Molecular rotational resonance (MRR) spectroscopy utilizes the microwave region of electromagnetic radiation, which, in terms of energy, corresponds to transitions between pure rotational energy levels of molecules. Combined with adiabatic cooling in a gas phase, MRR measurement provides a pure rotational spectrum of a molecule's ground vibrational state, which has absolute frequencies and extremely narrow linewidths. Such a spectrum is unique for each chemical structure because it precisely reflects the absolute positions in space for all atoms in a molecule and the corresponding three-dimensional mass distributions. Any small change in a position in space or the mass of any atom(s) between two different substances will result in a well-resolved change in their MRR spectra. Hence, MRR offers unparalleled chemical selectivity. This unique selectivity gives MRR a key advantage: mixtures, including mixtures of all types of isomers, can be analyzed directly without the need for chromatographic separation. As such, MRR has the potential to reduce the time of analyses of mixtures containing diverse volatile chemicals, including residual solvents listed in Residual Solvents 〈467〉.
This Stimuli article presents the development and validation of a continuous headspace-MRR method for analysis of selected Class 2 (moderate toxicity) residual solvents (per 〈467〉), including all of the low-volatility solvents from USP Residual Solvents Class 2—Mixture C RS. Solvents for this study were selected based on diversity of their boiling points to demonstrate MRR feasibility for analysis of a representative range of solvents. The data presented suggest that MRR can meet ICH and USP requirements for analysis of most of Class 2 and Class 3 residual solvents, and half of Class 1 residual solvents.
An attractive feature of using MRR for residual solvent analysis as an orthogonal technique is that it can bridge analytical gaps of conventional methods for analysis of low-volatility solvents such as those from USP Residual Solvents Class 2—Mixture C RS, dimethyl sulfoxide (DMSO), water-soluble acids, volatile amines, and others. Further, MRR is an online-capable technique that can be used for analysis of diverse volatile molecules not only in laboratory settings but also on the process floor. Therefore, MRR can be used at any stage of pharmaceutical development and manufacturing including support for process analytical technology (PAT) and quality by design (QbD) initiatives and continuous manufacturing.
USP REFERENCE STANDARDS FOR PURCHASE
USP Residual Solvents Class 2—Mixture A RSUSP Residual Solvents Class 2—Mixture B RS
USP Residual Solvents Class 2—Mixture C RS