Cyclodextrin Complex Formation with Water-Soluble Drugs: Conclusions from Isothermal Titration Calorimetry and Molecular Modeling

Cyclodextrin (CD) complexes are frequently used for enhancing the solubility or absorption of poorly water-soluble drugs. On the contrary, little is known about their complex formation with water-soluble drugs. Here, we have studied the interaction between 2-hydroxypropyl beta-CD (HP beta CD) and three water-soluble drugs, namely naloxone (NX), oxycodone (OC), and tramadol (TR), by isothermal titration calorimetry (ITC) combined with molecular modeling in view of the potential impact on drug release. The results showed that the complex formation of HP beta CD with all three drugs occurs spontaneously. The complexes formed with NX and OC were found to be 2NX:1HP beta CD and 3OC:2HP beta CD, respectively. TR was found to form 2 complexes with HP beta CD; of 1:2 and 1:1 complexation ratios. The binding of HP beta CD to NX was greater than to OC due to the higher hydrophobicity of the structure of the former. Moreover, the binding affinity of HP beta CD to TR was higher than to OC, which indicated the effect of the higher flexibility of the guest in increasing the binding affinity. In vitro drug release experiments from the various complexes revealed a significant impact of the stoichiometry of the complex on the release profiles. Accordingly, the co-administration of cyclodextrins with water-soluble drugs should be closely monitored, as it may result in unintentional complex formation that can potentially impact the drugs' gastrointestinal absorption.