- Email: [email protected]
Solubility evaluation and thermodynamic modeling of β-lapachone in water and ten organic solvents at different temperatures
Fluid Phase Equilibria 472 (2018) 1e8
Contents lists available at ScienceDirect
Fluid Phase Equilibria j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / fl u i d
Solubility evaluation and thermodynamic modeling of b-lapachone in water and ten organic solvents at different temperatures Ki Hyun Kim, Hee Kyung Oh, Bora Heo, Nam Ah Kim, Dae Gon Lim, Seong Hoon Jeong* College of Pharmacy, Dongguk University-Seoul, Gyeonggi 410-820, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 February 2018 Received in revised form 21 April 2018 Accepted 2 May 2018 Available online 5 May 2018
Although b-lapachone is a promising drug with pharmacological activity, issues concerning its low aqueous solubility are known. The objective of this study was to measure the solubility of b-lapachone in water and ten organic solvents at temperatures ranging from 298.15 K to 318.15 K under atmospheric pressure. The modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model were used to correlate experimentally obtained solubility values. Moreover, thermodynamic analysis of blapachone dissolution was performed based on experimental solubility data using the van't Hoff equation. The highest mole fraction solubility of b-lapachone at 298.15 K was found in acetone (2.05 102), followed by acetonitrile (1.80 102), ethyl acetate (8.53 103), 1-butanol (7.43 103), 1-propanol (6.69 103), 2-butanol (5.65 103), methanol (5.40 103), ethanol (4.99 103), 2-propanol (3.76 103), propylene glycol (3.06 103), and water (2.85 106). Correlation results showed that the modified Apelblat model was more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. Thermodynamic analysis indicated that b-lapachone dissolution was endothermic and entropydriven process in all solvents studied. Data on solubility and thermodynamic properties in various solvents obtained in this study could be helpful in formulation development, purification, and crystallization of b-lapachone. © 2018 Elsevier B.V. All rights reserved.
Keywords: b-Lapachone Solubility Correlation Thermodynamic properties
1. Introduction
b-Lapachone (CAS number: 4707-32-8, Fig. 1), also known as 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione, is a natural naphthoquinone first isolated from the lapacho tree (Tabebuia avellanedae). Its molecular formula and molecular weight are C15H14O3 and 242.27 g mol1, respectively. Due to its promising pharmacological and biological activity against various diseases, blapachone has been used as an anti-cancer [1], anti-inflammatory [2,3], anti-fungal, and anti-bacterial [4] agent. Its cytotoxic effect can be enhanced by NAD(P)H:quinone oxidoreductase 1 (NQO1), a flavoprotein overexpressed in various human cancers [5]. Furthermore, recent studies have shown that b-lapachone promoted collagen synthesis in human dermal fibroblasts (HDFs), suggesting its potential applicability as a cosmeceutical ingredient [6,7]. Despite the high potency of b-lapachone, it is practically insoluble in water, limiting formulation development especially in terms
* Corresponding author. College of Pharmacy, Dongguk University-Seoul, Donggukro 32, Ilsandonggu, Goyang Gyeonggi 410-820, Republic of Korea. E-mail address: [email protected] (S.H. Jeong). https://doi.org/10.1016/j.fluid.2018.05.005 0378-3812/© 2018 Elsevier B.V. All rights reserved.
of solid and liquid dosage forms. Solubility of b-lapachone in water at a temperature of 298.15 K has been reported as 0.038 mg mL1 [8] and measured to be 0.040 mg mL1 in this experiments. Low aqueous solubility has resulted in poor absorption and low oral bioavailability, indicating the need for strategies to enhance solubility of b-lapachone. Therefore, solubility of poorly water-soluble drugs in aqueous and organic solvents are important to study, because most pharmaceutical techniques for improving drug solubility and dissolution rate such as melt granulation, solid dispersion, micro-emulsion, and self micro-emulsifying drug development systems (SMEDDS) use aqueous or organic solvents. Solubility data in various solvents are also necessary in the production process. It is well known that crystallization is a crucial step to determine quality and yield of drugs [9]. Thermodynamic solubility data in various solvents can provide the basis for proper solvent selection and design of an optimized crystallization process. However, no studies have reported solubility of b-lapachone in various solvents. In this study, solubility of b-lapachone in methanol, ethanol, 1propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, propylene glycol, and water was obtained at
2
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
2.3. Solubility measurement
Fig. 1. Chemical structure of b-lapachone.
temperatures ranging from 298.15 K to 318.15 K under atmospheric pressure using the solid-liquid equilibrium method. The modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model were employed to correlate obtained experimental solubility. In addition, apparent thermodynamic properties during the dissolution of b-lapachone including Gibbs free energy change (DGd ), enthalpy change (DHd ), and entropy change (DSd ) were calculated from the solubility data using van't Hoff analysis. 2. Experimental 2.1. Materials
b-lapachone with mass fraction purity >99.9% was purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol, ethanol, and acetonitrile were purchased from Avantor Performance Materials (Center Valley, PA, USA). 1-Propanol, 2-propanol, 2-butanol, and acetone were purchased from Daejung Chemical & Metals Co., Ltd. (Siheung, Korea). 1-Butanol, ethyl acetate, and propylene glycol were purchased from Junsei Chemical Co., Ltd. (Tokyo, Japan). Detailed information about b-lapachone and solvents used is shown in Table 1.
Equilibrium solubility of b-lapachone in water and ten organic solvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2butanol, acetonitrile, acetone, ethyl acetate, and propylene glycol) was measured at temperatures ranging from 298.15 K to 318.15 K using a solid-liquid equilibrium method [10]. Five milliliters of each solvent were added to separate glass vials, and then an excess amount of b-lapachone was added to each vial. The solute-solvent mixtures were vortexed for 10 min, followed by shaking in a water bath (BS-21, Jeiotech Co., Ltd., Daejeon, Korea) at 100 rpm for 24 h. The temperature uncertainty of water bath was 0.1 K. Preliminary studies were performed with shaking times of 6 h, 12 h, 24 h, and 48 h to optimize saturation time. Results indicated that 24 h was optimal to establish solid-liquid equilibrium in the glass vial. After 24 h of shaking, the mixtures were kept static for 2 h at the same temperature to allow undissolved particles to settle. Subsequently, supernatants were filtered using 0.45 mm syringe filters, transferred to volumetric flasks, and weighed. After dilution with methanol, the concentration of b-lapachone was analyzed using a UV spectrophotometer (OPTIZEN POP, Mecasys Co., Ltd., Daejeon, Korea) at 256 nm. The standard calibration curve of b-lapachone was found to be linear in the concentration range of 0.5 mg mL1 to 8 mg mL1 (correlation coefficient ¼ 0.9999). All measurements were performed three times. Mole fraction solubility (xe ) of b-lapachone was calculated using the following equation:
xe ¼
m1 =M1 m1 =M1 þ m2 =M2
(1)
where m1 and m2 represent mass of b-lapachone and solvent, respectively. M1 and M2 represent molar mass of b-lapachone and solvent, respectively.
3. Results and discussion 2.2. Thermal analysis 3.1. Thermal analysis Melting temperature and enthalpy of fusion for b-lapachone were determined using differential scanning calorimetry (DSC) (Q2000, TA Instruments, New Castle, DE, USA). Accurately weighed samples (3 mg) of b-lapachone were sealed in an aluminum DSC pan. A blank pan was employed as a reference. In order to ensure isothermal starting conditions, the pans were kept at 273.15 K for 5 min before initiating analysis. DSC measurements were carried out at a scan rate of 10 K min1 from 273.15 K to 523.15 K under nitrogen flow of 50 mL min1.
