Fluid Phase Equilibria 357 (2013) 43–49

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Fluid Phase Equilibria

journal homepage: www.elsevier.com/locate/fluid

Measurement and correlation of solubilities of the poorly

water-soluble pharmaceutical compound etodolac by addition of
co-solvents
Yuma Naito a , Hiroyuki Matsuda a,∗ , Kazuya Shimomura a , Kiyofumi Kurihara a ,
Katsumi Tochigi a , Kazuo Tomono b
a
Department of Materials and Applied Chemistry, Nihon University, 1-8 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan
b
College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan

a r t i c l e i n f o a b s t r a c t

Article history: The purpose of this study is to measure the solubilities of poorly water-soluble drugs, and to enhance
Received 2 November 2012 their solubilities by adding co-solvents. Etodolac, a cyclooxygenase-2 (cox-2) inhibitor in non-steroid
Received in revised form 15 February 2013 anti-inflammatory drugs (NSAIDs), was selected as a model pharmaceutical compound. The solubili-
Accepted 27 May 2013
ties of etodolac were determined at 298.15 K in mixtures of water and the following six cyclodextrins
Available online 5 June 2013
(CDs) using high-performance liquid chromatography: ␣-CD, ␤-CD, ␥-CD, 2-hydroxypropyl-␤-CD, 2-
hydroxyethyl-␤-CD, and methyl-␤-CD. With the exception of ␥-CD, the experimental solubility data
Keywords:
were correlated using a modified Chrastil model. Additionally, the solubilization power of each corre-
Solubility
Poorly water-soluble pharmaceutical
lated co-solvent–solute system was evaluated using a log-linear model. Finally, the stability constants
Co-solvent were determined using the Takeru Higuchi–Connors solubility method.
Cyclodextrin © 2013 Elsevier B.V. All rights reserved.

1. Introduction In this study, we selected etodolac [(1,8-diethyl-1,3,4,9-

tetrahydropyrano [3–5,8] indol-1-yl) acetic acid: CAS Registry
Drug candidates with strong pharmacological activity are Number 41340-25-4], which is a cyclooxygenase-2 (cox-2)
increasingly being developed using combinatorial chemistry and inhibitor in NSAIDs [8], as the pharmaceutical compound for an
high-throughput screening [1–3]. As a result, the number of accumulation of solubility data and the enhancement of the sol-
drugs with decreased water solubility has increased because of ubility by adding a co-solvent. Cox-2 selective NSAIDs are ideal
increased molecular weights and more complex chemical struc- anti-inflammatory drugs that have minimum drug-related side
tures. In oral administration of medicines, the major route for drug effects, because they do not affect cox-1 activity. According to Bio-
administration, the drug should pass through the mesentery after pharmaceutics Drug Classification System, etodolac is a class II drug
disintegration and dissolution [4]. Thus, drug solubility has a signif- with low solubility (75 ␮g ml−1 ) and high permeability [9]. There-
icant influence on medical efficacy. There are a variety of methods fore, the solubility of this compound is a key determinant of its
for improving pharmaceutical solubilization, one being co-solvent oral bioavailability. CDs are macrocyclic oligosaccharides, contain-
addition. Therefore, the water solubility of a pharmaceutical and ing 6 (␣-CD), 7 (␤-CD), or 8 (␥-CD) d-glucose units. Since CDs have
the potential for enhancing solubility by addition of a co-solvent a special molecular structure comprising a hydrophobic internal
are essential properties for the pharmaceutical industry [5]. Our cavity and hydrophilic external surface, they can form an inclusion
group has recently determined the solubilities of salicylic acid as complex by including a hydrophobic drug into the internal cavity.
non-steroid anti-inflammatory drugs (NSAIDs) in five binary mix- CDs have been widely used in pharmaceutical industries, because
tures containing water [6], and the enhancement of the solubilities they are expected to enhance the solubility of poorly water-soluble
of famotidine, as an example of a poorly water-soluble pharmaceu- drugs [10]. However, natural CDs, in particular ␤-CD, which is
tical compound, has been investigated by adding five co-solvents: unlikely to form hydrogen bonds due to its structure, have limited
ethanol, polyethylene glycol (PEG) 400, ␤-cyclodextrin (␤-CD), PEG aqueous solubility. Therefore, chemically modified CDs have been
1000, and lauryl sulfate (SLS) [7]. used. Hydroxyl groups, which form hydrogen bonds, are a key factor
in hydrophobic properties and their substitution can dramatically
improve aqueous solubility [11].
∗ Corresponding author. Tel.: +81 3 3259 0814; fax: +81 3 3293 7572. The objective of this study was to understand the water sol-
E-mail address: [email protected] (H. Matsuda). ubility of etodolac by addition of six CDs: ␣-CD, ␤-CD and ␥-CD,

