title: Tapentadol enantiomers: Synthesis, physico-chemical characterization and cyclodextrin interactions.
abstract: The complete physico-chemical characterization of the single enantiomer analgesic drug R,R-tapentadol was quantitated in terms of protonation macro- and microconstants and octanol-water partition coefficient using pH-potentiometry, UV-pH and (1)H NMR-pH titrations. The protonation macroconstants were found to be logK1=10.59±0.01 and logK2=9.44±0.01, while the individual basicity of each protonation site was found to be logk(O)=9.94 and logk(N)=10.48 for the phenolate and tertiary amine functions, respectively. As a consequence, the zwitterionic form of tapentadol predominates in aqueous solutions. The potential optical impurity (S,S-tapentadol) was synthesized for the first time in a seven-step chiral synthetic procedure. The enantiomers of tapentadol were separated by cyclodextrin modified capillary zone electrophoresis. Over 15 cyclodextrins were investigated in terms of apparent complex stability and screened as chiral selectors, and the sulfated alpha-cyclodextrin was found to resolve the enantiomers with excellent resolution (Rs=16.2 and 9.1) at pH 4.75 and pH 9.0, respectively. The system containing 12mM selector in a 50mM TRIS-acetate buffer was amenable to detect S,S-tapentadol potential optical impurity at 0.1% concentration level.
authors.affiliation: Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes Endre Street 9, H-1092 Budapest, Hungary.
authors.forename: Ida
authors.initials: I
authors.lastname: Fejős
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.forename: Gergely
authors.initials: G
authors.lastname: Völgyi
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kazsoki
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: Weiming
authors.initials: W
authors.lastname: Chen
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Jiang
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
mesh_terms: D019075:Electrophoresis, Capillary; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009020:Morphine / Q000737:chemistry; D010636:Phenols / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry; D011199:Potentiometry; D011522:Protons; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D000077432:Tapentadol; D014867:Water / Q000737:chemistry; D047391:alpha-Cyclodextrins / Q000737:chemistry*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D010636:Phenols; D011522:Protons; D047391:alpha-Cyclodextrins; D047392:beta-Cyclodextrins; D014867:Water; D009020:Morphine; D000077432:Tapentadol; C031215:betadex; C032613:alpha-cyclodextrin
keywords: Capillary electrophoresis; Chiral separation; Enantioselective synthesis; Migration order; Protonation constant