The Directed Assembly of Materials - Crystal Growth and Nucleation of Substituted Benzoic Acids

Abstract

The crystal nucleation and growth of small organic molecules from solution plays a crucial part in solid form discovery, manufacturing processes and product efficacy in the pharmaceutical industry. A better understanding of the nucleation and crystal growth process could help us to direct the crystallisation process to achieve products with desired physical and chemical properties [1,2]. However, there is still a lack of knowledge of the controlling features of the molecular assembly process for nucleus and crystal formation. In this study, the nucleation and growth kinetics of a series of four structurally related carboxylic acids were measured and compared. Quantitative solubility data were measured which describes the equilibrium between crystals and saturated solutions at different temperatures and allows precise definition of supersaturation. A series of induction time measurement experiments were then performed at different supersaturations using the Crystal16 methodology [3,4]. These revealed the stochastic nature of nucleation and allowed determination of nucleation rates as a function of supersaturation and solvent for each chosen molecule. In addition, Fourier transform infrared spectroscopy (FTIR) spectroscopy was employed to examine the solvation state of carboxylic acid groups and highlight the existence of carboxylic acid dimers in solution [5]. After the nucleation process, the next stage is crystal growth. Direct measurements of crystal growth rates were made using two techniques, one on single crystals (small scale) and the other on a population consisting of a certain number of seed crystals (large scale) respectively [1,6]. All experiments were carried out isothermally at a temperature of 20 deg.C in different polarity solvents. This is the first time that such a comprehensive study of both nucleation and growth rates of a series of related molecules has been reported. Of particular interest in this work has been not only an exploration of the links between nucleation and growth kinetics but also of the importance of molecular conformation in determining the nucleation rates. This latter determined the choice of two of the acids, para-alkoxybenozic acid and para-alkylbenzoic acid which contain more than one molecule in their crystallographic asymmetric unit, each having a different conformation of the alkoxy and alkyl group respectively. By comparing the kinetics of these molecules with related molecules having restricted flexibility it was hoped to learn something of the role of conformation in determining nucleation rates. Here for the first time, this work aims to provide a direct link between the molecular attachment kinetics, conformational flexibility and the related solution chemistry.

Date of Award	1 Aug 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Roger Davey (Supervisor) & Thomas Vetter (Supervisor)