Abstract
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.
Highlights
Pharmaceutical cocrystals are multicomponent crystalline entities composed of an active pharmaceutical ingredient (API) and a coformer in a defined stoichiometric ratio [1,2,3].The API/coformer are held together by non-covalent interactions such as hydrogen bonds, π–π interactions and van der Waals forces
drug–drug eutectic solids (DDESs) can be defined as a conglomerate of APIs that have a lower melting point compared with their parent drugs and there is no evidence of intermolecular recognition between the constituents [24,25,26,27,28,29]
The preparation of the solid forms was performed by ball-milling of metformin hydrochloride (MET·HCl) with
Summary
Pharmaceutical cocrystals are multicomponent crystalline entities composed of an active pharmaceutical ingredient (API) and a coformer in a defined stoichiometric ratio [1,2,3].The API/coformer are held together by non-covalent interactions such as hydrogen bonds, π–π interactions and van der Waals forces. Pharmaceutics 2021, 13, 1926 of pharmaceutical cocrystals have gained a lot of interest in the last years, due to the fact that the presence of the coformer in the crystal lattice of the API modifies its original physicochemical and biological properties without covalent modification [4]. DDESs can be defined as a conglomerate of APIs that have a lower melting point compared with their parent drugs (components are immiscible in the solid state) and there is no evidence of intermolecular recognition between the constituents [24,25,26,27,28,29]. APIs in DDESs are non-isomorphous (size/shape mismatch), contrary to drug–drug solid solutions where the components have size/shape complementarity [23,24,30,31]. On the other hand, when drug–drug solid systems exhibit amorphous arrangements and weak molecular recognition between the constituents, they are denominated coamorphous [23,24,32,33,34,35,36]
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