DSC thermogram of b-lapachone is shown in Fig. 2. An endothermic peak at 428.99 K was evident, indicating melting temperature (Tm). Intensity and sharpness of the peak indicated the crystalline nature of the drug. The Tm value determined in this experiment was slightly lower than the value reported in the literature (430.45 K) [11], although it was within the range of experimental limits. This might have been due to differences in sample purity, equipment, or experimental conditions. In addition,
Table 1 Properties and sources of materials used in the study.a Solvent
Source
Molar mass (g$mol1)
Mass fraction purity (%)
Analysis method
b-Lapachone
Sigma-Aldrich Avantor Performance Materials Avantor Performance Materials Daejung Chemical & Metals Co., Daejung Chemical & Metals Co., Junsei Chemical Co., Ltd. Daejung Chemical & Metals Co., Avantor Performance Materials Daejung Chemical & Metals Co., Junsei Chemical Co., Ltd. Junsei Chemical Co., Ltd. Lab made
242.27 32.04 46.07 60.10 60.10 74.12 74.12 41.05 58.08 46.07 76.09 18.01
99.9 99.9 99.9 99.5 99.7 99.5 99.5 99.9 99.8 99.5 99.0 Double distilled
HPLCb GCc GC GC GC GC GC GC GC GC GC
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water a b c
Standard uncertainty for mass fraction u is u (c) ¼ ± 0.005. High performance liquid chromatography. Gas chromatography.
Ltd. Ltd. Ltd. Ltd.
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
3
Fig. 2. DSC thermogram of b-lapachone.
we performed integration of the endothermic peak to calculate enthalpy of fusion (DHfus ) (24.52 kJ mol1). The standard uncertainty of Tm was u (Tm) ¼ ± 0.88 K and standard uncertainty of DHfus was u (DHfus ) ¼ ± 0.51 kJ mol1. Based on the enthalpy of fusion, entropy of fusion (DSfus ) for b-lapachone was calculated to be 57.15 J mol-1 K-1 using the following equation:
DSfus ¼
DHfus
(2)
Tm
3.2. Experimental solubility of b-lapachone Experimental mole fraction solubility values (xe Þ of b-lapachone in methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, propylene glycol, and water over the temperature range of 298.15 Ke318.15 K are listed in Table 2, and graphically shown in Fig. 3. Solubility of blapachone in all solvents increased with an increase in temperature. At 298.15 K, mole fraction solubility in these solvents was
in the order of acetone (2.05 102) > acetonitrile 2 (1.80 10 ) > ethyl acetate (8.53 103) > 1-butanol (7.43 103) > 1-propanol (6.69 103) > 2-butanol 3 (5.65 10 ) > methanol (5.40 103) > ethanol (4.99 103) > 2-propanol (3.76 103) > propylene glycol (3.06 103) > water (2.85 106). Mole fraction solubility of blapachone was higher in non-alcoholic solvents such as acetone, acetonitrile, and ethyl acetate compared to that in alcoholic solvents. However, at 308.15 K, solubility in 1-butanol was higher than that in ethyl acetate, and when temperature was increased to 318.15 K, the order of solubility changed to acetone (3.42 102) > acetonitrile (3.25 102) > 1-butanol (2.03 102) > 1-propanol (2.03 102) > ethyl acetate (1.65 102) > 2-butanol (1.62 102) > methanol (1.53 102) > ethanol (1.34 102) > 2-propanol (1.11 102) > propylene glycol (7.24 103) > water 6 (6.12 10 ). The relative standard uncertainty of mole fraction solubility, ur (xe ) was lower than 1.70 102. Based on the results of the study, at 298.15 K, b-lapachone was found to be soluble in acetone, acetonitrile, and ethyl acetate, sparingly soluble in 1-
Table 2 Experimental mole fraction solubility of b-lapachone in water and ten organic solvents at a temperature range of 298.15e318.15 K under a pressure of 0.1 MPa.a Solvent
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
xe T/K ¼ 298.15
T/K ¼ 303.15
T/K ¼ 308.15
T/K ¼ 313.15
T/K ¼ 318.15
5.40 103 4.99 103 6.69 103 3.76 103 7.43 103 5.65 103 1.80 102 2.05 102 8.53 103 3.06 103 2.85 106
6.54 103 5.95 103 7.93 103 4.32 103 8.95 103 6.71 103 2.09 102 2.16 102 9.36 103 3.08 103 3.72 106
7.60 103 6.64 103 9.69 103 5.28 103 1.08 102 7.90 103 2.27 102 2.45 102 1.04 102 3.70 103 4.46 106
1.01 102 9.09 103 1.46 102 7.54 103 1.42 102 1.04 102 2.69 102 2.96 102 1.21 102 5.31 103 5.26 106
1.53 102 1.34 102 2.03 102 1.11 102 2.03 102 1.62 102 3.25 102 3.42 102 1.65 102 7.24 103 6.12 106
a Standard uncertainty of temperature is u (T) ¼ ± 0.1 K; Standard uncertainty of pressure is u (P) ¼ ± 10 kPa; Relative standard uncertainty of the mole fraction solubility is ur (xe ) ¼ ± 1.70 102.
4
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
Fig. 3. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the modified Apelblat model.
butanol, 1-propanol, 2-butanol, methanol, ethanol, and 2propanol, slightly soluble in propylene glycol, and practically insoluble in water following the USP classification of solubility. Results showed that the order of solubility was not in accordance with the order of solvent polarity, which indicated that b-lapachone dissolution was a complex process influenced not only by solvent polarity, but also by other factors including molecular size, solvent molecular structure, space conformation between solvent and solute, and ability to form hydrogen bonds [12,13]. In addition, solubility in 1-butanol and 1-propanol was higher than that in 2-butanol and 2-propanol. This might be attributed to solvent molecular structure. The hydroxyl group in 2-butanol and 2-propanol is located between CH3 groups, which could inhibit interaction between H atoms in solvent and O atoms in blapachone.
3.3. Correlation of experimental solubility with calculated solubility In order to find the appropriate model to describe solubility of blapachone in various solvents, solubility was correlated using three different models including the modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model. The modified Apelblat equation is a semi-empirical equation which has been used extensively in correlating solubility of solutes and temperature [14,15]. The equation is as follows:
lnxe ¼ A þ
B þ C lnðTÞ T
(3)
with
A¼
DHfus RTt
þ
DCp R
ð1 þ ln Tt Þ a
(4)
DCp DHfus B¼ bþ Tt þ RTt R
(5)
DCp
C¼
(6)
R
where xe is mole fraction solubility of b-lapachone, T is experimental absolute temperature, DHfus is melting enthalpy of b-lapachone, DCp is difference in heat capacity of b-lapachone between solid and liquid states, R is the universal gas constant, Tt is the triple point temperature of b-lapachone, and a and b are constant parameters. A, B, and C are model parameters and are presented in Table 3. The parameters A and B represent variation of the activity coefficient in solution and describe the influence of non-ideal solution behavior on solubility, while the parameter C represents the effect of temperature on enthalpy of fusion [16]. The Buchowski-Ksiazaczak lh model proposed by Buchowski is Table 3 Values of model parameters, RAD, and RMSD in the modified Apelblat model for blapachone in water and ten organic solvents. Solvent
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
Modified Apelblat model A
B
C
102 RAD
104 RMSD
2323.35 2476.08 2162.55 2590.45 1734.30 2562.60 689.41 1050.02 1888.84 3059.29 763.48
102014.67 109201.34 94179.02 113906.48 75160.57 112939.60 29057.94 45717.00 83672.08 136082.12 38531.70
346.81 369.37 323.24 386.62 259.29 382.38 103.19 156.70 281.43 455.82 113.56
2.49 2.50 2.21 1.02 1.22 2.38 1.46 1.62 1.93 2.94 0.87
2.23 1.91 3.68 0.79 1.52 2.50 3.68 5.02 2.58 1.65 4.28 104
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
an alternative model used to describe solid-liquid equilibrium behavior of b-lapachone [17], which was applied using the following equation:
DHfus R
1 1 Tm T
(8)
b T
(9)
where xe is mole fraction solubility of b-lapachone and T is the absolute temperature (K). The parameters a and b are model parameters and are listed in Table 5. Parameters in each model were obtained using nonlinear regression analysis of the equations. In addition, relative average deviation (RAD) and root-mean-square deviation (RMSD) were calculated to assess the thermodynamic models. RAD and RMSD are expressed in Eqs. (10) and (11), respectively.
