis within crystallisation solutions 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 solution but much lower propensities for the β-form’s “fingerprinting” OH⋯N and π–π stacking synthons. In contrast, data from the aqueous solution environment reveals a much greater propensity for the β-form’s π–π interaction synthons. IR dilution studies in acetonitrile in the carbonyl region reveal the presence of two CO 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. Similar data in ethanol shows a main CO stretching band with a shoulder peak suggesting a similar monomer vs. dimer speciation may exist in this solvent. The IR data is consistent with the organic solvent MD data, albeit the corresponding analysis for the aqueous solution was precluded due to the latter’s strong OH vibrational mode which restricted validation in aqueous solutions.

The interplay between the solution chemistry and crystallisability of eicosane in mixed toluene : acetone solutions is examined over the full compositional range from pure toluene to pure acetone, using a combination of polythermal crystallisation experiments and molecular modelling. Enthalpies of dissolution and mixing, as well as metastable zone widths increase with increasing acetone content, up to a mol fraction of 0.85 acetone, followed by a decrease in values to pure acetone solutions. Nucleation is found to occur via an instantaneous pathway for the pure solvent systems and also when toluene is in excess, in contrast to solutions where acetone is in excess, which are found to nucleate progressively. Rationalisation through molecular modelling highlights likely changes in the solution structure, whereby eicosane can be expected to be preferentially solvated by toluene, with this solvated cluster being surrounded by a ‘cage’ of acetone molecules. This proposed structure is consistent with a model whereby solute diffusion and hence clustering is hindered when acetone is in excess, decreasing the crystallisability of the solution and effecting a change in the mechanism of nucleation. However, above a critical acetone composition, the potential for complete toluene solvation is restricted and easier crystallisation is enabled.

Novel combination of crystallographic tomography and molecular modelling is used to examine the powder packing behaviour and crystal interactions for an organic polycrystalline powder bed.

A detailed inter-molecular (synthonic) analysis of terbutaline sulfate, an ionic addition salt for inhalation drug formulation, is related to its crystal morphology, the surface chemistry of the habit faces and hence to its crystal surface energy.

The design and construction of a growth cell for the precision measurement of face-specific single-crystal growth rates are presented. Accurate mechanical drawings in SolidWorks of the cell and individual components are provided, together with relevant construction models. A general methodology for its use in the measurement of single-crystal growth rates and their underpinning growth mechanism is presented and illustrated with representative data provided for the crystal growth of the {011} and {001} faces of RS-ibuprofen single crystals grown in ethanolic solutions. Analysis of these data highlights the utility of the methodology in morphological model development and crystallization process design.

Three separately developed software Molecular Dynamics packages at Daresbury Laboratory, namely DL_FIELD (DL_F), DL_POLY and DL_ANALYSER, have been integrated to form an efficient computational infrastructure to investigate the detailed solution chemistry of saturated benzoic acid in hexane solutions. These software capabilities are demonstrated, in combination with the Synthonic Engineering tools and density functional theory (DFT) calculations, to assess the extent that the solute-solute intermolecular synthonic interactions in solution mirrors the synthons in the crystal structure. The results show that the majority of the COOH groups are forming OH … O H-bonds, which are a combination of classic OH … O homo-dimers and three membered H-bonding clusters. The formation of pi-pi stacking interactions is observed, but in far fewer numbers than observed for the OH … O interactions. The DFT simulations of the IR spectra of the multiple benzoic acid aggregates extracted from the MD trajectories provides further in-depth analysis of previously published IR data, by matching simulated peaks to the experimental peaks, hence identifying the exact bonding modes that are responsible for such peaks. This study demonstrates the value of a multi-scale and multi-technique approach to exploring the molecular transition pathway from solution to crystal structure.

The crystallographic structures of the α- and β- polymorphic forms of para aminobenzoic acid are deconstructed into their constituent hydrogen bonding molecular structural building blocks of monomers, dimers, tetramers and octamers, where they are analysed using ab initio quantum mechanical calculations of their conformation and cluster stability in solution. The molecular conformation found in the β-form is less stable than the same found in the α-form for both the gas and solution phases, suggesting that this causes a slight increase in the barrier to the crystallisation of the β-form in comparison to the α-form. The solution populations of the self-associated OH⋯O H-bonding ‘classic carboxylic acid dimer’, present in the α- and not the β-structure, is calculated to dominate in acetonitrile, dimethyl sulfoxide, ethanol, ethyl acetate, methanol, nitromethane and water. It is observed that this classic dimer is least stable in water, compared to the other PABA crystallisation solvents, with the OH⋯N H-bonding interaction present in the β-form being the second most stable dimeric interaction. These results are discussed in terms of the crystallisability and polymorphic behaviour of the α and β forms of PABA from the afore mentioned crystallisation solvents, whilst detailing how this approach could be reproducible for a range of polymorphic crystalline materials.