Mechanochemical synthesis insights and solid-state characterization of quininium aspirinate, a glass-forming drug–drug salt

Abstract

Quinine (an antimalarial) and aspirin (a nonsteroidal anti-inflammatory drug) were combined into a new drug–drug salt, quininium aspirinate, C20H25N2O2 +·C9H7O4 −, by liquid-assisted grinding using stoichiometric amounts of the reactants in a 1:1 molar ratio, and water, EtOH, toluene, or heptane as additives. A tetrahydrofuran (THF) solution of the mechanochemical product prepared using EtOH as additive led to a single crystal of the same material obtained by mechanochemistry, which was used for crystal structure determination at 100 K. Powder X-ray diffraction ruled out crystallographic phase transitions in the 100–295 K interval. Neat mechanical treatment (in a mortar and pestle, or in a ball mill at 20 or 30 Hz milling frequencies) gave rise to an amorphous phase, as shown by powder X-ray diffraction; however, FT–IR spectroscopy unambiguously indicates that a mechanochemical reaction has occurred. Neat milling the reactants at 10 and 15 Hz led to incomplete reactions. Thermogravimetry and differential scanning calorimetry indicate that the amorphous and crystalline mechanochemical products form glasses/supercooled liquids before melting, and do not recrystallize upon cooling. However, the amorphous material obtained by neat grinding crystallizes upon storage into the salt reported. The mechanochemical synthesis, crystal structure analysis, Hirshfeld surfaces, powder X-ray diffraction, thermogravimetry, differential scanning calorimetry, FT–IR spectroscopy, and aqueous solubility of quininium aspirinate are herein reported.

Outstanding Advantages, Current Drawbacks, and Significant Recent Developments in Mechanochemistry: A Perspective View

“…Pioneer studies have demonstrated this for the syntheses of ZIF-6 (a MOF) [128], 2,3-diphenylquinoxaline [129], and the Diels-Alder cycloaddition of cyclopentadiene and N-4-tolylmaleimide [130]. The author has also observed that for the neat mechanochemical synthesis of quininium aspirinate, reactant consumption increases from partial to complete with a milling frequency increase from 10 to 30 Hz [85]. Although in some publications these effects have been interpreted based on increased amounts of mechanical energy input at increasing milling frequencies, quantitative relationships remain poorly explored.…”

“…Drug-drug combinations with synergistic properties (often salts or cocrystals) have been also prepared using mechanochemistry [84,85]. In comparison with cocrystal syntheses from solutions, mechanochemical reactions are advantageous toward avoiding problems due to the low solubility of any of the individual coformers.…”

“…This reveals a LAG liquid role more complex than simply acting as a lubricant enhancing diffusion among solids and promoting a reaction, and it suggests a templating role, which can be mediated through intermolecular interactions that involve the molecules of the LAG liquid and those of the reactants. As a related example, the addition of liquid additives was necessary to observe crystalline quininium aspirinate [85] upon grinding quinine and aspirin in 1:1 molar ratio, while neat grinding (in a ball mill or in a mortar and pestle) led to amorphous phases instead (determined by X-ray powder diffraction); but a mechanochemical reaction had also occurred in those, as univocally determined using FT-IR spectroscopy. These observations suggested that the liquid additives had roles promoting the crystallization of the product, also prone to form glass phases [85].…”

“…As a related example, the addition of liquid additives was necessary to observe crystalline quininium aspirinate [85] upon grinding quinine and aspirin in 1:1 molar ratio, while neat grinding (in a ball mill or in a mortar and pestle) led to amorphous phases instead (determined by X-ray powder diffraction); but a mechanochemical reaction had also occurred in those, as univocally determined using FT-IR spectroscopy. These observations suggested that the liquid additives had roles promoting the crystallization of the product, also prone to form glass phases [85]. Scheme 4.…”