Monitoring of multiple solvent induced form changes during high shear wet granulation and drying processes using...

Area of Science:

• Pharmaceutical Sciences
• Solid-State Chemistry
• Process Analytical Technology (PAT)

Background:

• Drug product processing can alter solid-state forms, impacting stability and bioavailability.
• Controlling drug form during manufacturing is crucial for consistent product quality.

Purpose of the Study:

• To monitor real-time drug form transformations during high shear wet granulation and drying.
• To investigate the influence of process parameters (water content, temperature, wet massing time, drying method) on drug form conversion.
• To develop quantitative models for predicting drug form concentrations.

Main Methods:

• Online Raman spectroscopy for real-time monitoring of drug forms.
• High shear wet granulation of Compound A at high drug load.
• Development of partial least square regression models using calibration standards.
• Comparative analysis of tray drying and fluid bed drying techniques.

Main Results:

• Observed complex conversions between non-solvated, hemi-hydrate, and apparent amorphous forms of Compound A.
• Non-solvated form converted to apparent amorphous form during water addition; hemi-hydrate formed during wet massing.
• Higher temperatures accelerated conversion rates; increased wet massing time increased hemi-hydrate levels.
• Fluid bed drying effectively "locked" drug form proportions achieved during granulation, unlike prolonged changes during tray drying.

Conclusions:

• Online Raman spectroscopy enables simultaneous real-time monitoring of multiple drug forms during granulation and drying.
• Process parameters significantly influence drug form transformation, highlighting the need for robust process design.
• Fluid bed drying offers advantages in maintaining consistent drug form compared to tray drying.