Elsevier

Fluid Phase Equilibria

Volume 417, 15 June 2016, Pages 62-69
Fluid Phase Equilibria

Solubility of d-phenylglycine methyl ester hydrochloride in water and in organic individual or mixed solvents: Experimental data and results of thermodynamic modeling

https://doi.org/10.1016/j.fluid.2016.02.020Get rights and content

Abstract

The solubility of d-phenylglycine methyl ester hydrochloride in water, methanol, ethanol, acetone, ethyl acetate, and toluene as well as in methanol-ethyl acetate and methanol-toluene binary mixtures with different compositions was measured under atmospheric pressure and from 283.15 K to 333.15 K using a dynamic laser method. Experimental data were correlated with the modified Apelblat, combined nearly ideal binary solvent/Redlich-Kister, and nonrandom two-liquid models. Computational results showed that the solubility of d-phenylglycine methyl ester hydrochloride increased monotonically with increasing temperature in individual and mixed solvents. It also increased monotonically with increasing methanol concentration in binary mixtures. The evaluation of model accuracy and applicability demonstrated that all models provided good fits. Changes in the standard enthalpy, entropy, and Gibbs free energy of d-phenylglycine methyl ester hydrochloride upon dissolution were calculated to obtain thermodynamics data. The results showed that the dissolution followed a non-spontaneous and endothermic process, and in most cases enthalpy was the main contributing parameter.

Introduction

Crystallization is the most common method to isolate dissolved drug molecules from the mother liquor as well as remove byproducts and other impurities during drug synthesis. Initial studies on crystallization usually relate to thermodynamics [1], [2]. In this process, the product yield depends on the balance between the solute and solution. Therefore, solubility data are essential when choosing suitable operating conditions and designing molds.

d-phenylglycine methyl ester hydrochloride (D-PMEH, CAS No.:19883-41-1, Fig. 1), a white or almost white crystalline powder, acts as an important intermediate in organic synthesis and is commonly used to produce cefaclor, cephalexin, and other β-lactam antibiotics. It also plays an essential role in biological synthesis, medicinal chemistry, food processing, and optically active material production [3]. In addition to possessing strong water absorbability, it displays more stability than d-phenylglycine methyl ester and is very easy to store and use when dry [4], [5].

Existing industrial processes rely on cooling crystallization to produce D-PMEH, but simple cooling generates very small amounts of solid precipitates because of temperature-dependent solubility, prompting the development of mother liquor circulation approaches to improve yields. However, these approaches involving an increase in cycling times have led to low-quality products by sharply reducing the purity of D-PMEH and changing its color to yellow. Anti-solvents such as ethyl acetate and toluene can dramatically decrease the solubility of D-PMEH in solution and cause crystallization. Therefore, these anti-solvents were added to D-PMEH solutions to enhance product quality and yield in this study.

The solubility of D-PMEH in individual and binary solvent systems is essential for the development of effective crystallization processes but has not been investigated to date.

From various measurement methods of solubility [6], [7], [8], [9], [10], [11], [12], [13], a laser monitoring observation technique [14], [15], [16], [17], [18] was selected to estimate the solubility of D-PMEH in six individual liquid including water, methanol, ethanol, acetone, ethyl acetate, and toluene as well as in methanol-ethyl acetate and methanol-toluene binary mixtures of different compositions between 283.15 K and 333.15 K under atmospheric pressure. Experimental data were correlated with the modified Apelblat, combined nearly ideal binary solvent (CNIBS)/Redlich–Kister (R–K), and nonrandom two-liquid (NRTL) models [19], [20], [21]. Changes in standard enthalpy, entropy, and Gibbs free energy upon dissolution of D-PMEH were calculated using these solubility data.

Section snippets

Materials and reagents

All material sources and mass fraction purities are given in Table 1. D-PMEH was purchased from North China Pharmaceutical Co., Ltd. Its mass fraction purity exceeded 98.5%, as determined by HPLC [22]. All experiments used DI water.

Apparatus

The solubility of D-PMEH was measured by a laser monitoring technique [14], [15], [16], [17], [18] in which a laser beam penetrated a jacketed vessel to assess solute dissolution. The laser monitoring apparatus (Fig. 2) consisted of a jacketed glass vessel (100 mL)

Solubility data

Table 2, Table 3, Table 4 list D-PMEH solubilities in individual liquid and binary mixtures. These D-PMEH solubilities are also shown in Fig. 3, Fig. 4, Fig. 5 for comparison.

The solubility of D-PMEH was more pronounced in methanol than in other investigated solvents and increased with increasing temperature in all solvents (Table 2, Table 3, Table 4 and Fig. 3, Fig. 4, Fig. 5). In general, it increased with increasing solvent polarity index. This high solubility in polar solvents along with

Conclusions

The solubility of D-PMEH in six individual liquid and two types of binary mixtures presenting different compositions was measured at atmospheric pressure and between 283.15 K and 333.15 K by a dynamic laser method. Experimental solubility data were fitted using modified Apelblat, (CNIBS)/R–K, and NRTL models. All models provided good fits. Changes in standard enthalpy, entropy, and Gibbs free energy upon dissolution of D-PMEH were calculated using the Apelblat semi empirical constants.

Acknowledgment

This study was supported by the Natural Science Foundation of Hebei Province (No. B2015206108), Hebei Food and Drug Administration (ZD2015026), and National Natural Science Foundation of China (No. 21406050). The authors also thank the Hebei Research Center of Pharmaceutical and Chemical Engineering and North China Pharmaceutical Co., Ltd. (NCPC) for their support.

References (33)

  • J. Qiu et al.

    Tetrahedron Lett.

    (2014)
  • S. Yu et al.

    Chemosphere

    (2008)
  • N. Sunsandee et al.

    J. Mol. Liq.

    (2013)
  • L. Wang

    J. Mol. Liq.

    (2013)
  • A. Noubigh et al.

    J. Chem. Thermodyn.

    (2012)
  • X.M. Jiang et al.

    Fluid Phase Equilibr.

    (2013)
  • B.S. Liu et al.

    Fluid Phase Equilibr.

    (2014)
  • L.C. Wang et al.

    Fluid Phase Equilibr.

    (2004)
  • T. Liu et al.

    Fluid Phase Equilibr.

    (2014)
  • H. Sun et al.

    Fluid Phase Equilibr.

    (2015)
  • S. Wang et al.

    Ind. Eng. Data

    (2006)
  • P. Wang et al.

    Fluid Phase Equilibr.

    (2011)
  • A. Apelblat et al.

    J. Chem. Thermodyn.

    (1999)
  • W.E.J. Acree

    Thermochim. Acta

    (1992)
  • M.Y. Tao et al.

    Fluid Phase Equilibr.

    (2013)
  • T. Li et al.

    Fluid Phase Equilibr.

    (2012)
  • Cited by (0)

    View full text