Chagas disease. Hydrophilic polymers applied to enhance the solubility of Benznidazole

BOMBARDIERE, M.E.; LEONARDI, D.; SALOMÓN, C.J.

Cordoba, Argentina

Congreso; I Reunión internacional de Ciencias Farmacéuticas (Ricifa).; 2010

Universidades de Córdoba y Rosario

  CHAGAS DISEASE. HYDROPHILIC POLYMERS APPLIED TO ENHANCE THE SOLUBILITY OF BENZNIDAZOLE. Bombardiere, M. E; Leonardi, D.; Salomón, C. J. Facultad de Ciencias Bioquímicas y Farmacéuticas. Universidad Nacional de Rosario IQUIR. Área Tecnología Farmacéutica Suipacha 531. 2000. Rosario. Argentina Tel 0341-4370477. E-mail: bombardiere@iquir-conicet.gov.ar Introduction Chagas disease is a major cause of morbidity and mortality in Latin America. Actually, it is also an emerging opportunistic infection among immunocompromised patients. One of the chosen drugs to treat this infection is benznidazole (BZL). The unique formulation available is a tablet of 100 mg and, however, despite of the growing incidence in pediatric populations, there is not any BZL liquid formulation. Therefore, in this work, different polymers were evaluated as carrier for improving the solubility of BZL, in order to preformulate liquid dosage forms of that compound. Materials and Methods BZL was a gift from Roche. Polyvinylpirrolidone K-30 (PVP) was kindly donated by ISP (Argentina). Pluronic was purchased from Merck. Polyethylene glycols (PEG6000 and PEG400) were purchased from Parafarm. Solid dispersions. The systems were prepared by the solvent method. 50 mg of BZL and the corresponding polymer were dissolved in 3 ml of ethanol and water respectively. Both solutions were mixed and the solvents were removed under reduce pressure at 50 ºC until complete evaporation. Physical mixtures. Powders were mixed in a mortar with a pestle until a homogeneous mixture was obtained. Solubility determinations. Drug solubility was determined by adding excess amounts of BZL solid dispersions to water at 25 ± 0.5 oC for 48 hs and then filtered. BZL concentrations were determined by UV spectroscopy at 324nm. Cosolvent systems. PEG400 and water mixed at different ratios were selected as cosolvents to study the solubility of BZL-PVP dispersions. Physicochemical characterization. Differential Scanning Calorimeter (DSC), Scanning Electron Microscope (SEM), and Nuclear magnetic resonance (NMR) were applied to analyze potential drug-polymer interactions. Results The solubility of BZL was greatly increased by means of PVP and Pluronic-based solid dispersions at 1:5 drug:polymer ratio, while PEG 6000 did not influence the drug solubility. In addition, water-PEG400 cosolvent mixtures were more efficient than water alone for improving BZL solubility, particularly at 9:1 PEG400:water ratio. By DSC, it was observed the complete absence of BZL crystalline peaks when dispersed into the polymers. SEM analysis showed that the solid dispersions appeared in the form of irregular particles in which the original morphology of both components disappeared and amorphous pieces of irregular size were present. Conclusions The increased solubility of BZL was achieved by solid dispersions as well as using cosolvent mixtures. The solid characterization of BZL-polymer mixtures showed that a decreased crystallinity, increased wettability, and reduction of drug particle size modified the drug solubility. In addition, NMR experiments provided potential to study the interactions of BZL with PVP.