Article pubs.acs.org/jced
Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Measurement and Correlation of the Solubility of 5‑Fluorouracil in Pure and Binary Solvents Rocío I. Zorrilla-Veloz,†,‡ Torsten Stelzer,*,‡,§ and Vilmalí Loṕ ez-Mejías*,‡,∥ †
Department of Biology, University of Puerto Rico - Río Piedras Campus, San Juan, Puerto Rico 00931, United States Crystallization Design Institute, Molecular Sciences Research Center, University of Puerto Rico, San Juan, Puerto Rico 00926, United States § Department of Pharmaceutical Sciences, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico 00936, United States ∥ Department of Chemistry, University of Puerto Rico - Río Piedras Campus, San Juan, Puerto Rico 00931, United States
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‡
S Supporting Information *
ABSTRACT: The solubility of 5-fluorouracil (5-FU), a widely used chemotherapeutic agent to treat solid tumors, which include colorectal, head and neck, breast, and lung cancer, was determined at temperatures ranging from 278.15 to 333.15 K in 11 pure solvents and binary water + ethanol solvent mixtures using the polythermal method. It was demonstrated that the solubility of 5-FU increases with increasing temperature in the pure solvents and at constant solvent composition in the solvent mixtures. Moreover, the solubility of 5-FU in the solvent mixtures exceeds its solubility in pure water and ethanol. The experimental solubility data of 5-FU in the pure solvents and solvent mixtures were correlated using the modified Apelblat and λh model equations. The predicted solubility data obtained agree with the experimental data based on the calculated relative deviation (RD) and the average relative deviation (ARD%) values. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risk to human health) solvents, and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to develop and engineer enhanced pharmaceutical processes and products based on this compound.
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different physicochemical properties, including solubility.11 Upon reviewing the available literature, limited quantitative solubility data for 5-FU in various solvents have been reported thus far.11−18 Therefore, a detailed study of the solubility of 5-FU enabled by comprehensive experimental data is needed. In this study, the solubility of 5-FU in 11 pure solvents, including acetone, acetonitrile, n-butanol, 1,4-dioxane, ethanol, ethyl acetate, methanol, isopropanol, 1-propanol, tetrahydrofuran, water, and binary water + ethanol solvent mixtures, was investigated at temperatures ranging from 278.15 to 333.15 K using the polythermal method19−25 in a Crystal16 multiple reactor system. The experimental solubility data of 5-FU in these solvents were correlated using the modified Apelblat and λh model equations, which enable both the interpolation and extrapolation of the measured solubility data. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risk to human health) solvents by the Food and Drug Administration,26 and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to
INTRODUCTION Oral ingestion is the most widely used drug delivery route because of its ease of administration, high patient compliance, cost-effectiveness, sterility, and flexibility in the development of solid dosage forms.1 In recent years, various studies have been reported broadly, aiming to develop peroral formulations for sitespecific delivery of the chemotherapeutic agent 5-fluorouracil (5-FU, Figure 1) to reduce systemic side effects often observed
Figure 1. Molecular structure of 5-fluorouracil (5-FU).
through its intravenous administration.2−10 One parameter needed to improve the development process of these formulation alternatives is the knowledge of the solubility of 5-FU in various solvents. Moreover, gaining access to solubility data for 5-FU is useful to improve industrial crystallization processes for the separation and purification of this highly prescribed pharmaceutical compound as well as to aid in the discovery of novel polymorphs of 5-FU that might present © XXXX American Chemical Society
Received: May 21, 2018 Accepted: September 14, 2018
A
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 1. Sources and Mass Fraction Purity of Materials with Corresponding Analysis Method chemical name
CAS registry number
source
percentage purity (%)a
purification method
analysis methoda
5-fluorouracil acetone acetonitrile n-butanol 1,4-dioxane ethanol (200 proof) ethyl acetate isopropanol methanol 1-propanol tetrahydrofuran
51-21-8 67-64-1 75-05-8 71-36-3 123-91-1 64-17-5 141-78-6 67-63-0 67-56-1 71-23-8 109-99-9
Sigma-Aldrich VWR Fisher Scientific Sigma-Aldrich Fisher Scientific Pharmco Aaper Fisher Scientific VWR VWR Alfa-Aesar Sigma-Aldrich
≥99.0 ≥99.5 99.8 99.9 99.0 ≥99.9 99.9 99.5 99.8 99.5 ≥99.9%
none none none none none none none none none none none
HPLC GC LC−MS FCC, FG LSC GC HPLC GC GC GC HPLC
solvent classification26 class class class class class class class class class class
3 2 3 2 3 3 3 2 3 2
a
Provided by the suppliers.
temperature at its maximum using the software CrystalClear (v 1.0.1.614).21−25,28 To ensure accuracy, the saturation temperature at a specific concentration was measured twice.20,29 The uncertainty of each saturated temperature was within ±0.1 K. The mole fraction solubility (xi) of 5-FU was calculated according to eq 1
develop and engineer enhanced pharmaceutical processes and products based on this compound.
