Synthesis of Metforminium Succinate by Melting. Crystal Structure, Thermal, Spectroscopic and Dissolution Properties

Abstract

The reaction by melt mixing at 220 °C of the antihyperglycemic drug metformin hydrochloride <strong>1</strong> with dehydrated sodium succinate yields efficiently the organic salt [MET]<sub>2</sub>[SUC] <strong>2</strong> (H-MET<sup>+</sup>= metforminium and SUC<sup>2-</sup> = succinate). Solid state CPMAS NMR <sup>13</sup>C spectroscopy experiments, powder X-ray diffraction and FT-IR results support the formation of the pharmaceutical salt <strong>2</strong> in good yields. Besides, the charged-assisted hydrogen bonding interactions of type N-H<sup>…-</sup>O(carboxylate) were thoroughly analyzed by single crystal X-Ray diffraction techniques. Thus, the pharmaceutical salt <strong>2</strong> possesses considerable thermal differences when compared to the pure starting reagents. In addition, intrinsic dissolution rate experiments in buffered aqueous solutions at pH= 6.8 showed a sustained-release behavior of the drug in <strong>2</strong> with a constant value of K<sub>int</sub> = 0.885 mg/min * cm<sup>2</sup>.

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

“…The chemical shifts assignment in the 15 N-SSNMR experiments presented in Table 1 was made by analogy to the assignments in solution obtained from HMBC and HSQC experiments (Supplementary Figures S2-S4, SM †). In addition, the chemical shifts for the nuclei 1 H, 13 C and 15 N [71,72] in d 6 -DMSO and D 2 O for MET•HCl have been previously reported [73]. In the 15 N-SSNMR spectra for MET•HCl we noted the presence of 4 signals as well as the reported NMR solution [72].…”

Paracellular Pathway Enhancement of Metformin Hydrochloride via Molecular Dispersion in Span 60 Microparticles

“…These results are in agreement with the results of the electron scanning microscope of the same product. The absence of drug melting endothermic peak as a result of its molecular dispersion in the Span 60 matrix did not indicate the role of the matrix in the drug thermal stability (Plata-Vargas et al, 2017). At the same time, a TGA thermogram of all Span 60-encapsulated drugs showed a delayed degradation effect compared to the pure drug ( Figures 3A, B ).…”

“…This endothermic transition stage is attributed to the melting of the pure metformin HCl (Bretnall and Clarke, 1998). A huge endothermic peak is also observed directly following the melting of the pure metformin HCl, which is due to the decomposition of the pure drug (Plata-Vargas et al, 2017). More details about the thermal degradation of metformin HCl were reported by Ramachandran et al (Ramukutty et al, 2014).…”

An Industrial Procedure for Pharmacodynamic Improvement of Metformin HCl via Granulation with Its Paracellular Pathway Enhancer Using Factorial Experimental Design

“…32 A huge endothermic peak is also observed directly following the melting of the pure metformin HCl, which is due to the decomposition of the pure drug. 44 More details about the thermal degradation of metformin HCl were also reported. 45 Comparing the DSC scan of the drug in the prepared granules with that of pure drug, it can be concluded that there is no change in the drug crystallinity from the pure form as a result of the granulation process.…”