Solution thermodynamics of simvastatin in pure solvents and binary solvent mixtures

doi:10.1016/j.fluid.2015.07.055

Fluid Phase Equilibria

Volume 406, 25 November 2015, Pages 77-90

https://doi.org/10.1016/j.fluid.2015.07.055 Get rights and content

Highlights

•
The experimental solubility data of simvastatin in pure solvents and binary solvent mixtures were determined by a gravimetrical method.
•
The experimental solubility data were correlated by several empirical models.
•
The Solubility–Polarity model was modified and used to interpret the dissolution behaviors of simvastatin.
•
The dissolution thermodynamic properties of simvastatin were calculated both in pure solvents and binary solvent mixtures.

Abstract

The solubility data of simvastatin in five pure solvents and binary solvent mixtures of isobutyl acetate and n-heptane were experimentally determined by a gravimetrical method under atmospheric pressure. It was found that the solubility of simvastatin increases with temperature rising in all investigated solvents. In binary solvent mixtures, the solubility of simvastatin increases with the decreasing of the mole fraction of n-heptane. The Solubility–Polarity model was modified and used to interpret the dissolution behaviors of simvastatin in binary solvent mixtures. The experimental solubility data in all investigated solvents were correlated by empirical models with the relative average deviation percentage between experimental and calculated solubility less than 5%. The thermodynamic properties of simvastatin, including the Gibbs energy change, the entropy and the enthalpy of dissolution process, were also calculated. The results indicate that the dissolution process of simvastatin is a spontaneous, endothermic and entropy-driving process in all solvent systems.

Introduction

Simvastatin (Fig. 1, CAS Registry No. 79902-63-9, hereinafter referred as SMV), is a member of the statin family, which occurs as a white to off-white crystalline powder. SMV is widely used to treat hypercholesterolemia as a cholesterol-lowering agent due to its well proven efficacy and safety behavior [1], [2], [3], [4].

It has been reported that SMV is practically insoluble in water (7.25 10⁻⁵ g L⁻¹ in water at 298.15 K) [5]. The poor aqueous solubility of pharmaceuticals is a main barrier for their formulation development [6], [7]. Solubility of pharmaceuticals is an extremely useful physicochemical property, and indispensable for designing and optimization of crystallization process. As an important unit operation for production of pharmaceuticals, the crystallization process which is used to purify SMV during its manufacturing will directly determine the quality of the products and the yield of the process. Although solubility data of SMV in a family of alcohols at various temperatures have been reported [8], it has been found that alcohols might not be the ideal solvents for the purification and refinement processes [9] of SMV since some problems such as wide size distribution and poor flowability of products exist. Furthermore, based on the dissolution characters of SMV, anti-solvent crystallization is generally used in the purification of SMV. Therefore, it is crucial to know the solubility data of SMV in good solvents, anti-solvents and the mixtures of these two kinds of solvents. From literature review, it was found that the solubility of SMV in various mixed solvents and pure esters have not been reported. In this work, the solubility data of SMV in five pure esters (methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate and isobutyl acetate) from 278.15 K to 318.15 K and binary solvent mixtures of isobutyl acetate with n-heptane from 278.15 K to 308.15 K were experimentally determined with a gravimetrical method under atmospheric pressure. The experimental solubility data were correlated by empirical models, including the non-random, two-liquid model (NRTL model) and the combined nearly ideal binary solvent (NIBS)/Redlich-Kister model (CNIBS/R-K model). Meanwhile, the Solubility–Polarity model was modified and applied for quantitative interpretation of the dissolution behaviors of SMV in binary solvent mixtures. Furthermore, the thermodynamic properties (the Gibbs energy, the enthalpy and the entropy) of dissolution process of SMV were also calculated and analyzed.