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EXPERIMENTAL SECTION Materials. Table 1 shows the CAS number, corresponding sources, purity (determined by chemical supplier), analysis method, and solvent classification of the materials employed in this study. Nanopurified water (18.23 MOhm/cm, pH 5.29, and mV = 76.8) was utilized as obtained from a water purification system Aries Filter (Gemini). All materials were used “as received” without further purification. Solubility Measurements. The polythermal method19−25 was used to determine the solubility of 5-FU in 11 pure solvents and binary water + ethanol solvent mixtures using a Crystal16 multiple reactor system (Technobis Crystallization Systems).22−25 Samples with different concentrations were prepared in sealed glass vials (Fisher Scientific) with an internal volume of 2 mL using a XP26 microbalance from Mettler Toledo (±0.002 mg) to weigh the solute and a MS104S analytical balance from Mettler Toledo (±0.1 mg) to weigh the pure solvents and solvent mixtures. The resulting suspensions were agitated using a magnetic stir bar (rare earth) at 700 rpm while heated from 278.15 to 333.15 K at 0.3 K/min. For acetone and 1,4-dioxane, the range of temperatures needed to be adjusted to 278.15 to 323.15 K and 285.15 to 333.15 K, respectively, due to the boiling (329.15 K)27 and melting point (284.95 K)27 restrictions for these solvents. Assuming that dissolution kinetics can be neglected,23 monitoring the transmission of light through the suspension can be used to determine the saturation
xi =
mi /Mi ∑i mi /Mi
(1)
where mi and Mi represent the mass (g) and molecular weight (g/mol) of the solute and solvents, respectively. Raman Spectroscopy. Raman spectra were recorded at room temperature in a Thermo Scientific DXR Raman microscope (Supporting Information). The commercial 5-FU was analyzed by Raman microscopy prior to the solubility measurements, and the solid-state was confirmed as the thermodynamically stable form of 5-FU (form I). All suspensions were measured by Raman microscopy after the experiments were completed, and it was confirmed that the yielded polymorph was 5-FU form I (Supporting Information). Powder X-ray Diffraction. Powder X-ray diffractograms (PXRD) were collected for all polycrystalline samples using a Rigaku XtaLAB SuperNova single microfocus Cu Kα radiation (λ = 1.5417 Å) source equipped with a HyPix3000 X-ray detector in transmission mode operating at 50 kV and 1 mA (Supporting Information). The commercial 5-FU was analyzed by PXRD prior to the solubility measurements, and the solid-state was confirmed as the thermodynamically stable
Table 2. Solubility of 5-FU (x1) In Water at Different Temperatures T (pressure, p = 101.3 kPa) Measured at a Heating Rate of 0.1 K/min and Compared to Faster Heating Rates (0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 1, 2, and 4 K/min) using RDa T/K
103 x1exp
102 RD0.2
102 RD0.3
102 RD0.4
102 RD0.5
102 RD0.6
280.6 289.6 294.0 305.3 313.0 317.5 322.6 330.9 average 102
0.90 1.23 1.47 2.10 2.88 3.36 4.02 5.53 RD
−0.358 0.258 0.271 −0.378 0.234 0.084 0.072 −0.440 −0.032
−0.179 0.521 0.254 −0.296 −0.256 0.283 −0.031 −0.354 −0.007
0.532 0.006 0.238 −0.510 −0.085 −0.147 0.062 0.181 0.034
−0.107 0.344 0.288 −0.367 −0.514 −0.126 0.052 0.311 −0.015
0.602 0.316 −0.142 −0.742 0.128 −0.021 0.114 0.231 0.061
102 RD0.7 0.918 0.232 −0.510 0.244 −0.105 0.010 0.301 0.156
102 RD1
102 RD2
102 RD4
1.751 0.578 0.569 0.071 0.234 −0.032 −0.010 0.491 0.457
1.854 0.760 0.715 0.386 0.445 0.429 0.422 0.616 0.703
4.331 1.647 1.359 0.570 1.095 0.792 0.840 1.519
a
Standard uncertainties u are u(T) = 3 K, ur(p) = 0.1, and ur(x1) = 0.01. x0.1K/min refers to the experimental mole fraction solubility of water measured at a heating rate of 0.1 K/min. RD0.2, RD0.3, RD0.4, RD0.5, RD0.6, RD0.7, RD1, RD2, and RD4 represent the corresponding relative deviations of the determined solubility with the heating rates 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 1, 2, and 4 K/min, respectively, using the polythermal method. B
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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equipped with a RCS40 single-stage refrigeration system and auto sampler. The calibration of the instrument was made with an indium standard (Tm = 429.75 K and ΔfusH = 28.54 J/g). Approximately 2 mg of 5-FU was weighed using a XP26 microbalance from Mettler Toledo (±0.002 mg) and placed on hermetically sealed aluminum pans. Samples were equilibrated at 298.15 K for 10 min prior to heating to 573.15 K under a N2 atmosphere (50 mL/min) at a rate of 10 K/min and temperature accuracy of 0.1 K. To ensure accuracy, the measurements were conducted five times and the average result of the onset temperatures was taken (Supporting Information).
