Analysis of Residual Solvents in Pharmaceuticals by Nexis™ GC-2030 + HS-20 (JP17 Supplement II, USP 467)

Importance of the Topic

Residual solvents in pharmaceuticals present potential health risks and demand precise monitoring to meet regulatory standards such as JP17 and USP 467. Among these, methyl isobutyl ketone (MIBK) was recently added to the JP17 Supplement II as a Class 2A solvent. Accurate quantification of MIBK and other residual solvents is vital for product safety and compliance, driving the need for robust analytical protocols.

Objectives and Overview of the Study

This application note evaluates the performance of the Shimadzu Nexis GC-2030 gas chromatograph coupled with the HS-20 headspace sampler for quantifying Class 2A residual solvents, focusing on MIBK. Two procedures (A and B) were applied to both water-soluble and water-insoluble matrices to assess sensitivity, separation, and compliance with JP17 and USP 467 guidelines.

Methodology

Two headspace GC methods were developed:

• Procedure A: Uses a polar column (SH-Rxi-624 Sil MS), split ratio 1:5, temperature program from 40 °C to 240 °C.
• Procedure B: Uses a wax column (SH-Stabilwax), split ratio 1:10, temperature ramp to 165 °C.

Both procedures were applied to:

• Water-soluble samples: Standard solutions of Class 2A solvents and MIBK prepared in aqueous media.
• Water-insoluble samples: Similar standards prepared in solvent-compatible matrices.

Used Instrumentation

• Gas chromatograph: Shimadzu Nexis GC-2030
• Headspace sampler: Shimadzu HS-20
• Detector: FID-2030 flame ionization detector
• Columns:
  • SH-Rxi-624 Sil MS (0.32 mm ID × 30 m, 1.8 μm) for Procedure A
  • SH-Stabilwax (0.32 mm ID × 30 m, 0.25 μm) for Procedure B

Main Results and Discussion

Both procedures demonstrated sufficient sensitivity for MIBK detection. In Procedure A, MIBK was well resolved from other Class 2A compounds in both matrices. By contrast, Procedure B showed co-elution of MIBK with acetonitrile, limiting its use for certain quality control applications. Method repeatability and resolution metrics met regulatory expectations.

Benefits and Practical Applications of the Method

• Compliant with JP17 and USP 467 for residual solvent analysis.
• Versatile handling of water-soluble and water-insoluble sample types.
• High sensitivity and robust separation enable reliable QC testing in pharmaceutical development and production.

Future Trends and Potential Applications

Advances may include:

• Integration of automated sample preparation to increase throughput.
• Use of multidimensional GC or alternative detectors for enhanced separation.
• Expansion to other emerging residual solvents and complex formulations.
• Data analytics and LIMS integration to streamline compliance documentation.

Conclusion

The Shimadzu Nexis GC-2030 with HS-20 enables accurate and compliant quantification of MIBK and related Class 2A residual solvents. Procedure A offers superior separation in both water-soluble and water-insoluble samples, fulfilling regulatory requirements for pharmaceutical quality control.

Reference

No external references provided in the original text.