Elsevier

Fluid Phase Equilibria

Volume 445, 15 August 2017, Pages 1-6
Fluid Phase Equilibria

Thermodynamic analysis of the solubility of polymorphic cytarabine in a variety of pure solvents

https://doi.org/10.1016/j.fluid.2017.04.021Get rights and content

Highlights

  • A systematic solubility of cybarabine in four pure solvents was firstly measured.

  • Different models were used to correlate the solubility data.

  • Activity coefficients in different solvents were estimated.

  • Polymorphic behavior of cybarabine has been observed.

Abstract

A systematic measurement of the solubility of cytarabine in water, methanol, ethanol, and ethanediol at atmospheric pressure has been carried out at temperature ranging from (293.15–333.15) K by a gravimetric method. The melting temperature, Tm, and molar fusion enthalpy, ΔHf, of cytarabine were measured using DSC. The results showed that the dissolution of cytarabine in all examined solvents is endothermic process. Subsequently, the experimental data were well correlated using modified Apelblat equation, λh equation, Wilson model, and NRTL model, respectively. Further, combining the measured solubility data and calculated ideal solubility data, activity coefficients of cytarabine in different solvents were estimated by neglecting the validity of heat capacity, which were then fitted to a van't Hoff like equation to estimate the mixing enthalpy, ΔHmix, and mixing entropy, ΔSmix, respectively. Moreover, polymorphic behavior of cytarabine has been observed, which was validated using DSC and PXRD analysis.

Graphical abstract

Brief Summary: Molar fraction solubility of cytarabine in water, methanol, ethanol, and ethanediol.

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Introduction

Solution crystallization is an essential separation and purification process in industrial manufacturing of active pharmaceutical ingredients (APIs) throughout its history [1]. Especially, in recent decades, the study of pharmaceutical crystallization has taken on even higher levels of importance because of the sustained growth of the criterion for the crystalline quality of APIs. Generally, to obtain crystals with desired quality, the crystallization process should be cautiously controlled, which requires an in-depth and improved understanding of the thermodynamic and kinetics properties of the crystallization process [2].

As one of the most important thermodynamic properties, solubility of a compound depends on a variety of factors such as chemical composition, solvents used for crystallization and the solution temperature. Usually, numerous potential solvents can be employed in the pharmaceutical crystallization. Determination and thermodynamic analysis of the solubility data are therefore crucial for solvent screening, crystal characteristic estimation (such as polymorph), and further process design. Besides, solubility in given system can also give valuable information concerning yield estimation, morphology and polymorph control [3], [4].

As an intravenous chemotherapeutic agent, cytarabine (CAS number 147-94-4) is widely used for treatment of white blood cell cancers such as acute myeloid leukemia, non-Hodgkin lymphoma, and lymphoblastic leukemia [5]. Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphate, which damages DNA when the cell cycle holds in the S phase (synthesis of DNA). Rapidly dividing cells, which require DNA replication for mitosis, are therefore most affected. Cytarabine also inhibits both DNA and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis [6]. Fig. 1 shows the chemical structure of Cytarabine. In industrial manufacturing, the final purification of cytarabine was achieved by solution crystallization [5]. As a variety of potential solvents can be used in the industrial crystallization process, determination of accurate solubility is then vital to the quick screening of favorable solvent and further to the crystallization process optimization. However, only limited solubility data of cytarabine in water have been reported so far in literatures [7], [8].

Hence, the present work mainly concerned with a systematic measurement of cytarabine solubility in water, methanol, ethanol, and ethanediol. The corresponding experiments were conducted under atmospheric pressure using a gravimetric method. Other thermodynamic information including the melting temperature, Tm, and molar fusion enthalpy at the melting temperature, ΔHf, of cytarabine were determined by DSC. Subsequently, the experimental data were correlated using the modified Apelblat equation, λh equation, Wilson model, and NRTL model, respectively. Further, combining the measured solubility data and calculated ideal solubility data, the activity coefficients were estimated based on the assumption of ΔCp = 0, which was then fitted to a van't Hoff-like equation to calculate the mixing enthalpy, ΔHmix, and entropy, ΔSmix. Besides, DSC and PXRD analysis was used to characterize the crystal structures of cytarabine equilibrated in the four pure solvents.

Section snippets

Apelblat equation

The modified Apelblat equation, which was originally proposed by Apelblat and Manzurola, was usually used to correlate the measured solubility data. The equation was described by Ref. [9].lnx1=A+BT+ClnTwhere x1 is the mole fraction solubility of solute at temperature T. A, B, and C are the empirical constants, respectively. All the three constants can be estimated by multivariate regression analysis.

λh equation

λh equation, which was proposed by Buchowski et al., can give an excellent solubility

Materials

Raw Cytarabine (supplied by Hisun Co., Ltd., China) was recrystallized one time in ethanediol by cooling crystallization. The purity was determined by HPLC (shimadzu LC-20A) and the mass fraction is higher than 99.5 wt.%. The organic solvents including methanol, ethanol and ethanediol were purchased from Shanghai Chemical Reagent Co. Ltd. and used without further purification. Their mass fractions are higher than 99 wt.%. The water used was distilled, and filtered (0.2 μm). The information of

Solubility measurement

Fig. 2 and Table 2 show the solubilities of cytarabine in water, methanol, ethanol, and ethanediol at a temperature range between (293.15–333.15) K. To verify the measurement reliability, solubility of cytarabine in water reported by Legoabe et al. was used as reference (marked with red circle in Fig. 2) [15]. It can be seen that the measured solubility data is coincident with that reported in literature.

Besides, it need to be mentioned that, for all examined systems, the solubility exhibited a

Conclusions

A systematic solubility of cytarabine in water, methanol, ethanol and ethanediol were experimentally measured at a temperature range between (293.15–333.15) K at atmospheric pressure using gravimetric method, which was then correlated using modified Apelblat equation, λh equation, Wilson model, and NRTL model, respectively. The results showed that the solubility of cytarabine in the four solvents exhibited a tendency of increasing with an increase on temperature, and the increasing rate

Acknowledgments

We thank the financial support by the National Natural Science Foundation of China (NSFC, No. 21406071), the Fundamental Research Funds for the Central Universities (No. 22A201514006), the Open Project of State Key Laboratory of Chemical Engineering (SKL-ChE-16C03), Shanghai Pujiang Program (No. 16PJD019), and Hisun Co. Ltd..

References (20)

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