title: Separation of alogliptin enantiomers in cyclodextrin-modified capillary electrophoresis: a validated method.
abstract: The single enantiomer drug, alogliptin (Alo, Nesina®) is a novel, orally available and selective dipeptidyl peptidase-4 inhibitor used for the treatment of type II diabetes. Following its pKa determination by CE-pH titration, a validated chiral CE method has been developed to separate Alo enantiomers. Preliminary screening of the native CDs and their ten derivatives revealed that sulfopropylated-γ-CD, sulfopropylated-β-CD and sulfopropylated-γ-CD, sulfobutyl-ether-β-CD (SBE-β-CD) and sulfobutyl-ether-γ-CD enabled enantioresolution. Furthermore, cavity size dependent enantiomer migration order reversal was observed between γ- and β-CD derivatives. To improve enantioseparation, buffer composition and pH, CD concentration, applied voltage, temperature, and injection parameters were optimized for the Alo/ SBE-β-CD system, yielding a resolution of 8.34. RSD percentage of the resolution value, migration times, and corrected peak areas were below 3 and 5% during testing repeatability and intermediate precision. LOD and LOQ values were found to be 2 and 6 μg/mL, respectively, for each enantiomer. Calibration lines ranging from 6 to 250 μg/mL were constructed with r(2) > 0.9997. Robustness could be successfully verified by using the Plackett-Burman statistical experimental design. The optimized system containing 5 mM SBE-β-CD in a 25 mM acetate buffer at pH 4.75 was found promising to detect 0.1% distomer in the presence of the API.
authors.affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
authors.forename: Ida
authors.initials: I
authors.lastname: Fejős
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Urbancsok
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
mesh_terms: D003505:Cyclodextrins / Q000737:chemistry*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000032:analysis / Q000737:chemistry* / Q000302:isolation & purification*; D019075:Electrophoresis, Capillary / Q000379:methods*; D057230:Limit of Detection; D016014:Linear Models; D010880:Piperidines / Q000032:analysis / Q000737:chemistry* / Q000302:isolation & purification*; D015203:Reproducibility of Results; D013237:Stereoisomerism; D014498:Uracil / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification
chemical_list: D003505:Cyclodextrins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010880:Piperidines; D014498:Uracil; C520853:alogliptin
keywords: Chiral separation; DPP-4 inhibitor; Enantiomer migration order; Nesina®; Synthesis