Table 3. Comparison of the Mole Fraction Solubility of 5-FU (x1) in Water at 293 and 298 K Obtained by Different Methods Measured at Pressure p = 101.3 kPa T/K
103 x1
293 293 293 298 298 298 298
1.41 1.53 2.70 1.70 1.49 1.81 2.48
refs this worka 16 17
this worka 13 18
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12
a
Refers to the calculated solubility data using Apelblat equation.
THERMODYNAMIC MODELS Modeling the experimental solubility data aids the interpolation and extrapolation of the measured solubility data, which allows for a better quantification of the solubility profile of 5-FU in these various solvents and solvent mixtures. Here modeling facilitates a broader understanding of the solution behavior of 5-FU.
form of 5-FU (form I). All suspensions were measured by PXRD after the experiments were completed, and it was confirmed that the yielded polymorph was 5-FU form I (Supporting Information). Differential Scanning Calorimetry. Differential scanning calorimetry (DSC) was performed using a DSC TA Q2000
Table 4. Experimental and Predicted Mole Fraction Solubility of 5-FU (x1) in Class 3 Solvents at Different Temperatures T and at Pressure p = 101.3 kPaa λh
Apelblat 3
exp
3
T/K
10 x1
10 x1
282.9 290.2 298.4 302.5 305.1 307.4 315.2 316.9 322.4
1.52 1.75 1.99 2.19 2.29 2.44 2.80 2.99 3.04
1.49 1.74 2.05 2.22 2.32 2.42 2.78 2.86 3.13
281.1 286.9 291.2 297.7 306.2 309.1 314.8 315.1 322.8 323.7 325.6 329.9
0.99 1.24 1.37 1.67 2.06 2.16 2.60 2.67 3.20 3.29 3.66 3.99
282.1 284.6 286.8 294.9 301.3 302.4 308.0 311.6 316.2 318.0 323.0 327.5 330.0
0.85 0.89 1.02 1.19 1.47 1.63 1.88 2.17 2.37 2.58 3.01 3.46 3.81
cal
2
10 RD
3
10 x1
cal
3
exp
10 RD
T/K
10 x1
1.51 1.75 2.05 2.21 2.32 2.42 2.78 2.86 3.14
1.05 0.16 −2.77 −0.65 −1.14 1.01 0.78 4.39 −3.35
280.1 283.0 287.8 299.5 303.4 306.3 314.8 325.8 327.0 331.5
0.58 0.59 0.86 1.03 1.21 1.41 1.82 2.60 2.67 3.13
Ethanol 1.04 −5.41 1.21 2.57 1.36 0.55 1.62 3.15 2.05 0.51 2.22 −2.83 2.60 −0.28 2.63 1.54 3.27 −2.22 3.35 −1.89 3.54 3.29 4.00 −0.25 Isopropanol 0.85 0.29 0.91 −3.04 0.97 4.75 1.25 −4.39 1.52 −3.32 1.57 3.54 1.88 0.39 2.10 3.15 2.43 −2.35 2.57 0.41 3.02 −0.37 3.49 −0.95 3.78 0.85
0.96 1.16 1.33 1.63 2.09 2.27 2.65 2.68 3.28 3.36 3.53 3.93
2.56 6.45 2.42 2.72 −1.42 −4.95 −2.09 −0.20 −2.58 −2.02 3.69 1.56
291.1 297.0 300.6 310.8 320.3 330.6
0.77 0.85 0.92 1.23 1.54 1.60 1.92 2.15 2.47 2.62 3.04 3.46 3.71
8.82 3.89 9.73 −3.40 −4.53 2.16 −1.81 0.94 −4.33 −1.24 −0.92 −0.07 2.61
280.8 282.4 291.2 294.5 298.4 302.2 308.6 313.0 315.1 318.3 322.3 324.3 326.2 C
3
10 x1
cal
2
10 RD
3
10 x1
102 RD
cal
0.53 0.60 0.72 1.11 1.27 1.40 1.85 2.60 2.69 3.08
7.88 −2.06 15.93 −7.14 −5.15 0.76 −1.55 0.06 −0.88 1.46
0.41 0.48 0.54 0.63 0.77 0.99
n-Butanol 0.59 −0.95 0.64 −9.40 0.75 12.64 1.10 −6.05 1.24 −3.20 1.37 2.99 1.81 0.85 2.59 0.52 2.69 −0.75 3.13 0.08 Ethyl Acetate 0.42 −3.88 0.48 0.50 0.51 4.99 0.63 −1.37 0.78 −1.27 0.99 0.50
0.41 0.47 0.51 0.65 0.79 0.98
−058 1.11 4.50 −3.44 −2.68 1.68
0.82 0.89 0.98 1.08 1.21 1.23 1.49 1.72 1.79 2.08 2.24 2.45 2.63
0.84 0.86 1.00 1.06 1.16 1.27 1.51 1.71 1.82 2.01 2.29 2.45 2.61
1-Propanol −3.19 3.03 −2.20 1.65 3.84 −3.30 −1.17 0.96 −1.75 3.22 −2.21 −0.23 0.69
0.71 0.74 0.97 1.07 1.20 1.34 1.60 1.79 1.90 2.06 2.27 2.39 2.50
13.88 16.61 0.24 0.88 0.40 −8.81 −7.26 −3.99 −5.89 1.06 −1.45 2.31 4.95
Acetone 2.03 0.41 −3.00 −0.98 −1.49 0.68 0.69 4.40 −2.93
λh
Apelblat 2
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 4. continued λh
Apelblat 3
