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

Abstract

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(N(2))) range of 124.5-254.3 Å(2) and the helium collision cross-section (Ω(He)) range of 63.0-178.8 Å(2). Absolute Ω(N(2)) 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(N(2)) values of 189.4 and 190.4 Å(2), respectively. These results demonstrate the ability of T-wave IM spectrometry to differentiate diastereomers differing in Ω(N(2)) value by only 1 Å(2), 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(N(2)) 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.

Divergent Coordination Chemistry: Parallel Synthesis of [2×2] Iron(II) Grid‐Complex Tauto‐Conformers

“…To confirm the distinct character of 1S and 1C (to discriminate between two quickly interconverting species), we used ion‐mobility mass spectrometry (IM‐MS, see SI7), a technique that can spatially separate complex cations under the influence of an electric field by affecting their motion by collisions with a buffer gas 22, 23. In this particular case, travelling‐wave IM‐MS was used to identify the two conformational isomers 1S and 1C , which have identical masses (Figure 3 a), by comparison of the experimentally inferred cross‐sections and computed cross‐sections based on DFT‐optimized structures 24, 25.…”

Anomerization of Acrylated Glucose During Traveling Wave Ion Mobility Spectrometry

“…Proposed mechanisms for the release of ammonia (a) alone or together with acrylic acid from the ammonium adduct of α-Glu-5A (with NH 4 + on acrylate at C2); (b) alone from the ammonium adduct of β-Glu-5A (with NH 4 + on acrylate at C1) separate the two anomers. Indeed, besides its ability to distinguish conformers, TWIMS is also powerful at separating structural isomers of small gas phase ions, as reported for anomers and epimers of monosaccharide methyl glycosides [42], cistrans isomers of terpyridine derivatives [43], as well as a variety of diastereoisomers [44][45][46][47]. The DMAC and THF samples were subjected to ESI-TWIMS-MS experiments where all ions generated during electrospray were injected into the TWIMS cell prior to be mass analyzed in the oa-TOF mass analyzer.…”

A Powerful Four-Dimensional Separation Method for Complex Samples

“…Since 2014, the Agilent 6560 (IM-qTOF-MS), a system using drift time IMS (DTIMS), is available [4]. IMS separates ions according to their size/shape-to-charge ratio and therefore has the ability to measure collision cross-sections (CCS or X) of the ions [5]. In comparison to TWIMS, where an analyte-dependent calibration has to be performed to determine CCS because a non-uniform electric field is used [6], DTIMS allows to calculate CCS directly from the observed drift times using the Mason-Schamp equation [7,8] and only an analyteindependent calibration is necessary for calculation of CCS with the single-field method [9].…”

“…In comparison to TWIMS, where an analyte-dependent calibration has to be performed to determine CCS because a non-uniform electric field is used [6], DTIMS allows to calculate CCS directly from the observed drift times using the Mason-Schamp equation [7,8] and only an analyteindependent calibration is necessary for calculation of CCS with the single-field method [9]. Several values for CCS, which are specific for certain substances, are available in the literature for different peptides [10][11][12][13], N-glycans [6], a few drug-like compounds [5], metabolites [14], lipids [15] or different biomolecules [16].…”

“…After the chromatographic separation an orthogonal gas phase electrophoretic separation, the ion mobility spectrometry in a drift tube, follows. The measured drift time allows the calculation of the collision cross-section via the MasonSchamp equation [5]. As a fourth separation dimension and the final detector, a high-resolution time-of-flight mass spectrometer (qTOF-MS) was used.…”