RAD ¼
N 1 X xi xc N xi
(10)
i¼1
RMSD ¼
xc Þ2 N
i¼1 ðxi
104 RMSD
10.71 9.82 12.84 11.55 10.73 10.84 5.07 4.55 5.18 8.39 0.77
4771.47 4531.88 5348.22 5138.35 4676.68 4798.38 2715.51 2530.98 2981.50 4268.03 3566.24
7.16 7.43 6.54 7.88 5.39 8.03 2.59 3.61 6.03 9.34 2.46
8.81 7.93 8.85 5.90 8.50 10.13 7.39 9.33 8.54 4.44 1.10 103
lapachone, respectively. Parameters in each model with RAD and RMSD are shown in Tables 3e5. Based on regressed values of parameters, calculated solubility and experimental solubility obtained using the modified Apelblat model, the BuchowskiKsiazaczak lh model, and the ideal model are shown graphically in Figs. 3 and 4, and Fig. 5, respectively. From results of correlating calculated solubility with experimental solubility, the modified Apelblat model showed the best correlation with the smallest RAD and RMSD values. In the modified Apelblat equation, none of the RAD values exceeded 2.94%, which indicated that the modified Apelblat model was appropriate for correlating solubility data of blapachone at temperatures ranging from 298.15 K to 318.15 K. However, in the Buchowski-Ksiazaczak lh model and the ideal model, results showed good fitting of solubility data in some solvents but not in others. Data in Figs. 3, Fig. 4, and Fig. 5 also showed that the modified Apelblat model was more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. In the ideal model in particular, experimental solubility did not show good fitting at high temperatures (313.15 Ke318.15 K), indicating that blapachone solutions might be non-ideal in this temperature range and therefore result in activity coefficient s 1. Solubility data and correlation equations obtained from this study can be used to design and optimize extraction, crystallization, and purification processes of b-lapachone.
(11) 3.4. Apparent thermodynamic analysis
Table 4 Values of model parameters, RAD, and RMSD in the Buchowski-Ksiazaczak lh model for b-lapachone in water and ten organic solvents.
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
102 RAD
#1 2
where N is number of experimental points, and xi and xc is experimental mole fraction solubility and calculated solubility of b-
Solvent
b
=
"P N
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
a
where xe is mole fraction solubility of b-lapachone, g is activity coefficient of b-lapachone, and DHfus is enthalpy of fusion. However, within a temperature range away from the critical region, activity coefficient of the solute would be less affected by temperature [19]. In a specific temperature range, assuming the solution to be ideal (g ¼ 1), Eq. (8) can be simplified to the ideal solution equation [20].
lnxe ¼ a þ
Ideal model
(7)
where xe is mole fraction solubility of b-lapachone, T is experimental absolute temperature, and Tm is normal melting temperature of b-lapachone in Kelvin. The value of Tm was found to be 428.99 K with thermal analysis. The parameters l and h are model parameters and are listed in Table 4. The ideal model is another universal equation for the solubility equilibrium based on thermodynamic principles. The equation can be expressed as follows [18]:
ln xe g ¼
Table 5 Values of model parameters, RAD, and RMSD in the ideal model for b-lapachone in water and ten organic solvents. Solvent
lð1 xe Þ 1 1 ¼ lh ln 1 þ xe T Tm
5
In order to examine dissolution behavior of b-lapachone in different solvents, apparent thermodynamic analysis was per formed on the basis of solubility data. Enthalpy change (DHd ), Gibbs free energy change (DGd ), and entropy change (DSd ) for dissolution of b-lapachone in each solvent were obtained using van't Hoff analysis, which can be expressed with the following equation [21]:
Buchowski-Ksiazaczak lh model
l
h
102 RAD
104 RMSD
1.31 0.91 2.69 1.34 1.35 1.52 0.24 0.22 0.19 0.38 8.02 105
4229.05 5766.60 2238.40 4432.64 3857.50 3715.02 10767.46 11235.46 16363.97 12988.17 4.05 107
8.91 9.19 6.36 7.94 6.12 9.59 2.75 3.26 6.28 8.80 2.58
7.49 6.79 7.20 4.75 7.27 8.57 6.84 8.67 7.87 3.81 1.06 103
DHd ¼ R
vln xe vð1=TÞ
(12)
where xe is mole fraction solubility, R is the universal gas constant (8.314 J mol-1 K-1), and T is the absolute temperature. Enthalpy change of dissolution (DHd ) can be obtained from the slope of the solubility curve, the so-called van't Hoff plot, where ln xe is plotted against T 1. Over a limited temperature range (20 K in this experiment), change in heat capacity of the solution can be assumed to be constant, and hence DHd would also be valid for the mean temperature. Therefore, Eq. (12) can be expressed as follows:
6
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
Fig. 4. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the Buchowski-Ksiazaczak lh model.
Fig. 5. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the ideal model.
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
7
Fig. 6. Mole fraction solubility of b-lapachone versus temperature (1/T e 1/Tmean) in water and ten organic solvents.
DHd ¼ R
vln xe vð1=T 1=Tmean Þ
(13)
where Tmean is mean temperature of the experimental temperature range (308.15 K). Gibbs free energy change of dissolution can be calculated using the following equation:
DGd ¼ RTmean intercept ¼ DHd Tmean DSd
(14)
where the intercept can be calculated from plots of ln xe against (1/ T e 1/Tmean) (Fig. 6). Finally, entropy change of dissolution (DSd Þ can be obtained using Eq. (15) from Eq. (14)
DSd ¼
DHd DGd
(15)
Tmean
Values of thermodynamic parameters of b-lapachone in water and ten organic solvents are listed in Table 6, along with %xH and %xTS values. The parameters %xH and %xTS represent relative contribution of enthalpy and entropy, respectively, to b-lapachone dissolution, and were calculated using the following equations:
D H 100 %xH ¼ d DH þ T DS
(16)
T DS d 100 ¼ DH þ T DS
(17)
d
%xTS
d
d
d
The DHd values for dissolution of b-lapachone in all solvents were positive (21.04e44.47 kJ mol1), indicating that the dissolution was an endothermic process [22]. The results explain increased solubility of b-lapachone with increase in temperature. High values
Table 6 Thermodynamic parameters of b-lapachone dissolution in water and ten organic solvents at the mean temperature of 308.15 K.a Solvent
DHd (kJ$mol1)
DGd (kJ$mol1)
DSd (J$mol1$K1)
%xH
%xTS
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
39.67 37.68 44.47 42.72 38.88 39.89 22.58 21.04 24.79 35.48 29.65
12.23 12.51 11.56 13.13 11.40 12.13 9.58 9.38 11.53 13.99 31.62
89.06 81.68 106.78 96.04 89.17 90.10 42.18 37.85 43.04 69.76 6.41
59.11 59.95 57.47 59.08 58.59 58.96 63.46 64.34 65.14 62.27 93.75
40.89 40.05 42.53 40.92 41.41 41.04 36.54 35.66 34.86 37.73 6.25
a
Standard uncertainty of temperature is u (T) ¼ ± 0.1 K.
