Molecular Simulation Analyses of Polymorphism Control Factors by the Example of Carbamazepine Forms I-IV: A Blueprint for Industrial Drug Formulation?

A Gadelmeier and M Macht and D Zahn, JOURNAL OF PHARMACEUTICAL SCIENCES, 111, 2898-2906 (2022).

DOI: 10.1016/j.xphs.2022.06.001

We outline comparably simple molecular simulation techniques to elucidate the interactions that determine the polymorphism of carbamazepine. Starting from the established GAFF molecular mechanics model, only a small series of tailor-made improvements is needed to tackle the subtle differences in the interaction energies of polymorphs I - IV. On this basis, molecular dynamics simulations provide melting enthalpies at < 1 kcal/mol accuracy (0.2 kcal/mol for forms I-III) as compared to the experiment. Yet, the predicted stability ranking of III > I > II > IV only partially reproduces the experimentally observed III > I > IV > II series. Despite this limitation, we demonstrate how insights from molecular simulation offer the elucidation of possible factors for polymorph control. Apart from characterizing bulk crystals, we outline the evaluation of size-dependent profiles of crystallite formation energy. Contrasting the contributions of bulk, surface and edge terms to the formation energy of nano-scale precipitates, we suggest a multi-step nucleation mechanism leading from amorphous aggregates to crystallites. We argue that carbamazepine aggregates of less than e100 molecules adopt a spherical shape to minimize edge/surface energy - overcompensating the loss in bulk energy inherent to non-crystalline ordering in the inner core. In turn, for large crystallites polymorph form III is preferred, whilst suitable spatial confinement to crystallites of 100-500 carbamazepine molecules appears to promote form II. (C) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

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