Thermodynamic analysis of the solubility of polymorphic cytarabine in a variety of pure solvents
Graphical abstract
Brief Summary: Molar fraction solubility of cytarabine in water, methanol, ethanol, and ethanediol.
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].where 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)
- et al.
Solubility and polymorphic forms of antibiotic lasalocid sodium in different organic solvents
Fluid Phase Equil.
(2014) - et al.
E. Solubilities of o-acetylsalicylic, 4-aminosalicylic, 3,5-dinitrosalicylic, and p-toluic acid, and magne-sium-DL-aspartate in water from T= (278 to 348) K
J. Chem. Thermodyn.
(1999) - et al.
Correlation of solubility and calculation of thermodynamic properties of guanidine nitrate in different solvents
Fluid Phase Equil.
(2015) - et al.
Thermodynamic modeling of activity coefficient and prediction of solubility: Part 2. Semipredictive or semiempirical models
J. Pharm. Sci.
(2006) - et al.
Thermodynamic study of binary mixtures containing 1-butylpyridinium tetrafluoroborate and methanol, or ethanol
J. Chem. Thermodyn.
(2010) - et al.
- et al.
Crystallization of Organic Compounds – An Industrial Perspective
(2009) - et al.
Water activity-mediated control of crystalline phases of an active pharmaceutical ingredient
Org. Process Res. Dev.
(2007) - et al.
DNA-binding study of anticancer drug cytarabine by spectroscopic and molecular docking techniques
Nucl., Nucleot. Nucleic Acids
(2016) - et al.
Development of cytarabine prodrugs and delivery systems for leukemia treatment
Expert Opin. Drug Deliv.
(2010)
Cited by (10)
Thermodynamic properties of evaporative crystallization of high-salt wastewater
2023, Chemical Engineering Research and DesignSolubility and thermodynamics of polymorphic indomethacin in binary solvent mixtures
2019, Journal of Molecular LiquidsCitation Excerpt :Empirical models, including the modified Apelblat equation, CNIBS/R–K model, Jouyban–Acree model, λh model and so on, are widely used because of their simplicity and convenience in practical use [41,42]. Semi-theoretical models, such as Wilson model and NRTL model, based on the theory of local composition, are also very useful approaches for interpolating and extrapolating the thermodynamic data [43]. Particularly, it has been proven that the NRTL model tends to be more applicable in the modelling of incompletely miscible systems (such as acetone–heptane) [44].
Note on the thermodynamic analysis of the solubility of polymorphic cytarabine in a variety of pure solvents
2019, Fluid Phase EquilibriaDetermination and correlation of the solubility and thermodynamic parameters of 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside in pure organic solvents
2018, Journal of Molecular LiquidsCitation Excerpt :Tm is the mean extrapolated onset temperature. The solubility of THSG in the different organic solvents was determined by gravimetric analysis [17–20]. First, an excess amount of THSG was added to 30 mL of each of the selected organic solvents in jacketed glass vessels.
Solubility and mixing thermodynamic properties of (2,4,6-trimethylbenzoyl) diphenylphosphine oxide in pure and binary solvents
2018, Fluid Phase EquilibriaCitation Excerpt :The PXRD patterns were obtained from a powder X-ray diffraction equipment (Rigaku D/MAX 2500, Cu Kα radiation 0.15418 nm) over a range of diffraction angle from 2° to 40° with a scanning speed of 8° min−1 in the context of a voltage of 40 kV and a current of 100 mA. The gravimetric method, which is favored by many researchers [14–16], was adopted in this work. The experimental equipment mainly consisted of jacked glass vessel, thermostat (Julabo CF41, Germany), and electromagnetic stirring.
Phase Transition Enthalpy Measurements of Organic Compounds. An Update of Sublimation, Vaporization, and Fusion Enthalpies from 2016 to 2021
2022, Journal of Physical and Chemical Reference Data