Measurement and Correlation of Solubility of Theobromine

Article pubs.acs.org/jced

Measurement and Correlation of Solubility of Theobromine, Theophylline, and Caffeine in Water and Organic Solvents at Various Temperatures Jialun Zhong, Ning Tang, Behnaz Asadzadeh, and Weidong Yan* Department of Chemistry, Zhejiang University, Hangzhou 310027, China S Supporting Information *

ABSTRACT: The solubility of theobromine, theophylline, and caffeine in water and five organic solvents including methanol, ethanol, 1-propanol, ethyl acetate, and acetone was determined by a high performance liquid chromatography method at T = (288.15 to 328.15) K and atmospheric pressure. It was found that the solubility of theobromine, theophylline, and caffeine in these solvents increased with increasing temperature. The empirical Apelblat equation and universal quasichemical model were used to correlate the experimental solubility. The results showed that both models can satisfactorily correlate the solubility data. The crystal forms of the solutes in equilibrium with the saturated solution were analyzed using scanning electron microscopy and powder X-ray diffraction.

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solubility data of caffeine in different solvents were reported.4,5 Pobudkowska6 reported the solubilities of theobromine, theophylline, and 7-(b-hydroxyethyl) theophylline in water, ethanol, and 1-octanol. The solubility of theobromine, theophylline, and caffeine in supercritical carbon dioxide and mixed solvents has been reported in the literature.7−10 The information in regard to measurement of solubility of theobromine, theophylline, and caffeine in organic solvents is scarce. So, it seems that the study of the solubility of mentioned compounds at various solvents is necessary. In this work, the solubility of theobromine, theophylline, and caffeine in water, methanol, ethanol, 1-propanol, ethyl acetate, and acetone was determined by high performance liquid chromatography (HPLC) at T = (288.15 to 328.15) K and atmospheric pressure. The obtained experimental data were correlated with the Apelblat equation and universal quasichemical (UNIQUAC) model. In addition, the crystal forms of the solutes in equilibrium with the saturated

INTRODUCTION Caffeine, theobromine, and theophylline are xanthine derivatives existing widely in natural. The molecular structures of theobromine, theophylline, and caffeine are shown in Figure 1. Theobromine, theophylline, and caffeine are very similar in molecular structures. These nitrogenous substances show various physiological effects1 on various body systems, including the central nervous, cardiovascular, gastrointestinal, respiratory, and renal systems.2 Theophylline can be used for the diseases corresponding to cramps of smooth muscles in bronchis. Theobromine acts as the spasmolytic agent and a diuretic, while caffeine is used for the relief of headache.3 Theobromine is the main alkaloids in cocoa beans and green tea contain approximately 2−5% caffeine by dry weight. These bioactive constituents usually exist as mixtures in cocoa beans, coffee beans, tea, and guarana. The requests for decaffeination and obtaining fine chemicals and pharmaceuticals from the mixtures are growing. Solvent crystallization and liquid−liquid extraction are important techniques in the separation and purification process in the pharmaceutical industries. Therefore, the study of physicochemical and thermal properties of these xanthine derivatives has more importance in the pharmacy and food industry. In this way, several studies have been performed. The © 2017 American Chemical Society

Special Issue: Memorial Issue in Honor of Ken Marsh Received: January 22, 2017 Accepted: June 14, 2017 Published: June 27, 2017 2570

DOI: 10.1021/acs.jced.7b00065 J. Chem. Eng. Data 2017, 62, 2570−2577

Journal of Chemical & Engineering Data

Article

Figure 1. Chemical structure of theobromine (A), theophylline (B), caffeine (C).

Table 1. Sources, Purity (Suppliers’ Data), Purification Method and Determination Method of Chemicals in This Study chemicals

CASRN

sources

purity

theobromine theophylline caffeine benzil acetonitrile methanol ethanol 1-propanol ethyl acetate acetone

83-67-0 58-55-9 58-08-2 134-81-6 75-05-8 67-56-1 64-17-5 71-23-8 141-78-6 67-64-1

J&K Scientific J&K Scientific Sky Herb Energy Chemical Sinopharm Chemical Sinopharm Chemical Sinopharm Chemical Sinopharm Chemical Sinopharm Chemical Sinopharm Chemical

