Development of a green GC-FID method for residual solvent analysis in paliperidone nanocrystal formulations: Validation and greenness assessment

Abstract

Introduction

Residual solvents like dimethyl sulfoxide (DMSO), commonly used in the formulation of paliperidone nanocrystals, require stringent quantification to ensure safety and regulatory compliance. This study presents the development of a novel, sensitive, and specific Gas Chromatography-Flame Ionization Detector (GC-FID) method for their accurate determination.

Methodology

Paliperidone nanocrystals were prepared by the antisolvent precipitation method. A novel analytical method was developed by using gas chromatography for residual solvent analysis present in nanocrystals. The analytical method utilized an Rtx column (dimensions: 30.0 mm x 0.25 mm) with nitrogen gas as the carrier and methanol as the diluent. The developed gas chromatography method was validated as per ICH Q2 (R1) guidelines.

Results

Analysis via GC-FID yielded a prominent peak for the residual solvent, dimethyl sulfoxide (DMSO), at a retention time of 1.819 minutes under a pressure of 170.3 kPa and a flow rate of 28 mL/min. The GC oven temperature commenced at 50 °C and was maintained for 3 minutes. Subsequently, a programmed ramp of 10 °C/minute was applied until a final temperature of 100 °C was reached, which was then held for 3 minutes. The detector temperature was constant at 250 °C. Validation following ICH guidelines confirmed method specificity, sensitivity and linearity within a 2–10 µL/mL range. The Limit of Detection (LOD) and Limit of Quantification (LOQ) were found to be 0.0047 µL/mL and 0.0136 µL/mL, respectively. The residual solvent DMSO in the 1 mg of paliperidone nanocrystal sample was found to be 21.91 ppm. Greenness and whiteness evaluation were performed for the developed method.

Conclusion

This novel GC-FID method offers a robust and dependable analytical approach for the determination of residual solvents in paliperidone nanocrystals and has an application in the routine quality control analysis. Moreover, the method aligns with green analytical chemistry principles by incorporating low solvent consumption, reduced waste generation, and energy-efficient operation, thereby supporting environmentally sustainable pharmaceutical quality control.