Molecular simulation of size-dependent crystal stability and water solubility of carbamazepine polymorphs: Guides to tailor drug formulation

While molecular simulations are by now well-established for predicting bulk crystal structures and their lattice energy, here we present an approach to predicting the stability of finite precipitates in different solvent scenarios. Mimicking carbamazepine formulation from apolar solution, we outline size-dependent energy profiles for crystallites of polymorphs I-III and amorphous particles, respectively. In particular, crystal nucleation barriers are computed as functions of supersaturation and contrasted to the size-dependent stability profiles of the competing polymorphs. On this basis, we argue that carbamazepine follows a two-step nucleation process starting from amorphous precipitates of spherical shape. These indeed reflect the thermodynamically preferred state of aggregates counting up to ∼100 carbamazepine molecules. In turn, larger aggregates experience thermodynamic driving to self-organization into crystalline arrangements. Crystallites of up to ∼1000 molecules showed an energetic preference of form II, whilst thermodynamic stability of form III applies to larger crystals. Tailoring critical nucleus size and energy from different degrees of supersaturation, our models suggest routes to promote nucleation of carbamazepine form II from apolar solution. In turn, immersing our series of crystallite/precipitate models in water, we re-evaluate size-dependent polymorph stability - and predict relative solubility in water. On this basis, boosts in relative solubility by 100 and 200 % are suggested for 50 and 25 nm scale spatial confinements (e.g. solid dispersion in polymer solutions), respectively.