Residual Solvents in Spironolactone by Headspace GC/FID and Agilent J&W DB-Select 624UI

Significance of the Topic

Residual solvent analysis plays a pivotal role in pharmaceutical quality control to ensure patient safety and regulatory compliance. Spironolactone, a widely used potassium‐sparing diuretic with antimineralocorticoid and antiandrogenic properties, is produced using organic solvents that may remain as impurities. Monitoring these residuals protects against potential toxicity and supports adherence to pharmacopeial standards.

Objectives and Overview

This study demonstrates a robust headspace GC/FID method using an Agilent J&W DB-Select 624UI column and nitrogen carrier gas to quantify seven residual solvents in spironolactone API. Key goals include:

• Achieve baseline resolution of methanol, ethanol, acetone, tetrahydrofuran (THF), ethyl acetate, pyridine, and N,N-dimethylformamide (DMF).
• Evaluate repeatability of retention times and peak areas.
• Replace helium with nitrogen to reduce cost and supply risk.

Methodology and Sample Preparation

Static headspace sampling was performed on an Agilent 7697A headspace sampler coupled to an Agilent 7890A GC with an FID. Sample preparation steps:

1. Weigh 1.00 g spironolactone into a 20 mL headspace vial.
2. Add 1 mL 1-propanol internal standard solution (1 mg/mL in DMSO).
3. Dilute to 10 mL with DMSO and seal vial.
4. For spiked standards, transfer 5 mL stock solution into vials, add internal standard, and dilute to volume.

Chromatographic conditions:

• Column: DB-Select 624UI, 30 m × 0.53 mm × 3 µm.
• Carrier gas: Nitrogen, constant flow 4.5 mL/min.
• Oven program: 40 °C (8 min), ramp to 200 °C at 45 °C/min, hold 3 min.
• Headspace: equilibration 80 °C for 30 min, loop 110 °C, transfer line 130 °C.
• Injection: split 3:1, injection port 200 °C, FID at 250 °C.

Instrumentation

• Gas chromatograph: Agilent 7890A GC with FID detector.
• Headspace sampler: Agilent 7697A.
• Column: Agilent J&W DB-Select 624UI.
• Vials and caps: 20 mL headspace vials, crimp caps with septa optimized for low bleed.

Main Results and Discussion

The Van Deemter analysis indicated that nitrogen achieves satisfactory efficiency at slightly lower linear velocities, yielding a total run time of ~14 minutes. Chromatograms of spiked and sample solutions showed complete separation of all target solvents with sharp, symmetric peaks attributed to the ultra-inert column surface.

• Tailing factors ranged from 0.86 to 1.19, demonstrating excellent peak shape even for basic analytes like pyridine.
• Retention time RSD was below 0.04 %, and peak area RSD below 1.64 % across six injections, confirming method precision.
• Theoretical plate counts exceeded 8,000 for small alcohols and surpassed 700,000 for higher-boiling DMF, indicating high column efficiency.

Benefits and Practical Applications

The described approach offers several advantages:

• Cost reduction by substituting nitrogen for helium without sacrificing chromatographic performance.
• High inertness prevents analyte adsorption and peak distortion.
• Reliable quantification of low-level residual solvents in compliance with pharmacopeial limits.
• Applicability to routine QA/QC and batch release testing of spironolactone and similar APIs.

Future Trends and Opportunities

Advancements likely to further enhance residual solvent analysis include:

• Automation of headspace sample preparation to increase throughput and reproducibility.
• Integration of mass spectrometric detection for confirmatory analysis and lower detection limits.
• Development of greener solvent alternatives and miniaturized sampling to reduce environmental impact.
• Expansion of ultra-inert column chemistries to accommodate an even broader range of polar and basic analytes.

Conclusion

The headspace GC/FID method utilizing an Agilent J&W DB-Select 624UI column and nitrogen carrier gas delivers an economical, precise, and robust solution for monitoring residual solvents in spironolactone. The high inertness and efficiency of the column, combined with excellent repeatability, make this approach well suited for pharmaceutical quality control.

References

1. Macdonald, F. Dictionary of Pharmacological Agents. CRC Press, pp. 1832–1833 (1997).
2. National Pharmacopoeia Committee. Chinese Pharmacopoeia. Chemical Industry Press, Beijing, pp. 1171 (2010).