New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility

Abstract

Salts of the antiviral drug Arbidol (umifenovir) with pharmaceutically relevant benzoate and salicylate anions were obtained, and their crystal structures were described. For Arbidol salicylate, an unstable solvate with acetonitrile was also found and characterized. Analysis of the conformational preferences of the Arbidol molecule in the crystal structures showed that it adopts two types of conformations, namely "open" and "closed", both of which correspond to local conformational energy minima of the isolated molecule. Thermal stability of the Arbidol salicylate solvates with chloroform and acetonitrile was analyzed by means of differential scanning calorimetry and thermogravimetric analysis. The standard thermodynamic functions of the salt formation were determined. The Gibbs energy change of the process was found to be negative, indicating that the formation of the salts from individual components is a spontaneous process. The dissolution study of the Arbidol salts performed in aqueous buffer solutions with pH 1.2 and 6.8 showed that both salts dissolve incongruently to form an Arbidol hydrochloride monohydrate at pH 1.2 and an Arbidol base at pH 6.8, respectively.

Improving the Solubilization and Bioavailability of Arbidol Hydrochloride by the Preparation of Binary and Ternary β-Cyclodextrin Complexes with Poloxamer 188

“…However, no pharmacokinetic nor metabolite studies were performed from this mode of administration. In addition, salt engineering techniques were also used to prepare the methanesulfonic salt [ 12 ] and salicylate anions form [ 13 ] of ADL in order to improve the aqueous solubility and bioavailability. The methanesulfonic salt of arbidol exhibited a relatively higher peak plasma concentration (Cmax) and an increased area under curve (AUC0-t) compared with a commercial product indicating the improved bioavailability of the drug; however, it was not statistically justified.…”

Two-component molecular crystals: evaluation of the formation thermodynamics based on melting points and sublimation data

“…As a rule, such information is obtained by co-crystal equilibrium solubility experiments conducted at different temperatures. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] However, there are works where two independent techniquessolubility calorimetry (to analyze the enthalpic term) and solubility measured by the saturation method (to analyze the Gibbs energy)are used to determine all the thermodynamic parameters. For example, Oliveira et al 32 studied the thermodynamics of [Carbamazepine + Saccharin] co-crystal formation by this method.…”

Crystal Structures, Thermal Analysis, and Dissolution Behavior of New Solid Forms of the Antiviral Drug Arbidol with Dicarboxylic Acids

“…However, it has been shown that in arbidol salts, there are two most common types of hydrogen bonds, forming ) 10 ( 2 2 R graph set supramolecular synthons [21]. In our previous work, salts of the antiviral drug arbidol with pharmaceutically relevant benzoate and salicylate anions have been obtained [23]. The ) 10 ( 2 2 R graph set supramolecular synthon was observed in both salts.…”