0378-3812/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.fluid.2013.05.025
44 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49

Table 1 Table 2
Overview of chemicals used in this study. Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water
(2) + ␣-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are denoted
Component Source Purity Water by u(T), u(x30 ), and u(x1 ), respectively.
content [%]
x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%)
Etodolac Biochemical agent (97.0%) –
␣-CD First-grade (97.0%) 2.4 0.0000 0.65 ±0.66 0.0060 1.41 ±0.71
␥-CD Wako Pure 2.4 0.0010 0.93 ±4.49 0.0071 1.44 ±0.95
2-HP-␤-CD Chemical 1.7 0.0020 1.08 ±1.22 0.0080 1.52 ±1.02
Special-grade (97.0%)
2-HE-␤-CD Industries, Ltd. 2.2 0.0030 1.18 ±0.64 0.0090 1.60 ±0.82
M-␤-CD 2.5 0.0040 1.26 ±1.08 0.0099 1.67 ±1.78
Methanol HPLC-grade (>99.0%) – 0.0050 1.36 ±2.30
␤-CD Nihonshokuhinkako – 3.0 a
u(T) = ±0.05 K.
Co., Ltd. b
u(x30 ) = ±0.0001.
Water Distillated water – – c
u(x1 ) = ±2.59%.
d
ıx1 is the relative standard deviation [%].

