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

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.

Diversity of Solid Forms Promoted by Ball Milling: Characterization and Intrinsic Dissolution Studies of Pioglitazone Hydrochloride and Fluvastatin Sodium Drug–Drug Systems

“…In our case, building a binary phase diagram makes it possible to determine the most stable molar ratio of the coamorphous mixture [ 24 , 25 ]. As mentioned in Section 2.2.11 , for molar proportions 2:1; 4:1; 6:1; 8:1, and 10:1, the appearance of two endothermic events (solidus and liquidus points) was clear ( Figure S10 ).…”

“…It should be noted that these samples were run at a heating rate of 10 °C/min. However, in the case of molar ratios 1:1; 1:2; 1:4; 1:6; 1:8, and 1:10, this differentiation of the solidus and liquidus points was not so evident, and they were run at 2 °C/min since we have previously seen that, to improve the visualization precision in some thermal events, it is necessary to change the rates heating [ 25 ]. These samples were run on a Netzsch STA 449 F3 Jupiter simultaneous thermal analyzer.…”

Mechanochemical synthesis of drug–drug eutectics of the antibacterial agent, linezolid

“…[10][11][12][13] The increased surface area of the components confers to dissolution rate increments at par with amorphous solids and solid dispersions. 14,15 The use of eutectics in pharmaceutical formulations is quite advantageous because (1) in a eutectic, the crystalline constituents make it more stable than its amorphous counterparts; (2) eutectics are easy to synthesize and scale up; and (3) because they are not considered new chemical entities, they do not require clinical trials. 5,11,16 Despite their enhanced critical properties related to product performance, such as solubility, stability, and bioavailability, organic eutectics have been relatively unexplored compared to salts and cocrystals.…”