title: Development and validation of a cyclodextrin-modified capillary electrophoresis method for the enantiomeric separation of vildagliptin enantiomers.
abstract: The enantiomers of vildagliptin, an orally available and selective dipeptidyl-peptidase-4 inhibitor used for the treatment of type II diabetes, have been separated by CD-modified CZE, using uncoated fused-silica capillary. After screening 13 negatively charged CD derivatives as potential chiral selectors, sulfobutyl-ether-α-CD (SBE-α-CD) was selected for the enantioseparation. For the optimization, a factorial analysis study was performed by orthogonal experimental design. Six experimental factors were chosen as variable parameters: temperature, applied voltage, chiral selector and BGE concentrations, pH, and the parameters of the hydrodynamic injection. The optimized system still was not considered final as the second peak (S-enantiomer) migrated too close to the EOF, resulting in a potential inaccuracy during the determination of the chiral impurity. To fine-tune the method "one factor at a time" variation approach was applied. The final method (applying 15°C capillary temperature, 40 mbar × 4 s hydrodynamic injection, 25 kV voltage in 75 mM acetate-Tris buffer [pH 4.75] containing 20 mM SBE-α-CD as chiral selector) was validated according to the ICH guideline. RSD percentage of the resolution value, migration times, and corrected peak areas were below 5% during testing repeatability and intermediate precision. LOD and LOQ values were found to be 2.5 and 7.5 μg/mL, respectively. The method is considered linear in the 7.5-180 μg/mL range for the R-enantiomer. The robustness of the method was justified using Plackett-Burmann statistical experimental design.
authors.affiliation: Department of Pharmacognosy, Semmelweis University, Budapest, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kazsoki
authors.affiliation: Department of Pharmacognosy, Semmelweis University, Budapest, Hungary.
authors.forename: Ida
authors.initials: I
authors.lastname: Fejős
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd, Budapest, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.affiliation: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Science Park, Guangzhou, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Science Park, Guangzhou, P. R. China.
authors.forename: Wenhui
authors.initials: W
authors.lastname: Hu
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd, Budapest, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.affiliation: Department of Pharmacognosy, Semmelweis University, Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification; D003505:Cyclodextrins / Q000737:chemistry*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D019075:Electrophoresis, Capillary / Q000379:methods*; D006863:Hydrogen-Ion Concentration; D007004:Hypoglycemic Agents / Q000737:chemistry*; D057230:Limit of Detection; D009570:Nitriles / Q000737:chemistry / Q000302:isolation & purification*; D011759:Pyrrolidines / Q000737:chemistry / Q000302:isolation & purification*; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013696:Temperature; D000077597:Vildagliptin
chemical_list: D003505:Cyclodextrins; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane
keywords: Cyclodextrin; DPP-4 inhibitor; Enantiomeric impurity; Enantioseparation; Orthogonal experimental design