and three ␤-CD derivatives: 2-hydroxypropyl-␤-CD (2-HP-␤-CD), Table 3

2-hydroxyethyl-␤-CD (2-HE-␤-CD), and methyl-␤-CD (M-␤-CD). Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water
These compounds were tested as co-solvents to enhance the sol- (2) + ␤-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are denoted
ubility of etodolac in water at 298.15 K using high-performance by u(T), u(x30 ), and u(x1 ), respectively.
liquid chromatography (HPLC). The experimental solubility data for x30 .b x1 ×105 c ıx1 d (%) x30 .b x1 ×105 c ıx1 d (%)
five water/co-solvent mixtures, excluding ␥-CD, were correlated
0.0000 0.65 ±0.66 0.0020 1.02 ±0.38
using the modified Chrastil model [12]. We also evaluated the sol-
0.0001 0.70 ±0.55 0.0023 1.03 ±0.72
ubilization power of each of the five correlated co-solvent–solute 0.0002 0.73 ±0.13 0.0025 1.05 ±2.30
systems using a log-linear model [13]. Finally, the stability 0.0003 0.75 ±0.82 0.0028 1.07 ±1.89
constants were evaluated using the Takeru Higuchi–Connors solu- 0.0004 0.79 ±0.48 0.0030 1.10 ±0.50
0.0005 0.81 ±1.36 0.0033 1.11 ±1.01
bility method [14].
0.0006 0.83 ±0.35 0.0035 1.12 ±0.96
0.0007 0.85 ±3.93 0.0038 1.16 ±4.56
2. Experimental 0.0008 0.88 ±0.99 0.0040 1.18 ±3.75
0.0009 0.91 ±0.69 0.0045 1.22 ±0.23
0.0010 0.93 ±0.40 0.0048 1.26 ±3.51
2.1. Materials
0.0012 0.94 ±0.48 0.0053 1.30 ±0.59
0.0013 0.95 ±3.87 0.0055 1.32 ±2.84
The biochemical agent etodolac (97.0% purity), first-grade ␣- 0.0016 0.97 ±0.39 0.0060 1.36 ±1.39
CD (97.0% purity), special-grade ␥-CD (97.0% purity), 2-HP-␤-CD 0.0018 0.99 ±4.40
(97.0% purity), 2-HE-␤-CD (97.0% purity) and M-␤-CD (97.0% a
u(T) = ±0.05 K.
purity) were used. HPLC grade methanol was used as the mobile b
u(x30 ) = ±0.0001.
phase. The above chemicals were obtained from Wako Pure Chem-
c
u(x1 ) = ±2.54%.
d
ıx1 is the relative standard deviation [%].
ical Industries, Ltd., Osaka, Japan. ␤-CD was purchased from Nihon
Shokuhin Kako Co., Ltd., Tokyo, Japan. All chemicals were used
as received. CDs contain the water of crystallization [15]. There- mole fraction was estimated to be ±0.0001. An excess of etodolac
fore, the water content in pure CDs was determined by measuring was added to each mixture of known composition. Etodolac was
the weight of pure CDs before and after drying. Water was passed dissolved using a thermostatic water bath at 298.15 K for 24 h. The
through an ion exchanger and distilled with a resistivity less than uncertainty of the temperature was estimated to be ±0.05 K. As well
18.3 M cm. Overview of chemical in this study is summarized in as being used to establish the calibration curve, a specific amount
Table 1. of 2-methylbenzoic acid was added to the solutions as an inter-
nal standard material, and the insoluble solid phase was separated
2.2. Apparatus using a 0.45 ␮m pore size membrane filter (Millipore, Billerica, MA,
USA). Finally, the peak area for etodolac absorbance was deter-
Solubilities were determined using an experimental apparatus mined by HPLC (flow rate 0.8 mL min−1 , wavelength 280 nm). The
based on HPLC [6]. This measurement system mainly consists of a solubility of etodolac was determined on the basis of the mea-
UV–vis detector, constant flow pump, column, injector, and chro- sured peak area, the calibration curve, and the added mass of
matocoder. A Senshu Pak PEGASIL ODS SP 100 (Senshu Scientific 2-methylbenzoic acid. Each experimental data point was an aver-
Co., Ltd., Tokyo, Japan) was applied to the column. A SSC-5410 age of three experiments measuring the mole fraction solubilities.
model UV–vis detector (Senshu Scientific Co., Ltd.) was used. A 9:1 Details of the solubility measurements have been described in our
volumetric ratio mixture of methanol and 0.1% aqueous phosphate previous papers [6].
solution was used as the mobile phase.
3. Results and discussion
2.3. Solubility measurements
The solubilities of etodolac (1) at 298.15 K in the six water (2)
Prior to the solubility measurements, a calibration curve of and co-solvent (3) mixtures were measured and the experimental
etodolac was established using the internal standard method. 2- solubility data are listed in Tables 2–7. The experimental solubility
Methylbenzoic acid was used an internal standard material. The data are also illustrated in Figs. 1–6. In these figures, the mole frac-
precision of this calibration curve was R2 = 0.9999, where R2 is the tion of etodolac is plotted against the mole fraction of co-solvent
determination coefficient. The liquid mole fraction of the binary on a solute-free basis. The solubility data were determined up to
mixed solvents was determined gravimetrically (digital balance the saturation solubilities of the co-solvents in water. The solubili-
model XP 504, Mettler Toledo, Columbus, OH, with a sensitivity ties of etodolac in all six water/co-solvent mixtures increased with
of 0.1 mg and a maximum load of 520 g). The uncertainty in the an increase of the mole fraction of the co-solvent. However, the
 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49 45

