Characterization of drug–drug salt forms of metformin and aspirin with improved physicochemical properties

Abstract

A salt between two old drugs was synthesized and two phases were discovered with improved physicochemical properties.

Multicomponent Crystal of Metformin and Barbital: Design, Crystal Structure Analysis and Characterization

“…As drawn in Figure 7 a, consistent with the TGA thermogram of the desolvate, there was only a relatively prominent endothermic peak; no endothermic peak caused by endothermic desolvation which was different from the endothermic peak of the solvate at 95.72 °C due to desolvation in Figure 7 b was observed. In the DSC curve of the desolvate, the intersection of the maximum slope of the front of the peak and the baseline extension line was the melting point of Met–Bar (213.97 °C), which was much higher than that of Met (112.5 °C) [ 12 , 13 ] and Bar (190 °C) [ 32 ] but lower than that of Met·HCl (223–226 °C). Combined with the TGA thermogram, it was proved that the melting of Met–Bar occurred before decomposition at 216.38 °C.…”

“…Besides, it is known from the literature that Met is highly hygroscopic. It absorbed a large amount of water after 60% RH, and the weight change was as high as 60% at 80% RH, causing the drug to deliquesce in a short period of time due to the sorption of water [ 12 , 13 , 15 ]. The structures determined the properties, whether new crystals synthesized by design were able to improve the properties of individual components.…”

“…In recent years, more and more attention has been given to the field of multicomponent crystals including salts or cocrystals [ 7 , 8 ] because they are superior to compound preparations and provide an alternative for pharmaceutical combination application [ 9 , 10 , 11 ]. Through the action of ionic bonds or non-covalent bonds, active pharmaceutical ingredients (APIs) and crystal co-formers (CCFs) are combined into one unit cell without changing the covalent structure of the drug molecule, which may not only improve druggability, stability, and bioavailability by altering the solubility, moisture absorption, and other physicochemical or mechanical properties of APIs, but also interact with different drug targets, causing a synergistic effect between drugs, a new choice for solid pharmaceutical preparations [ 12 , 13 , 14 , 15 ].…”

“…The imine groups of Met can also interact with sulfonyl groups of gliclazide or tolbutamide or amide groups of acesulfame via the N–H···O and N–H···N hydrogen bonds building heterosynthon B to establish intermolecular interactions [ 12 , 21 ]. In addition, metformin can also construct supramolecular heterodimers with deprotonated aspirin via synthon C [ 13 ]. Not only that, the introduction of CCFs has changed the way of connection and stacking between metformin molecules, showing better physicochemical and pharmaceutical properties, and significantly improved moisture absorption and stability [ 12 , 13 , 15 , 21 ].…”

“…In addition, metformin can also construct supramolecular heterodimers with deprotonated aspirin via synthon C [ 13 ]. Not only that, the introduction of CCFs has changed the way of connection and stacking between metformin molecules, showing better physicochemical and pharmaceutical properties, and significantly improved moisture absorption and stability [ 12 , 13 , 15 , 21 ]. In the existing literature, metformin has been proven to be a promising co-former with multiple hydrogen bond donors and acceptors during the formation of multicomponent crystals, making it suitable as an API for this experiment.…”