Development of a targeted polymorph screening approach for a complex polymorphic and highly solvating API.

Area of Science:

• Pharmaceutical Science
• Materials Science
• Crystallography

Background:

• Identifying the most stable crystalline form of an active pharmaceutical ingredient (API) is essential for drug development.
• Complex polymorphic profiles and stable solvate formation pose significant challenges during polymorph screening.
• The case involves a highly polymorphic compound with numerous anhydrous and solvated forms.

Purpose of the Study:

• To overcome challenges in polymorph screening for a complex API with a propensity for solvate formation.
• To develop novel screening approaches to identify key anhydrous forms.
• To confirm the stability of the selected development form.

Main Methods:

• Initial polymorph screening using conventional techniques.
• Advanced analysis of crystal structure and conformational relationships.
• Development of targeted high-temperature desolvation screening approaches.
• Execution of over 100 experiments using the devised methods.

Main Results:

• Conventional screening predominantly yielded solvates and missed critical anhydrous forms.
• Targeted screening approaches successfully produced only known anhydrous forms.
• No new anhydrous forms were discovered despite extensive experimentation.
• The developed methods circumvented solvation issues common in conventional screening.

Conclusions:

• The advanced screening strategies were critical for overcoming solvation challenges.
• The results provide high confidence in the stability of the current development form.
• The likelihood of a more stable anhydrous form existing is low.