The optimization of process analytical technology for the inline quantification of multiple drugs in fixed dose...

Area of Science:

• Pharmaceutical Technology
• Analytical Chemistry
• Process Engineering

Background:

• Uncontrolled hypertension leads to premature death globally.
• Fixed-dose combinations (FDCs) improve patient compliance compared to polypharmacy.
• Current Process Analytical Technology (PAT) often focuses on single-drug quantification in continuous manufacturing.

Purpose of the Study:

• To develop non-destructive, inline Process Analytical Technology (PAT) tools for simultaneous quantification of Hydrochlorothiazide (HCTZ) and Ramipril (RMP).
• To enable real-time quality control during the continuous manufacturing of FDCs.
• To advance PAT applications for multicomponent pharmaceutical systems.

Main Methods:

• Manufacturing of HCTZ and RMP calibration sets using hot melt extrusion.
• Inline Raman spectroscopy for real-time analysis of extrudates.
• Principal component analysis (PCA) and Partial Least Squares (PLS) regression for model development.

Main Results:

• Optimized wavenumber regions identified for HCTZ (200-400, 630-730 cm⁻¹) and RMP (980-1100 cm⁻¹).
• PLS models demonstrated excellent linearity (R² ≥ 0.974) and accuracy (RMSEcv ≤ 1.586%).
• Validation showed good predictability with low RMSEP values (≤ 1.237%).

Conclusions:

• Raman spectroscopy, coupled with chemometrics, enables simultaneous inline quantification of multiple drugs in FDCs.
• This facilitates robust in-process quality control for continuous pharmaceutical manufacturing.
• The developed PAT tools support the production of complex multicomponent drug formulations.