≥0.99 ≥0.99 ≤0.50 ≥0.99 ≥0.99 ≥0.99 ≥0.99 ≥0.99 ≥0.99 ≥0.99

purification method

recrystallization

determination method HPLC HPLC HPLC HPLC GC GC GC GC GC GC

0.5 to 1 mL solutions were drawn using preheated injectors with 0.45 μm filters. The injector with saturated solutions was weighed on the analytical balance (Sartorius CPA225D, Germany, uncertainty of u(m) = 0.01 mg). Then the solutions were diluted with water or methanol to 10 or 50 mL in the volumetric flask. For HPLC analysis, the standard solutions of theobromine, theophylline, and caffeine were prepared by dissolving the accurately weighed standard substances into the methanol. The HPLC analysis was performed on HPLC (LC-100, Wufeng, Shanghai, China) connected with an UV detector, a Phenomenex Luna C18 100A column (250 mm × 4.6 mm, 5 μm), and a 20 μL injector loop. The mobile phase was composed of acetonitrile (A) and 0.1% formic acid aqueous solution (B). The volume ratio of A/B was 12:88. The flow rate was 1.0 mL·min−1 and detective wavelength at 280 nm. The column was kept at 30 °C. Thermodynamic Properties Analysis. The fusion enthalpies and the melting temperatures of theobromine, theophylline and caffeine were determined by the differential scanning calorimeter (DSC) (Q100, TA Corporation). The reference compound used for DSC calibration was indium. The determined heat of fusion and melting temperature of indium were 28.37 J·g−1 and 156.50 °C. About 3.80 mg (u(m) = 0.01 mg) theophylline and caffeine were weighed and sealed in an aluminum pan to perform the analysis, respectively. The temperature range was from 50 to 300 °C for theophylline and 50 to 270 °C for caffeine. The experiments were performed under a nitrogen atmosphere of 50 mL·min−1, and the heating rate was 10 K·min−1. The determination of melting temperatures, onset point and end, peak maximum, endothermic peaks, and fusion enthalpies were completed by using the TA Universal Analysis software. Thermogravimetric analysis (TGA) was carried out on a thermogravimetric analyzer (SDT Q600, TA Instruments USA). The analysis was performed in a nitrogen atmosphere of 50 mL·min−1 and the heating rate was 5 K·min−1. The determination of mass loss, onset point and end, and the

solution were characterized using scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD).

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EXPERIMENTAL SECTION Materials. A 100 g sample of caffeine yellow powder (Skyherb Technologies Co., Ltd., China, ≤ 50%) was dissolved in 3.5 L of 95% ethanol, extracted with ultrasound for 30 min, and filtered. The filtrate was evaporated under vacuum to remove the ethanol. The residue was again dissolved in water and extracted twice with dichloromethane. Then the dichloromethane phases were combined and evaporated under vacuum. About 25 g of crystal caffeine was obtained after recrystallization with ethanol three times. It was dried in an air-circulating oven (Jinghong DNG-9070A, Shanghai, China) at T = 368.2 K for 4 h. The purity (≥98%) was determined by HPLC. The reference substance of caffeine (≥98%) was purchased from Chengdu Biopurify Phytochemicals Ltd. (China). The purchased theobromine, theophylline, and caffeine were kept in a vacuum drying oven (Jinghong DZF-6020, Shanghai, China) with a vacuum pump (Vacuubrand, MZ 2C NT, Germany) at 328.15 K for 1 day before using. All the organic solvents were analytical grade. Molecular sieves (3 to 4) Å were submerged in the solvents before using. Water was purified by using the quartz sub-boiling purifier. The pH value of deionized water (6.4) was determined by Waterproof pH Scan 2 Tester (Eutech Instruments Ltd. USA). The description of materials used in this work is listed in Table 1. Solubility Measurement. The graduated glass tubes with threading caps (10 cm3) were fulfilled with excess solid solute and 10 mL of solvents. Each sample under the same conditions was placed in three glass tubes and sealed. The sealed tubes were placed into the thermostatic water bath (THD-2006, Ningbo Tianheng Instrument Works Co., Ltd., China). The temperature was determined by platinum resistance thermometer (JM 6200, Tianjin Jinming Instrument CO., Ltd., China) with an uncertainty of u(T) = 0.01 K. The glass tubes were kept in the water bath for 24 h. The glass tubes were shaken every 2 h during the first 12 h. After solid−liquid equilibrium has been reached, 2571



