Experimental and Modeling Studies on the Solubility of 2-Chloro-N-(4-methylphenyl)propanamide (S1) in Binary Ethyl Acetate + Hexane, Toluene + Hexane, Acetone + Hexane, and Butanone + Hexane Solvent Mixtures Using Polythermal Method

Abstract

The solubility of 2-chloro-N-(4-methylphenyl)propanamide (S1) in ethyl acetate + hexane mixtures between the temperatures of 273.43 to 327.67 K, in toluene + hexane mixtures from 273.24 to 331.62 K, in acetone + hexane mixtures from 269.81 to 318.8 butanone + hexane mixtures between 267.10 and 322.92 were determined using the polythermal method. In situ focused beam reflectance measurement (FBRM) was used to characterize the dissolution properties and to provide S1's saturation temperature profile as a function of concentration. It was demonstrated that the solubility of S1 increases with increasing temperature at constant solvent composition. The experimental solubility data were correlated using Apelblat, λh, and phase equilibria with NRTL (nonrandom two liquid) model equations, and the predicted solubility data obtained agree sufficiently with the experimental data based on the relative deviation (RD%) and average relative deviation (ARD%) values. The Apelblat and λh model equation provides a convenient operational model of engineering interest to calculate the solubility of S1 quickly and easily, although it does not take the solvent composition into account, therefore needing separate parameters for each different solvent compositions. Therefore, the phase equilibria with NRTL model equation is used to provide a more comprehensive model that illustrates the effect of solvent composition on the solubility more apparently. One general set of NRTL parameters has the capability of describing all solvent compositions. Additionally, the melting temperature, T m and the molar fusion enthalpy, Δ fus H, (394.83 K and 26.77 kJ mol −1 respectively) of S1 were determined by differential scanning calorimetry (DSC).

Structure of 2-chloro-N-(p-tolyl)propanamide

“…Single crystals for X-ray analysis were grown by slow evaporation of a toluene solution at room temperature. Spectroscopic data for the obtained product matched that reported in the literature (Pascual et al, 2017).…”

“…As part of this work we have been examining the continuous crystallization of 2-chloro-N-(p-tolyl)propanamide, 1, a key intermediate of -thio--chloroacrylamides, a class of compound that has shown importance in the literature as synthetically viable APIs (Murphy et al, 2007;Foley et al, 2011;) that can undergo transformations; such as Diels-Alder cycloadditions (Kissane et al, 2010a), 1,3-dipolar cycloadditions (Kissane et al, 2010b), sulfide group (Kissane et al, 2010c,d) and nucleophilic substitution . To design and understand a continuous crystallization process for 1, an extensive solubility study was conducted examining the compound's solubility characteristics in common organic solvents (Pascual et al, 2017). During this study, an improved bi-phasic synthesis was developed and crystals from two different continuous crystallization process runs were isolated to detect and characterize any variability of the crystalline material produced.…”

Measurement and Correlation of the Solubility of 5-Fluorouracil in Pure and Binary Solvents

“…The polythermal method − was used to determine the solubility of 5-FU in 11 pure solvents and binary water + ethanol solvent mixtures using a Crystal16 multiple reactor system (Technobis Crystallization Systems). − Samples with different concentrations were prepared in sealed glass vials (Fisher Scientific) with an internal volume of 2 mL using a XP26 microbalance from Mettler Toledo (±0.002 mg) to weigh the solute and a MS104S analytical balance from Mettler Toledo (±0.1 mg) to weigh the pure solvents and solvent mixtures. The resulting suspensions were agitated using a magnetic stir bar (rare earth) at 700 rpm while heated from 278.15 to 333.15 K at 0.3 K/min.…”

“…For acetone and 1,4-dioxane, the range of temperatures needed to be adjusted to 278.15 to 323.15 K and 285.15 to 333.15 K, respectively, due to the boiling (329.15 K) and melting point (284.95 K) restrictions for these solvents. Assuming that dissolution kinetics can be neglected, monitoring the transmission of light through the suspension can be used to determine the saturation temperature at its maximum using the software CrystalClear (v 1.0.1.614). − , To ensure accuracy, the saturation temperature at a specific concentration was measured twice. , The uncertainty of each saturated temperature was within ±0.1 K.…”

“…Upon reviewing the available literature, limited quantitative solubility data for 5-FU in various solvents have been reported thus far. − Therefore, a detailed study of the solubility of 5-FU enabled by comprehensive experimental data is needed. In this study, the solubility of 5-FU in 11 pure solvents, including acetone, acetonitrile, n- butanol, 1,4-dioxane, ethanol, ethyl acetate, methanol, isopropanol, 1-propanol, tetrahydrofuran, water, and binary water + ethanol solvent mixtures, was investigated at temperatures ranging from 278.15 to 333.15 K using the polythermal method − in a Crystal16 multiple reactor system. The experimental solubility data of 5-FU in these solvents were correlated using the modified Apelblat and λ h model equations, which enable both the interpolation and extrapolation of the measured solubility data.…”