[×10-5] 2.0 [×10-3] 1.0

0.8
1.5

0.6
1.0

x1
x1

0.4

0.5
0.2

0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.5 1.0 1.5 2.0 2.5
x30
[×10-2] x30 [×10-2]

Fig. 1. Experimental solubilities of etodolac (1) in binary mixture water (2) + ␣-CD Fig. 4. Experimental solubilities of etodolac (1) in binary mixture water (2) + 2-HP-
(3) at 298.15 K. 䊉, this study; —, modified Chrastil. ␤-CD (3) at 298.15 K. 䊉, this study; —, modified Chrastil.

[×10-5] 2.0 [×10-3] 1.0

0.8
1.5

0.6
1.0
x1

x1

0.4

0.5
0.2

0.0 0.0
0.0 1.0 2.0 3.0 4.0 5.0 6.0 0.0 0.5 1.0 1.5 2.0 2.5
x30 [×10-3] x30 [×10-2]
Fig. 2. Experimental solubilities of etodolac (1) in binary mixture water (2) + ␤-CD Fig. 5. Experimental solubilities of etodolac (1) in binary mixture water (2) + 2-HE-
(3) at 298.15 K. 䊉, this study; —, modified Chrastil. ␤-CD (3) at 298.15 K. 䊉, this study; —, modified Chrastil.

[×10-5] 2.0 [×10-3] 2.5

2.0
1.5

1.5
1.0
x1

x1

1.0

0.5
0.5

0.0 0.0
0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.5 1.0 1.5 2.0 2.5
x30 [×10-2] x30 [×10-2]

Fig. 3. Experimental solubilities of etodolac (1) in binary mixture water (2) + ␥-CD Fig. 6. Experimental solubilities of etodolac (1) in binary mixture water (2) + M-␤-
(3) at 298.15 K. 䊉, this study. CD (3) at 298.15 K. 䊉, this study; —, modified Chrastil.
46 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49

Table 4 Table 7
Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water
(2) + ␥-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are denoted (2) + M-␤-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are
by u(T), u(x30 ), and u(x1 ), respectively. denoted by u(T), u(x30 ), and u(x1 ), respectively.

x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%)

0.0000 0.65 ±0.66 0.0040 0.32 ±1.85 0.0000 0.65 ±0.66 0.0110 79.67 ±0.76
0.0004 0.87 ±2.73 0.0050 0.31 ±4.20 0.0010 2.69 ±2.53 0.0120 95.80 ±0.84
0.0008 0.86 ±3.11 0.0060 0.43 ±4.43 0.0020 5.82 ±3.67 0.0130 110.91 ±0.82
0.0010 0.77 ±1.22 0.0070 0.59 ±3.60 0.0030 9.67 ±1.59 0.0140 124.13 ±0.43
0.0020 0.52 ±0.75 0.0080 0.69 ±3.41 0.0040 14.93 ±2.02 0.0150 143.41 ±0.80
0.0030 0.30 ±1.82 0.0090 0.81 ±1.93 0.0050 20.91 ±1.80 0.0160 158.41 ±1.20
0.0060 27.32 ±3.94 0.0170 178.51 ±2.26
a
u(T) = ±0.05 K.
0.0070 35.16 ±0.46 0.0180 198.66 ±0.26
b
u(x30 ) = ±0.0001.
0.0080 45.56 ±0.83 0.0190 216.82 ±1.70
c
u(x1 ) = ±2.56%.
0.0090 56.56 ±0.65 0.0200 235.97 ±1.58
d
ıx1 is the relative standard deviation [%].
0.0100 68.21 ±2.61
a
u(T) = ±0.05 K.
Table 5 b
u(x30 ) = ±0.0001.
Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water
(2) + 2-HP-␤-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are c
u(x1 ) = ±2.27%.
denoted by u(T), u(x30 ), and u(x1 ), respectively. d
ıx1 is the relative standard deviation [%].

