Structural Characterization of Drug-like Compounds by Ion Mobility Mass Spectrometry: Comparison of Theoretical and Experimentally Derived Nitrogen Collision Cross Sections

We present the use of drug-like molecules as a traveling wave (T-wave) ion mobility (IM) calibration sample set, covering the m/z range of 122.1–609.3, the nitrogen collision cross-section (Ω_N2) range of 124.5–254.3 Ų and the helium collision cross-section (Ω_He) range of 63.0–178.8 Ų. Absolute Ω_N2 and Ω_He values for the drug-like calibrants and two diastereomers were measured using a drift-tube instrument with radio frequency (RF) ion confinement. T-wave drift-times for the protonated diastereomers betamethasone and dexamethasone are reproducibly different. Calibration of these drift-times yields T-wave Ω_N2 values of 189.4 and 190.4 Ų, respectively. These results demonstrate the ability of T-wave IM spectrometry to differentiate diastereomers differing in Ω_N2 value by only 1 Ų, even though the resolution of these IM experiments were ∼40 (Ω/ΔΩ). Demonstrated through density functional theory optimized geometries and ionic electrostatic surface potential analysis, the small but measurable mobility difference between the two diastereomers is mainly due to short-range van der Waals interactions with the neutral buffer gas and not long-range charge-induced dipole interactions. The experimental RF-confining drift-tube and T-wave Ω_N2 values were also evaluated using a nitrogen based trajectory method, optimized for T-wave operating temperature and pressures, incorporating additional scaling factors to the Lennard-Jones potentials. Experimental Ω_He values were also compared to the original and optimized helium based trajectory methods.