Characterization, phase solubility and molecular modeling of alpha-cyclodextrin/pyrimethamine inclusion complex
Marcia Valeria Gaspar de Araujo1, Osmir F L Macedo, Cristiane da Cunha Nascimento
1Departamento de Química, Universidade Federal de Sergipe, Av. Marechal Rondon s/n, Campus Universitário Prof. José Aloísio de Campos, CEP 491000-000, São Cristóvão, SE, Brazil.
Researchers created a pyrimethamine (PYR) and alpha-cyclodextrin (alpha-CD) inclusion complex, enhancing PYR solubility. This complex formation was confirmed using various analytical techniques, indicating potential for improved drug delivery.
Area of Science:
- Pharmaceutical Chemistry
- Supramolecular Chemistry
- Drug Delivery Systems
Background:
- Pyrimethamine (PYR) is a dihydrofolate reductase inhibitor used as an antimalarial and antiparasitic drug.
- Improving the solubility and bioavailability of poorly soluble drugs like PYR is crucial for effective therapeutic outcomes.
- Cyclodextrins, particularly alpha-cyclodextrin (alpha-CD), are widely used as complexing agents to enhance drug properties.
Purpose of the Study:
- To prepare and characterize an inclusion complex between pyrimethamine (PYR) and alpha-cyclodextrin (alpha-CD).
- To investigate the stoichiometry and inclusion mechanism of the PYR-alpha-CD complex.
- To evaluate the impact of complexation on PYR's physical properties, specifically its solubility.
Main Methods:
- Phase-solubility studies to determine the effect of alpha-CD concentration on PYR solubility.
- Job's plot analysis using fluorescence spectroscopy to determine host-guest stoichiometry.
- Differential Scanning Calorimetry (DSC) to confirm complex formation by analyzing thermal properties.
- Two-dimensional (1)H NMR spectroscopy (ROESY) and molecular modeling to elucidate the inclusion mode.
Main Results:
- Phase-solubility diagram indicated a linear increase in PYR solubility with increasing alpha-CD concentration, suggesting soluble complex formation.
- Job's plot analysis revealed a 1:1 host-guest stoichiometry for the PYR-alpha-CD complex.
- DSC measurements showed the absence of the PYR melting endotherm, confirming its inclusion within the alpha-CD cavity.
- ROESY NMR and molecular modeling indicated that the p-chlorophenyl ring of PYR penetrates into the alpha-CD cavity.
Conclusions:
- A stable 1:1 inclusion complex between pyrimethamine and alpha-cyclodextrin was successfully prepared.
- Complexation significantly enhanced the solubility of pyrimethamine.
- The inclusion mechanism involves the insertion of the p-chlorophenyl ring of PYR into the alpha-CD cavity, providing insights for drug formulation.
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