exp
T/K
10 x1
280.1 282.5 290.8 294.5 304.4 312.1 317.5 323.0
0.91 0.93 1.24 1.47 2.10 2.88 3.37 4.02
3
cal
10 x1
2
10 RD
Water (w3 = 0) 0.84 6.79 0.93 −0.55 1.29 −4.04 1.49 −1.09 2.14 −2.03 2.81 2.68 3.37 0.12 4.04 −0.60
3
cal
10 x1
λh
Apelblat 2
T/K
10 RD
0.84 0.93 1.29 1.49 2.15 2.81 3.37 4.03
3
exp
10 x1
3
2
cal
10 x1
10 RD
3
cal
10 x1
102 RD
7.59 0.08 −3.97 −1.20 −2.33 2.47 0.06 −0.43
a
cal Standard uncertainties u are u(T) = 3 K, ur(p) = 0.1, ur(x1) = 0.01. xexp 1 refers to the experimental mole fraction solubility. x1 refers to the calculated solubility data using Apelblat and λh model equations. RD represents the corresponding relative deviation.
Table 5. Experimental and Predicted Mole Fraction Solubility of 5-FU (x1) in Class 2 Solvents at Different Temperatures T and at Pressure p = 101.3 kPaa λh
Apelblat
λh
Apelblat
T/K
103 x1exp
103 x1cal
102 RD
103 x1cal
102 RD
T/K
103 x1exp
103 x1cal
290.3 294.6 299.1 300.3 306.6 307.6 316.0 320.2 329.0 332.3
0.46 0.53 0.62 0.66 0.81 0.83 1.02 1.21 1.43 1.62
0.46 0.54 0.63 0.65 0.80 0.82 1.05 1.18 1.47 1.59
Acetonitrile 0.55 −1.60 −1.81 0.76 1.83 1.00 −3.01 3.06 −3.29 1.78
0.47 0.55 0.63 0.65 0.79 0.81 1.04 1.17 1.47 1.60
−2.18 −3.10 −2.24 0.56 2.47 1.73 −1.94 3.90 −3.40 1.13
290.2 291.3 300.9 305.2 306.4 310.4 313.3 313.9 318.0 319.5 322.8 329.8
1.12 1.23 1.58 1.76 1.87 2.05 2.18 2.25 2.47 2.58 2.84 3.32
1.15 1.19 1.58 1.78 1.84 2.04 2.21 2.24 2.49 2.59 2.81 3.33
280.0 287.7 295.8 306.8 318.4 326.0 328.8
1.65 2.16 2.89 3.79 5.02 5.81 6.61
1.71 2.18 2.78 3.77 5.05 6.04 6.42
Methanol −3.70 −0.92 3.70 0.64 −0.48 −3.84 2.90
1.74 2.19 2.78 3.74 5.03 6.04 6.44
−5.22 −1.39 3.92 1.26 −0.07 −3.91 2.62
279.6 287.0 293.2 303.8 308.7 314.6 325.2 328.6
2.46 2.73 2.89 3.28 3.49 3.67 4.18 4.54
2.50 2.70 2.88 3.26 3.46 3.72 4.26 4.46
102 RD 1,4-Dioxane −3.20 2.70 0.34 −0.96 1.54 0.34 −1.29 0.44 −0.76 −0.45 1.11 −0.15 Tetrahydrofuran −1.50 1.23 0.35 0.63 0.81 −1.37 −2.08 1.80
103 x1cal
102 RD
1.16 1.20 1.58 1.78 1.84 2.04 2.21 2.24 2.49 2.59 2.81 3.33
−3.47 2.47 0.31 −0.94 1.58 0.40 −1.21 0.52 −0.69 −0.39 1.13 −0.27
2.44 2.68 2.90 3.30 3.50 3.75 4.25 4.42
0.82 1.69 −0.18 −0.63 −0.39 −2.25 −1.65 2.79
a cal Standard uncertainties u are u(T) = 3 K, ur(p) = 0.1, ur(x1) = 0.01. xexp 1 refers to the experimental mole fraction solubility. x1 refers to the calculated solubility data using Apelblat and λh model equations. RD represents the corresponding relative deviation.
Modified Apelblat Equation. The modified Apelblat eq 2 is a widely used semiempirical model, which correlates the solubility of the solute in neat or mixed solvents as a function of the temperature20,21,28,30 ln x1 = A +
B + C ln T T
where x1 is the mole fraction solubility of 5-FU, T and Tm are the absolute temperature and melting temperature of 5-FU in Kelvin (K), and λ and h are the model parameters representing the nonideal properties of the solution system and the excess mixture enthalpy of solution, respectively. To model the modified Apelblat and λh equations, Origin (OriginLab Corporation) was used. The nonlinear curve-fitting problem was solved using the Levenberg−Marquardt algorithm. To evaluate the goodness of fit between the experimental and the predicted solubility data, the relative deviation (RD) and the average relative deviation (ARD%) were calculated using eqs 4 and 5, respectively
(2)
