Abstract

Pyrimethamine (PYR), a drug effective against protozoan parasites, such asToxoplasma gondii and Plasmodium falciparum, is poorly water soluble and exhibits marked variation in oral bioavailability. This study was aimed at investigating the possibility and extent of enhancement of the dissolution properties of PYR via complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) as well as characterization of the complex formation of the drug with the cyclodextrin. The interaction between PYR and HP-β-CD in solution was studied by phase solubility analysis while binary systems of the compounds at 1:1 molar ratios were prepared by using the physical mixture, kneading, co-evaporation and freeze-drying methods. The binary systems were characterized using differential scanning calorimetry (DSC), powder x-ray diffractometry (PXRD) and Fourier transform infrared (FT-IR) spectroscopy. Phase solubility studies revealed an A_L-type diagram indicating a 1:1 stoichiometric inclusion complex and a stability constant value of 914 M^-1. Solubility and dissolution rates of PYR and the binary systems were determined and found to be markedly enhanced by cyclodextrin complexation. The extent of enhancement of dissolution properties was dependent on the preparation method of the complex, and the product prepared by the freeze-drying method was shown to have the most superior dissolution efficiency than the other binary systems. The PXRD patterns and DSC curves especially for the co-evaporated and freeze-dried systems indicated strong drug amorphization and/or inclusion of PYR in the CD cavities. The results of this study suggest that the complexation of PYR with HP-β-CD could reduce variability in the drug absorption and improve therapeutic efficacy of the drug through increased drug dissolution efficiency.

Key words: Pyrimethamine, 2-hydroxypropyl-β-cyclodextrin, complexation, enhanced dissolution, physicochemical characterization.