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Table 2. Experimental Solubility Data for Theobromine, Theophylline, and Caffeine in Different Solvents at T = (288.15 to 328.15) K and p = 0.1 MPaa 105x1 T/K

water

288.07 298.10 308.93 318.62 328.15

105x1 methanol

3.09 4.73 6.93 10.01 14.48

2.82 4.34 7.00 11.02 16.33

T/K 288.15 298.20 308.19 318.16 328.16

104x1 T/K

water

288.06 298.16 308.16 318.13 328.19

methanol

3.25 6.30 9.91 14.10 21.64

7.70 13.70 21.72 29.82 39.41

T/K 288.01 297.95 308.01 318.11 328.09

103x1

a

T/K

water

ethanol

T/K

288.01 298.11 308.09 318.11 328.15

1.23 1.61 2.27 2.96 3.98

0.78 1.32 2.04 3.22 4.69

288.24 298.17 308.17 318.20 328.12

ethanol Theobromine 1.38 2.26 3.85 6.31 10.61 104x1 ethanol Theophylline 8.00 11.60 17.30 25.41 31.92 103x1 methanol Caffeine 1.34 1.89 2.80 4.26 6.63

105x1 1-propanol

T/K

ethyl acetate

acetone

1.18 2.06 3.71 6.37 10.90

288.13 297.99 308.08 318.07 328.17

1.04 1.59 2.28 3.33 4.94

1.47 2.23 2.99 4.57 6.77 104x1

1-propanol

T/K

ethyl acetate

acetone

9.12 13.58 20.36 31.33 42.34

288.02 298.15 308.15 318.15 328.10

5.02 6.73 9.01 11.00 14.08

6.67 9.30 12.41 14.73 18.02 103x1

1-propanol

T/K

ethyl acetate

acetone

1.17 1.77 2.82 4.53 7.16

288.24 298.09 308.21 318.15 328.18

2.70 3.54 4.88 6.89 9.24

2.79 3.63 5.28 7.28 9.53

ur (x) = 0.02; u (p) = 5 kPa; u (T) = 0.01 K

literature data11 are 0.63% in acetone and 1.57% in acetonitrile, respectively. This indicates that this method is accurate and can be applied in measuring the solubility of theobromine, theophylline, and caffeine. The solubility values of theobromine, theophylline, and caffeine in water, methanol, ethanol, 1-propanol, ethyl acetate, and acetone are reported in Table 2. All presented experimental solubility mole fractions are the average of the replicates from three glass tubes under the same equilibrium conditions. The relative standard deviations of the results (RSDs) are listed in Table S2. As shown in this table, the RSD values are greater at higher temperatures. The comparison of experimental solubility data (partial) for theobromine, theophylline, and caffeine in this work and the reported data from the literature4−6,10 is listed in Table S3−S5 and graphically shown in Figure S1−S3. As shown in these tables and figures, most of the solubility values are nearly close to each other. However, the measured values for the solubility of theobromine and caffeine, in water in this work are not in agreement with the literature values reported by Pobudkowska6 and Han,5 respectively. These deviations may be due to differences in purity source of compound, determination method, and the crystal forms of the solutes. Furthermore, the solubility data are plotted in Figure 2. It can be seen that the solubility of theobromine in pure solvents follows the order methanol > 1-propanol ≥ ethanol > acetone > ethyl acetate. The solubility of theophylline follows the order 1propanol ≥ methanol > ethanol > acetone > ethyl acetate. The solubility of caffeine follows the order acetone ≥ ethyl acetate >1propanol ≥ methanol > ethanol. As observed in these Figures, in the whole range of solvents the solubility values increase with increasing temperature. The comparison of solubility values indicates that the solubility behavior in water is different from other organic pure solvents.

temperature range of reaction interval were completed by using the TA Universal Analysis software. Validation of the Measurement Method. To validate the measurement method in this work, the solubility of benzil in acetone and acetonitrile was determined by a HPLC method at T = 298.15 K and atmospheric pressure. Identity of the Crystals in the Solid−Liquid Equilibrium. To prepare the crystals, theobromine, theophylline, and caffeine were dissolved in different solvents at 328.15 K and then the solutions were cooled naturally. The obtained crystals of the solutes in equilibrium with the saturated solution were used to observe by scanning electron microscopy (SEM) (SU8010, Hitachi, Japan). The accelerating voltage of SEM is 3.0 kV. Also, powder X-ray diffraction (PXRD) data were recorded on a Rigaku D/MAX 2550/PC for Cu Kα (λ = 1.5406 Å).

