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

• Published in: Analytical chemistry (Washington) 2012-01, Vol.84 (2), p.1026-1033
• Main Authors: Campuzano, Iain, Bush, Matthew F, Robinson, Carol V, Beaumont, Claire, Richardson, Keith, Kim, Hyungjun, Kim, Hugh I
• Format: Article
• Language: English
• Subjects: Betamethasone - analysis; Betamethasone - chemistry; Calibration; Chemical compounds; Dexamethasone - analysis; Dexamethasone - chemistry; Helium; Ions; Mass Spectrometry - instrumentation; Mass Spectrometry - methods; Models, Theoretical; Molecules; Nitrogen; Nitrogen - chemistry
• ISSN: 0003-2700; 1520-6882
• DOI: 10.1021/ac202625t

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 (ΩN2 ) range of 124.5–254.3 Å2 and the helium collision cross-section (ΩHe) range of 63.0–178.8 Å2. Absolute ΩN2 and ΩHe 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 ΩN2 values of 189.4 and 190.4 Å2, respectively. These results demonstrate the ability of T-wave IM spectrometry to differentiate diastereomers differing in ΩN2 value by only 1 Å2, 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 ΩN2 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 ΩHe values were also compared to the original and optimized helium based trajectory methods.