Solubilization of sulfamerazine by complexation with cyclodextrin

C. ALOISIO; A. DELRIVO; A. ZOPPI; M.R. LONGHI

Ribeirão Preto, San Pablo, Brazil

Congreso; 7th International Congress of Pharmaceutical Sciences, CIFARP; 2009

Faculdade de Ciencias Farmacêuticas de Ribeirão Preto, USP. Brasil

INTRODUCTION Sulfamerazine (SMR)) is an antibacterial, which like many sulphonamides, is sparingly soluble in water (16 mg/ml at 20 0C, in neutral pH). This fact gives rise to difficulties in the pharmaceutical formula-tion. To overcome this drawback, the increase of the aqueous solubility of SMR is very important. Cyclodextrins (CDs) are cyclic oligosaccharides used in pharmaceutical formulations to enhance solubility, dissolution rate, stability and bioavailability by means of the formulation of inclusion com-plexes. METHODS The binding constants (Ks) and the stoichiometry for the complexes were determined in water and in buffer solutions of pH 2 and 8, by means of phase-solubility studies. The different pH values were used to study the influence of the ionization state of the drug on the complexation with CDs. In solid state, the binary systems , prepared by means of simple physical mixture (PM) or by lyophili-zation (LYO), were studied by Infrared Espectoscopy (IR), Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG). METHODS The binding constants (Ks) and the stoichiometry for the complexes were determined in water and in buffer solutions of pH 2 and 8, by means of phase-solubility studies. The different pH values were used to study the influence of the ionization state of the drug on the complexation with CDs. In solid state, the binary systems , prepared by means of simple physical mixture (PM) or by lyophili-zation (LYO), were studied by Infrared Espectoscopy (IR), Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG). RESULTS With both CDs were obtained soluble complexes of type AL indicating the presence of 1:1 host-guest complexes, ex-cept with ß-CD at pH 8. In this last case, curves of type AN were obtained denoting the formation of 2:1 host-guest complexes (according to Higuchi and Connors) (Fig. 3). Complexes between SMR and M-ß-CD were found to be unsta-ble in solution of pH=2 . For this reason they haven?t been considered for DSF studies at that pH. M-ß-CD demonstrated to confer a high solubility to the drug, regarding the ß-CD (Table 1). In turn, a higher solubility is achieved using a combined approach of pH adjustment and complexation with CDs, since the ionized drug has higher water solubility compared with that of the non-ionized one. Even though, the Ks and the solubility increment are lower at pH 8 in comparison with water. The results obtained with IR, DSC and TG show that true inclusion complexes, SMR:ß-CD and SMR:M-ß-CD are formed, when they were prepared by means of lyophilization. The physical mixtures studies present signals that can be attributed to interactions between the drug and each ligand, respectively. CONCLUSION An important increment in water solubility was obtained for SMR, mainly in the case of the complexes formed with M-ß-CD, wich will allow the use of these complexes in the formulation of pharmaceutical products containing this drug as active ingredient.