(25a) Understanding and Predicting the Efficacy of Tailor Made Additives on the Crystallisation of p-Aminobenzoic Acid

Unwanted crystallization is a major concern in a number of chemical industries, affecting fuels, agrochemicals, pharmaceuticals and food. The ability to overcome this issue by disrupting the crystallization process, through the use of additives, has been a long studied area of crystallization science and engineering ¹. Since the work of Lahav, Leiserowitz and colleagues at the Weizmann Institute of Science^2,3, a large number of research studies have focussed on tailor-made additives (TMAs), whereby an additive with a very similar molecular structure to a target crystallization compound is used to inhibit aspects of the crystallization process. The majority of work has focussed on crystal growth inhibition, however, more recently the ability of TMAs to inhibit nucleation has been a growing area of research.

This work focuses on the nucleation of alpha-p-aminobenzoic acid (pABA) from ethanol solution, in the presence of TMAs. pABA in ethanol solution is known to nucleate through carboxylic group H-bonding dimer formation, with the crystal structure formed also containing strong amine-carboxyl group H-bonding and Ï€-Ï€ stacking interactions ⁴. TMAs that could potentially disrupt pABA-pABA dimer formation as well as the formation of the previously described synthonic interactions were chosen to study their effect on pABA nucleation inhibition form ethanol solution.

Seven TMAs were chosen and molecular modelling using an intermolecular grid search was undertaken to screen and understand the dominant molecular interactions between pABA and the TMAs, in terms of synthonic interaction energies. Two TMAs were found to have stronger interactions to pABA than pABA itself, forming competitive carboxylic H-bonding dimers, these were 4-amino-2-methoxybenzoic acid (AMBA2), 4-amino-3-nitrobenzoic acid (ANBA3). These TMAs had the same molecular structure of pABA, but with methoxy or nitro groups attached, respectively. From calculated atomic charge energies, the nitro group of ANBA3 was assessed to be able to disrupt the subsequent binding of pABA molecules into the crystal structure through electrostatic interactions.

A polythermal experimental screen was performed to assess the intermolecular grid search’s ability to predict TMA efficacy. The experimental results corroborated findings from the modelling results, with ANBA3 being the most effective nucleation inhibitor followed by AMBA2.

Nucleation kinetics were assessed for pABA vs. pABA-ANBA3 in ethanol solution using the KBHR approach. It was found that pABA nucleates by instantaneous nucleation, whereas the pABA-ANBA3 nucleates by progressive nucleation. The interfacial tension was found to also increase in the presence of ANBA3.

References

1) J. W. Mullin, Crystallization, Butterworth-Heinemann, Oxford, 4th ed., 2001.

2) L. Addadi, Z. Berkovitch Yellin, N. Domb, E. Gati, M. Lahav and L. Leiserowitz, Nature, 1982, 296, 21–26.

3) I. Weissbuch, L. Addadi, M. Lahav and L. Leiserowitz, Science, 1991, 253, 637–645.

4) D. Toroz, I. Rosbottom, T. D. Turner, D. M. C. Corzo, R. B. Hammond, X. Lai and K. J. Roberts, Faraday Discuss., 2015, 179, 79–114.