8
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
of DHd indicate strong temperature dependence of solubility [23]. Moreover, positive DHd indicated that energies of newly formed bonds between b-lapachone and solvent molecules were not strong enough to compensate the energy needed for breaking original solute-solute and solvent-solvent intermolecular bonds [24]. As can be seen from the data, DGd values for all solvents were positive 1 (9.38e31.62 kJ mol ), and lower DGd values corresponded to higher solubility. Positive DGd values indicated that dissolution of b-lapachone was non-spontaneous and b-lapachone could be easily recrystallized from the solvents. The DSd values were positive for all solvents except water (37.85e106.78 J mol-1 K-1), indicating entropy-driven dissolution of b-lapachone. Furthermore, the main contributor to DGd during dissolution was enthalpy, because %xH values in all solvents were 57.47. 4. Conclusion In this study, solid-liquid equilibrium solubility of b-lapachone in water and ten organic solvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, and propylene glycol) was measured at temperatures ranging from 298.15 K to 318.15 K. In all solvents, solubility increased with increase in temperature. At 298.15 K, b-lapachone was considered soluble in acetone, acetonitrile, and ethyl acetate, sparingly soluble in 1-butanol, 1-propanol, 2-butanol, methanol, ethanol, and 2propanol, slightly soluble in propylene glycol, and practically insoluble in water. Experimental solubility data was correlated with calculated solubility and the modified Apelblat model was found to be more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. Thermodynamic parameters of dissolution including enthalpy, Gibbs free energy, and entropy were obtained using van't Hoff analysis. Solubility data and thermodynamic properties in various solvents obtained in this study can provide theoretical basis and guidance for formulation development, purification, and crystallization of b-lapachone. Declaration of interest The authors report no conflicts of interest. Acknowledgements This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (NRF-2014M3A9A9073811) and Basic Science Research Program through the National Research Foundation of Korea(NRF), funded by the Ministry of Science, ICT & Future Planning (2015R1A1A1A05000942). References [1] J.H. Lee, J. Cheong, Y.M. Park, Y.H. Choi, Down-regulation of cyclooxygenase-2 and telomerase activity by b-lapachone in human prostate carcinoma cells, Pharmacol. Res. 51 (2005) 553e560. [2] D.-O. Moon, Y.H. Choi, N.-D. Kim, Y.-M. Park, G.-Y. Kim, Anti-inflammatory effects of b-lapachone in lipopolysaccharide-stimulated BV2 microglia, Int.
Immunopharm. 7 (2007) 506e514. [3] S.J. Byun, Y. Son, B.H. Cho, H.-T. Chung, H.-O. Pae, b-Lapachone, a substrate of NAD (P) H: quinone oxidoreductase, induces anti-inflammatory heme oxygenase-1 via AMP-activated protein kinase activation in RAW264. 7 macrophages, J. Clin. Biochem. Nutr. 52 (2013) 106e111. [4] P. Guiraud, R. Steiman, G.-M. Campos-Takaki, F. Seigle-Murandi, M.S. de Buochberg, Comparison of antibacterial and antifungal activities of lapachol and b-lapachone, Planta Med. 60 (1994) 373e374. [5] E. Blanco, E.A. Bey, Y. Dong, B.D. Weinberg, D.M. Sutton, D.A. Boothman, J. Gao, b-Lapachone-containing PEGePLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells, J. Contr. Release 122 (2007) 365e374. [6] K.H. Kim, S.-H. Park, P. Adhikary, J.H. Cho, N.-G. Kang, S.H. Jeong, Stability of blapachone upon exposure to various stress conditions: resultant efficacy and cytotoxicity, Chem. Pharm. Bull. 64 (2016) 381e389. [7] S.-H. Park, S.H. Jeong, S.-W. Kim, b-lapachone regulates the transforming growth factor-besmad signaling pathway associated with collagen biosynthesis in human dermal fibroblasts, Biol. Pharm. Bull. 39 (2016) 524e531. [8] N. Nasongkla, A.F. Wiedmann, A. Bruening, M. Beman, D. Ray, W.G. Bornmann, D.A. Boothman, J. Gao, Enhancement of solubility and bioavailability of blapachone using cyclodextrin inclusion complexes, Pharm. Res. (N. Y.) 20 (2003) 1626e1633. [9] Y. Li, W. Yang, T. Zhang, C. Wang, K. Wang, Y. Hu, Solubility of omeprazole sulfide in different solvents at the range of 280.35e319.65 K, J. Solut. Chem. 42 (2013) 2342e2353. [10] E.-S. Ha, Y.-R. Lee, M.-S. Kim, Solubility of dronedarone hydrochloride in six pure solvents at the range of 298.15 to 323.15 K, J. Mol. Liq. 216 (2016) 360e363. [11] M.S. Cunha-Filho, B. Dacunha-Marinho, J.J. Torres-Labandeira, R. MartínezPacheco, M. Landin, Characterization of b-lapachone and methylated bcyclodextrin solid-state systems, AAPS PharmSciTech 8 (2007) 68e77. [12] S. Zong, J. Wang, Y. Xiao, H. Wu, Y. Zhou, Y. Guo, X. Huang, H. Hao, Solubility and dissolution thermodynamic properties of lansoprazole in pure solvents, J. Mol. Liq. 241 (2017) 399e406. [13] M.-j. Liu, H.-l. Fu, D.-p. Yin, Y.-l. Zhang, C.-c. Lu, H. Cao, J.-y. Zhou, Measurement and correlation of the solubility of enrofloxacin in different solvents from (303.15 to 321.05) K, J. Chem. Eng. Data 59 (2014) 2070e2074. [14] A. Apelblat, E. Manzurola, Solubilities of L-aspartic, DL-aspartic, DL-glutamic, p-hydroxybenzoic, o-anisic, p-anisic, and itaconic acids in water from T ¼ 278 K to T ¼ 345 K, J. Chem. Thermodyn. 29 (1997) 1527e1533. [15] A. Apelblat, E. Manzurola, Solubilities ofo-acetylsalicylic, 4-aminosalicylic, 3, 5-dinitrosalicylic, andp-toluic acid, and magnesium-DL-aspartate in water from T¼(278 to 348) K, J. Chem. Eng. Data 31 (1999) 85e91. [16] C. Cheng, Y. Cong, C. Du, J. Wang, H. Zhao, Thermodynamic modelling for solubility of 4-nitrobenzaldehyde in different solvents at temperature range from (273.15 to 313.15) K and mixing properties of solutions, J. Chem. Thermodyn. 104 (2017) 50e60. [17] H. Buchowski, A. Ksiazczak, S. Pietrzyk, Solvent activity along a saturation line and solubility of hydrogen-bonding solids, J. Phys. Chem. 84 (1980) 975e979. [18] Y. Yang, Y. Hu, Q. Zhang, L. Cheng, C. Cao, W. Yang, F. Shen, Experimental measurement and thermodynamic models for solideliquid equilibrium of hyodeoxycholic acid in different organic solvents, J. Mol. Liq. 202 (2015) 17e22. [19] J.M. Prausnitz, R.N. Lichtenthaler, E.G. de Azevedo, Molecular Thermodynamics of Fluid-phase Equilibria, Pearson Education, London, 1998. [20] E.-S. Ha, D.-H. Kuk, D.-H. Ha, W.-Y. Sim, I.-h. Baek, J.-S. Kim, M.-S. Kim, Determination and correlation of solubility of sarpogrelate hydrochloride in eight solvents at different temperatures, J. Mol. Liq. 237 (2017) 141e145. [21] M.A. Ruidiaz, D.R. Delgado, F. Martínez, Y. Marcus, Solubility and preferential solvation of indomethacin in 1, 4-dioxane þ water solvent mixtures, Fluid Phase Equil. 299 (2010) 259e265. [22] K. Nam, E.-S. Ha, J.-S. Kim, D.-H. Kuk, D.-H. Ha, M.-S. Kim, C.-W. Cho, S.J. Hwang, Solubility of oxcarbazepine in eight solvents within the temperature range T ¼ (288.15e308.15) K, J. Chem. Thermodyn. 104 (2017) 45e49. € der, L.M. Santos, I.M. Marrucho, J.A. Coutinho, Prediction of aqueous [23] B. Schro solubilities of solid carboxylic acids with COSMO-RS, Fluid Phase Equil. 289 (2010) 140e147. [24] L. Ding, B. Wang, F. Wang, J. Dong, G. Zhou, H. Li, Measurement and correlation of the solubility of dipyrone in ten mono and water þ ethanol mixed solvents at temperatures from (293.15 to 332.85) K, J. Mol. Liq. 241 (2017) 742e750.