x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%)

0.0000 0.65 ±0.66 0.0110 30.53 ±1.20

0.0010 2.33 ±1.17 0.0120 35.92 ±1.30 AP AL
0.0020 4.18 ±1.43 0.0130 41.73 ±0.20
0.0030 6.34 ±1.30 0.0140 48.12 ±1.73
0.0040 8.76 ±1.98 0.0150 54.26 ±1.14
0.0050 11.26 ±0.97 0.0160 60.35 ±0.44 AN
0.0060 13.12 ±4.56 0.0170 66.46 ±0.58
0.0070 15.70 ±3.58 0.0180 73.88 ±0.57
±0.30 ±1.72
0.0080 18.60 0.0190 81.09
Dtotal
0.0090 21.93 ±1.67 0.0200 87.34 ±0.70
0.0100 26.20 ±0.22
a
u(T) = ±0.05 K.
b
u(x30 ) = ±0.0001.
BS
c
u(x1 ) = ±2.63%.
d
ıx1 is the relative standard deviation [%].

BI
Table 6
Experimental mole fraction solubilities of etodolac (1) in binary mixtures of water
(2) + 2-HE-␤-CD (3) at 298.15 K.a The uncertainties of temperature, x30 , and x1 are
denoted by u(T), u(x30 ), and u(x1 ), respectively.
CDtotal
x30 b
x1 ×105 c ıx1 d (%) x30 b
x1 ×105 c ıx1 d (%) Fig. 7. Outline of solubility behaviors with CD. –, solubility behavior.

0.0000 0.65 ±0.66 0.0110 23.63 ±0.95

0.0010 2.16 ±1.64 0.0120 26.41 ±0.39 and ␤-CD system showed an AN type solubility curve, in which the
0.0020 3.67 ±1.18 0.0130 29.00 ±0.74
0.0030 5.58 ±0.69 0.0140 32.11 ±0.36
guest solubility increases linearly with CD concentration and devi-
0.0040 7.29 ±0.50 0.0150 35.26 ±1.12 ates negatively from a straight line. The 2-HP-␤-CD, 2-HE-␤-CD and
0.0050 9.08 ±0.83 0.0160 38.88 ±0.97 M-␤-CD systems showed an AP type, in which the solubility first
0.0060 11.00 ±0.33 0.0170 42.58 ±0.58 increases linearly with CD concentration as is the case of AN type,
0.0070 13.42 ±0.38 0.0180 46.76 ±0.39
then deviates positively from the straight line. The ␥-CD system
0.0080 15.65 ±1.32 0.0190 50.54 ±1.72
0.0090 17.90 ±1.42 0.0200 53.65 ±0.49 showed a BS type solubility curve, in which the solubility decreases
0.0100 20.42 ±0.25 after first linearly increasing. The experimental results show that
a
u(T) = ±0.05 K.
larger enhancement in etodolac solubility can be achieved using
b
u(x30 ) = ±0.0001. chemically modified CDs, compared with natural CDs. The order of
maximum solubility of etodolac in chemically modified CDs was
c
u(x1 ) = ±0.99%. M-␤-CD > 2-HP-␤-CD > 2-HE-␤-CD.
d
ıx1 is the relative standard deviation [%].

4. Data reduction
solubility of etodolac in co-solvent ␥-CD decreased at higher mole
fractions unlike the other co-solvents. The maximum mole fraction 4.1. Modified Chrastil model
solubilities in co-solvents ␣-CD, ␤-CD, ␥-CD, 2-HP-␤-CD, 2-HE-␤-
CD and M-␤-CD, were 1.7 × 10−5 , 1.4 × 10−5 , 8.1 × 10−6 , 8.7 × 10−4 , In our previous study, we have performed a correlation of the
5.4 × 10−4 , and 2.4 × 10−3 , respectively. These values were 2.6, 2.1, solubilities in the water/liquid co-solvent mixtures using the local
1.2, 134, 83, and 363 times higher than the mole fraction solubil- composition models [6,7]. However, the co-solvent used in this
ity in pure water, 6.5 × 10−6 . According to Higuchi and Conners study is a solid at room temperature. When the local composition
[14], there are several types of solute solubility behavior versus models were applied to data reduction for the solubilities in the
the concentration of CDs. Fig. 7 illustrates an outline of these sol- water/solid co-solvent mixtures, the determination of the binary
ubility behaviors. The solubility behavior of etodolac for the ␣-CD interaction parameters between solute and co-solvent in these
 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49 47

