Solution thermodynamics of simvastatin in pure solvents and binary solvent mixtures
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 , the relative dielectric constants (ϵr) 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 Tm and fusion enthalpy ΔfusH 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]:
Solute melts at Tm, 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.where ΔdisG, ΔfusG, ΔcG and ΔmixG, ΔdisH, ΔfusH, ΔcH 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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