Study on polycyclic macromolecular drug solid stability: A case exploration of methylcobalamin

Area of Science:

• Pharmaceutical Science
• Solid-State Chemistry
• Drug Development

Background:

• Methylcobalamin (MeCbl), a vital Vitamin B12 derivative, is crucial for human physiology and clinical applications.
• Its complex structure, hygroscopicity, and light sensitivity pose significant challenges for stable pharmaceutical formulation.
• Understanding and controlling MeCbl's solid-state properties is essential for effective drug development.

Purpose of the Study:

• To investigate the solid-state stability of methylcobalamin (MeCbl) hydrates.
• To explore solid-solid phase transformation (SSPT) pathways for MeCbl.
• To establish methods for stable preparation and large-scale production of MeCbl.

Main Methods:

• Solid-solid phase transformation (SSPT) experiments were designed based on MeCbl hydrate structures.
• Characterization techniques included Powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, HPLC, and dynamic vapor sorption.
• Optimization of crystallization processes involved ultrasound-assisted and seeding-introduced strategies.

Main Results:

• Three distinct MeCbl hydrate powders with unique structures (isolated site and channel water molecules) were discovered.
• Drying conditions and ambient humidity were identified as critical factors controlling the final solid form.
• Inter-conversion relationships between the hydrate forms under heating and humidity changes were established.

Conclusions:

• Stable preparation of MeCbl hydrates is achievable by controlling drying and humidity.
• Optimized crystallization processes, including ultrasound and seeding, enable controlled particle size and enhance production.
• This research paves the way for the stable, large-scale manufacturing of methylcobalamin bulk drug.