Characterization of the hydrochlorothiazide: β-cyclodextrin inclusion complex. Experimental and theoretical methods

Area of Science:

• Physical Chemistry
• Supramolecular Chemistry
• Pharmaceutical Sciences

Background:

• Hydrochlorothiazide (HCT) is a widely prescribed antihypertensive medication.
• Understanding the complexation of HCT with cyclodextrins is crucial for drug formulation and delivery.
• Native beta-cyclodextrin (β-CD) is a common host molecule for drug complexation.

Purpose of the Study:

• To investigate the physicochemical and molecular interactions between HCT and β-CD.
• To elucidate the binding mode, thermodynamics, and stability of the HCT:β-CD inclusion complex.
• To determine the influence of pH and temperature on the complexation behavior.

Main Methods:

• Isothermal titration calorimetry (ITC) at multiple temperatures and pH values.
• Proton nuclear magnetic resonance spectroscopy ((1)H NMR).
• Phase solubility analysis and molecular modeling.

Main Results:

• Formation of soluble 1:1 inclusion complexes between HCT and β-CD was confirmed.
• Good agreement was observed between experimental techniques (ITC, phase solubility, NMR) and computational methods.
• Complexation is enthalpy-driven, with hydrogen bonding playing a key role; solvation energy limits affinity.
• HCT inclusion mode is dependent on its ionization state, with lower affinity at higher ionization states and temperatures.

Conclusions:

• The HCT:β-CD complex formation is thermodynamically favorable and primarily driven by enthalpy.
• Molecular interactions and the ionization state of HCT significantly influence complex stability and binding.
• These findings provide valuable insights for the rational design of HCT formulations using β-CD.