Solid-State Evaluation of a Newly Emerged Polymorph for Early-Stage Pharmaceutical Development

Area of Science:

• Pharmaceutical Solid-State Chemistry
• Drug Substance Development
• Crystallization Science

Background:

• Early-stage development of GDC-6599 identified Form A as the most stable polymorph.
• Crystal structure prediction (CSP) suggested more stable polymorphs existed.
• A new polymorph, Form M, was discovered during kilogram-scale API batch crystallization.

Purpose of the Study:

• To characterize and evaluate the newly discovered polymorph (Form M) of GDC-6599.
• To compare the stability and properties of Form M against the established Form A.
• To assess the impact of Form M on drug product performance and manufacturing.

Main Methods:

• Polymorph screening and crystallization development.
• Powder X-ray diffraction (PXRD) for pattern analysis.
• Differential scanning calorimetry (DSC) for thermal analysis.
• Slurry competition (SC) for stability assessment.
• Quantitative PXRD method development for process control.
• Intrinsic solubility and biopharmaceutical assessments.

Main Results:

• Form M's PXRD pattern matched the top-ranked CSP prediction.
• Enantiotropic relationship between Form A and Form M confirmed by DSC and SC, with Form M being more stable.
• A quantitative PXRD method was developed to control Form A percentage during crystallization.
• Form M exhibited 56% of Form A's intrinsic solubility, aligning with thermodynamic predictions.
• Biopharmaceutical assessments indicated no significant impact on drug performance at relevant doses.

Conclusions:

• Form M is the thermodynamically more stable polymorph and is recommended for API manufacturing and solid dosage form development.
• Form A is suitable for suspension formulations and early clinical studies, offering flexibility in development.
• The findings provide crucial data for informed solid-form selection in pharmaceutical development.