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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.

■ INTRODUCTION
Caffeine, theobromine, and theophylline are xanthine derivatives
solubility data of caffeine in different solvents were reported.4,5
Pobudkowska6 reported the solubilities of theobromine,
existing widely in natural. The molecular structures of theophylline, and 7-(b-hydroxyethyl) theophylline in water,
theobromine, theophylline, and caffeine are shown in Figure 1. ethanol, and 1-octanol. The solubility of theobromine, theophyl-
Theobromine, theophylline, and caffeine are very similar in line, and caffeine in supercritical carbon dioxide and mixed
molecular structures. These nitrogenous substances show solvents has been reported in the literature.7−10 The information
various physiological effects1 on various body systems, including in regard to measurement of solubility of theobromine,
the central nervous, cardiovascular, gastrointestinal, respiratory, theophylline, and caffeine in organic solvents is scarce. So, it
and renal systems.2 Theophylline can be used for the diseases seems that the study of the solubility of mentioned compounds at
corresponding to cramps of smooth muscles in bronchis.
various solvents is necessary. In this work, the solubility of
Theobromine acts as the spasmolytic agent and a diuretic,
while caffeine is used for the relief of headache.3 Theobromine is theobromine, theophylline, and caffeine in water, methanol,
the main alkaloids in cocoa beans and green tea contain ethanol, 1-propanol, ethyl acetate, and acetone was determined
approximately 2−5% caffeine by dry weight. These bioactive by high performance liquid chromatography (HPLC) at T =
constituents usually exist as mixtures in cocoa beans, coffee (288.15 to 328.15) K and atmospheric pressure. The obtained
beans, tea, and guarana. The requests for decaffeination and experimental data were correlated with the Apelblat equation and
obtaining fine chemicals and pharmaceuticals from the mixtures universal quasichemical (UNIQUAC) model. In addition, the
are growing. crystal forms of the solutes in equilibrium with the saturated
Solvent crystallization and liquid−liquid extraction are
important techniques in the separation and purification process
Special Issue: Memorial Issue in Honor of Ken Marsh
in the pharmaceutical industries. Therefore, the study of
physicochemical and thermal properties of these xanthine Received: January 22, 2017
derivatives has more importance in the pharmacy and food Accepted: June 14, 2017
industry. In this way, several studies have been performed. The Published: June 27, 2017

© 2017 American Chemical Society 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 purification method determination method
theobromine 83-67-0 J&K Scientific ≥0.99 HPLC
theophylline 58-55-9 J&K Scientific ≥0.99 HPLC
caffeine 58-08-2 Sky Herb ≤0.50 recrystallization HPLC
benzil 134-81-6 Energy Chemical ≥0.99 HPLC
acetonitrile 75-05-8 Sinopharm Chemical ≥0.99 GC
methanol 67-56-1 Sinopharm Chemical ≥0.99 GC
ethanol 64-17-5 Sinopharm Chemical ≥0.99 GC
1-propanol 71-23-8 Sinopharm Chemical ≥0.99 GC
ethyl acetate 141-78-6 Sinopharm Chemical ≥0.99 GC
acetone 67-64-1 Sinopharm Chemical ≥0.99 GC

solution were characterized using scanning electron microscopy 0.5 to 1 mL solutions were drawn using preheated injectors with
(SEM) and powder X-ray diffraction (PXRD). 0.45 μm filters. The injector with saturated solutions was

