Synthesis, Characterization, and Intrinsic Dissolution Studies of Drug–Drug Eutectic Solid Forms of Metformin Hydrochloride and Thiazide Diuretics
Guadalupe Coyote-Dotor,
José C. Páez-Franco,
Daniel Canseco-González,
Alejandra Núñez-Pineda,
Alejandro Dorazco-González,
Inés Fuentes-Noriega,
Alfredo R. Vilchis-Néstor,
Joelis Rodríguez-Hernández,
David Morales-Morales,
Juan Manuel Germán-Acacio
Affiliations
Guadalupe Coyote-Dotor
Red de Apoyo a la Investigación, Coordinación de la Investigación Científica-UNAM, Instituto Nacional de Ciencias Médicas y Nutrición SZ, Ciudad de México 14000, Mexico
José C. Páez-Franco
Red de Apoyo a la Investigación, Coordinación de la Investigación Científica-UNAM, Instituto Nacional de Ciencias Médicas y Nutrición SZ, Ciudad de México 14000, Mexico
Daniel Canseco-González
CONACYT-Laboratorio Nacional de Investigación y Servicio Agroalimentario y Forestal, Universidad Autónoma de Chapingo, Texcoco de Mora 56230, Mexico
Alejandra Núñez-Pineda
Centro Conjunto de Investigación en Química Sustentable CCIQS UAEM-UNAM Carretera Toluca-Atlacomulco km 14.5, Toluca 50200, Mexico
Alejandro Dorazco-González
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Ciudad de México 04510, Mexico
Inés Fuentes-Noriega
Laboratorio de Biofarmacia, Departamento de Farmacia, Facultad de Química, UNAM, Ciudad de México 04510, Mexico
Alfredo R. Vilchis-Néstor
Centro Conjunto de Investigación en Química Sustentable CCIQS UAEM-UNAM Carretera Toluca-Atlacomulco km 14.5, Toluca 50200, Mexico
Joelis Rodríguez-Hernández
Centro de Investigación en Química Aplicada (CIQA), Boulevard Enrique Reyna Hermosillo No. 140, Saltillo 25294, Mexico
David Morales-Morales
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Ciudad de México 04510, Mexico
Juan Manuel Germán-Acacio
Red de Apoyo a la Investigación, Coordinación de la Investigación Científica-UNAM, Instituto Nacional de Ciencias Médicas y Nutrición SZ, Ciudad de México 14000, Mexico
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 (χMET·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 (χMET·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 (ΔHfus and ΔSfus) 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.