Exploring Carbamazepine Polymorph Crystal Growth in Water by Enhanced Sampling Simulations

Area of Science:

• Pharmaceutical Science
• Materials Science
• Computational Chemistry

Background:

• Carbamazepine (CBZ) exhibits polymorphism, where different crystal forms can significantly impact drug efficacy and bioavailability.
• Understanding the crystallization pathways of CBZ is crucial for controlling its solid-state properties.

Purpose of the Study:

• To investigate the thermodynamic favorability of different carbamazepine (CBZ) polymorphs during secondary nucleation.
• To elucidate the molecular mechanisms governing CBZ crystallization using computational simulations.
• To identify key factors influencing the preferential formation of specific CBZ crystal forms.

Main Methods:

• Utilized molecular dynamics simulations with an enhanced sampling scheme to model CBZ adsorption onto surfaces of different polymorphs.
• Developed a novel approach to compute free energy profiles for molecule adsorption, focusing on orientations aligned with crystal structures.
• Rescaled adsorption free energy to isolate contributions consistent with crystal growth.

Main Results:

• Thermodynamic analysis indicated a preference for the most stable polymorphs (Form III and Form I) over the dihydrate.
• The dihydrate, often the primary crystallization product, showed less favorable thermodynamics, suggesting a nonclassical crystallization pathway.
• Surface hydrophobicity was identified as a significant factor influencing the energetics of CBZ adsorption and crystal growth.

Conclusions:

• The study provides a thermodynamic ranking of CBZ polymorphs, offering insights into their growth pathways.
• Findings suggest that CBZ crystallization may involve nonclassical mechanisms, deviating from simple nucleation and growth.
• Understanding these molecular pathways is vital for controlling CBZ polymorphism and ensuring consistent drug performance.