Towards an understanding of the nucleation of alpha-para amino benzoic acid from ethanolic solutions: a multi-scale approach.

D. Toroz,X. Lai,I. Rosbottom,T. D. Turner,K. J. Roberts,D. M. C. Corzo,R. B. Hammond

doi:10.1039/c4fd00275j

Abstract

The molecular assembly and subsequent nucleation of para-amino benzoic acid (PABA) from ethanolic solutions is probed using a multi-scale and multi-technique approach. This is applied by examining and interrelating information regarding the molecular, solution-state, cluster, solid-state and surface structures to understand why the alpha form of PABA is crystallised in preference to its low temperature beta form. Calculations suggest that conformational changes within the solute molecule play little or no role in directing the nucleation of either the alpha or beta crystal forms. Combined ab initio and molecular dynamics calculations of the stability of small clusters in solution suggests that the hydrogen-bonded carboxylic acid dimers, present in the alpha structure, are the most stable in solution and play a major role in the self-assembly and polymorphic expression of the alpha form in ethanol in preference to the beta form. These calculations are in good agreement with X-ray small-angle scattering analysis which reveals the presence of PABA clusters in ethanol which are consistent with the size and shape of a carboxylic acid dimer. SAXS studies also reveal the presence of larger cluster structures in a size range 10-40 nm which appear to grow, perhaps reflecting a change in the balance between monomers and dimers within the solution during the nucleation process. The results of crystallisation-kinetics experiments indicate an instantaneous nucleation mechanism where the number of instantaneously nucleated crystallites is calculated to be 1360-660 nuclei per ml and the subsequent growth is found to be only rate limited by diffusion of the growth unit to the crystallite surface. A linear dependence of growth rate with respect to supersaturation is observed for the (0 1 -1) capping face, which is associated with strong π-π stacking interactions. This is consistent with a solid-on-solid mechanism associated with surface roughened growth and concomitant poor lattice-perfection. Conversely, the side (1 0 -1) surface has a growth mechanism consistent with a 2D nucleation birth and spread mechanism. Hence, these mechanisms result in very fast growth along the b-axis and the needle-like morphology that is observed for alpha-PABA.

Highlights

Research into the molecular-scale mechanism that underpins the directed assembly of crystalline materials from the solution phase into a solid-state structure through a crystallisation process is currently of signi cant interest.[1,2] The crystallisation of organic crystals is important to the pharmaceutical and ne chemicals industries in terms of their application as crystalline ingredients or formulation components as used for a variety of materials and products such as drugs, pigments, agrochemicals and confectionery
This study reveals that the dominant nucleation of the alpha form of para-amino benzoic acid (PABA) over the beta form in ethanolic solutions is most likely due to the stability and favourable formation of H-bonding carboxylic acid dimers in solution
The lack of signi cant change between the gas phase stable conformers and conformers in the crystal structure suggests that the intermolecular interactions, rather than any conformational change, play the most signi cant role in crystallisation of the material

Summary

Introduction

Research into the molecular-scale mechanism that underpins the directed assembly of crystalline materials from the solution phase into a solid-state structure through a crystallisation process is currently of signi cant interest.[1,2] The crystallisation of organic crystals is important to the pharmaceutical and ne chemicals industries in terms of their application as crystalline ingredients or formulation components as used for a variety of materials and products such as drugs, pigments, agrochemicals and confectionery. Both the nucleation and growth stages are important with respect to their role in directing many of the key physico-chemical properties (see Fig. 1) of a crystal and/or the same when formulated into a product Such attributes can be important in terms of a material's or product's practical utility and subsequent performance.[3,4,5,6] Examination of Fig. 1 reveals the importance of being able to understand and potentially control the initial stages of the crystallisation process and, in particular, the inter-relationship between the structural nature of the initial nucleated clusters and the kinetics associated with their formation and the physical and chemical properties of the crystalline materials produced.[7,8]

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Conclusion