■ EXPERIMENTAL SECTION
Materials. A 100 g sample of caffeine yellow powder
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
(Skyherb Technologies Co., Ltd., China, ≤ 50%) was dissolved volumetric flask. For HPLC analysis, the standard solutions of
in 3.5 L of 95% ethanol, extracted with ultrasound for 30 min, and theobromine, theophylline, and caffeine were prepared by
filtered. The filtrate was evaporated under vacuum to remove the dissolving the accurately weighed standard substances into the
ethanol. The residue was again dissolved in water and extracted methanol.
twice with dichloromethane. Then the dichloromethane phases The HPLC analysis was performed on HPLC (LC-100,
were combined and evaporated under vacuum. About 25 g of Wufeng, Shanghai, China) connected with an UV detector, a
crystal caffeine was obtained after recrystallization with ethanol Phenomenex Luna C18 100A column (250 mm × 4.6 mm, 5 μm),
three times. It was dried in an air-circulating oven (Jinghong and a 20 μL injector loop. The mobile phase was composed of
DNG-9070A, Shanghai, China) at T = 368.2 K for 4 h. The purity acetonitrile (A) and 0.1% formic acid aqueous solution (B). The
(≥98%) was determined by HPLC. The reference substance of volume ratio of A/B was 12:88. The flow rate was 1.0 mL·min−1
caffeine (≥98%) was purchased from Chengdu Biopurify and detective wavelength at 280 nm. The column was kept at 30
Phytochemicals Ltd. (China). °C.
The purchased theobromine, theophylline, and caffeine were Thermodynamic Properties Analysis. The fusion en-
kept in a vacuum drying oven (Jinghong DZF-6020, Shanghai, thalpies and the melting temperatures of theobromine, theophyl-
China) with a vacuum pump (Vacuubrand, MZ 2C NT, line and caffeine were determined by the differential scanning
Germany) at 328.15 K for 1 day before using. All the organic calorimeter (DSC) (Q100, TA Corporation). The reference
solvents were analytical grade. Molecular sieves (3 to 4) Å were compound used for DSC calibration was indium. The
submerged in the solvents before using. Water was purified by determined heat of fusion and melting temperature of indium
using the quartz sub-boiling purifier. The pH value of deionized
were 28.37 J·g−1 and 156.50 °C. About 3.80 mg (u(m) = 0.01
water (6.4) was determined by Waterproof pH Scan 2 Tester
mg) theophylline and caffeine were weighed and sealed in an
(Eutech Instruments Ltd. USA). The description of materials
used in this work is listed in Table 1. aluminum pan to perform the analysis, respectively. The
Solubility Measurement. The graduated glass tubes with temperature range was from 50 to 300 °C for theophylline and
threading caps (10 cm3) were fulfilled with excess solid solute 50 to 270 °C for caffeine. The experiments were performed
and 10 mL of solvents. Each sample under the same conditions under a nitrogen atmosphere of 50 mL·min−1, and the heating
was placed in three glass tubes and sealed. The sealed tubes were rate was 10 K·min−1. The determination of melting temper-
placed into the thermostatic water bath (THD-2006, Ningbo atures, onset point and end, peak maximum, endothermic peaks,
Tianheng Instrument Works Co., Ltd., China). The temperature and fusion enthalpies were completed by using the TA Universal
was determined by platinum resistance thermometer (JM 6200, Analysis software. Thermogravimetric analysis (TGA) was
Tianjin Jinming Instrument CO., Ltd., China) with an carried out on a thermogravimetric analyzer (SDT Q600, TA
uncertainty of u(T) = 0.01 K. The glass tubes were kept in the Instruments USA). The analysis was performed in a nitrogen
water bath for 24 h. The glass tubes were shaken every 2 h during atmosphere of 50 mL·min−1 and the heating rate was 5 K·min−1.
the first 12 h. After solid−liquid equilibrium has been reached, The determination of mass loss, onset point and end, and the
2571 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data Article

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 105x1 105x1
T/K water methanol T/K ethanol 1-propanol T/K ethyl acetate acetone
Theobromine
288.07 3.09 2.82 288.15 1.38 1.18 288.13 1.04 1.47
298.10 4.73 4.34 298.20 2.26 2.06 297.99 1.59 2.23
308.93 6.93 7.00 308.19 3.85 3.71 308.08 2.28 2.99
318.62 10.01 11.02 318.16 6.31 6.37 318.07 3.33 4.57
328.15 14.48 16.33 328.16 10.61 10.90 328.17 4.94 6.77
104x1 104x1 104x1
T/K water methanol T/K ethanol 1-propanol T/K ethyl acetate acetone
Theophylline
288.06 3.25 7.70 288.01 8.00 9.12 288.02 5.02 6.67
298.16 6.30 13.70 297.95 11.60 13.58 298.15 6.73 9.30
308.16 9.91 21.72 308.01 17.30 20.36 308.15 9.01 12.41
318.13 14.10 29.82 318.11 25.41 31.33 318.15 11.00 14.73
328.19 21.64 39.41 328.09 31.92 42.34 328.10 14.08 18.02
103x1 103x1 103x1
T/K water ethanol T/K methanol 1-propanol T/K ethyl acetate acetone
Caffeine
288.01 1.23 0.78 288.24 1.34 1.17 288.24 2.70 2.79
298.11 1.61 1.32 298.17 1.89 1.77 298.09 3.54 3.63
308.09 2.27 2.04 308.17 2.80 2.82 308.21 4.88 5.28
318.11 2.96 3.22 318.20 4.26 4.53 318.15 6.89 7.28
328.15 3.98 4.69 328.12 6.63 7.16 328.18 9.24 9.53
a
ur (x) = 0.02; u (p) = 5 kPa; u (T) = 0.01 K

