Physicochemical study and characterization of the trimethoprim/2-hydroxypropyl-γ-cyclodextrin inclusion complex

Area of Science:

• Pharmaceutical Chemistry
• Supramolecular Chemistry
• Materials Science

Background:

• Trimethoprim is an antibiotic with limited solubility.
• Cyclodextrins (CDs) are known to enhance drug solubility and bioavailability.
• 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) is a derivative with improved water solubility.

Purpose of the Study:

• To prepare and characterize a trimethoprim/HP-γ-CD inclusion complex.
• To investigate the physicochemical properties and structural aspects of the complex.
• To understand the inclusion mechanism and orientation within the cyclodextrin cavity.

Main Methods:

• Phase-solubility studies at varying temperatures (20 °C and 35 °C).
• ROESY (Rotating-frame Overhauser Effect SpectroscopY) NMR measurements.
• Semiempirical molecular modeling calculations.

Main Results:

• Association constants (K(1:1)) decreased with increasing temperature, indicating exothermic complexation.
• The K(1:1) values were comparable to those of the parent γ-CD.
• ROESY and molecular modeling confirmed that the 3,4,5-trimethoxybenzyl ring of trimethoprim is included in the HP-γ-CD cavity via the larger rim.

Conclusions:

• The trimethoprim/HP-γ-CD complex formation is thermodynamically favorable.
• The inclusion complex formation enhances the properties of trimethoprim.
• The study provides insights into the molecular interactions governing drug-cyclodextrin complexation.