Evaluation of Solvent Compatibilities for Headspace-SIFT-MS Analysis of Pharmaceutical Products

Abstract

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.

Quantitative Analysis of NDMA in Drug Products: A Proposed High-Throughput Approach Using Headspace–SIFT-MS

“…Note that this needs to be investigated in a future study; limited drug-product samples precluded its evaluation here. For some matrices, residual solvent levels in headspace may be so high that quantitative analysis using SIFT-MS is not possible [20] and/or solvents could interfere with the measurement of the It is, however, conceded that the MHE-SIFT-MS approach will not always be advantageous. For example, for very short sample runs the set-up time and time to report a first result will likely be better for LC-MS/MS unless the calibration for MHE-SIFT-MS is durable longer-term (e.g., weekly calibration).…”

“…Triplicate measurements were obtained for 300 mg samples and gave relative standard deviations (RSDs) in the ranges 1.5-2.7% and 3.6-5.5% for products R1 and R2, respectively. The data are summarized in Figure S3, where the over-reporting of O 2 +• is evident (due to the consumption of the reagent ion signal [20,26]). These data used the full six-injection MHE approach with no internal standard, as is common practice with SIFT-MS [35].…”

“…High levels of residual solvent may impact the calculation of concentrations in SIFT-MS due to excessive consumption of the reagent ions [20,26]. High concentrations are evident in the non-linear headspace responses to drug product mass for H 3 O + and O 2 +• -a phenomenon that needs to be understood and mitigated in method development [26].…”

“…Using the procedure described in Section 2.2.2, calibration curves were generated over two ranges for the three product ions used to target NDMA (see Figure S2 in the Supplementary Materials). The presence of solvent in the standard (methanol in the higher range and methanol plus acetone in the lower range) resulted in non-linear (quadratic) calibration curves for product ions H 3 O + and O 2 +• for the reasons described in Section 2.2.1 [20], while the curve for NO + was linear due to this reagent ion's much lower sensitivity to methanol [32] and moderate sensitivity to acetone [33]. The latter was used as a diluent in the lower concentration region to attempt the stimulation of a non-linear response in NO + , but the NO + remained robust.…”

“…A direct analysis of the high-polarity volatile nitrosamines-with no derivatization-has been described previously [19]. Utilizing this capability for quantitative drug product analysis is non-trivial because conventional dissolution approaches developed for chromatographic techniques typically use organic solvents, whereas water is strongly preferred as a solvent for SIFT-MS due to its low reactivity under soft chemical ionization [20]. However, low-molecular-weight nitrosamines such as NDMA partition poorly for headspace from water due their high solubility [21] (p. 30).…”