Effect of solution thermodynamics on the purification of two isomorphic steroids by solution crystallization
Introduction
Crystallization is an important separation technology, and is widely used in the chemical and many other industries for the purification of products during their final stages of manufacturing (Charles et al., 1987, Wey and Karpinski, 2002). But when two compounds are similar in molecular and crystal structure, i.e. isomorphic compounds, the system may be forming a solid solution and then pure product cannot be obtained via a single crystallization stage. In these cases, multiple recrystallizations are needed to get the relatively pure component.
-Hydroxy--epoxyprogesterone and -epoxy-progesterone (in this paper, they are abbreviated as HEP and EP, respectively) are two important steroid compounds (Fig. 1), which serve as intermediates of hormone pharmaceuticals (Xu, 2001). In industry, HEP is obtained from EP through fermentation, but due to the low conversion ratio , the product comprises a mass of “impurity”: unconverted starting materials (EP) (Peterson et al., 1955, Ercoli et al., 1955, Zhang and Zhang, 1987, Yang et al., 2001). It is very difficult to separate these two steroids, multiple recrystallization are required to obtain the pure product. To light on the incorporation mechanism of the impurity, we have shown in our early work that the impurity (EP) and the desired product HEP are isomorphic compounds and can form a solid solution through lattice substitution (Wang et al., 2004a, Wang et al., 2004b, Nie et al., 2006 ). It is known that when isomorphic compounds incorporate at small levels by substitution, the equilibrium distribution of the impurities in the interfacial region is determined by the thermodynamics (Rosenberger, 1979). The incorporation can be characterized by a distribution (segregation) coefficient, K, numerically equal to the ratio of impurity concentration in the solid phase, , to that in the liquid phase, (solvent free basis), assuming both phases are at equilibrium at a given temperature. Thus, when crystallization occurs very slowly, the crystal has an impurity concentration (Burton et al., 1953).
One of the important factors of solution thermodynamics which has an effect on the distribution of the impurities is solubility. Rosenberger and Riveros (1974) derived a relationship between the segregation coefficients for the crystallization of alkali halides from pure water to the heats of dissolution and solubilities of the halides in water. Then Chernov (1984) highlighted Ruff's rule: for mutually isomorphic inorganic salts that co-crystallize from solution, the lower the impurity solubility in a given liquid solvent as compared to the macrocomponent, the more that impurity is incorporated into the crystalline material. In recent years, Givand et al., 2001, Givand et al., 2002 and Teja et al. (2002) have studied the isomorphic amino acid system and have shown that amino acid crystals nucleated and grown from impure solutions are controlled, to a large extent, by the ratio of the pure-component solubility of the primary solute (or product) to that of the impurity in the same solvent. However, most of these researches were focused on the crystallization of inorganic or organic compounds from aqueous solution, and few attempts were made to study the systems containing both organic solute and organic solvent, especially for the steroid compounds studied in this paper. In this study, a system of two isomorphic steroids was studied and the distribution of the impurity (EP) in several different organic solvent systems was determined. Then a good solvent system was selected to be used for separating two steroids by crystallization. This work can be used to a separation process for the two steroids.
Section snippets
Materials
HEP and EP were obtained from Tianjin Tianyao Pharmaceutical Co. Ltd., China. Their purities, determined by HPLC, are better than 99.0%. The methanol, ethanol, acetone, ethyl acetate, acetic acid, -dimethyl formamide (DMF), chloroform and toluene (purchased from Tianjin Chemical Reagent Co., China) used for experiments were of analytical reagent grade and without any treatment before use. Their purities are better than 99.5%.
Crystallization and measurement of the distribution coefficient
Crystallization experiments were designed and conducted similar to
Relative solubility of HEP and EP in different solvents at
Pure-component solubilities of the two steroids in different solvents were measured in our previous work (Nie and Wang, 2005; Nie et al., 2005, Nie et al., 2006). The solubility data of HEP and EP in the same solvent were used to calculate the pure-component relative solubility of two solutes. The relative solubility is defined aswhere is the pure-component solubility of species i in a given solvent, and component 2 is the desired product and component 3 is an
Conclusions
The present study reports several crystallization experiments of -hydroxy--epoxyprogesterone (HEP) from different solvents with a small content of -epoxyprogesterone (EP) in solution, and the distribution coefficients of EP between the crystal phase and the solution phase were measured at the same time. The experimental results indicate that the distribution of the impurity depends on the solubility of the impurity relative to the product. The bigger the relative solubility of
Acknowledgment
Partial support of this research by Tianjin Tianyao Pharmaceutical Co. Ltd. and the State Research Center of Industrialization for Crystallization Technology (SRCICT) of Tianjin University is gratefully acknowledged.
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