Crystallization behavior of mannitol in frozen aqueous solutions

Area of Science:

• Physical Chemistry
• Materials Science
• Pharmaceutical Sciences

Background:

• Mannitol is a crucial excipient in pharmaceutical formulations, particularly for lyophilization.
• Understanding its crystallization behavior in frozen states is vital for formulation stability and efficacy.
• Factors influencing mannitol's solid-state properties during freezing require thorough investigation.

Purpose of the Study:

• To investigate the impact of cooling rate on mannitol crystallization in frozen aqueous solutions.
• To determine the influence of phosphate buffers and polyvinylpyrrolidone (PVP) on mannitol's crystallization behavior.
• To characterize the physical states of mannitol in frozen and thawed solutions.

Main Methods:

• Low-temperature differential scanning calorimetry (DSC) for thermal analysis.
• Powder X-ray diffractometry (PXRD) for structural characterization.
• Controlled cooling rates to study crystallization kinetics.

Main Results:

• Rapid cooling (20°C/min) inhibited mannitol crystallization, yielding an amorphous state.
• Slower cooling rates (10°C and 5°C/min) resulted in partial mannitol crystallization.
• The amorphous freeze-concentrate exhibited two glass transitions at -32°C and -25°C.
• Mannitol crystallized as mannitol hydrate upon heating past glass transition temperatures.
• Increased polyvinylpyrrolidone (PVP) concentration prolonged the induction time for mannitol hydrate crystallization.
• Phosphate buffers at concentrations ≥100 mM significantly inhibited mannitol crystallization.

Conclusions:

• Cooling rate is a critical factor controlling mannitol crystallization in frozen solutions.
• Phosphate buffers and polyvinylpyrrolidone (PVP) act as crystallization inhibitors or modifiers.
• The findings provide insights into controlling mannitol's solid-state form during freeze-drying processes.