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RESULTS AND DISCUSSION Solubility Results. The solubility (x1) of solute can be calculated by eq 1: x1 =

mA /MA mA /MA + mB /MB

(1)

mA and mB refer to the masses of the solute and solvent, respectively. MA and MB represent the molecule weights of the solute and solvent. The experimental data of the validation measurement are listed in Table S1. To evaluate the reliability of the experimental method in this work, the solubility of benzil was obtained as 0.159 in water and 0.0645 in acetonitrile at T = 298.15 K and atmospheric pressure. The results are obtained from the average of the three replicates. The relative standard deviations of the results (RSDs) are 1.08% and 1.94%, and the deviations with the 2572



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Figure 2. Solubility values of theobromine (A), theophylline (B), and caffeine (C) in selected solvents.

Table 3. Physicochemical Properties of the Xanthine Derivatives: Melting Temperature, Tm and Enthalpy of Fusion, ΔfusH at p = 0.1 MPaa solute

a

Tm/Ka

ΔfusH/(kJ·mol−1)a

Tlit m/K b

theobromine theophylline

545.18

caffeine

509.07

622.03 544.43b 544.0c 510.75b 505.4d

28.92 19.44

Δf uslitH/(kJ·mol−1) 57.42b 22.81b 30.43c 20.95b 17.9d

u(Tm) = 0.5 K; ur(ΔfusH) = 0.03; u(p) = 5 kPa. bReference 3. cReference 14. dReference 15.

replacement of protons on the ring by a methyl group that leads to decreased polarity. The solubility behavior of the studied samples show that, due to the high variation of the solubility in organic pure solvents at different temperatures, these compounds can be recrystallized separated and purified using proper organic solvents at certain temperatures.

Also, solubility results show that in organic solvents the solubility of caffeine is higher than theophylline. Table 2 indicates that theobromine solubility is fairly low as compared with that of theophylline and caffeine. This can be explained by the existence of relatively strong intermolecular bonds and the tendency of molecules to form clusters.12,13 Also we attributed the higher solubility of caffeine in ethyl acetate and acetone to the 2573



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Figure 3. SEM images of theobromine (A), theophylline (B), and caffeine (C) particles crystallized in different solvents: (1) water, (2) methanol, (3) ethanol, (4) 1-propanol, (5) ethyl acetate, (6) acetone.

Thermodynamic Properties of Theobromine, Theophylline, and Caffeine. The fusion enthalpies and melting temperature of theobromine, theophylline, and caffeine are collected in Table 3. Experimental TGA of theobromine and heat flow from DSC measurement of theophylline and caffeine are shown in Figure S4. Figure S4A of the experimental TGA of theobromine shows that, determination the melting point of theobromine is difficult, because of theobromine starting to sublimate in the aluminum sample pan. When the temperature was increased to higher than 563.15 K, the sublimating

theobromine was crystallized in the pipe of the differential scanning calorimeter. Therefore, to protect the differential scanning calorimeter (Q100, TA Corporation) from the sublimating theobromine, the determination of theobromine melting point was not performed. Theobromine and theophylline are isomers. There are only different positions of the methyl group in the molecular structures. However, theobromine has a higher melting point than theophylline. This phenomenon can be attributed to the intermolecular hydrogen bonding between the carbonyl groups 2574