Contents lists available at ScienceDirect
Fluid Phase Equilibria j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / fl u i d
Solubility evaluation and thermodynamic modeling of b-lapachone in water and ten organic solvents at different temperatures Ki Hyun Kim, Hee Kyung Oh, Bora Heo, Nam Ah Kim, Dae Gon Lim, Seong Hoon Jeong* College of Pharmacy, Dongguk University-Seoul, Gyeonggi 410-820, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 19 February 2018 Received in revised form 21 April 2018 Accepted 2 May 2018 Available online 5 May 2018
Although b-lapachone is a promising drug with pharmacological activity, issues concerning its low aqueous solubility are known. The objective of this study was to measure the solubility of b-lapachone in water and ten organic solvents at temperatures ranging from 298.15 K to 318.15 K under atmospheric pressure. The modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model were used to correlate experimentally obtained solubility values. Moreover, thermodynamic analysis of blapachone dissolution was performed based on experimental solubility data using the van't Hoff equation. The highest mole fraction solubility of b-lapachone at 298.15 K was found in acetone (2.05 102), followed by acetonitrile (1.80 102), ethyl acetate (8.53 103), 1-butanol (7.43 103), 1-propanol (6.69 103), 2-butanol (5.65 103), methanol (5.40 103), ethanol (4.99 103), 2-propanol (3.76 103), propylene glycol (3.06 103), and water (2.85 106). Correlation results showed that the modified Apelblat model was more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. Thermodynamic analysis indicated that b-lapachone dissolution was endothermic and entropydriven process in all solvents studied. Data on solubility and thermodynamic properties in various solvents obtained in this study could be helpful in formulation development, purification, and crystallization of b-lapachone. © 2018 Elsevier B.V. All rights reserved.
Keywords: b-Lapachone Solubility Correlation Thermodynamic properties
1. Introduction
b-Lapachone (CAS number: 4707-32-8, Fig. 1), also known as 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione, is a natural naphthoquinone first isolated from the lapacho tree (Tabebuia avellanedae). Its molecular formula and molecular weight are C15H14O3 and 242.27 g mol1, respectively. Due to its promising pharmacological and biological activity against various diseases, blapachone has been used as an anti-cancer [1], anti-inflammatory [2,3], anti-fungal, and anti-bacterial [4] agent. Its cytotoxic effect can be enhanced by NAD(P)H:quinone oxidoreductase 1 (NQO1), a flavoprotein overexpressed in various human cancers [5]. Furthermore, recent studies have shown that b-lapachone promoted collagen synthesis in human dermal fibroblasts (HDFs), suggesting its potential applicability as a cosmeceutical ingredient [6,7]. Despite the high potency of b-lapachone, it is practically insoluble in water, limiting formulation development especially in terms
* Corresponding author. College of Pharmacy, Dongguk University-Seoul, Donggukro 32, Ilsandonggu, Goyang Gyeonggi 410-820, Republic of Korea. E-mail address: [email protected] (S.H. Jeong). https://doi.org/10.1016/j.fluid.2018.05.005 0378-3812/© 2018 Elsevier B.V. All rights reserved.
of solid and liquid dosage forms. Solubility of b-lapachone in water at a temperature of 298.15 K has been reported as 0.038 mg mL1 [8] and measured to be 0.040 mg mL1 in this experiments. Low aqueous solubility has resulted in poor absorption and low oral bioavailability, indicating the need for strategies to enhance solubility of b-lapachone. Therefore, solubility of poorly water-soluble drugs in aqueous and organic solvents are important to study, because most pharmaceutical techniques for improving drug solubility and dissolution rate such as melt granulation, solid dispersion, micro-emulsion, and self micro-emulsifying drug development systems (SMEDDS) use aqueous or organic solvents. Solubility data in various solvents are also necessary in the production process. It is well known that crystallization is a crucial step to determine quality and yield of drugs [9]. Thermodynamic solubility data in various solvents can provide the basis for proper solvent selection and design of an optimized crystallization process. However, no studies have reported solubility of b-lapachone in various solvents. In this study, solubility of b-lapachone in methanol, ethanol, 1propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, propylene glycol, and water was obtained at
2
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
2.3. Solubility measurement
Fig. 1. Chemical structure of b-lapachone.
temperatures ranging from 298.15 K to 318.15 K under atmospheric pressure using the solid-liquid equilibrium method. The modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model were employed to correlate obtained experimental solubility. In addition, apparent thermodynamic properties during the dissolution of b-lapachone including Gibbs free energy change (DGd ), enthalpy change (DHd ), and entropy change (DSd ) were calculated from the solubility data using van't Hoff analysis. 2. Experimental 2.1. Materials
b-lapachone with mass fraction purity >99.9% was purchased from Sigma-Aldrich (St. Louis, MO, USA). Methanol, ethanol, and acetonitrile were purchased from Avantor Performance Materials (Center Valley, PA, USA). 1-Propanol, 2-propanol, 2-butanol, and acetone were purchased from Daejung Chemical & Metals Co., Ltd. (Siheung, Korea). 1-Butanol, ethyl acetate, and propylene glycol were purchased from Junsei Chemical Co., Ltd. (Tokyo, Japan). Detailed information about b-lapachone and solvents used is shown in Table 1.
Equilibrium solubility of b-lapachone in water and ten organic solvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2butanol, acetonitrile, acetone, ethyl acetate, and propylene glycol) was measured at temperatures ranging from 298.15 K to 318.15 K using a solid-liquid equilibrium method [10]. Five milliliters of each solvent were added to separate glass vials, and then an excess amount of b-lapachone was added to each vial. The solute-solvent mixtures were vortexed for 10 min, followed by shaking in a water bath (BS-21, Jeiotech Co., Ltd., Daejeon, Korea) at 100 rpm for 24 h. The temperature uncertainty of water bath was 0.1 K. Preliminary studies were performed with shaking times of 6 h, 12 h, 24 h, and 48 h to optimize saturation time. Results indicated that 24 h was optimal to establish solid-liquid equilibrium in the glass vial. After 24 h of shaking, the mixtures were kept static for 2 h at the same temperature to allow undissolved particles to settle. Subsequently, supernatants were filtered using 0.45 mm syringe filters, transferred to volumetric flasks, and weighed. After dilution with methanol, the concentration of b-lapachone was analyzed using a UV spectrophotometer (OPTIZEN POP, Mecasys Co., Ltd., Daejeon, Korea) at 256 nm. The standard calibration curve of b-lapachone was found to be linear in the concentration range of 0.5 mg mL1 to 8 mg mL1 (correlation coefficient ¼ 0.9999). All measurements were performed three times. Mole fraction solubility (xe ) of b-lapachone was calculated using the following equation:
xe ¼
m1 =M1 m1 =M1 þ m2 =M2
(1)
where m1 and m2 represent mass of b-lapachone and solvent, respectively. M1 and M2 represent molar mass of b-lapachone and solvent, respectively.
3. Results and discussion 2.2. Thermal analysis 3.1. Thermal analysis Melting temperature and enthalpy of fusion for b-lapachone were determined using differential scanning calorimetry (DSC) (Q2000, TA Instruments, New Castle, DE, USA). Accurately weighed samples (3 mg) of b-lapachone were sealed in an aluminum DSC pan. A blank pan was employed as a reference. In order to ensure isothermal starting conditions, the pans were kept at 273.15 K for 5 min before initiating analysis. DSC measurements were carried out at a scan rate of 10 K min1 from 273.15 K to 523.15 K under nitrogen flow of 50 mL min1.
DSC thermogram of b-lapachone is shown in Fig. 2. An endothermic peak at 428.99 K was evident, indicating melting temperature (Tm). Intensity and sharpness of the peak indicated the crystalline nature of the drug. The Tm value determined in this experiment was slightly lower than the value reported in the literature (430.45 K) [11], although it was within the range of experimental limits. This might have been due to differences in sample purity, equipment, or experimental conditions. In addition,
Table 1 Properties and sources of materials used in the study.a Solvent
Source
Molar mass (g$mol1)
Mass fraction purity (%)
Analysis method
b-Lapachone
Sigma-Aldrich Avantor Performance Materials Avantor Performance Materials Daejung Chemical & Metals Co., Daejung Chemical & Metals Co., Junsei Chemical Co., Ltd. Daejung Chemical & Metals Co., Avantor Performance Materials Daejung Chemical & Metals Co., Junsei Chemical Co., Ltd. Junsei Chemical Co., Ltd. Lab made
242.27 32.04 46.07 60.10 60.10 74.12 74.12 41.05 58.08 46.07 76.09 18.01
99.9 99.9 99.9 99.5 99.7 99.5 99.5 99.9 99.8 99.5 99.0 Double distilled
HPLCb GCc GC GC GC GC GC GC GC GC GC
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water a b c
Standard uncertainty for mass fraction u is u (c) ¼ ± 0.005. High performance liquid chromatography. Gas chromatography.
