Elsevier

Chemical Engineering Science

Volume 61, Issue 18, September 2006, Pages 5962-5968
Chemical Engineering Science

Effect of solution thermodynamics on the purification of two isomorphic steroids by solution crystallization

https://doi.org/10.1016/j.ces.2006.05.018Get rights and content

Abstract

11α-Hydroxy-16α,17α-epoxyprogesterone (HEP) and 16α,17α-epoxy-progesterone (EP) are two isomorphic steroid pharmaceutical intermediates and form substitutional solid solution when crystallized from solution. In this paper, the crystallization process of HEP from different solution systems that comprise small amounts of EP was studied. The distribution coefficients of EP between crystal phase and solution phase were determined. The distribution of EP in two phases depends on the relative solubility of two steroids in the same solvent to a large extent. The crystal purity significantly increases with the increase of the relative solubility of the impurity (EP) to the primary solute (HEP) in the same solvent. The mixed solvent of toluene+chloroform was found to afford great purity enhancement for the studied steroid system. A simple linear relationship was observed between the distribution coefficients and the relative solubilities in the toluene+chloroform system.

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.

11α-Hydroxy-16α,17α-epoxyprogesterone and 16α,17α-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 (45%), 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, xsol, to that in the liquid phase, xliq (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 xsol=Kxliq (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, N,N-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 20C

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 X320 of two solutes. The relative solubility X320 is defined asX320=x30/x20,where xi0 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 11α-hydroxy-16α,17α-epoxyprogesterone (HEP) from different solvents with a small content of 16α,17α-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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