Improving water solubility of nateglinide by complexation of β-cyclodextrin

Inclusion complex of anionic nateglinide (NTG) with β-cyclodextrin (βCD) has been prepared to improve the water solubility of NTG. The mechanism of the complexation was elucidated using isothermal titration calorimetry and molecular modeling study. The solubility of NTG increased linearly with increasing the concentration of βCD and decreased gradually over 6 mM βCD in the solution. The maximum solubility of NTG in the presence of βCD was nine times more than that of NTG only. The stoichiometry (n), association constant (K), and thermodynamic parameters (ΔG, ΔH, ΔS) for the complexation were estimated: n = 1.0, K = 5.8 × 103 M−1, ΔG = −21.5 kJ mol−1, ΔH = −15.7 kJ mol−1, and ΔS = 19.5 J mol−1 K−1 at pH 7.0 and 298.15 K. The conformations and solvation energies for two types of the inclusion complex, type A penetrating the isopropyl cyclohexyl group of NTG into the βCD cavity and type B penetrating the phenyl group of NTG, were calculated. It was indicated that anionic NTG could strongly form the inclusion complex of type A complex with βCD at 1:1 molar ratio to increase the solubility in aqueous solution.