Solubility correlation and thermodynamic analysis of two forms of Metaxalone in different pure solvents

doi:10.1016/j.fluid.2015.09.013

Fluid Phase Equilibria

Volume 409, 15 February 2016, Pages 1-6

https://doi.org/10.1016/j.fluid.2015.09.013 Get rights and content

Abstract

The solubility data of two forms of MTX in ethanol, isopropanol, ethyl acetate and toluene was measured over the temperature range from 283.15 K to 323.15 K using shake flask method under atmospheric pressure. The experimental results indicated that the solubility of both forms of MTX increased as the temperature increased. And it was clear that the solubility of form B was lower than the solubility of form A at the same state. The experimental data was correlated by the modified Apelblat equation, the polynomial equation and the Buchowski–Ksiazczak λh equation. All these thermodynamic models gave satisfactory correlation results, with the polynomial equation showing better fitting degree than the other two equations. The results of thermodynamic parameters (△H_d > 0, △S_d > 0, △G_d > 0) indicated an endothermic, entropy driven and nonspontaneous dissolution process of MTX in selected pure solvents.

Introduction

Metaxalone (MTX) is a muscle relaxant used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions. Chemically, it is 5-[(3, 5-dimethylphenoxy) methyl]-1, 3-oxazolidin-2-one (Fig. 1) [1]. New therapeutic applications of MTX have been recently reported for the treatment of diabetic neuropathy and chronic daily headache [2].

Crystallization is important in the pharmaceutical industry as a separation process for intermediates and often servers as the final step in the manufacture of active pharmaceutical ingredients (APIs) [3]. The solubility of a crystalline compound provides vital thermodynamic information required to design crystallization processes, engineer the crystal size distribution and understand the phases which nucleate in the case of multiple-phase systems. Polymorphs are solid phases of the same compound but with different crystal structures. These different crystal structures exist due to the different molecular arrangements of the molecules giving rise to differences in free energy and thus solubility [4]. Hence, it is necessary to study the solubility properties of polymorph for the purpose of separation and purification through crystallization process.

The existence of polymorphism in MTX has been reported in the patent literature, which revealed two forms (A and B) that are characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared (FT-IR) spectroscopy [5]. Aitipamula et al. [6] reported the relative stability information of the two polymorphs of MTX. DSC thermograms of Form A and Form B were recorded at the heating rate of 5 °C min⁻¹. Both forms showed a single sharp endotherm in the temperature range of 121–123 °C, with the melting endotherms observed at 121.9 ± 0.1 °C (△H_fus = 137.1 J g⁻¹) and 122.2 ± 0.1 °C (△H_fus = 119.3 J g⁻¹) for Form A and Form B respectively. It was suggested that the polymorphs of MTX were enantiotropically related according to the Burger and Ramberger's heat of fusion rule, as the higher melting form showed a lower heat of fusion [7].

For expanding the fields of usage and purification of MTX, and considering the solubility studies of MTX has not been reported, in this work, the solubility data of two forms of MTX in ethanol, isopropanol, ethyl acetate, and toluene was measured from 283.15 K to 323.15 K using shake flask method.

Section snippets

Materials

MTX was provided by Jiawei Pharmaceutical Co.,Ltd., which is a white crystalline powder with crystal gloss in the light. It's form was proved to be form A, which was characterized by powder X-ray diffraction (XRPD). Another form of MTX, form B, was prepared by our lab through crystallization process. The pure form B was confirmed by comparing its XRPD pattern with that from Ref. [6]. Each form of MTX's mass fraction was more than 99.5% determined by HPLC. All of the reagents used in this work

Solubility data of two forms of MTX

The solubility data of the two forms of MTX was listed in Table 2, Table 3, respectively. Fig. 2 showed the corresponding solubility curves. Combining the data in Table 2, Table 3 and Fig. 2, it could be found that the solubility of both forms of MTX increased as the temperature increased. And it was obvious that the solubility of form B was lower than the solubility of form A at the same state. Both forms of MTX were slightly soluble in toluene while quite soluble in isopropanol, ethanol and

Conclusions

The solubility data of two forms of MTX in four different pure solvents was determined by shake flask method at temperature ranging from 283.15 K to 323.15 K. In the selected pure solvents, the solubility of both forms of MTX showed a strong dependence on temperature except in toluene. The modified Apelblat equation, polynomial equation and Buchowski–Ksiazczak λh equation were used to describe the experimental data. It turned out that all the selected thermodynamic models could give

Acknowledgment

This work was supported by National Natural Science Foundation of China (No. 81102391) and the Shanghai Committee of Science and Technology (Grant 12DZ1930702).

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¹: These authors contributed equally to this work.

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Solubility correlation and thermodynamic analysis of two forms of Metaxalone in different pure solvents

Abstract

Introduction

Section snippets

Materials

Solubility data of two forms of MTX

Conclusions

Acknowledgment

J. Pharm. Anal.

Thermochim. Acta

Fluid Phase Equilib.

J. Chem. Thermodyn.

J. Mol. Liq.

Fluid Phase Equilib.

Fluid Phase Equilib.

Fluid Phase Equilib.

Fluid Phase Equilib.

Fluid Phase Equilib.

J. Mol. Liq.

J. Mol. Liq.