where x1 is the mole fraction solubility of 5-FU, T is the absolute temperature in Kelvin (K), and A, B, and C are the empirical model parameters. The values of A and B represent the variation in the solubility activity coefficient, whereas the value of C reflects the effect of the temperature on the fusion enthalpy.21,28 λh Equation. Buchowski et al.31 published a semiempirical equation that is frequently employed to correlate solubility and temperature,20,21,28,30 which is given in eq 3 ÄÅ ÉÑ ÅÅ i1 λ(1 − x1) ÑÑÑ 1 zyz Å Å ÑÑ = λhjjjj − lnÅÅ1 + z Ñ j ÅÅÇ Ñ x1 Tm zz{ (3) ÑÖ kT
RDi =
cal x1,exp i − x1, i
ARD% = D
x1,exp i
100 N
(4) N
∑ i=1
cal x1,exp i − x1, i
x1,exp i
(5) DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 6. Experimental and Predicted Mole Fraction Solubility of 5-FU (1) in Water (2) + Ethanol (3) at Different Temperatures T and at Pressure p = 101.3 kPaa λh
Apelblat T/K
103 x1exp
103 x1cal
102 RD
281.4 284.0 284.3 289.0 293.5 294.4 297.2 303.4 304.3 307.1 309.5 313.5 324.0 324.9 329.8
0.89 0.93 0.97 1.23 1.46 1.51 1.81 2.18 2.25 2.49 2.78 3.25 4.76 4.88 5.86
279.9 292.7 302.2 312.0 323.5 330.7
0.83 1.62 2.54 4.00 6.28 7.85
w3= 0.08 0.87 2.05 0.98 −4.72 0.99 −2.03 1.22 0.89 1.47 −0.62 1.52 −0.76 1.71 5.65 2.19 −0.44 2.26 −0.78 2.53 −1.86 2.77 0.47 3.23 0.59 4.75 0.15 4.91 −0.66 5.84 0.27 w3 = 0.26 0.77 7.16 1.62 0.11 2.61 −2.79 4.00 −0.12 6.21 1.14 7.88 −0.47
282.7 287.9 294.4 299.7 304.4 313.8 322.2 323.5 327.0 330.4
2.11 2.64 3.28 4.00 4.52 6.30 8.11 8.50 9.39 10.61
w3 = 0.65 2.17 −2.91 2.61 1.27 3.28 0.00 3.92 2.00 4.59 −1.49 6.24 0.94 8.15 −0.48 8.49 0.07 9.47 −0.93 10.53 0.69
λh
Apelblat
103 x1cal
102 RD
T/K
103 x1exp
0.85 0.96 0.97 1.20 1.46 1.52 1.71 2.20 2.27 2.55 2.79 3.25 4.76 4.92 5.82
4.51 −2.67 −0.10 1.93 −0.21 −0.45 5.67 −0.87 −1.26 −2.44 −0.13 0.00 0.04 −0.70 0.68
281.2 285.2 292.7 302.0 312.1 323.5 329.5 332.9
0.84 0.99 1.51 2.30 3.55 5.36 6.65 8.05
0.92 1.69 2.59 3.90 6.12 7.98
−10.51 −4.71 −2.21 2.52 2.55 −1.63
280.5 282.9 288.8 293.5 302.5 317.0 324.1 331.0
1.48 1.56 1.87 2.53 3.57 6.24 8.15 10.19
2.09 2.55 3.26 3.94 4.63 6.31 8.19 8.52 9.46 10.46
0.92 3.30 0.48 1.62 −2.37 −0.13 −0.97 −0.27 −0.79 1.38
103 x1cal
102 RD
103 x1cal
102 RD
w3 = 0.17 0.89 −5.88 1.06 −7.97 1.49 1.20 2.23 3.11 3.42 3.61 5.43 −1.21 6.89 −3.62 7.89 2.39
0.83 1.02 1.46 2.24 3.47 5.48 6.89 7.81
0.83 −3.14 2.86 2.57 2.13 −2.19 −3.66 3.01
w3 = 0.44 1.39 6.67 1.55 0.75 2.02 −7.99 2.47 2.39 3.59 −0.74 6.27 −0.47 8.07 1.00 10.23 −0.37
1.38 1.55 2.02 2.47 3.59 6.28 8.07 10.23
6.78 0.84 −7.95 2.40 −0.77 −0.55 0.99 −0.35
a
Standard uncertainties u are u(T) = 3 K, ur(p) = 0.1, ur(x1) = 0.01, and ur(w3) = 0.00003. xexp 1 refers to the experimental mole fraction solubility. xcal 1 refers to the calculated solubility data using Apelblat and λh model equations. w3 is the mass fraction of ethanol (3) in a binary water (2) + ethanol (3) mixture. RD represents the corresponding relative deviation. cal where xexp 1,i and x1,i are the ith experimental and predicted mole fraction solubility, respectively, and N is the total number of experimental values.
