Dispersive Raman Spectroscopy for Quantifying Amorphous Drug Content in Intact Tablets.

Area of Science:

• Pharmaceutical Sciences
• Analytical Chemistry
• Materials Science

Background:

• Process-induced phase changes in active pharmaceutical ingredients (APIs) can compromise drug stability, shelf life, and bioperformance.
• Accurate quantification of amorphous content is crucial for ensuring drug product quality and efficacy.

Purpose of the Study:

• To develop and validate a dispersive Raman spectroscopy method for the nondestructive, high-throughput quantification of amorphous conversion in drug products.
• To establish Raman spectroscopy as a viable alternative to traditional methods for at-line monitoring of API phase changes.

Main Methods:

• Development of a quantitative Raman spectroscopy method using partial least squares (PLS) regression.
• Calibration using solid-state nuclear magnetic resonance (ssNMR) spectroscopy as the reference method.
• Preparation of calibration tablets with varying proportions of amorphous and crystalline MK-A subjected to controlled compressive forces.

Main Results:

• PLS predictions of amorphous content using Raman spectroscopy showed strong correlation (R² = 0.987) with ssNMR quantification.
• The method achieved high predictive accuracy with a root-mean-squared error of prediction of 1.5% w/w amorphous MK-A.
• The developed method is capable of quantifying up to 50% w/w amorphous conversion within a compressive stress range of 60-320 MPa.

Conclusions:

• Dispersive Raman spectroscopy provides a fast, sensitive, and high-throughput (<5 min/tablet) method for quantitating amorphous conversion.
• This technique enables nondestructive at-line monitoring of critical API phase changes.
• Raman spectroscopy is a promising tool for quality control and process understanding in pharmaceutical manufacturing.