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 Gladys Kate Pascual, † Philip Donnellan, † Brian Glennon, † Vamsi Krishna Kamaraju, ‡ and Roderick C. Jones* ,† † Synthesis and Solid State Pharmaceutical Centre (SSPC), School of Chemical and Bioprocess Engineering, University College Dublin, Belfield, Dublin 4, Ireland ‡ APC Ltd, Cherrywood Business Park, Loughlinstown, Co Dublin, Ireland * S Supporting Information 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 mix- tures 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 conve- nient 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). ■ INTRODUCTION Functionalized α-thio-β-chloroacrylamides derivatives are gain- ing increasing interest in the literature as synthetically viable advanced pharmaceutical intermediates 1-3 (API) that can undergo transformations, such as Diels-Alder cycloadditions, 4 1,3-dipolar cycloadditions, 5 and sulfide group 6,7 and nucleophilic substitutions (Figure 1). 8 β-chloroacrylamides have complex synthetic pathways which have provided unique opportunities for developing novel mecha- nistic elucidation methods using real time monitoring techniques, such as reactIR and reactNMR. 2 Such work has shown that due to the complex cascade nature of the overall reaction pathway, desired product purity profiles are highly dependent on starting material purity. 1-3 Consequently, 2-chloro-N-(4-methylphenyl) propanamide (S1), a precursor in the multistep synthesis of (Z)-3-chloro-2-(phenylthio)-N-(p-tolyl)acrylamide (P1, an API of interest to this group, Scheme 1), requires extensive purification via crystallization before use in order to obtain clean product profiles. The solubility characteristics of a particular solute-solvent pair have considerable influence upon the design and optimi- zation of any crystallization 9-11 and therefore a detailed under- standing of this solubility behavior based upon comprehensive Received: March 22, 2017 Accepted: August 25, 2017 Figure 1. Generalized structure of α-thio-β-chloroacrylamides. Article pubs.acs.org/jced © XXXX American Chemical Society A DOI: 10.1021/acs.jced.7b00288 J. Chem. Eng. Data XXXX, XXX, XXX-XXX