Mecanismo de acción y óptima selección de codisolventes en formas farmacéuticas

Abstract

Solubility is an inherent physico-chemical property of drugs. The acknowledge of the factors that conduct the process of solubility constitute an important requirement in technology and the development of pharmaceutical substances. The aim of this memory is the characterization of the solubility of four active substances (allopurinol and probenecid, used to treat hyperuricemia and its complications, and magnesic dypirone and sodium naproxen like analgesic and/or antipyretic) in a mixed solvent battery of varying percentage of dissolvent mixture, which covers a huge range of polarity(14-48MPa1/2), and at several temperatures (15-35ºC). Experimental solubility is firstly determined in saturated concentrations at several temperatures and different co-solvent mixtures by spectrophotometric techniques. Solubility profiles are represented by the determined solubility expressed in molar fraction versus solvent solubility parameter, which represents the solvent polarity in ethanol-water, ethyl acetate-ethanol and hexane-ethyl acetate system. The solubility profile can be related to the polarity of each drug. One or two maximum profile could be found. Two peaks are indicative of chameleonic effect, which can be quantitatively described in terms of cavity formation and specific and non-specific interactions, represented by Hildebrand solubility parameter and acid-base solubility parameters. By the other hand, solubility parameter of the drugs and other characteristics which could give an idea of the soluble behavior of a drug, are determined and characterized for all substances. Solubility predicts models are a tool designed to save economic and logistic resources by the theoretical estimation of the solubility. Several mathematical models of predicting solubility are tested in this work, demonstrating that the application of the estimations models is a useful advantage. Another element that affects the mechanism that manages the solubility of the solutes is the thermodynamics factors. The thermodynamic magnitudes are extensively studied in this work. Enthalpy, entropy and free energy Gibbs in dissolution, mixed or transfer process are determined. An enthalpy-entropy compensation analysis confirms the two different mechanisms involved in solubility. Enthalpy versus dissolution energies plot is non-linear for allopurinol and probenecid, changing the slope from positive to negative above particulars proportions. Compensation analysis for these drugs shows that at polar regions, the structure of the mixture itself determines solubility, meanwhile at larger co-solvent concentrations, solute-solvent interactions are the dominant mechanism depending of the nature of the solute. Both salt derivatives shows a linear behavior above the heat of solution versus mixture composition plot, where not a defined maximum is observed. These drugs have a single maximum drug solubility profile, where the peak is localized in the water-ethanol region. A linear enthalpy-entropy compensation is observed in the two mixture fractions, however a change in the slope suggest that the change of solubility is determined by a single mechanism: enthalpy.