Solubilidad de fármacos y sus dispersiones sólidas en sistemas disolventes

Zusammenfassung

Celecoxib and etoricoxib are two potent anti-inflammatory inhibitors selective for COX-2, with reduced aqueous solubility, belong to class II (low solubility, high permeability) of the biopharmaceutical classification system and limited dissolution rate, which affects not only to its oral bioavailability, but also to the processes of elaboration of medicines or their intermediate processes, such as the preparation of solutions. So, the studies of solubility and prediction of solubility become valuable information to optimize the process of preformulation in liquid pharmaceutical forms. Both the study and prediction of the solubility of celecoxib and etoricoxib was performed in the water-ethanol cosolvent system, and ethanol-ethyl acetate at 15-35 ° C. Different mathematical models were used whose results allowed to demonstrate their advantages as a tool in the development of medicines and with the consequent saving of time and resources. The materials’ properties and their interactions can be estimated from the solubility parameters of the components of a formulation. In this paper the Hildebrand solubility parameter has been used as a measure of the cohesion between molecules of the same nature and to predict the adhesion between molecules of different nature. The solubility profile in comparison to the solubility parameter obtained for the two drugs, showed a single maximum of solubility, confirming a finding previously encountered by our research group, in which drugs with solubility parameters lower than 25 MPa½ will have a maximum solubility. Besides using the cosolvency, the preparation of solid dispersions was explored as a viable alternative to improve the rate of dissolution and the solubility of poorly soluble active ingredients in water. It was found that the modification of the crystallinity of these principles in solid dispersions is a correct choice to visibly increase this thermodynamic property. The thermodynamic study is especially interesting in the preformulation of drugs, since it is necessary to determine their solubility in a solvent or mixture of solvents at different temperatures to predict the precipitation of the drug. The thermodynamic magnitudes, enthalpy, entropy and Gibbs free energy of solution, mixture and transfer were obtained and the enthalpy-entropy compensation analysis was performed. The results obtained were useful to identify changes in the mechanism of action of a cosolvent system and to verify the existence of extrathermodynamic relations of enthalpy-entropy compensation. For both drugs there are two dominant mechanisms, enthalpy and entropy, dependent on the composition of the solvent and related to the co-solvent action of the solvent mixtures studied.