Table 8
Determined parameters and deviations between experimental and calculated solubilities of etodolac (1) in binary mixtures of water (2) + co-solvent (3) at 298.15 K using the
modified Chrastil model.

Water (2) + ␣-CD (3) Water (2) + ␤-CD (3) Water (2) + 2-HP-␤-CD (3) Water (2) + 2-HE-␤-CD (3) Water (2) + M-␤-CD (3)

˛ −8.30427 −8.48104 −4.98853 −5.13314 −3.93190

 0.57578 0.58770 1.69129 1.37284 1.78850

k  15.27877 6.69060 16.03842 7.63042 5.36708
x1  a 1.85 × 10−7 2.35 × 10−7 9.44 × 10−6 5.02 × 10−6 1.05 × 10−5
 av.
x1  5.11 × 10−7
9.41 × 10 −7
2.46 × 10 −5
1.06 × 10−5
5.00 × 10−5
 max. NDP  
a 
x1  = x1,exptl − x1,calcd  /NDP, where NDP is the number of data points.
av. k=1 k

models is impossible, because the solubility in pure co-solvent can- Table 9

Solubilization power and correlation coefficients of the five co-solvents with
not be determined.
etodolac.
On the other hand, the modified Chrastil model [12], which was
proposed by Gonzlez et al., have been widely used to correlate the Co-solvent ˚ (volume fraction R2 log(x1sat )water
range of co-solvent)
experimental solubility data with co-solvent in supercritical car-
bon dioxide [16–18]. This model takes into account the co-solvent 4.157 (0.000–0.052) 0.9832 −5.189
␣-CD
contribution to the solubility. Gonzlez et al. considered a forma- 1.089 (0.052–) 0.9828 −5.049

tion of a solute–co-solvent–solvent complex: A + kB + C ↔ ABk C , 5.879 (0.000–0.034) 0.9317 −5.189

␤-CD
where A is the solute, B is carbon dioxide, and C is the co-solvent. 0.579 (0.034–) 0.9923 −5.042
In this study, we applied the modified Chrastil model to correlate 7.351 (0.000–0.117) 0.9837 −5.189
2-HP-␤-CD
etodolac solubilities in the water/co-solvent mixtures, substituting 2.880 (0.117–) 0.9984 −4.717
water for carbon dioxide (B). The modified Chrastil model is shown 8.341 (0.000–0.123) 0.9726 −5.189
2-HE-␤-CD
in Eq. (1): 2.777 (0.123–) 0.9977 −4.594
˛ 
k  9.277 (0.000–0.137) 0.9799 −5.189
x1sat = water (x30 ) exp +ˇ (1) M-␤-CD
−4.537
T 3.797 (0.137–) 0.9954

where water is the density of water, x30 is the mole fraction of co-
solvent (3) in the mixed solvent in the absence of solute (1), k is solvents. According to Eq. (2), HTotal would be positive, which
the association number of water (2),  is the association number of indicates that the association is an endothermic process.
the co-solvent, and ˛ is a function of the enthalpy of solvation and
enthalpy of vaporization, given by Eq. (2): 4.2. Solubilization power