temperature range of reaction interval were completed by using literature data11 are 0.63% in acetone and 1.57% in acetonitrile,
the TA Universal Analysis software. respectively. This indicates that this method is accurate and can
Validation of the Measurement Method. To validate the be applied in measuring the solubility of theobromine,
measurement method in this work, the solubility of benzil in theophylline, and caffeine.
acetone and acetonitrile was determined by a HPLC method at T The solubility values of theobromine, theophylline, and
= 298.15 K and atmospheric pressure. caffeine in water, methanol, ethanol, 1-propanol, ethyl acetate,
Identity of the Crystals in the Solid−Liquid Equili- and acetone are reported in Table 2. All presented experimental
brium. To prepare the crystals, theobromine, theophylline, and solubility mole fractions are the average of the replicates from
caffeine were dissolved in different solvents at 328.15 K and then three glass tubes under the same equilibrium conditions. The
the solutions were cooled naturally. The obtained crystals of the relative standard deviations of the results (RSDs) are listed in
solutes in equilibrium with the saturated solution were used to Table S2. As shown in this table, the RSD values are greater at
observe by scanning electron microscopy (SEM) (SU8010, higher temperatures. The comparison of experimental solubility
Hitachi, Japan). The accelerating voltage of SEM is 3.0 kV. Also, data (partial) for theobromine, theophylline, and caffeine in this
powder X-ray diffraction (PXRD) data were recorded on a work and the reported data from the literature4−6,10 is listed in
Rigaku D/MAX 2550/PC for Cu Kα (λ = 1.5406 Å). Table S3−S5 and graphically shown in Figure S1−S3. As shown

■ RESULTS AND DISCUSSION


Solubility Results. The solubility (x1) of solute can be
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
calculated by eq 1: not in agreement with the literature values reported by
Pobudkowska6 and Han,5 respectively. These deviations may
mA /MA be due to differences in purity source of compound,
x1 = determination method, and the crystal forms of the solutes.
mA /MA + mB /MB (1)
Furthermore, the solubility data are plotted in Figure 2. It can
mA and mB refer to the masses of the solute and solvent, be seen that the solubility of theobromine in pure solvents
respectively. MA and MB represent the molecule weights of the follows the order methanol > 1-propanol ≥ ethanol > acetone >
solute and solvent. ethyl acetate. The solubility of theophylline follows the order 1-
The experimental data of the validation measurement are propanol ≥ methanol > ethanol > acetone > ethyl acetate. The
listed in Table S1. To evaluate the reliability of the experimental solubility of caffeine follows the order acetone ≥ ethyl acetate >1-
method in this work, the solubility of benzil was obtained as propanol ≥ methanol > ethanol.
0.159 in water and 0.0645 in acetonitrile at T = 298.15 K and As observed in these Figures, in the whole range of solvents the
atmospheric pressure. The results are obtained from the average solubility values increase with increasing temperature. The
of the three replicates. The relative standard deviations of the comparison of solubility values indicates that the solubility
results (RSDs) are 1.08% and 1.94%, and the deviations with the behavior in water is different from other organic pure solvents.
2572 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data Article

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 Tm/Ka Tlit
m/K ΔfusH/(kJ·mol−1)a Δf uslitH/(kJ·mol−1)
b
theobromine 622.03 57.42b
theophylline 545.18 544.43b 28.92 22.81b
544.0c 30.43c
caffeine 509.07 510.75b 19.44 20.95b
505.4d 17.9d
a
u(Tm) = 0.5 K; ur(ΔfusH) = 0.03; u(p) = 5 kPa. bReference 3. cReference 14. dReference 15.

