Synthesis, Characterization, and Intrinsic Dissolution Studies of Drug-Drug Eutectic Solid Forms of Metformin Hydrochloride and Thiazide Diuretics

The mechanochemical synthesis of drug-drug solid forms containing metformin hydrochloride (MET & BULL;HCl) and thiazide diuretics hydrochlorothiazide (HTZ) or chlorothiazide (CTZ) is reported. Characterization of these new systems indicates formation of binary eutectic conglomerates, i.e., drug-drug eutectic solids (DDESs). Further analysis by construction of binary diagrams (DSC screening) exhibited the characteristic V-shaped form indicating formation of DDESs in both cases. These new DDESs were further characterized by different techniques, including thermal analysis (DSC), solid state NMR spectroscopy (SSNMR), powder X-ray diffraction (PXRD) and scanning electron microscopy-energy dispersive X-ray spectroscopy analysis (SEM-EDS). In addition, intrinsic dissolution rate experiments and solubility assays were performed. In the case of MET & BULL;HCl-HTZ (chi(MET & BULL;HCl) = 0.66), we observed a slight enhancement in the dissolution properties compared with pure HTZ (1.21-fold). The same analysis for the solid forms of MET & BULL;HCl-CTZ (chi(MET & BULL;HCl) = 0.33 and 0.5) showed an enhancement in the dissolved amount of CTZ accompanied by a slight improvement in solubility. From these dissolution profiles and saturation solubility studies and by comparing the thermodynamic parameters (& UDelta;H-fus and & UDelta;S-fus) of the pure drugs with these new solid forms, it can be observed that there was a limited modification in these properties, not modifying the free energy of the solution (& UDelta;G) and thus not allowing an improvement in the dissolution and solubility properties of these solid forms.