Ltd. Ltd. Ltd. Ltd.
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
3
Fig. 2. DSC thermogram of b-lapachone.
we performed integration of the endothermic peak to calculate enthalpy of fusion (DHfus ) (24.52 kJ mol1). The standard uncertainty of Tm was u (Tm) ¼ ± 0.88 K and standard uncertainty of DHfus was u (DHfus ) ¼ ± 0.51 kJ mol1. Based on the enthalpy of fusion, entropy of fusion (DSfus ) for b-lapachone was calculated to be 57.15 J mol-1 K-1 using the following equation:
DSfus ¼
DHfus
(2)
Tm
3.2. Experimental solubility of b-lapachone Experimental mole fraction solubility values (xe Þ of b-lapachone in methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, propylene glycol, and water over the temperature range of 298.15 Ke318.15 K are listed in Table 2, and graphically shown in Fig. 3. Solubility of blapachone in all solvents increased with an increase in temperature. At 298.15 K, mole fraction solubility in these solvents was
in the order of acetone (2.05 102) > acetonitrile 2 (1.80 10 ) > ethyl acetate (8.53 103) > 1-butanol (7.43 103) > 1-propanol (6.69 103) > 2-butanol 3 (5.65 10 ) > methanol (5.40 103) > ethanol (4.99 103) > 2-propanol (3.76 103) > propylene glycol (3.06 103) > water (2.85 106). Mole fraction solubility of blapachone was higher in non-alcoholic solvents such as acetone, acetonitrile, and ethyl acetate compared to that in alcoholic solvents. However, at 308.15 K, solubility in 1-butanol was higher than that in ethyl acetate, and when temperature was increased to 318.15 K, the order of solubility changed to acetone (3.42 102) > acetonitrile (3.25 102) > 1-butanol (2.03 102) > 1-propanol (2.03 102) > ethyl acetate (1.65 102) > 2-butanol (1.62 102) > methanol (1.53 102) > ethanol (1.34 102) > 2-propanol (1.11 102) > propylene glycol (7.24 103) > water 6 (6.12 10 ). The relative standard uncertainty of mole fraction solubility, ur (xe ) was lower than 1.70 102. Based on the results of the study, at 298.15 K, b-lapachone was found to be soluble in acetone, acetonitrile, and ethyl acetate, sparingly soluble in 1-
Table 2 Experimental mole fraction solubility of b-lapachone in water and ten organic solvents at a temperature range of 298.15e318.15 K under a pressure of 0.1 MPa.a Solvent
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
xe T/K ¼ 298.15
T/K ¼ 303.15
T/K ¼ 308.15
T/K ¼ 313.15
T/K ¼ 318.15
5.40 103 4.99 103 6.69 103 3.76 103 7.43 103 5.65 103 1.80 102 2.05 102 8.53 103 3.06 103 2.85 106
6.54 103 5.95 103 7.93 103 4.32 103 8.95 103 6.71 103 2.09 102 2.16 102 9.36 103 3.08 103 3.72 106
7.60 103 6.64 103 9.69 103 5.28 103 1.08 102 7.90 103 2.27 102 2.45 102 1.04 102 3.70 103 4.46 106
1.01 102 9.09 103 1.46 102 7.54 103 1.42 102 1.04 102 2.69 102 2.96 102 1.21 102 5.31 103 5.26 106
1.53 102 1.34 102 2.03 102 1.11 102 2.03 102 1.62 102 3.25 102 3.42 102 1.65 102 7.24 103 6.12 106
a Standard uncertainty of temperature is u (T) ¼ ± 0.1 K; Standard uncertainty of pressure is u (P) ¼ ± 10 kPa; Relative standard uncertainty of the mole fraction solubility is ur (xe ) ¼ ± 1.70 102.
4
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
Fig. 3. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the modified Apelblat model.
butanol, 1-propanol, 2-butanol, methanol, ethanol, and 2propanol, slightly soluble in propylene glycol, and practically insoluble in water following the USP classification of solubility. Results showed that the order of solubility was not in accordance with the order of solvent polarity, which indicated that b-lapachone dissolution was a complex process influenced not only by solvent polarity, but also by other factors including molecular size, solvent molecular structure, space conformation between solvent and solute, and ability to form hydrogen bonds [12,13]. In addition, solubility in 1-butanol and 1-propanol was higher than that in 2-butanol and 2-propanol. This might be attributed to solvent molecular structure. The hydroxyl group in 2-butanol and 2-propanol is located between CH3 groups, which could inhibit interaction between H atoms in solvent and O atoms in blapachone.
3.3. Correlation of experimental solubility with calculated solubility In order to find the appropriate model to describe solubility of blapachone in various solvents, solubility was correlated using three different models including the modified Apelblat model, the Buchowski-Ksiazaczak lh model, and the ideal model. The modified Apelblat equation is a semi-empirical equation which has been used extensively in correlating solubility of solutes and temperature [14,15]. The equation is as follows:
lnxe ¼ A þ
B þ C lnðTÞ T
(3)
with
A¼
DHfus RTt
þ
DCp R
ð1 þ ln Tt Þ a
(4)
DCp DHfus B¼ bþ Tt þ RTt R
(5)
DCp
C¼
(6)
R
where xe is mole fraction solubility of b-lapachone, T is experimental absolute temperature, DHfus is melting enthalpy of b-lapachone, DCp is difference in heat capacity of b-lapachone between solid and liquid states, R is the universal gas constant, Tt is the triple point temperature of b-lapachone, and a and b are constant parameters. A, B, and C are model parameters and are presented in Table 3. The parameters A and B represent variation of the activity coefficient in solution and describe the influence of non-ideal solution behavior on solubility, while the parameter C represents the effect of temperature on enthalpy of fusion [16]. The Buchowski-Ksiazaczak lh model proposed by Buchowski is Table 3 Values of model parameters, RAD, and RMSD in the modified Apelblat model for blapachone in water and ten organic solvents. Solvent
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
Modified Apelblat model A
B
C
102 RAD
104 RMSD
2323.35 2476.08 2162.55 2590.45 1734.30 2562.60 689.41 1050.02 1888.84 3059.29 763.48
102014.67 109201.34 94179.02 113906.48 75160.57 112939.60 29057.94 45717.00 83672.08 136082.12 38531.70
346.81 369.37 323.24 386.62 259.29 382.38 103.19 156.70 281.43 455.82 113.56
2.49 2.50 2.21 1.02 1.22 2.38 1.46 1.62 1.93 2.94 0.87
2.23 1.91 3.68 0.79 1.52 2.50 3.68 5.02 2.58 1.65 4.28 104
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
an alternative model used to describe solid-liquid equilibrium behavior of b-lapachone [17], which was applied using the following equation:
DHfus R
1 1 Tm T
(8)
b T
(9)
where xe is mole fraction solubility of b-lapachone and T is the absolute temperature (K). The parameters a and b are model parameters and are listed in Table 5. Parameters in each model were obtained using nonlinear regression analysis of the equations. In addition, relative average deviation (RAD) and root-mean-square deviation (RMSD) were calculated to assess the thermodynamic models. RAD and RMSD are expressed in Eqs. (10) and (11), respectively.
