Molecular dynamics simulations of the mechanically induced crystallization of carbamazepine’s trigonal polymorph, CBZ(II)

Abstract The present study investigates the mechanism by which the thermodynamically stable form of carbamazepine, CBZ(III), transforms to the trigonal polymorph, CBZ(II), during ball milling in the presence of palmitic acid. Crystal-structure and lattice-energy analyses were performed, and molecular dynamics (MD) simulations provided insight into crystal-surface and molecular-level phenomena underpinning the phase transformation. The PIXEL formalism and the all-atom Coulomb–London–Pauli method reproduced the experimentally observed stability order between CBZ(III) and CBZ(II). MD indicates limited miscibility between CBZ and palmitic acid—both at crystal surfaces and in the melt. The transformation proceeds via surface fluidization of CBZ(III) and hydrophobic-interaction–driven aggregation of CBZ around palmitic-acid alkyl chains. MD of palmitic-acid inclusion in CBZ(II) channels, together with pore analyses, suggests that stable inclusion would require lattice dilation. Trajectory inspection further shows frequent guest–wall repulsive contacts that can expel palmitic acid from the voids. Further work is warranted to test whether the transformation mechanism proposed for the polymorphic transformation of CBZ(III)→CBZ(II) generalizes to other mechanically induced solid-state transformations.