Aromatic stacking in benzoic acid derivatives: nucleation rate and molecular dynamics study

Nucleation is a fundamental step in the crystallisation process, with paramount importance, among others, in pharmaceutical processes. Aromatic rings are a common structural motif in drug molecules, and their tendency to engage in stacking interactions has been hypothesised to significantly influence nucleation behaviour [1]. In this work, we present a combined experimental and computational investigation into how stacking interactions affect nucleation in aromatic systems. We focus on benzoic acid derivatives (Figure 1) due to their structural simplicity and well-characterized behaviour [2,3]. Nucleation rate experiments were performed on 4-bromo- and 4-(methoxycarbonyl)benzoic acids, measuring induction times at five levels of supersaturation in isopropanol at 20 °C, using the Crystal16 automated crystalliser. To account for the stochasticity of the process, each experiment was repeated 80 times, resulting in 400 data points per compound. The results were compared with literature data for related compounds, each exhibiting different stacking strengths [1,4]. Molecular Dynamics simulations were carried out using the free and open-source MiCMoS software [5,6], allowing us to model the liquids of these derivatives both above and below their melting points. By analysing the frequency and duration of stacking interactions at different temperatures, we observed a correlation between stacking propensity and nucleation rate. These findings support the hypothesis that stacking interactions play a critical role in driving nucleation and provide a framework for predicting nucleation tendencies in aromatic compounds based on molecular features. Reference 1. Aromatic stacking – a key step in nucleation, A. J. Cruz-Cabeza, R. J. Davey, S. S. Sachithananthan, R. Smith, S. K. Tang, T. Vetter, Y. Xiao, Chem. Commun., 2017, 53, 7905-7908 2. Molecular dynamics investigation of benzoic acid in confined spaces, L. Sironi, G. Macetti, L. Lo Presti, Phys. Chem. Chem. Phys., 2023, 25, 28006-28019 3. Nanoscale inhomogeneities in undercooled benzoic acid: A molecular dynamics study, L. Sironi, G. Macetti, L. Lo Presti, J. Mol. Liq., 2024, B414, 126141 4. Can molecular flexibility control crystallization? The case of para substituted benzoic acids, S. K. Tang, R. J. Davey, P. Sacchi, A. J. Cruz-Cabeza, Chem. Sci., 2021, 12, 993-1000 5. Classical molecular dynamics simulation of molecular crystals and materials: old lessons and new perspectives, G. Macetti, L. Sironi, L. Lo Presti, Comprehensive Computational Chemistry, Elsevier, 2024, 777-803 6. Molecular dynamics simulation of organic materials: structure, potentials and the MiCMoS computer platform, A. Gavezzotti, L. Lo Presti, S. Rizzato, CrystEngComm, 2022, 24, 922-930