title: Assessing Physicochemical Properties of Drug Molecules via Microsolvation Measurements with Differential Mobility Spectrometry.
abstract: The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion's transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKaand pKbvalues, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS's ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers' different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.
authors.affiliation: SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada.
authors.forename: J C Yves
authors.initials: JC
authors.lastname: Le Blanc
authors.affiliation: SCIEX , 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada.
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Schneider
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jefry
authors.initials: J
authors.lastname: Shields
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Federico
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Stroh
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Kauffman
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Kung
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Ieritano
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Evan
authors.initials: E
authors.lastname: Shepherdson
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Mitch
authors.initials: M
authors.lastname: Verbuyst
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Luke
authors.initials: L
authors.lastname: Melo
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Moaraj
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: Dalia
authors.initials: D
authors.lastname: Naser
authors.affiliation: Pfizer Global Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: John S
authors.initials: JS
authors.lastname: Janiszewski
authors.affiliation: Department of Chemistry, University of Waterloo , 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: W Scott
authors.initials: WS
authors.lastname: Hopkins
authors.affiliation: SCIEX, 71 Four Valley Drive, Concord, Ontario, L4K 4V8, Canada; Department of Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, N2L 3G1, Canada.
authors.forename: J Larry
authors.initials: JL
authors.lastname: Campbell