title: Interactions of non-charged tadalafil stereoisomers with cyclodextrins: capillary electrophoresis and nuclear magnetic resonance studies.
abstract: The single isomer drug R,R-tadalafil (Cialis) contains two chiral centers thus four stereoisomers (R,R-, S,S-, S,R- and R,S-tadalafil) exist, however, only the most potent inhibitor, the R,R-tadalafil is in clinical use. In our study, over 20 charged cyclodextrin (CD) derivatives were studied for enantiospecific host-guest type interactions in CD-modified capillary electrophoresis. Tadalafil stereoisomers are non-charged; therefore, their electrophoretic separation poses a challenge. Several candidates of both positively and negatively charged hosts were found to be effective for the enantioseparation. Eight out of the beta derivatives and three of alpha derivatives (including sulfated, sulfoalkylated, carboxyalkylated and amino derivatives) resolved all four stereoisomers partially or completely. Cavity size-dependent absolute enantiomer migration order (EMO) reversals were observed in the case of sulfopropyl-alpha (EMO: R,S; S,R; R,R; S,S) and sulfopropyl-beta (S,S; R,R; S,R; R,S) derivatives, while substituent-dependent partial EMO reversals were detected for sulfobutyl-ether-alpha (R,S; S,R; S,S; R,R) and sulfated-alpha-CD (R,R; S,S; R,S; S,R) selectors. Complexation-induced (1)H NMR chemical shift changes reflected that the benzodioxole moiety plays a major role in cavity size-dependent EMO reversal. Sulfobutyl-ether-alpha-CD was the only selector that provided the desired EMO in which the clinically applied eutomer R,R-tadalafil migrates last. Finally, an electrophoretic method applying a background electrolyte (BGE) containing 75 mM Tris-acetic acid buffer (pH 4.75) and 7 mM sulfobutyl-ether-alpha-CD was developed for the baseline resolution of all isomers at 25 °C and +25 kV applied voltage.
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, H-1092 Budapest, Hőgyes Endre u. 9, Hungary.
authors.forename: Ida
authors.initials: I
authors.lastname: Fejős
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, H-1092 Budapest, Hőgyes Endre u. 9, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kazsoki
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd., H-1097 Budapest, Illatos út 7, Hungary.
authors.forename: Tamás
authors.initials: T
authors.lastname: Sohajda
authors.affiliation: Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Ede
authors.initials: E
authors.lastname: Márványos
authors.affiliation: Egis Pharmaceuticals Plc., Chemical Research Division, P.O. Box 100, H-1475 Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Volk
authors.affiliation: Cyclolab Cyclodextrin Research & Development Laboratory Ltd., H-1097 Budapest, Illatos út 7, Hungary.
authors.forename: Lajos
authors.initials: L
authors.lastname: Szente
authors.affiliation: Semmelweis University, Department of Pharmaceutical Chemistry, H-1092 Budapest, Hőgyes Endre u. 9, Hungary; Semmelweis University, Department of Pharmacognosy, H-1085 Budapest, Üllői út 26, Hungary. Electronic address: beni.szabolcs@pharma.semmelweis-univ.hu.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Béni
mesh_terms: D002243:Carbolines / Q000737:chemistry*; D003505:Cyclodextrins / Q000737:chemistry*; D019075:Electrophoresis, Capillary; D009682:Magnetic Resonance Spectroscopy; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry*; D013237:Stereoisomerism; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D003505:Cyclodextrins; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil
keywords: Chiral separation; Cialis; Cyclodextrin; Enantiomer migration order; NMR; Synthesis