Isothermal Crystallization Monitoring and Time-Temperature-Transformation of Amorphous GDC-0276: Differential...

Area of Science:

• Materials Science
• Physical Chemistry
• Pharmaceutical Science

Background:

• Amorphous pharmaceuticals require stabilization to prevent cold crystallization, impacting their efficacy as amorphous pharmaceutical ingredients (APIs).
• Understanding crystallization kinetics is crucial for developing stable amorphous solid forms.

Purpose of the Study:

• To investigate the isothermal crystallization kinetics of GDC-0276 using differential scanning calorimetry and rheometry.
• To compare the sensitivity of rheological measurements versus differential scanning calorimetry in detecting early crystallization events.
• To model crystallization kinetics using a modified Johnson-Mehl-Avrami (JMA) equation incorporating viscosity and determine solid-liquid interfacial tension.

Main Methods:

• Isothermal crystallization studies of GDC-0276.
• Differential scanning calorimetry (DSC) and rheometric measurements.
• Application of the Johnson-Mehl-Avrami (JMA) equation and a modified JMA model.
• Construction of time-temperature-transformation (TTT) diagrams.
• Comparison with melting point depression measurements.

Main Results:

• Crystallization kinetics of GDC-0276 followed the JMA equation.
• Rheological measurements demonstrated higher sensitivity in detecting early nucleation and crystallization onset compared to DSC.
• A modified JMA model, incorporating viscosity dependence, successfully described the temperature-dependent crystallization kinetics and TTT diagrams.
• Solid-liquid interfacial tension was determined via crystallization kinetics modeling and compared with results from nanoporous glass confinement.

Conclusions:

• Rheometry provides enhanced sensitivity for monitoring early-stage crystallization in amorphous pharmaceuticals.
• The modified JMA model effectively captures the temperature dependence of crystallization kinetics, aiding in the prediction of TTT diagrams.
• Accurate determination of solid-liquid interfacial tension is critical for understanding and controlling crystallization processes in amorphous APIs.