Dynamic Crystallization Pathways of Polymorphic Pharmaceuticals Revealed in Segmented Flow with Inline Powder X-ray...

Area of Science:

• Materials Science
• Chemical Engineering
• Crystallization Science

Background:

• Pharmaceutical polymorph transitions are crucial for drug manufacturing and efficacy.
• Crystallization is sensitive to environmental factors, making precise control challenging.
• In situ monitoring is vital for understanding complex crystallization mechanisms.

Purpose of the Study:

• To investigate pharmaceutical crystallization mechanisms using a segmented flow crystallizer.
• To elucidate polymorph transition pathways for urea: barbituric acid (UBA) and carbamazepine (CBZ).
• To demonstrate the utility of in situ synchrotron powder X-ray diffraction (PXRD) in controlled environments.

Main Methods:

• Utilized a segmented flow crystallizer for reproducible reaction conditions.
• Employed in situ synchrotron powder X-ray diffraction (PXRD) to monitor crystallization in real-time.
• Conducted seeded and unseeded crystallization runs for UBA and CBZ.

Main Results:

• Observed a polymorph progression from UBA III to UBA I, influenced by seeding.
• Demonstrated that UBA I seeds promote the formation of UBA I, while UBA III seeds still allow transformation.
• Uncovered mixing-dependent kinetics for the CBZ form II to III transformation.

Conclusions:

• Coupling controlled reaction environments with in situ XRD is essential for studying polymorphic materials.
• In situ measurements provide critical insights into crystallization pathways and polymorph control.
• Flow crystallization offers a reproducible platform for investigating pharmaceutical solid-state transformations.