Article

together with the stacking interactions between two layers of theobromine12 while the interaction in theophylline is weaker. It seems that the position of the hydrogen atom in theobromine causes the intermolecular hydrogen bonding between the carbonyl groups and the hydrogen atom. Crystals in the Solid−Liquid Equilibrium. Crystal habits of theobromine, theophylline, and caffeine in the solid−liquid equilibrium were characterized by scanning electron microscopy (SEM) and powder X-ray diffraction (PXRD). As can be seen from Figure 3, the crystal habits of theobromine in different solvents all show a granular shape. The crystals of theophylline equilibrated in methanol, ethanol, and 1-propanol are flake-like and plate-like in ethyl acetate and acetone, and rod-like in water. The crystals of caffeine equilibrated in solvents show a rod-like shape and needle-shaped particles. Representative PXRD diffraction patterns of crystals for theobromine, theophylline, and caffeine in the solid−liquid equilibrium are shown in Figure 4. As can be seen from Figure 4A, the diffraction patterns of the theobromine crystals are nearly the same. Figure 4 panels B and C show that the crystals of theophylline and caffeine in water were different from the samples which were used to determine the solubility. It means that the forms of the solutes in solid−liquid equilibrium for the water systems were theophylline monohydrate and caffeine hydrate, respectively. It was confirmed by thermogravimetric measurements and shown in Figure 5. As shown in Figure 5A, the weight loss of theophylline monohydrate was 8.45% when the temperature was higher than 333 K. The weight percentage of water in theophylline monohydrate was 9.09%. While in Figure 5B, the weight loss of caffeine hydrate was 1.56%. Caffeine hydrate is nonstoichiometric in terms of its water content and under ambient atmospheric conditions transforms over several days to the anhydrous β-phase.16 In Figure 4B, the intensity of the reflection peaks at diffraction angles (2θ) of 7.16, 14.28, 21.53, and 36.43 was stronger in methanol, ethanol, and 1propanol especially in ethyl acetate and acetone. However, the intensity at diffraction angles (2θ) of 12.51 was weaker in all solvents. This can be attributed to the crystal habits of theophylline being flake-like and even plate-like in acetone and ethyl acetate. It seems that the variations in peak intensity of the same samples are related to the changes in the orientation of the crystal habits. Calculation with Apelblat Equation and UNIQUAC Equation Model. The empirical Apelblat equation and the UNIQUAC model17−21 were used to correlate the experimentally measured solubility data. A description of these approaches, Tables S6 and S7 with values of the adjustable parameters, and Figures S5 and S6 showing the correlations are provided in the Supporting Information. Both can be used to satisfactorily fit the solubility data but the empirical Apelblat equation with three parameters yields a better fit than the UNIQUAC model.

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CONCLUSIONS The solubility values of theobromine, theophylline, and caffeine in water, methanol, ethanol, 1-propanol, ethyl acetate, and acetone were determined by HPLC at T = (288.15 to 328.15) K and atmospheric pressure. In all studied solvents, the solubility of theobromine, theophylline, and caffeine increased with increasing temperature. The fusion enthalpies and melting temperature of theobromine, theophylline, and caffeine have been determined. Crystal habits of theobromine, theophylline, and caffeine in the solid−liquid equilibrium were characterized. The crystal forms of solids equilibrated with the saturated solutions are rod-

Figure 4. PXRD diffraction patterns of crystals in various solvents: theobromine (A), theophylline (B), caffeine (C).

like shapes or needle-shaped particles. Theophylline monohydrate and caffeine hydrate were formed in the solid−liquid equilibrium. The Apelblat equation and UNIQUAC model were used to correlate the experimental solubility data. It was found that both models can satisfactorily correlate the solubility data for the studied systems. 2575



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Figure 5. Experimental TGA measurement of theophylline monohydrate (A) and caffeine hydrate (B).

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ASSOCIATED CONTENT

the empirical Apelblat equation; theobromine, theophylline, and caffeine solubility line in this work and dashed line calculated by UNIQUAC equation; approaches of the Apelblat equation and the UNIQUAC model (PDF)

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b00065. RSDs of experimental solubility data for theobromine, theophylline and caffeine in different solvents; comparison of experimental solubility data for theobromine, theophylline, and caffeine in this work and the literature; parameters of the Apelblat and UNIQUAC equations; graphical comparison of solubility values of theobromine in water and ethanol, theophylline in water, ethanol, ethyl acetate, and acetone, and caffeine in water, ethanol, methanol, and ethyl acetate; experimental TGA measurement of theobromine and DSC measurement of theophylline and caffeine; theobromine, theophylline, and caffeine solubility line in this work and dashed line calculated by

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AUTHOR INFORMATION

Corresponding Author

*Tel.: +86-571-87951430. Fax: +86-571-87951895. E-mail: [email protected]. ORCID

Weidong Yan: 0000-0002-5125-310X Notes

The authors declare no competing financial interest. 2576



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Measurement and Correlation of Solubility of Theobromine

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