the experimental data of 0.1 K/min. Analysis of these results showed that the averaged RD (to maintain positive or negative deviation information compared to ARD%) negligibly deviates around the null value when employing heating rates between 0.1 and 0.5 K/min (Supporting Information). However, the RD significantly increases with increasing heating rates for those >0.5 K/min. Consequently, a heating rate of 0.3 K/min was chosen for these experiments because it provides accuracy and fast solubility measurement.32,33 To evaluate the accuracy of the experimental solubility data obtained within this work using the polythermal method, the solubility of 5-FU in water was compared to the values available in the literature at 293 and 298 K, where different experimental methods have been employed to determine the solubility of this compound (Table 3).12,13,16−18 The literature data for the mole fraction solubility of 5-FU reported have an average value of 2.1 ± 0.8 × 10−3 at 293 K and 1.9 ± 0.5 × 10−3 at 298 K, respectively. Thus the solubility
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RESULTS AND DISCUSSION Validation of Heating Rate Employed in the Polythermal Method. The solubility of 5-FU in water was measured with heating rates of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 1, 2, and 4 K/min at temperatures ranging from 278.15 to 333.15 K. Because the solubility data for 5-FU in water are only available in the literature for 293 and 298 K,12−14,16−18 it was decided to employ the solubility of 5-FU measured at 0.1 K/min as reference to calculate the RD of the experimentally determined saturation temperature and concentration for all other (faster) heating rates with respect to 0.1 K/min (RD0.1 K/min = 0). The experimental solubility data of 5-FU in pure water measured at 0.1 K/min are listed in Table 2, along with the relative deviation of the faster heating rates from E
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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Table 7. Optimized Values for the Parameters in the Apelblat and λh Model Equations and the Resulting ARD% Employed for the Correlation of the Mole Fraction Solubility of 5-FU (1) in Various Class 2 and 3 Pure Solvents and Binary Water (2) + Ethanol (3) Solvent Mixturesa model λh
Apelblat solvent
A
B
C
ADR%
λ
h
acetone
10.66867
−2212.556
−1.65721
0.0229
0.02007
76381.1977
acetonitrile
68.17773
−5886.206
−9.80091
0.0719
0.04272
64162.0539
21.13558
0.3279
0.13675
22907.695
0.60162
0.0276
0.06815
36465.826 27391.7757
n-butanol 1,4 dioxane
−138.7222 −2.00072
3411.2897
0.0584 0.3073 0.9315
−2371.396
0.0474
ethanol
−143.582
4039.7747
21.6969
0.1054
0.09573
ethyl acetate
−157.8742
5166.3342
23.32903
0.0872
0.01022
isopropanol
−159.1775
4458.583
24.15712
0.0791
0.14766
20382.0467
−3337.098
−2.78791
0.2434
0.12263
19641.7891
15744.0
59.61261
0.0516
0.05661
44081.4716
13.14725
0.0165
0.00687
0.1600
0.28507
methanol 1-propanol
21.25928 −399.2188
ADR%
0.5111 194575.163 0.0978 0.9114 0.4005 0.9955
tetrahydrofuran
−90.40494
water
−19.364
−2217.7
3.58592
w3 = 0.08
−37.03418
−1698.274
6.38797
0.1197
0.53642
6850.83441
w3 = 0.17
−79.36338
12.84324
1.0455
1.0341
3922.24957
w3 = 0.26
205.25737
−29.35793
0.8401
0.99141
3974.03797
w3 = 0.44
4.18866
0.34679
0.1563
0.91069
4034.93538
w3 = 0.65
−68.23803
10.86173
0.0844
0.48364
6478.29947
2893.7494
109520.47 0.0266 11552.0926 0.2833
water + ethanol
−24.23278 −13158.26 −3568.717 226.01743
0.2676 0.3024 2.3300 0.1817 0.3169
a
w3 is the mass fraction of ethanol (3) in water (2).
