Towards an Accurate Atomistic Description of Procaine Crystals: Force Field Development and MD Simulation of Solid-to-Liquid Phase Transitions

Abstract

Rational design of crystalline materials is crucial for material science and pharmaceutical development, requiring molecular modeling as a powerful complementary tool. This study employs molecular dynamics (MD) simulations to investigate the thermal stability, structural evolution, and melting mechanisms of crystalline procaine base across a temperature range of 23 to 373 K. To evaluate potential finite-size and boundary effects, two distinct computational setups were considered: a bulk crystal model under periodic boundary conditions (System I, 600 molecules) and an isolated nanocrystal in vacuum (System II, 1188 molecules). Both systems demonstrate well-preserved long-range positional ordering from 23 to 313 K, followed by the appearance of a plastic crystalline state with enhanced rotational freedom between 323 and 333 K. At 343 K, a heterogeneous, surface-initiated phase transition to an isotropic melt occurs, which closely matches the experimental melting point of procaine free-base of 334-337 K. MD analysis reveals remarkably slow melting kinetics at 333-343 K, where a crystalline core persists for over 300 ns before complete melting at 500 ns. We found that the thermal breakdown of the crystal lattice strongly correlates with a breakage of the intermolecular hydrogen-bonding 3D network between procaine molecules. Radial distribution function (RDF) analysis shows a sharp shift in the primary amino nitrogen correlations (N10···N10) towards short-distances upon melting, whereas short-range hydrogen-bond N10···O9 distances remain spatially invariant in the liquid phase. Mean square displacement (MSD) of procaine molecules demonstrates a dramatic transition from restricted lattice vibrations below 333 K to active fluid diffusion above 343 K. These findings are accompanied by rotational autocorrelation functions transition from long-time orientational persistence in the solid state (23-333 K) to rapid exponential relaxation in the melt (343-373 K). Finally, unconstrained melting of System II produces a spherical nanodroplet driven by surface tension minimization, confirming that the performance of the developed OPLS-AA FF model.