RAD ¼
N 1 X xi xc N xi
(10)
i¼1
RMSD ¼
xc Þ2 N
i¼1 ðxi
104 RMSD
10.71 9.82 12.84 11.55 10.73 10.84 5.07 4.55 5.18 8.39 0.77
4771.47 4531.88 5348.22 5138.35 4676.68 4798.38 2715.51 2530.98 2981.50 4268.03 3566.24
7.16 7.43 6.54 7.88 5.39 8.03 2.59 3.61 6.03 9.34 2.46
8.81 7.93 8.85 5.90 8.50 10.13 7.39 9.33 8.54 4.44 1.10 103
lapachone, respectively. Parameters in each model with RAD and RMSD are shown in Tables 3e5. Based on regressed values of parameters, calculated solubility and experimental solubility obtained using the modified Apelblat model, the BuchowskiKsiazaczak lh model, and the ideal model are shown graphically in Figs. 3 and 4, and Fig. 5, respectively. From results of correlating calculated solubility with experimental solubility, the modified Apelblat model showed the best correlation with the smallest RAD and RMSD values. In the modified Apelblat equation, none of the RAD values exceeded 2.94%, which indicated that the modified Apelblat model was appropriate for correlating solubility data of blapachone at temperatures ranging from 298.15 K to 318.15 K. However, in the Buchowski-Ksiazaczak lh model and the ideal model, results showed good fitting of solubility data in some solvents but not in others. Data in Figs. 3, Fig. 4, and Fig. 5 also showed that the modified Apelblat model was more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. In the ideal model in particular, experimental solubility did not show good fitting at high temperatures (313.15 Ke318.15 K), indicating that blapachone solutions might be non-ideal in this temperature range and therefore result in activity coefficient s 1. Solubility data and correlation equations obtained from this study can be used to design and optimize extraction, crystallization, and purification processes of b-lapachone.
(11) 3.4. Apparent thermodynamic analysis
Table 4 Values of model parameters, RAD, and RMSD in the Buchowski-Ksiazaczak lh model for b-lapachone in water and ten organic solvents.
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
102 RAD
#1 2
where N is number of experimental points, and xi and xc is experimental mole fraction solubility and calculated solubility of b-
Solvent
b
=
"P N
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
a
where xe is mole fraction solubility of b-lapachone, g is activity coefficient of b-lapachone, and DHfus is enthalpy of fusion. However, within a temperature range away from the critical region, activity coefficient of the solute would be less affected by temperature [19]. In a specific temperature range, assuming the solution to be ideal (g ¼ 1), Eq. (8) can be simplified to the ideal solution equation [20].
lnxe ¼ a þ
Ideal model
(7)
where xe is mole fraction solubility of b-lapachone, T is experimental absolute temperature, and Tm is normal melting temperature of b-lapachone in Kelvin. The value of Tm was found to be 428.99 K with thermal analysis. The parameters l and h are model parameters and are listed in Table 4. The ideal model is another universal equation for the solubility equilibrium based on thermodynamic principles. The equation can be expressed as follows [18]:
ln xe g ¼
Table 5 Values of model parameters, RAD, and RMSD in the ideal model for b-lapachone in water and ten organic solvents. Solvent
lð1 xe Þ 1 1 ¼ lh ln 1 þ xe T Tm
5
In order to examine dissolution behavior of b-lapachone in different solvents, apparent thermodynamic analysis was per formed on the basis of solubility data. Enthalpy change (DHd ), Gibbs free energy change (DGd ), and entropy change (DSd ) for dissolution of b-lapachone in each solvent were obtained using van't Hoff analysis, which can be expressed with the following equation [21]:
Buchowski-Ksiazaczak lh model
l
h
102 RAD
104 RMSD
1.31 0.91 2.69 1.34 1.35 1.52 0.24 0.22 0.19 0.38 8.02 105
4229.05 5766.60 2238.40 4432.64 3857.50 3715.02 10767.46 11235.46 16363.97 12988.17 4.05 107
8.91 9.19 6.36 7.94 6.12 9.59 2.75 3.26 6.28 8.80 2.58
7.49 6.79 7.20 4.75 7.27 8.57 6.84 8.67 7.87 3.81 1.06 103
DHd ¼ R
vln xe vð1=TÞ
(12)
where xe is mole fraction solubility, R is the universal gas constant (8.314 J mol-1 K-1), and T is the absolute temperature. Enthalpy change of dissolution (DHd ) can be obtained from the slope of the solubility curve, the so-called van't Hoff plot, where ln xe is plotted against T 1. Over a limited temperature range (20 K in this experiment), change in heat capacity of the solution can be assumed to be constant, and hence DHd would also be valid for the mean temperature. Therefore, Eq. (12) can be expressed as follows:
6
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
Fig. 4. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the Buchowski-Ksiazaczak lh model.
Fig. 5. Mole fraction solubility of b-lapachone at different temperatures in water and ten organic solvents. Dashed lines indicate calculated solubility in each solvent based on the ideal model.
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
7
Fig. 6. Mole fraction solubility of b-lapachone versus temperature (1/T e 1/Tmean) in water and ten organic solvents.
DHd ¼ R
vln xe vð1=T 1=Tmean Þ
(13)
where Tmean is mean temperature of the experimental temperature range (308.15 K). Gibbs free energy change of dissolution can be calculated using the following equation:
DGd ¼ RTmean intercept ¼ DHd Tmean DSd
(14)
where the intercept can be calculated from plots of ln xe against (1/ T e 1/Tmean) (Fig. 6). Finally, entropy change of dissolution (DSd Þ can be obtained using Eq. (15) from Eq. (14)
DSd ¼
DHd DGd
(15)
Tmean
Values of thermodynamic parameters of b-lapachone in water and ten organic solvents are listed in Table 6, along with %xH and %xTS values. The parameters %xH and %xTS represent relative contribution of enthalpy and entropy, respectively, to b-lapachone dissolution, and were calculated using the following equations:
D H 100 %xH ¼ d DH þ T DS
(16)
T DS d 100 ¼ DH þ T DS
(17)
d
%xTS
d
d
d
The DHd values for dissolution of b-lapachone in all solvents were positive (21.04e44.47 kJ mol1), indicating that the dissolution was an endothermic process [22]. The results explain increased solubility of b-lapachone with increase in temperature. High values
Table 6 Thermodynamic parameters of b-lapachone dissolution in water and ten organic solvents at the mean temperature of 308.15 K.a Solvent
DHd (kJ$mol1)
DGd (kJ$mol1)
DSd (J$mol1$K1)
%xH
%xTS
Methanol Ethanol 1-Propanol 2-Propanol 1-Butanol 2-Butanol Acetonitrile Acetone Ethyl acetate Propylene glycol Water
39.67 37.68 44.47 42.72 38.88 39.89 22.58 21.04 24.79 35.48 29.65
12.23 12.51 11.56 13.13 11.40 12.13 9.58 9.38 11.53 13.99 31.62
89.06 81.68 106.78 96.04 89.17 90.10 42.18 37.85 43.04 69.76 6.41
59.11 59.95 57.47 59.08 58.59 58.96 63.46 64.34 65.14 62.27 93.75
40.89 40.05 42.53 40.92 41.41 41.04 36.54 35.66 34.86 37.73 6.25
a
Standard uncertainty of temperature is u (T) ¼ ± 0.1 K.
