Solubility Measurements and Correlation of MBQ-167 in Neat and Binary Solvent Mixtures

Abstract

MBQ-167 is a novel, small-molecule dual inhibitor of Rac and Cdc42, small GTPases that are involved in cytoskeletal organization, cell cycle progression, and cell migration. In an in vivo mouse model, MBQ-167 has been shown to significantly reduce mammary tumor growth and metastasis and is currently undergoing preclinical studies for the treatment of metastatic cancer. To date, no solubility data have been reported for this compound. For this reason, the present study aims to determine the solubility of this compound in eight neat solvents (acetonitrile, 1-butanol, 2-butanol, ethanol, ethyl acetate, methanol, 1-propanol, and 2-propanol) and two binary solvent mixtures [ethyl acetate (2) + heptane (3) and ethanol (2) + water (3)] between the temperatures of 278.15 and 333.15 K. The results obtained employing the polythermal method show that the solubility of MBQ-167 increases with an increase in temperature in all neat solvents used within this study. Moreover, in the two binary solvent mixtures, the solubility of this compound increases with increasing temperature and decreases with an increasing mass fraction of the antisolvent (heptane or water). The experimental solubility data were correlated using the modified Apelblat and λh model equations. The predicted solubility data acquired from the Apelblat and λh model equations correlate well with the experimental solubility data as indicated by the low ARD % (≤1.8304 and ≤6.5366, respectively). No solvent-mediated polymorphic phase transitions were observed while performing the solubility studies, and no other solid forms were detected after the recrystallization in the solvents and solvent mixtures. The solubility data determined here can offer pathways to develop pharmaceutical crystallization processes that can further the translation of MBQ-167 into a clinical setting.

Solubility, Solvent Effect, and Solvation Performance of MBQ-167 in Aqueous Cosolvent Solutions

“…All XRD diffraction patterns present sharp peaks at different angles (2θ) that demonstrate the crystalline nature of the solid phases recovered (Figure S1) in different solvent systems investigated. Besides, the characteristic peaks of diffraction spectrum for excess solids with neat solvents and solvent blends are similar to that of MBQ-167 (raw material) and reported for equilibrated solids with neat solvents and solvent mixtures . As a result, we are not able to find distinguished changes in the XRD scans determined after and before equilibration.…”

“…The solubility magnitudes of MBQ-167 in neat solvents of acetonitrile, ethanol, n -propanol, and isopropanol and ethanol (1) + water (2) mixture at three composition points ( w 1 = 0.54, 0.64, and 0.76) achieved by us through interpolation and that reported by Jiménez Cruz and co-workers are all visualized in Figure S2 in the Supporting information. Carefully examining Figure S2, we may observe that the solubility values of MBQ-167 obtained by us agree well with that reported in the literature . The values of RAD are all no greater than 5%.…”

“…The melting temperature, T fus = 425.63 K, and the corresponding melting enthalpy, Δ fus H = 30.10 kJ·mol –1 , for crystalline drug of MBQ-167 are available from in ref . Using these melting properties, the activity coefficients of MBQ-167 at 298.15 K (expressed as natural logarithm) are readily acquired based on the solubility of MBQ-167 in the n -propanol/ethanol/acetonitrile/isopropanol + water blends studied herein and are listed in Table S3 in the Supporting Information.…”

“…Unfortunately, the physiochemical properties of MBQ-167 in solution systems, especially in aqueous mixtures, have not yet been studied. Only the mole fraction solubilities of MBQ-167 in eight pure solvents (2-butanol, acetonitrile, 1-butanol, ethanol, methanol, ethyl acetate, 2-propanol, and 1-propanol) and two binary blended solvents (ethyl acetate + heptane and ethanol + water) with several cosolvent compositions were recently reported, in conjunction with some computational methodologies. Nevertheless, the solubility magnitudes of MBQ-167 in neat water and aqueous solution systems have not yet been investigated systematically.…”

Solubility Measurement and Data Correlation of Metformin Hydrochloride in Four Aqueous Binary Solvents and Three Pure Solvents from 283.15 to 323.15 K

“…Finally, the average relative deviation (ARD %) and root-mean-square deviation (rmsd) − are used to verify the accuracy of the experimental data. The expressions are shown in eqs and …”