Multimodal inclusion complexes between barbiturates and 2-hydroxypropyl-β-cyclodextrin in aqueous solution: Isothermal titration microcalorimetry, 13C NMR spectrometry, and molecular dynamics simulation

✍ Scribed by Hatsumi Aki; Tokihiro Niiya; Yukiko Iwase; Magobei Yamamoto

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 273 KB
• Volume: 90
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.1072

✦ Synopsis

Multiple types (structures) of inclusion complexes between barbiturates and 2-hydroxypropyl-b-cyclodextrin (HPCD) were evaluated by isothermal titration microcalorimetry and 13 C NMR spectroscopy. The geometries of the inclusion complexes were suggested by molecular dynamics simulation. Barbituric acid (BA), barbital (B), amobarbital (AB), pentobarbital (PB), secobarbital (SB), cyclobarbital (CB), and phenobarbital (PHB) were used as barbiturates with different substituents on the barbituric acid ring and compared for inclusion types in aqueous solution. The association constants (K), stoichiometries, and thermodynamic parameters change in free energy (DG) change in enthalpy (DH), and change in entropy [DS] for each type of complex were determined from the calorimetric data. The inclusion complexation was largely entropy driven because of hydrophobic interactions. The values of K increased in the order BABABPBSBCBPHB. Barbiturates, except B and BA, form two types of inclusion complex with a 1:1 stoichiometry in the un-ionized forms. The ®rst type of inclusion complex with high af®nity (K 1 ) was characterized by small negative values of DH 1 and large positive DS 1 , where the substituent R2 of the barbiturate was initially inserted into the cavity of HPCD through hydrophobic interactions. There was a good relationship between DG 1 obtained from the calorimetric data for the ®rst type of inclusion complex and DG R2 calculated from the changes in 13 C Nuclear Magnetic Resonance (NMR) chemical shifts for the substituent R2 of barbiturates. These types were very stable in aqueous solution at various pHs. The second type of complex, with low af®nity (K 2 ), was characterized by large negative values of DH 2 and small positive DS 2 , re¯ecting van der Waals' interactions in the un-ionized forms of barbiturates at pH values less than pK a . The values of K 2 were markedly decreased to `10 3 M À1 as the barbiturates were ionized over pH 8. Thus, in the second type, the barbituric acid ring contributed to forming the complexes. The geometries were stabilized by hydrogen bond formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups on the rim of the cyclodextrin. The 13 C NMR chemical shifts of C4 and C6 carbons in the barbituric acid ring were moved up®eld signi®cantly by the inclusion complexation. On the other hand, B and BA could form only one type of complex, the lidtype supramolecular complex with small association constants.