title: Doubly charged trimeric cluster ions: effective in mutual chiral recognition of tadalafil and three proton pump inhibitors.
abstract: Mutual chiral recognition of four stereoisomers of tadalafil and three pairs of enantiomers of proton pump inhibitors (PPIs) including pantoprazole, lansoprazole, and omeprazole, as well as quantitative analysis of enantiomeric excess is achieved on the basis of the competitive fragmentation of doubly charged trimeric NiIIcluster ions. Compared with a singly charged trimeric cluster ion, a doubly charged trimeric cluster ion was proved efficient in the recognition of chiral drugs with one or multiple chiral centers, due to its rich fragmentation ions. Upon collision-induced dissociation (CID), the cluster ion [NiII(PPIs)(tadalafil)2]2+yielded two diagnostic ions [tadalafil + H]+and [tadalafil - benzo[d][1,3]dixoloe]+through electrospray ionization quadrupole time-of-flight mass spectrometry. The abundance ratio of the two fragment ions relied mainly on the configuration of PPIs and tadalafil, and therefore the chiral selectivity (Rchiral) of one enantiomer relative to the others is different. The chiral recognition of all four stereoisomers of tadalafil was achieved by using S configuration PPIs as references, and S-omeprazole showed the best selectivity. The Rchiralvalues for R,R/S,S, R,S/S,R, R,R/R,S and R,R/S,R-tadalafils were 1.47, 1.17, 2.37, and 2.10, respectively. In a reciprocal process, the Rchiralwas 1.36 and 1.31 for R/S-pantoprazole and R/S-lansoprazole, respectively, by using R,R-tadalafil as a reference. Although omeprazole is a racemic drug, it can also be discriminated with S-omeprazole. Calibration curves were constructed with favorable correlation coefficients (r2> 0.991) by relating the ln(Rchiral) values to the isomeric composition in a mixture. The sensitivity of the methodology allows mixtures to be analyzed for the enantiomeric excess (ee) by recording the ratios of fragment ion abundances in a mass spectrum. The sensitivity of the methodology allowed the determination of enantiomeric impurities of 5% molar composition in individual compounds present in mixtures; the diastereoisomeric impurity of R,R-tadalafil could be quantified even at 1%. We believe that the developed method not only has scientific significance in qualitative and quantitative chiral analyses of tadalafil and PPIs, but also provides great opportunity for enabling the discrimination on a wide range of chiral drugs.
authors.affiliation: Institute of Drug Metabolism and Analysis, College of Pharmaceutical Sciences, Hangzhou 310058, Zhejiang, PR China. suncuirong@zju.edu.cn zengsu@zju.edu.cn and Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, Zhejiang, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Drug Metabolism and Analysis, College of Pharmaceutical Sciences, Hangzhou 310058, Zhejiang, PR China. suncuirong@zju.edu.cn zengsu@zju.edu.cn.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Chai
authors.affiliation: Department of Quality Control, Zhejiang Huahai Pharmaceutical Ltd, Taizhou, China.
authors.forename: Wenquan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, PR China.
authors.forename: Yuanjiang
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Institute of Drug Metabolism and Analysis, College of Pharmaceutical Sciences, Hangzhou 310058, Zhejiang, PR China. suncuirong@zju.edu.cn zengsu@zju.edu.cn.
authors.forename: Cuirong
authors.identifier: http://orcid.org/0000-0002-4479-8013
authors.initials: C
authors.lastname: Sun
authors.affiliation: Institute of Drug Metabolism and Analysis, College of Pharmaceutical Sciences, Hangzhou 310058, Zhejiang, PR China. suncuirong@zju.edu.cn zengsu@zju.edu.cn and Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou 310058, Zhejiang, PR China.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
mesh_terms: D007477:Ions / Q000737:chemistry; D009853:Omeprazole / Q000737:chemistry*; D054328:Proton Pump Inhibitors / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D000068581:Tadalafil / Q000737:chemistry*
chemical_list: D007477:Ions; D054328:Proton Pump Inhibitors; D000068581:Tadalafil; D009853:Omeprazole