data presented in this work lie within the experimental error of the published data. DSC Results. The average onset melting temperature (Tm) of 5-FU was determined as 555.66 ± 0.26 K (Supporting Information) and was used to calculate the mole fraction solubility (xcal 1 ) using the λh model equation. The onset melting temperature obtained in this study is within the experimental error of the average value (554 ± 3 K) presented in the published literature (Supporting Information).11,34−36 Solubility Data. The experimentally measured mole fraction solubility of 5-FU in pure solvents and the RD between the experimental and predicted solubility is divided into Tables 4 and 5 based on the solvent classification.26 The experimentally measured mole fraction solubility of 5-FU in the Class 3 solvents acetone, n-butanol, ethanol, ethyl acetate, isopropanol, 1-propanol, and water is shown in Table 4, whereas for the Class 2 solvents acetonitrile, 1,4-dioxane, methanol, and tetrahydrofuran are shown in Table 5. The solubility in the binary water + ethanol solvent mixtures and the RD between the experimental and predicted solubility are listed in Table 6. The experimental solubility data were correlated using the Apelblat and λh model equations, and the optimized values for all equations were obtained using Origin. The application of these model equations is of interest because it permits the direct
calculation of the solubility for 5-FU in various pure solvents and solvent mixtures. The correlation parameters and ARD% for the Apelblat and λh model equations are listed in Table 7. The predicted solubility data obtained employing the two model equations agree well with the experimental solubility data obtained employing the polythermal method, as demonstrated by the low RD and ARD% values. It was found that for all Class 2 and 3 pure solvents and binary solvent mixtures the Apelblat model equation gives better correlation results compared with the λh model equation, except for water + ethanol (w3 = 0.17). Figures 2−4 present the experimental and correlated mole faction solubility of 5-FU based on the modified Apelblat model equation in each pure solvent and the binary water + ethanol solvent mixtures. Figures presenting the λh model equation can be found in the Supporting Information. From Figures 2 to 4, it can be seen that the solubility of 5-FU increases with an increase in temperature in all pure solvents and at constant solvent composition in the solvent mixtures. Figure 4 depicts the effect of the solvent composition on the solubility of 5-FU in binary water + ethanol solvent mixtures. It can be seen that the solubility of 5-FU in the solvent mixtures exceeds its solubility in either of the pure solvents, water and ethanol, for temperatures above 290 K. Below 290 K, the F
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
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method enabled by the use of a Crystal16 multiple reactor system. To provide a general quantification of the solubility profiles, the experimental data were correlated using the Apelblat and λh model equations. The predicted solubility data obtained employing the two model equations agree well with the experimental solubility data obtained employing the polythermal method, as demonstrated by the low RD and ARD% values. Although these models do not take into consideration the solvent composition and require separate parameters for each solvent, the Apelblat and λh model equations provide a straightforward approach to calculate the solubility of 5-FU in various solvents and solvent mixtures. The selected solvents are categorized as either Class 2 or 3 (less toxic and lower risks to human health),26 and hence the correlated and experimentally derived solubility data of 5-FU presented provide a pathway to develop and engineer enhanced pharmaceutical processes and products based on this compound.
