Predictive Calculation of the Crystallization Tendency of Model Pharmaceuticals in the Supercooled State from Molecular Dynamics Simulations

Abstract

Molecular dynamics (MD) simulations were used to perform a comparative study of the crystallization tendency from the melt of two model pharmaceutical compounds: felodipine and nifedipine. Two crystalline polymorphs of nifedipine (N(α), N(β)) and felodipine (FI, FII) have been studied. Calculations were performed on liquid and crystal systems separately in order to determine their main physical properties (diffusivity, density, and enthalpy). A fair agreement was found between the simulation and the known experimental data confirming the ability of the force field GAFF to reproduce accurately the experimental data for both compounds. Simulations of the crystal-liquid interface enabled the determination of the melting temperature and the interfacial free energy of the different polymorphs. Guided by the classical nucleation theory (CNT) predictions and different growth mechanism models (normal, two-dimensional, and screw dislocation), the nucleation and growth rates have been determined. The present investigation particularly raises the very important role of the solid-liquid interfacial free energy and its interplay with the driving force during the crystallization. The origin of the higher crystallization tendency of nifedipine with respect to felodipine is discussed from the present computed kinetic and thermodynamical factors.

Impact of chirality on the Glass Forming Ability and the crystallization from the amorphous state of 5-ethyl-5-methylhydantoin, a chiral poor glass former

“…xylene liquid can undergo cooling and vitrify, whereas for para-xylene isomer crystallization takes place in the same cooling conditions (Alba et al, 1990). The tendency to crystallize (or to vitrify reversibly) can be related to numerous parameters: dynamics (viscosity or molecular mobility), thermodynamics (the driven force of crystallization) (Baird et al, 2012;Gerges and Affouard, 2015), kinetics and structural (the complexity to rebuild the bond networks between molecules after melting) (Baird et al, 2012). None of these different parameters can be neglected when it comes to fully understand the GFA of a compound or its crystallization propensity.…”

Insight From Molecular Dynamics Simulations on the Crystallization Tendency of Indomethacin Polymorphs in the Undercooled Liquid State

“…36 Recently, CFM was also used by the authors to estimate the interfacial free energy of nifedipine and felodipine polymorphs. 37 Both ACM and CFM show marked advantages and disadvantages. ACM is usually considered as more precise than CFM to obtain the solid-liquid interfacial free energy γ but it is less precise to measure the anisotropy in γ. ACM requires systems of relatively small sizes made of about N = 10 000 atoms while for CFM simulations larger systems are necessary of about 50 000 to 100 000 atoms.…”

Application of the Classical Nucleation Theory for Quasi-real Systems Differ in Dipole Moment Value – the Role of Diffusion

“…Consequently, using the CFM the 𝛾 values have been calculated for metallic compounds, [57][58][59]64 alloys, 65,66 and a few molecular systems 67 including pharmaceuticals. [68][69][70] Hence we decided to employ CFM to determine 𝛾 for studied herein systems. The use of CFM requires creation of the biphasic box.…”