A Structural−Kinetic Approach to Model Face-Specific Solution/Crystal Surface Energy Associated with the Crystallization of Acetyl Salicylic Acid from Supersaturated Aqueous/Ethanol Solution

Abstract

Classical homogeneous nucleation theory has been integrated with molecular modeling techniques to model the effects of cluster shape-anisotropy associated with nucleation from solution. In this approach, the geometric shape of a crystal nucleus is modeled assuming it equates to the predicted growth morphology of the resultant macroscopic crystal with the later simulated via an attachment energy model using empirical intermolecular force calculations adopting the atom-atom approximation. A new coupled model integrating nucleation theory, morphological simulation and solvent binding calculations, has been developed and combined with experimental nucleation data for the case example of acetyl salicylic acid (aspirin) crystallizing from an aqueous/ ethanol solution. Nucleation parameters, such as critical nucleus size and specific surface energy, have been calculated and compared for the cases of both isotropic (spherical) and anisotropic (polyhedral) nucleus models. A comparison between nucleation data modeled on the basis of both shaped polyhedral and spherical clusters reveals a larger critical nucleus size for the anisotropic (D equivalent ) 16.54 Å at 40°C) compared to the isotropic (D ) 13.07 Å at 40°C) shape model. Theoretical molecular modeling calculations of the specific surface energy anisotropy in solution show the specific surface energy for the habit planes of aspirin to vary from 3.65 mJ/m 2 for the dominant {100} facet to 113 mJ/m 2 for the minor {1 h11} facet. A comparison between the dominant crystal habit planes, notably, the hydrophilic {100} and hydrophobic {002}, reveals them to be more differentiated in terms of their specific surface energy in solution (3.65 and 10.90 mJ/m 2 ) than in a vacuum (829 and 904 mJ/m 2 ), respectively, in good agreement with their known surface chemistry. The total, specific surface energy (41.9 mJ/m 2 ) in solution calculated via molecular modeling for the polyhedral-shaped clusters was found to be somewhat larger, but still in pleasing general agreement with that calculated from experimental nucleation data as determined using induction time measurements assuming a spherical nucleus (3.99 mJ/m 2 ). The potential for the further development of this overall modeling approach is reviewed.

Nucleation mechanism and kinetics from the analysis of polythermal crystallisation data: methyl stearate from kerosene solutions

“…However, this approach is derived by making use of traditional expressions that rely on a number of simplifications and therefore there is more that could be done in the future, specifically to address the underlying molecular-scale interactions which are bound to be involved in directing and controlling the nucleation process [30,31] . Clearly, an understanding of the nucleation kinetics at the molecular level is also required.…”

“…This is the case for many industrial materials such as fuels, confectionery products, pharmaceuticals and fine chemicals. In this regard, the shape of the particle needs further quantification, in a manner which draws down on the now comparatively routine application of the molecular modelling of dimers [32,33] , clusters [34][35][36][37][38] , surfaces [30,39,40] , point defects and additives [41][42][43][44][45] action on crystallisation. Such molecular scale modelling can be expected to have an impact e.g.…”

“…Similarly, the use of the classical nucleation theory for derivation of some of the expressions presented implies interfacial tension corresponding to the crystal equilibrium form, whereas in practice this parameter can vary significantly between the crystallographic forms that are present in the external crystal morphology. In this case, molecular modelling using grid search methods can be used to examine molecule/surface binding and to calculate the interfacial tensions as a function of solution composition [30,39,40] . This has been achieved through characterising the strength of the various surface-specific (extrinsic) synthons that contribute to the growth of the different habit faces [35] , i.e.…”

“…This approach could be applied, e.g., to segment the calculated interfacial tensions as obtained from the model, to yield the inter-relationship between nucleus shape and surface chemistry with the resulting interfacial tensions derived for the individual crystal habit planes [30,39] . This is valuable given, its potential application through the use of the Gibb-Thompson expression, to calculate solubility enhancement as a function of reduced crystal size [40] .…”

In Silico Prediction of Growth and Dissolution Rates for Organic Molecular Crystals: A Multiscale Approach

“…To demonstrate our approach, the dissolution rates for aspirin were predicted and validated by comparison with experimental assessment of aspirin dissolution using a Jamin-type interferometer [53], as described in Section 7 of the manuscript. Aspirin was chosen as a model substance as it is a well-studied compound, where the literature provides a broad array of information like crystal structure [54], polymorphs [55,56], morphology [57], critical nucleus size [58] needed to initialize the multiscale simulation protocol, as well as experimental data on crystal dissolution [59,60] for comparison with the simulation results and validation of the different steps of our protocol. Thus, all of the simulation results presented in the paper are for molecular aspirin crystals.…”