Molecular dynamics simulations of organic crystal dissolution: The lifetime and stability of the polymorphic forms of para-amino benzoic acid in aqueous environment

Para-amino benzoic acid (PABA) manifests crystalline solid-state properties that are typical of a class of chemical compounds with important industrial applications. Hence, it is particularly worthwhile to investigate the lifetime and stability of representative molecular-clusters of two polymorphic forms of PABA in aqueous solution using molecular dynamics simulations. Simulations of 5 ns duration in the isothermal-isobaric ensemble (constant particle number, pressure and temperature (NPT) ensemble) were performed for the two polymorphic forms at three different temperatures 0 °C, 50 °C and 100 °C. The simulations revealed that at 0 °C the representative molecular-clusters of the two polymorphic forms remain ordered while at 50 °C the molecular packing within the clusters becomes partially disordered for both polymorphic forms and at 100 °C the clusters lose long-range order rapidly and come to resemble liquid drops. Care should be taken when assessing the relative stability of polymorphic forms, as a function of temperature, from such computational experiments which explore the dissolution of nano-scale crystals. The long range order of the clusters of the α-form at 50 °C and 100 °C was, respectively, partially and completely lost after 5 ns which merits further investigation given that the α-form is the high-temperature stable polymorph. Importantly, the initial shape of clusters, as well as the number of solute molecules they contained, affected the extent to which order was lost and how rapidly the loss occurred. Given that the classical nucleation theory predicts a finite probability that clusters significantly larger than the critical size, in terms of number of molecules, may dissolve, building clusters containing a greater number of molecules could improve the simulated stability of the α polymorph at 50 °C and 100 °C. Furthermore, the simulations revealed that the selection of a suitable electrostatic potential is very important for the description of the dissolution process of the nano-sized crystals.