Also, solubility results show that in organic solvents the solubility replacement of protons on the ring by a methyl group that
of caffeine is higher than theophylline. Table 2 indicates that leads to decreased polarity.
theobromine solubility is fairly low as compared with that of The solubility behavior of the studied samples show that, due
theophylline and caffeine. This can be explained by the existence to the high variation of the solubility in organic pure solvents at
of relatively strong intermolecular bonds and the tendency of different temperatures, these compounds can be recrystallized
molecules to form clusters.12,13 Also we attributed the higher separated and purified using proper organic solvents at certain
solubility of caffeine in ethyl acetate and acetone to the temperatures.
2573 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data Article

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, Theo- theobromine was crystallized in the pipe of the differential
phylline, and Caffeine. The fusion enthalpies and melting scanning calorimeter. Therefore, to protect the differential
temperature of theobromine, theophylline, and caffeine are scanning calorimeter (Q100, TA Corporation) from the
collected in Table 3. Experimental TGA of theobromine and heat sublimating theobromine, the determination of theobromine
flow from DSC measurement of theophylline and caffeine are melting point was not performed.
shown in Figure S4. Figure S4A of the experimental TGA of Theobromine and theophylline are isomers. There are only
theobromine shows that, determination the melting point of different positions of the methyl group in the molecular
theobromine is difficult, because of theobromine starting to structures. However, theobromine has a higher melting point
sublimate in the aluminum sample pan. When the temperature than theophylline. This phenomenon can be attributed to the
was increased to higher than 563.15 K, the sublimating intermolecular hydrogen bonding between the carbonyl groups
2574 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data 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 1-
propanol 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 experimen-
tally 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.

■ CONCLUSIONS
The solubility values of theobromine, theophylline, and caffeine
in water, methanol, ethanol, 1-propanol, ethyl acetate, and Figure 4. PXRD diffraction patterns of crystals in various solvents:
acetone were determined by HPLC at T = (288.15 to 328.15) K theobromine (A), theophylline (B), caffeine (C).
and atmospheric pressure. In all studied solvents, the solubility of
theobromine, theophylline, and caffeine increased with increas- like shapes or needle-shaped particles. Theophylline mono-
ing temperature. The fusion enthalpies and melting temperature hydrate and caffeine hydrate were formed in the solid−liquid
of theobromine, theophylline, and caffeine have been deter- equilibrium. The Apelblat equation and UNIQUAC model were
mined. Crystal habits of theobromine, theophylline, and caffeine used to correlate the experimental solubility data. It was found
in the solid−liquid equilibrium were characterized. The crystal that both models can satisfactorily correlate the solubility data for
forms of solids equilibrated with the saturated solutions are rod- the studied systems.
2575 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data Article

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


*
ASSOCIATED CONTENT
S Supporting Information
the empirical Apelblat equation; theobromine, theophyl-
line, and caffeine solubility line in this work and dashed
The Supporting Information is available free of charge on the line calculated by UNIQUAC equation; approaches of the
ACS Publications website at DOI: 10.1021/acs.jced.7b00065. Apelblat equation and the UNIQUAC model (PDF)


RSDs of experimental solubility data for theobromine,
theophylline and caffeine in different solvents; comparison
of experimental solubility data for theobromine, theophyl- AUTHOR INFORMATION
line, and caffeine in this work and the literature; Corresponding Author
parameters of the Apelblat and UNIQUAC equations; *Tel.: +86-571-87951430. Fax: +86-571-87951895. E-mail:
graphical comparison of solubility values of theobromine yanweidong@zju.edu.cn.
in water and ethanol, theophylline in water, ethanol, ethyl
acetate, and acetone, and caffeine in water, ethanol, ORCID
methanol, and ethyl acetate; experimental TGA measure- Weidong Yan: 0000-0002-5125-310X
ment of theobromine and DSC measurement of theophyl-
Notes
line and caffeine; theobromine, theophylline, and caffeine
solubility line in this work and dashed line calculated by The authors declare no competing financial interest.
2576 DOI: 10.1021/acs.jced.7b00065
J. Chem. Eng. Data 2017, 62, 2570−2577
Journal of Chemical & Engineering Data


Article

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2577 DOI: 10.1021/acs.jced.7b00065


J. Chem. Eng. Data 2017, 62, 2570−2577

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