−HTotal
˛= (2) We evaluated the solubilization power of the five co-solvents,
R
investigated in this study, except ␥-CD, using the following log-
where HTotal is the total reaction (formation of solvation com- linear model [14]:
plexes and vaporization) enthalpy of the solution process. ˇ is a
function of the association number and the molecular weights of log x1sat = log(x1sat )water + ˚V (5)
the solute, solvent, and co-solvent. In this study, Eq. (1) was simpli- where x1sat is the mole fraction solubility in the mixed solvent,
fied because all the experimental solubility data were measured at (x1sat )water is the mole fraction solubility in pure water, ˚ is the
298.15 K. In addition, when Eq. (1) was applied to the calculation of solubilization power of the co-solvent, and V is the volume fraction
the solubilities, a significant error between the experimental and of the co-solvent in the mixed solvent. The value of ˚ was deter-
correlated results for solubilities in pure water occurred. Thus, in mined by a linear least-square regression of log x1sat versus V, setting
this study, the solubility of etodolac in pure water, x0 , was added log(x1sat )water as the intercept. The calculated solubilization powers
to the model, as shown in Eq. (3): for the co-solvents are summarized in Table 9 and a plot of log x1sat
k  versus V is illustrated in Fig. 8. For the five co-solvents, the values of
x1sat = water (x30 ) exp(˛) + x0 (3)
˚ determined using all compositions resulted in significantly low
The value of water is that reported by Riddick et al. determination coefficients. The determination of ˚ was therefore
(0.99705 g cm−3 at 298.15 K) [19]. The fitting parameters in Eq. divided into two composition ranges, similar to our previous study
(3), ˛, k, and , were determined so that the objective function [7]. As can be seen in Table 9, the order of the solubilization powers
(Fobj ) was minimized for each system by means of the Marqurdt was M-␤-CD > 2-HE-␤-CD > 2-HP-␤-CD > ␤-CD > ␣-CD.
algorithm [20]:
4.3. Stability constant

NDP
2
sat sat
Fobj = (x1,exptl − x1,calcd ) (4)
k When there is formation of inclusion complexes, the stability
k=1
constant is often the key factor to explaining the various results
The determined parameters and absolute deviations of the solu- obtained [21]. For all complexation processes, including those
bilities obtained with the modified Chrastil model are summarized associated with CDs, knowledge of the stability constant kc (the
in Table 8. Correlation of the solubilities in water/␥-CD was not equilibrium constant for a drug–CD interaction) is crucial, because
performed, because this solubility behavior was of the BS type. The these values provide an index of change in the physicochemical
correlated results from this model are compared with the experi- properties such as a host–guest binding. For complexation, the
mental solubility data in Figs. 1, 2 and 4–6. These correlated results stability constant km:n (associated with the interaction of n drug
show that the modified Chrastil model was able to represent the molecules with m CD molecules) can be shown as [11]:
experimental solubilities with reasonable correlation accuracy. As km:n
can be seen in Table 8, the parameter ˛ is negative in all five mixed m D + n CD←→Dm · CDn (6)
48 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49

-2.5 5. Conclusions

The solubilities of etodolac in six mixed solvents at 298.15 K,

-3.0
containing water and six CDs, ␣-CD, ␤-CD, ␥-CD, 2-HP-␤-CD, 2-
HE-␤-CD and M-␤-CD, were determined. The solubilities increased
-3.5 with increasing of co-solvent, with the exception of ␥-CD, for which
the solubility of etodolac decreased when the co-solvent composi-
log x1sat

