Polymorphic phase transitions: Macroscopic theory and molecular simulation.

Area of Science:

• Solid-state chemistry
• Materials science
• Computational chemistry

Background:

• Solid-state transformations are critical in pharmaceuticals, with unexpected polymorphic changes causing product failure.
• Exploiting metastable polymorphs requires ensuring their stability against solid-state transformation.
• A molecular-level understanding is needed to address these challenges and advance technology.

Purpose of the Study:

• To provide a comprehensive review of state-of-the-art molecular simulation methods for modeling polymorph stability and solid-state transitions.
• To revisit the theoretical framework of phase transitions, including classification, mechanisms, and kinetics.
• To illustrate the application of molecular simulations in understanding polymorphic transitions.

Main Methods:

• Review of molecular simulation techniques for crystal structure prediction and polymorph screening.
• Analysis of methods for simulating phase coexistence, phase diagrams, and crystal-crystal transitions (displacive, reconstructive, diffusive).
• Examination of simulation studies on defect effects and nanoscale phase stability and transitions.

Main Results:

• Molecular simulations provide time-resolved, molecular-level insights into solid-state processes, surpassing experimental limitations.
• The review covers diverse simulation applications, from crystal structure prediction to nanoscale phase transitions.
• Current methods offer significant understanding and scope for investigating polymorphic transitions.

Conclusions:

• Molecular simulations are essential for understanding and predicting solid-state transformations in materials and pharmaceuticals.
• Advancements in simulation methods and hardware promise in silico design of dosage forms and drug delivery systems.
• Rational control of polymorphism in drug development can be achieved through molecular simulation insights.