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Since the initial 2018 recall of angiotensin receptor blockers due to unacceptable levels of mutagenic N-nitrosodimethylamine (NDMA) impurity, numerous drug products delivering diverse active pharmaceutical ingredients (APIs) have been recalled. Regulators and the industry are working together to understand and address this widescale problem. Conventional analysis of NDMA utilizes liquid or gas chromatography-based procedures that can involve complicated sample preparation and slow sample analysis. Selected ion flow tube mass spectrometry (SIFT-MS) analyses NDMA directly in the gas phase using soft chemical ionization, with an LOQ of 2 ng g−1. Through the novel application of the multiple headspace extraction (MHE) technique, NDMA was quantified directly and rapidly from the drug product without dissolution, at levels well below the regulatory acceptable intake of 96 ng day−1. A comparative analysis of recalled metformin using MHE-SIFT-MS and a conventional liquid chromatography–mass spectrometry/mass spectrometry (LC-MS/MS) method showed good agreement. Use of the novel MHE-SIFT-MS approach may enable a wider screening of drug products to be conducted, since it provides around a three-fold increase in daily sample throughput. [ABSTRACT FROM AUTHOR]

Procedures for determination of the residual solvent and volatile impurity content in pharmaceutical products usually rely on dissolution in a solvent, followed by headspace-gas chromatography (HS-GC) analysis. Whereas chromatographic systems can utilize a wide variety of solvents, direct-injection mass spectrometry (DIMS) techniques have fewer solvent options, because elimination of the chromatographic column means that the instrument is more susceptible to saturation. Since water has the lowest impact, it has almost always been the default solvent for DIMS. In this study, selected ion flow tube mass spectrometry (SIFT-MS)—a DIMS technique—was applied to the systematic evaluation of the proportion of solvent that can be utilized (with aqueous diluent) without causing instrument saturation and while maintaining satisfactory analytical performance. The solvents evaluated were N,N-dimethylacetamide (DMAC), N,N-dimethylformamide (DMF), 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), methanol, and triacetin. All solvents are compatible with headspace-SIFT-MS analysis at 5% (min) in water, while DMI, DMAC, and DMSO can be used at higher concentrations (50, 100, and 25%, respectively), though suffering substantial diminution of the limit of quantitation for non-polar analytes at higher proportions of non-aqueous solvent. Analytical performance was also evaluated using linearity, repeatability, and recovery measurements. This work demonstrates that organic solvents diluted in water can be utilized with headspace-SIFT-MS and provide an approach for evaluation of additional diluent solvents. [ABSTRACT FROM AUTHOR]

Residual solvents in pharmaceutical excipients, active pharmaceutical ingredients (APIs), and finished products are usually analyzed using gas chromatography (GC)-based techniques according to a pharmacopeial monograph, such as the United States Pharmacopeia's (USP) chapter <467>. GC analyses are often slow, which limits sample throughput. Selected ion flow tube mass spectrometry (SIFT-MS) removes the rate-limiting chromatographic separation step, potentially offering faster sample analyses. This approach was demonstrated recently with the publication of an alternative SIFT-MS procedure which was successfully validated against the performance criteria in USP chapter <1467>. The present study expands upon the previous work by conducting a head-to-head comparison of GC-flame ionization detection (GC-FID) and SIFT-MS procedures. The results obtained in this cross-platform study demonstrated similar performance for the GC-FID and SIFT-MS procedures for linearity (R2 > 0.94 and 0.97, respectively) and repeatability (<17%RSD and <10%RSD). For accuracy and recovery, acceptance criteria (within 20%) were achieved for most compounds across the two drug products (SIFT-MS suffered fewer failures, possibly due to shorter wait times prior to analysis). Additionally, SIFT-MS analyzed samples over 11-fold faster than GC-FID, increasing daily sample throughput and reducing the time taken to determine the result. This study therefore suggests that residual solvent analysis using SIFT-MS may support workflow improvements for pharmaceutical manufacturers. [ABSTRACT FROM AUTHOR]