Tapentadol enantiomers

Synthesis, physico-chemical characterization and cyclodextrin interactions

Ida Fejos, Yang He, Gergely Völgyi, Adrienn Kazsoki, Jin Sun, Weiming Chen, Tamás Sohajda, Lajos Szente, Xiangrui Jiang, S. Béni

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 1H 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 logkO=9.94 and logkN=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.

Original languageEnglish
Pages (from-to)594-601
Number of pages8
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume88
DOIs
Publication statusPublished - Jan 25 2014

Fingerprint

Enantiomers
Cyclodextrins
Protonation
Potentiometry
Impurities
Octanols
Capillary Electrophoresis
Alkalinity
Electrophoresis
Titration
Amines
Macros
Analgesics
Buffers
Acetates
Nuclear magnetic resonance
tapentadol
Water

Keywords

  • Capillary electrophoresis
  • Chiral separation
  • Enantioselective synthesis
  • Migration order
  • Protonation constant

ASJC Scopus subject areas

  • Analytical Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Spectroscopy
  • Clinical Biochemistry

Cite this

Tapentadol enantiomers : Synthesis, physico-chemical characterization and cyclodextrin interactions. / Fejos, Ida; He, Yang; Völgyi, Gergely; Kazsoki, Adrienn; Sun, Jin; Chen, Weiming; Sohajda, Tamás; Szente, Lajos; Jiang, Xiangrui; Béni, S.

In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 88, 25.01.2014, p. 594-601.

Research output: Contribution to journalArticle

Fejos, Ida ; He, Yang ; Völgyi, Gergely ; Kazsoki, Adrienn ; Sun, Jin ; Chen, Weiming ; Sohajda, Tamás ; Szente, Lajos ; Jiang, Xiangrui ; Béni, S. / Tapentadol enantiomers : Synthesis, physico-chemical characterization and cyclodextrin interactions. In: Journal of Pharmaceutical and Biomedical Analysis. 2014 ; Vol. 88. pp. 594-601.
@article{663c6999342e4419b2a24df8524b5cdd,
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 1H 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 logkO=9.94 and logkN=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.",
keywords = "Capillary electrophoresis, Chiral separation, Enantioselective synthesis, Migration order, Protonation constant",
author = "Ida Fejos and Yang He and Gergely V{\"o}lgyi and Adrienn Kazsoki and Jin Sun and Weiming Chen and Tam{\'a}s Sohajda and Lajos Szente and Xiangrui Jiang and S. B{\'e}ni",
year = "2014",
month = "1",
day = "25",
doi = "10.1016/j.jpba.2013.10.005",
language = "English",
volume = "88",
pages = "594--601",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
issn = "0731-7085",
publisher = "Elsevier",

}

TY - JOUR

T1 - Tapentadol enantiomers

T2 - Synthesis, physico-chemical characterization and cyclodextrin interactions

AU - Fejos, Ida

AU - He, Yang

AU - Völgyi, Gergely

AU - Kazsoki, Adrienn

AU - Sun, Jin

AU - Chen, Weiming

AU - Sohajda, Tamás

AU - Szente, Lajos

AU - Jiang, Xiangrui

AU - Béni, S.

PY - 2014/1/25

Y1 - 2014/1/25

N2 - 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 1H 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 logkO=9.94 and logkN=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.

AB - 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 1H 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 logkO=9.94 and logkN=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.

KW - Capillary electrophoresis

KW - Chiral separation

KW - Enantioselective synthesis

KW - Migration order

KW - Protonation constant

UR - http://www.scopus.com/inward/record.url?scp=84887399226&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887399226&partnerID=8YFLogxK

U2 - 10.1016/j.jpba.2013.10.005

DO - 10.1016/j.jpba.2013.10.005

M3 - Article

VL - 88

SP - 594

EP - 601

JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

SN - 0731-7085

ER -