Section snippets

Materials and reagents

Simvastatin (≥99%, mass) was provided by PKU Health Care Co., Ltd. of China. The identification of SMV samples was confirmed by X-ray power diffraction (XPRD) pattern. The organic solvents (methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and n-heptane) selected in this work are analytical reagents. More details about these materials are listed in Table 1. All the materials were directly used without any further purification in the experiments.

Thermal analysis

Differential

The Solubility–Polarity model

Effects of solvent on solubility of solute are pervasive but not fully understood. The empirical rule, namely “like dissolves like”, is widely used as the qualitative description for the effects. Due to the absence of clear definition and direct measuring method of polarity of solvents, the empirical polarities ${(E}_{T}^{N})$ , the relative dielectric constants (ϵ_r) and the dipole moments (μ) are usually used as the criterions of solvent polarity. However, the visual correlation of either the empirical

Identification and characterization

The X-ray power diffraction (XPRD) patterns of SMV are shown in Fig. 2. The DSC data of SMV are shown in Fig. 3. The XPRD pattern verifies that only one crystalline form of SMV was used in all experiments. No new polymorph was observed. The melting temperature T_m and fusion enthalpy Δ_fusH of SMV which can be obtained from DSC data are 415.1 K and 30.13 kJ mol⁻¹, respectively.

Experimental solubility data

Experimental mole fraction solubility data of SMV in all solvent systems at investigated temperatures are listed in Table 2

Thermodynamic properties

The dissolution process could be represented by the following hypothetic stages [21], [22]: ${S o l u t e}_{(s o l i d)} \overset{f u s i o n}{\to} {S o l u t e}_{(l i q u i d)} a t T_{m} \overset{c o o l i n g}{\to} {S o l u t e}_{(l i q u i d)} a t T \overset{m i x i n g}{\to} {S o l u t e}_{(s o l u t i o n)}$

Solute melts at T_m, then cools to T, finally mixes with the solvent at T. This approximation permits us to calculate the partial thermodynamic properties of the overall dissolution process as following. $Δ_{d i s} G = Δ_{f u s} G + Δ_{c} G + Δ_{m i x} G$ $Δ_{d i s} H = Δ_{f u s} H + Δ_{c} H + Δ_{m i x} H$ $Δ_{d i s} S = Δ_{f u s} S + Δ_{c} S + Δ_{m i x} S$ where Δ_disG, Δ_fusG, Δ_cG and Δ_mixG, Δ_disH, Δ_fusH, Δ_cH and Δ

Conclusions

The solubility of SMV in five pure solvents and one kind of binary solvent mixtures were determined and correlated. The solubility of SMV increases with the temperature rising in all tested solvent systems. In pure solvents, the dissolution behaviors of SMV follow the “like dissolves like” rule. In the binary solvent mixtures of isobutyl acetate and n-heptane, the solubility of SMV decreases with the increasing of n-heptane content. The Solubility–Polarity model was modified and applied to

Acknowledgements

This research is financially supported by National Natural Science Foundation of China (No. 21376165) and Key Project of Tianjin Science and Technology Supporting Program (No. 13ZCZDNC02000).

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View full text

Solution thermodynamics of simvastatin in pure solvents and binary solvent mixtures

Highlights

Abstract

Introduction

Section snippets

Materials and reagents

Thermal analysis

The Solubility–Polarity model

Identification and characterization

Experimental solubility data

Thermodynamic properties

Conclusions

Acknowledgements

J. Chem. Thermodyn.

J. Mol. Struct.

Fluid Phase Equilib.

Physica

Thermochim. Acta.

Fluid Phase Equilib.

J. Chem. Thermodyn.

Eur. J. Pharm. Biopharm.

Fluid Phase Equilib.

J. Chem. Thermodyn.

J. Chem. Thermodyn.

J. Mol. Liq.

Energetics and structure of simvastatin

Mol. Pharm.

Simvastatin

Acta Cryst.

Simvastatin: structure solution of two new low-temperature phases from synchrotron powder diffraction and ss-NMR

Struct. Chem.