8
K.H. Kim et al. / Fluid Phase Equilibria 472 (2018) 1e8
of DHd indicate strong temperature dependence of solubility [23]. Moreover, positive DHd indicated that energies of newly formed bonds between b-lapachone and solvent molecules were not strong enough to compensate the energy needed for breaking original solute-solute and solvent-solvent intermolecular bonds [24]. As can be seen from the data, DGd values for all solvents were positive 1 (9.38e31.62 kJ mol ), and lower DGd values corresponded to higher solubility. Positive DGd values indicated that dissolution of b-lapachone was non-spontaneous and b-lapachone could be easily recrystallized from the solvents. The DSd values were positive for all solvents except water (37.85e106.78 J mol-1 K-1), indicating entropy-driven dissolution of b-lapachone. Furthermore, the main contributor to DGd during dissolution was enthalpy, because %xH values in all solvents were 57.47. 4. Conclusion In this study, solid-liquid equilibrium solubility of b-lapachone in water and ten organic solvents (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, acetonitrile, acetone, ethyl acetate, and propylene glycol) was measured at temperatures ranging from 298.15 K to 318.15 K. In all solvents, solubility increased with increase in temperature. At 298.15 K, b-lapachone was considered soluble in acetone, acetonitrile, and ethyl acetate, sparingly soluble in 1-butanol, 1-propanol, 2-butanol, methanol, ethanol, and 2propanol, slightly soluble in propylene glycol, and practically insoluble in water. Experimental solubility data was correlated with calculated solubility and the modified Apelblat model was found to be more accurate than the Buchowski-Ksiazaczak lh model and the ideal model. Thermodynamic parameters of dissolution including enthalpy, Gibbs free energy, and entropy were obtained using van't Hoff analysis. Solubility data and thermodynamic properties in various solvents obtained in this study can provide theoretical basis and guidance for formulation development, purification, and crystallization of b-lapachone. Declaration of interest The authors report no conflicts of interest. Acknowledgements This research was supported by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (NRF-2014M3A9A9073811) and Basic Science Research Program through the National Research Foundation of Korea(NRF), funded by the Ministry of Science, ICT & Future Planning (2015R1A1A1A05000942). References [1] J.H. Lee, J. Cheong, Y.M. Park, Y.H. Choi, Down-regulation of cyclooxygenase-2 and telomerase activity by b-lapachone in human prostate carcinoma cells, Pharmacol. Res. 51 (2005) 553e560. [2] D.-O. Moon, Y.H. Choi, N.-D. Kim, Y.-M. Park, G.-Y. Kim, Anti-inflammatory effects of b-lapachone in lipopolysaccharide-stimulated BV2 microglia, Int.
Immunopharm. 7 (2007) 506e514. [3] S.J. Byun, Y. Son, B.H. Cho, H.-T. Chung, H.-O. Pae, b-Lapachone, a substrate of NAD (P) H: quinone oxidoreductase, induces anti-inflammatory heme oxygenase-1 via AMP-activated protein kinase activation in RAW264. 7 macrophages, J. Clin. Biochem. Nutr. 52 (2013) 106e111. [4] P. Guiraud, R. Steiman, G.-M. Campos-Takaki, F. Seigle-Murandi, M.S. de Buochberg, Comparison of antibacterial and antifungal activities of lapachol and b-lapachone, Planta Med. 60 (1994) 373e374. [5] E. Blanco, E.A. Bey, Y. Dong, B.D. Weinberg, D.M. Sutton, D.A. Boothman, J. Gao, b-Lapachone-containing PEGePLA polymer micelles as novel nanotherapeutics against NQO1-overexpressing tumor cells, J. Contr. Release 122 (2007) 365e374. [6] K.H. Kim, S.-H. Park, P. Adhikary, J.H. Cho, N.-G. Kang, S.H. Jeong, Stability of blapachone upon exposure to various stress conditions: resultant efficacy and cytotoxicity, Chem. Pharm. Bull. 64 (2016) 381e389. [7] S.-H. Park, S.H. Jeong, S.-W. Kim, b-lapachone regulates the transforming growth factor-besmad signaling pathway associated with collagen biosynthesis in human dermal fibroblasts, Biol. Pharm. Bull. 39 (2016) 524e531. [8] N. Nasongkla, A.F. Wiedmann, A. Bruening, M. Beman, D. Ray, W.G. Bornmann, D.A. Boothman, J. Gao, Enhancement of solubility and bioavailability of blapachone using cyclodextrin inclusion complexes, Pharm. Res. (N. Y.) 20 (2003) 1626e1633. [9] Y. Li, W. Yang, T. Zhang, C. Wang, K. Wang, Y. Hu, Solubility of omeprazole sulfide in different solvents at the range of 280.35e319.65 K, J. Solut. Chem. 42 (2013) 2342e2353. [10] E.-S. Ha, Y.-R. Lee, M.-S. Kim, Solubility of dronedarone hydrochloride in six pure solvents at the range of 298.15 to 323.15 K, J. Mol. Liq. 216 (2016) 360e363. [11] M.S. Cunha-Filho, B. Dacunha-Marinho, J.J. Torres-Labandeira, R. MartínezPacheco, M. Landin, Characterization of b-lapachone and methylated bcyclodextrin solid-state systems, AAPS PharmSciTech 8 (2007) 68e77. [12] S. Zong, J. Wang, Y. Xiao, H. Wu, Y. Zhou, Y. Guo, X. Huang, H. Hao, Solubility and dissolution thermodynamic properties of lansoprazole in pure solvents, J. Mol. Liq. 241 (2017) 399e406. [13] M.-j. Liu, H.-l. Fu, D.-p. Yin, Y.-l. Zhang, C.-c. Lu, H. Cao, J.-y. Zhou, Measurement and correlation of the solubility of enrofloxacin in different solvents from (303.15 to 321.05) K, J. Chem. Eng. Data 59 (2014) 2070e2074. [14] A. Apelblat, E. Manzurola, Solubilities of L-aspartic, DL-aspartic, DL-glutamic, p-hydroxybenzoic, o-anisic, p-anisic, and itaconic acids in water from T ¼ 278 K to T ¼ 345 K, J. Chem. Thermodyn. 29 (1997) 1527e1533. [15] A. Apelblat, E. Manzurola, Solubilities ofo-acetylsalicylic, 4-aminosalicylic, 3, 5-dinitrosalicylic, andp-toluic acid, and magnesium-DL-aspartate in water from T¼(278 to 348) K, J. Chem. Eng. Data 31 (1999) 85e91. [16] C. Cheng, Y. Cong, C. Du, J. Wang, H. Zhao, Thermodynamic modelling for solubility of 4-nitrobenzaldehyde in different solvents at temperature range from (273.15 to 313.15) K and mixing properties of solutions, J. Chem. Thermodyn. 104 (2017) 50e60. [17] H. Buchowski, A. Ksiazczak, S. Pietrzyk, Solvent activity along a saturation line and solubility of hydrogen-bonding solids, J. Phys. Chem. 84 (1980) 975e979. [18] Y. Yang, Y. Hu, Q. Zhang, L. Cheng, C. Cao, W. Yang, F. Shen, Experimental measurement and thermodynamic models for solideliquid equilibrium of hyodeoxycholic acid in different organic solvents, J. Mol. Liq. 202 (2015) 17e22. [19] J.M. Prausnitz, R.N. Lichtenthaler, E.G. de Azevedo, Molecular Thermodynamics of Fluid-phase Equilibria, Pearson Education, London, 1998. [20] E.-S. Ha, D.-H. Kuk, D.-H. Ha, W.-Y. Sim, I.-h. Baek, J.-S. Kim, M.-S. Kim, Determination and correlation of solubility of sarpogrelate hydrochloride in eight solvents at different temperatures, J. Mol. Liq. 237 (2017) 141e145. [21] M.A. Ruidiaz, D.R. Delgado, F. Martínez, Y. Marcus, Solubility and preferential solvation of indomethacin in 1, 4-dioxane þ water solvent mixtures, Fluid Phase Equil. 299 (2010) 259e265. [22] K. Nam, E.-S. Ha, J.-S. Kim, D.-H. Kuk, D.-H. Ha, M.-S. Kim, C.-W. Cho, S.J. Hwang, Solubility of oxcarbazepine in eight solvents within the temperature range T ¼ (288.15e308.15) K, J. Chem. Thermodyn. 104 (2017) 45e49. € der, L.M. Santos, I.M. Marrucho, J.A. Coutinho, Prediction of aqueous [23] B. Schro solubilities of solid carboxylic acids with COSMO-RS, Fluid Phase Equil. 289 (2010) 140e147. [24] L. Ding, B. Wang, F. Wang, J. Dong, G. Zhou, H. Li, Measurement and correlation of the solubility of dipyrone in ten mono and water þ ethanol mixed solvents at temperatures from (293.15 to 332.85) K, J. Mol. Liq. 241 (2017) 742e750.