Enhancement of Sulpahmerazine solubility by its interaction with meglumine

ALOISIO, C.; LONGHI, MR.

Cordoba, Argentina.

Congreso; 1ra Reunion Internacional de Ciencias Farmaceuticas (RICiFA); 2010

Departamentos de Farmacia de las Facultades de Ciencias Quimicas de la Universidad Nacional de Cordoba y de Ciencias Bioquimicas y Farmaceuticas de la Universidad Nacional de Rosario.

Introducción: Sulfamerazina (SMR) es un fármaco con características de ácido débil (pKa1 2,6; pKa2 6,9) que presenta actividad antimicrobiana. En su forma cristalina, es escasamente soluble en agua (16 mg/ml at 20 0C, that presents antibacterial activity In its crystalline form, is sparingly soluble in water in neutral pH). This fact gives rise to difficulties in the pharmaceutical formulation. To overcome this drawback, the generation of its amorphous form may be the solution. Meglumine (N-methyl-D-glucamine) (MEG) is a polyhydroxy base capable to interact with weak acid drugs to obtain greater water solubility products. Consequently, the bioavailability of the drug could be improved and so its therapeutic efficiency. Materials and methods: The binding constants (Ks) and the stoichiometry for the SMR:MEG systems were determined in water and in Phosphate buffer solutions of pH 2, 7 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 interaction with MEG. In solid state, the binary systems, prepared by means of simple physical mixture (PM) or by lyophilization (LYO), were studied by Infrared Espectoscopy (IR), Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG).Results: Soluble systems of AL type diagrams were obtained (according to Higuchi and Connors) indicating the presence of 1:1 systems, except at pH 2. In this case the phase solubility plot lacks of a tendency, not allowing to determinate the Ks and stoichiometry, and showing a 2 folds decrease in the solubility of SMR. At water (Ks=3,4 x1011), pH 7 (Ks=2,4 x103) and pH 8 (Ks= 9,15 x 102) solubility enhancements of about 2400, 54 and 41 have been respectively observed. The solid state studies showed that an amorphous SMR:MEG system is obtained when it is prepared by means of lyophilization. This fact is important for the bioavailability of the drug when it is administrated in solid pharmaceutical formulations.Conclusions: An important increment of SMR solubility and high binding constants were obtained for SMR:MEG system, mainly in water. Also it presented amorphous form in solid state. These facts gives rise to include this product in pharmaceutical formulations which contains SMR as active ingredient and so will improve its therapeutic performance.