Tackling quantitative polymorphic analysis through fixed-dose combination tablets production. Pyrazinamide...

Area of Science:

• Analytical Chemistry
• Pharmaceutical Sciences
• Spectroscopy

Background:

• Tuberculosis treatment relies on fixed-dose combination (FDC) drugs like Pyrazinamide (PZA), Rifampicin (RIF), Isoniazid (ISH), and Ethambutol (ETB).
• PZA has multiple polymorphs, but only Form α is suitable for pharmaceutical use due to stability and bioavailability.
• Traditional methods for polymorph quantification face limitations with complex pharmaceutical formulations like FDC tablets.

Purpose of the Study:

• To develop and validate a Near Infrared Spectroscopy (NIR) coupled with Partial Least Squares (PLS) regression strategy for quantifying PZA Form α.
• To assess the method's accuracy in both PZA drug substance (raw material) and PZA/RIF/ISH-FDC tablets.
• To provide a reliable analytical tool for ensuring PZA polymorphic purity throughout pharmaceutical manufacturing.

Main Methods:

• Development of two PLS models: one for PZA drug substance (ternary mixture of polymorphs) and one for FDC tablets (including RIF, ISH, and excipients).
• Optimization of NIR-PLS models using a radial optimization approach with specific pre-treatment methods (MSC-D' and SNV-D').
• Validation of the models through assessment of bias, systematic errors, and recovery rates in both drug substance and FDC tablet samples.

Main Results:

• Both NIR-PLS models demonstrated high accuracy and reliability, with satisfactory recoveries (102.5 ± 3.1% for drug substance, 98.7 ± 1.5% for FDC tablets).
• The method accurately predicted PZA Form α content in commercial drug substance (0.98 ± 0.01 w/w) and in intact, sectioned, and powdered FDC tablets (e.g., 0.984 ± 0.003 w/w).
• The methodology proved effective even when PZA Form α was analyzed in FDC formulations fortified with other PZA polymorphs.

Conclusions:

• The developed NIR-PLS strategy offers an effective and accurate alternative for quantifying PZA Form α in pharmaceutical products.
• This method is suitable for monitoring polymorphic purity across various stages of pharmaceutical manufacturing, from raw materials to finished FDC tablets.
• The study highlights the potential of NIR spectroscopy as a powerful tool for quality control in complex drug formulations.