(T1430-08-43) Rapid Residual Solvent Analysis using SIFT-MS for USP Method < 467 >

Purpose: Real-time mass spectrometry provides an attractive option for scale-up of manufacturing processes in the pharmaceutical industry. An alternative procedure for United States Pharmacopeia Residual Solvents method < 467 > was tested and validated using Selected-Ion Flow Tube Mass Spectrometry (SIFT-MS).

Methods: A Voice200ultra instrument (Syft Technologies, Christchurch, NZ) equipped with a GERSTEL MPS Robotic Pro (Mulheim, Germany) was used to test and validate the USP < 467 > method. Calibration standards were prepared using official USP reference standards (USP, Bethesda, MD) for Class 1, Class 2 – Mixture A and Class 2 – Mixture B. Samples were prepared offline by dissolving pharmaceutical tablets (acetaminophen, aspirin, ibuprofen) in water and aliquoting 6 mL of solution into 20 mL headspace vials. Samples were incubated in two six-place agitators at 60°C for 45 min prior to sampling of the headspace and subsequent injection into the SIFT-MS instrument through a GERSTEL septumless sampling head. A 2.5 mL aliquot of headspace was removed via a heated syringe and injected into the SIFT-MS at 50 µL/s, with a zero-air make-up flow through the inlet to ensure that the total flow into the instrument was 25 mL/min.

Results: Validation of a quantitative procedure for Class 2A and B residual solvents using SIFT-MS was conducted according to USP < 1467 > using official reference standards for the preparation of standard solutions and spiked sample solutions. Spiked sample solutions were prepared with the sample matrix spiked at five levels covering the range of interest. These were 50%, 75%, 100%, 120%, and 150% of the control limit defined by the permitted daily exposure for a given solvent. The validation of the alternative procedure for Class 2 – Mixture A and Mixture B met all acceptance criteria for the quantitation test in Procedure C, with the exception of pyridine and hexane. Class 1 performance was evaluated in terms of Limit Procedure B, which requires a system suitability test where the signal-to-noise (S/N) ratio for benzene is to be greater than 5. A S/N ratio of 13 was achieved for benzene, and significantly higher ratios were achieved for the other Class 1 solvents. Precision (repeatability) was also excellent, with all quantitation ions giving a %RSD of < 4% from six replicate analyses.

Conclusion: SIFT-MS successfully provided an alternative procedure to USP < 467 >, quantifying residual solvents in pharmaceutical products. The analytical performance metrics recommended by USP < 1467 > for validating alternative methodologies were met for all Class 2A and Class 2B residual solvents in Procedure C using SIFT-MS. The acceptance criteria in Procedure B (chromatography limit test) on Class 1 residual solvents were met easily, including the system suitability test for benzene. The simultaneous chromatography-free analysis of all components at one time allows for one-minute measurements per sample, increasing throughput 16-fold over traditional GC-FID residual solvent methods (Figure 1). This validation approach can also be applied to on-line monitoring of residual solvents using SIFT-MS.

References: High-throughput residual solvent analysis using selected ion flow tube mass spectrometry (SIFT-MS). Pharmacopeia Forum Volume 47, Issue 6, Stimuli to the Revision Process. Edmond Biba, Mark J. Perkins, Vaughan S. Langford. November, 2021


Figure 1. Comparison of traditional GC-FID analysis throughput (top) with the newly validated SIFT-MS analysis throughput (bottom).