Determination of amorphous content in the pharmaceutical process environment

Area of Science:

• Pharmaceutical Sciences
• Materials Science
• Analytical Chemistry

Background:

• Amorphous and crystalline states exhibit distinct chemical and physical properties.
• Amorphous regions impact drug bioavailability and material processability.
• Crystalline forms can destabilize amorphous systems by acting as nucleation sites.

Purpose of the Study:

• To quantify amorphous content in a pharmaceutical process environment.
• To evaluate near-infrared (NIR) and Raman spectroscopy for amorphous content determination.
• To assess the influence of multivariate modeling, preprocessing, and sampling on quantification accuracy.

Main Methods:

• Process-induced amorphization of alpha-lactose monohydrate via milling.
• Study of amorphous lactose and trehalose crystallization under high humidity.
• Application of NIR and Raman spectroscopy with multivariate analysis.
• Optimization of data preprocessing (e.g., Standard Normal Variate) and sampling area.

Main Results:

• Both NIR and Raman spectroscopy, coupled with multivariate methods, are suitable for quantitative analysis.
• Standard Normal Variate (SNV) transformation improved model performance.
• Increased sampling area enhanced the accuracy of NIR spectroscopy models (RMSEP of 2.7% for amorphous lactose).
• Raman spectroscopy achieved low RMSEPs (2.3% for lactose, 2.5% for trehalose).

Conclusions:

• Spectroscopic techniques and multivariate modeling offer a viable approach for determining amorphous content in pharmaceutical processes.
• Model performance is sensitive to preprocessing methods and sampling area.
• Comprehensive consideration of all physical forms and the process environment is crucial for optimal multivariate model performance.