-4.0 tion exceeded a fixed quantity. The experimental solubility data for
the other co-solvent systems were represented using a modified
Chrastil model, and reasonable correlation accuracy was obtained.
-4.5 In addition, for each of the five co-solvents (i.e., except ␥-CD) the
solubilization power was evaluated using a log-linear model. The
-5.0 order of the solubilization power was M-␤-CD > 2-HE-␤-CD > 2-HP-
␤-CD > ␤-CD > ␣-CD. Finally, the stability constants for each of the
-5.5 five co-solvents were evaluated using the Takeru Higuchi–Connors
0.0 0.1 0.2 0.3 0.4 0.5 0.6 solubility method. The order of the stability constant was M-␤-
V CD > 2-HP-␤-CD > 2-HE-␤-CD > ␤-CD > ␣-CD. From these results, it
can be concluded that chemically modified CDs are more suitable
Fig. 8. Plot of log x1sat versus volume fraction of co-solvent V for five co-solvent mix-
co-solvents than natural CDs for an enhancement of the solubilities
tures: , water (2) + ␣-CD (3); , water (2) + ␤-CD (3); , water (2) + 2-HP-␤-CD (3);
⊕, water (2) + 2-HE-␤-CD (3); ♦, water (2) + M-␤-CD (3), —, log-linear model. of etodolac.

Table 10 List of symbols

Stability constant and correlation coefficients of the five co-solvents with etodolac. CDtotal total concentration of CD in solution (mM)
Co-solvent Slope of initial straight line R2 kc Dtotal total concentration of drug in solution (mM)
(mM range of co-solvent) D0 solubility of the drug in water (mM)
␣-CD 0.0023 (0.000–110.98) 0.9652 6.39
Fobj objective function
␤-CD 0.0048 (0.000–22.14) 0.9754 13.43 HTotal total reaction enthalpy of the solution process in the mod-
2-HP-␤-CD 0.0184 (0.000–166.69) 0.9956 52.47 ified Chrastil model (J mol−1 )
2-HE-␤-CD 0.0159 (0.000–166.53) 0.9958 45.34 k solvent association number in the modified Chrastil
M-␤-CD 0.0282 (0.000–166.64) 0.9622 80.97
model
kc stability constant (L mol−1 )
6 NDP number of data points per system
R gas constant = 8.314 (J mol−1 K−1 )
R2 determination coefficient in the calibration curve of
5
etodolac
T absolute temperature (K)
4 V volume fraction of the co-solvent in the mixed solvent
Dtotal (mM)

x solute saturation solubility mole fraction

3 ıx1 relative standard deviation of the solute saturation solu-
bility mole fraction
2 xi0 binary solvent mole fraction on a solute free basis
(x1sat )i saturated mole fraction solubility of solute in pure solvent
1   i
x1  average absolute deviation between experimental and
av.
0   calculated x1
0 50 100 150 200 x1  maximum deviation between experimental and calcu-
max.
CDtotal (mM) lated x1

Fig. 9. Phase-solubility diagrams of etodolac in five co-solvent mixtures: , water

Greek letters
(2) + ␣-CD (3); , water (2) + ␤-CD (3); , water (2) + 2-HP-␤-CD (3); ⊕, water (2) + 2-
HE-␤-CD (3); ♦, water (2) + M-␤-CD (3); –, initial straight line. ˛ function of the enthalpy of solvation and enthalpy of
vaporization in the modified Chrastil model
ˇ function of association number and molecular weights of
where D is the drug in solution. In the case of the formation of
solute, solvent, and co-solvent in the modified Chrastil
a 1:1 inclusion complex, the stability constant k1:1 can be obtained
model
from the slope of the initial straight-line portion of the phase
˚ co-solvent solubilization power
solubility diagram, using the Takeru Higuchi–Connors solubility
 co-solvent association number
method [14]:
 density (g cm−3 )
slope
kc = (7)
D0 (1 − slope) Superscript
where D0 is the solubility of the drug in water. The calculated sta- sat saturation
bility constants for the co-solvents are summarized in Table 10,
and initial straight-line portions of the phase solubility diagram of Subscripts
etodolac are illustrated in Fig. 9. As can be seen from Table 10, the 0, 1, 2, 3, m, n components 0, 1, 2, 3, m, and n
order of the stability constant value was M-␤-CD > 2-HP-␤-CD > 2- calcd calculated
HE-␤-CD > ␤-CD > ␣-CD. exptl experimental
 Y. Naito et al. / Fluid Phase Equilibria 357 (2013) 43–49 49

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