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

• Main Authors: Guadalupe Coyote-Dotor (Author), José C. Páez-Franco (Author), Daniel Canseco-González (Author), Alejandra Núñez-Pineda (Author), Alejandro Dorazco-González (Author), Inés Fuentes-Noriega (Author), Alfredo R. Vilchis-Néstor (Author), Joelis Rodríguez-Hernández (Author), David Morales-Morales (Author), Juan Manuel Germán-Acacio (Author)
• Format: Book
• Published: MDPI AG, 2021-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/pharmaceutics13111926; 1999-4923
• Keywords: drug-drug eutectic solid forms; mechanochemical reactions; intrinsic dissolution experiments; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 13, Iss 11, p 1926 (2021)

The mechanochemical synthesis of drug-drug solid forms containing metformin hydrochloride (MET·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·HCl-HTZ (χ_MET·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·HCl-CTZ (χ_MET·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 (ΔH_fus and ΔS_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 (ΔG) and thus not allowing an improvement in the dissolution and solubility properties of these solid forms.