Figure 2. Experimental and correlated solubility data of 5-FU in Class 3 solvents. △, acetone; +, n-butanol; ◇, ethanol; ■, ethyl acetate; ○, isopropanol; ◆, 1-propanol; □, water; , calculated using modified Apelblat equation.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.8b00425. Detailed experimental procedures for the solubility curves of 5-FU in acetone, acetonitrile, n-butanol, 1,4dioxane, ethanol, ethyl acetate, methanol, isopropanol, 1propanol, tetrahydrofuran, water, and binary water + ethanol solvent mixtures, Raman spectra, powder X-ray diffractograms, and DSC thermographs (PDF)
Figure 3. Experimental and correlated solubility data of 5-FU in Class 2 solvents. ○, acetonitrile; △, 1-4 dioxane; □, methanol; ◇, tetrahydrofuran; , calculated using modified Apelblat equation.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (T.S.). *E-mail:
[email protected] (V.L.-M.). ORCID
Torsten Stelzer: 0000-0003-3881-0183 Vilmalí López-Mejías: 0000-0003-2138-8414 Funding
This work was supported primarily by the National Institutes of Health’s Maximizing Access to Research Careers Program (5T34GM007821-38). Infrastructure support was provided in part by a grant from the National Institute on Minority Health and Health Disparities (8G12MD007600). This work was also supported in part by the Puerto Rico Institute for Functional Nanomaterials (EPS-100241). We thank the New York University’s Materials Research Science and Engineering Center for proving the opportunity to participate in the Student−Faculty Program during the summer of 2016 (DMR1420073). The Rigaku XtaLAB SuperNova single-crystal X-ray micro diffractometer was acquired through the support of the National Science Foundation under the Major Research Instrumentation Program (CHE-1626103).
Figure 4. Experimental and correlated solubility data of 5-FU (1) in binary water (2) + ethanol (3) solvent mixtures. ◆, w3 = 0 (water); +, w3 = 0.08; ○, w3 = 0.17; △, w3 = 0.26; ◇, w3 = 0.44; □, w3 = 0.65; ■, w3 = 1 (ethanol); −, calculated using modified Apelblat equation.
solvent mixtures w3 = 0.08 and w3 = 0.17 possess a solubility below pure ethanol and similar to pure water, which can be explained with the low ethanol content in these mixtures, leading to a similar crossover in the solubility curves, as can be observed for pure ethanol and water below 290 K. In addition, the calculated solubility using the modified Apelblat equation for w3 = 0.26 intersects with the solubility calculated for w3 = 0.08 and w3 = 0.17. However, the solubility correlated with the λh equation does not show this intersection (Supporting Information); therefore, it can be inferred that this is an artifact of the modified Apelblat equation.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the support from Amy Wagner from Technobis Crystallization Systems.
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CONCLUSIONS The solubility data for 5-FU in 11 pure solvents and binary water + ethanol solvent mixtures were experimentally measured at temperatures between 278.15 and 333.15 K using the polythermal
NOMENCLATURE 5-FU 5-fluorouracil A, B, C empirical model parameters for Apelblat equation G
DOI: 10.1021/acs.jced.8b00425 J. Chem. Eng. Data XXXX, XXX, XXX−XXX
Journal of Chemical & Engineering Data ARD% DSC PXRD h m M RD T Tm w x1 xcal 1 xexp 1
Article
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average relative deviation differential scanning calorimetry powder X-ray diffraction model parameter for λh equation representing excess mass (g) molecular mass (g·mol−1) relative deviation absolute temperature (K) melting temperature of 5-FU (K) mass fraction of solvent mixture compositions mole fraction solubility of 5-FU (mol) calculated mole fraction solubility of 5-FU (mol) experimental mole fraction solubility of 5-FU (mol)
Greek Symbols
λ
model parameter for λh equation representing nonideal properties of the system ΔfusH molar enthalpy of fusion
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