Research Note pubs.acs.org/IECR
Solubility of Racemic Potassium 2‑(1-Hydroxypentyl)-benzoate in Six Solvents at 298.15−333.15 K Huan Zhao, Zihui Meng, Min Xue, Peng Wang, and Zhibin Xu* School of Chemical & Environmental Engineering, Beijing Institute of Technology, Beijing 100081, China S Supporting Information *
ABSTRACT: The solubility of racemic potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) in methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone from 298.15 to 333.15 K was measured by an equilibrium method. The solubility data of dl-PHPB in six different solvents was correlated by the modified Apelblat equation. The correlation coefficients were observed in the range of 0.993 to 0.998, indicating a good fit. The results showed that the mole fraction solubility of dl-PHPB in methanol (6.22 × 10−2), ethanol (2.58 × 10−2), n-propanol (2.39 × 10−2), and isopropyl alcohol (6.72 × 10−3) was significantly higher than in acetone (2.58 × 10−4) and ethyl acetate (8.02 × 10−5) at 298.15 K. The experiment data would be useful for optimizing purification and recrystallization processes of dl-PHPB in industry.
1. INTRODUCTION Racemic potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB, C12H15KO3; CAS, 685886-82-2; molecular weight, 246.34; Figure 1) is the prodrug for racemic 3-n-butylphthalide (dl-
literature. Therefore, in this work, the economical and commonly used solvents of methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone were chosen, and the solubility of dl-PHPB in each solvent in the range of 298.15−333.15 K was measured. At the same time, an equilibrium method was used to measure the solubility of dlPHPB.11 The experimental data was correlated by the modified Apelblat equation at 298.15 to 333.15 K.12 The experimental data would be useful in industry for optimizing purification and recrystallization processes of dl-PHPB.
Figure 1. Chemical structure of dl-PHPB and dl-NBP.
2. EXPERIMENTAL SECTION 2.1. Materials. The crude dl-PHPB(C12H15KO3) was synthesized according to the patent,7 and the purity was determined by HPLC as 98.0%. Methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone of analytical grade were purchased from local suppliers without further purification. 2.2. Measurement of dl-PHPB Solubility. The solubility of dl-PHPB was measured at temperatures of 298.15 to 333.15 K by the equilibrium method. In the process of measurement, an excess amount of dl-PHPB powder was added to 5 mL of each solvent in the glass vials. Then the vial was placed in a thermostatic water bath and stirred magnetically at 400 rpm for about 5 h. The uncertainty of the temperature was ±0.1 K. After the stirring was complete, the solution was kept for another 10 h at a constant temperature without stirring.13−15 After thermodynamic equilibrium was established, a portion of the upper clear solution was withdrawn by a syringe with a 0.22 μm membrane, and then transferred into a preweighted bottle with a weight of m1. The weight of the bottle containing the sample was measured as m2. M3 was the weight of the glass vial with sample after the solvent was evaporated. The mole fraction
NBP, Figure 1). dl-NBP was approved in 2002 by the State Food and Drug Administration (SFDA) of China as a new drug for the treatment of ischemic stroke. Various studies demonstrated that dl-NBP exhibits significant biological activities such as improving microcirculation, decreasing brain infarct volume, regulating energy metabolism, inhibiting platelet aggregation, and reducing thrombus formation.1−4However, dlNBP is difficult to use intravenously because of its poor aqueous solubility, hence limiting its clinical application.5,6 To overcome this problem, a water-soluble prodrug dl-PHPB was designed and synthesized.7 It was found that dl-PHPB could reduce the infarct volume and improve neurobehavioral deficits in the transient focal cerebral ischemic rat model.8 dl-PHPB could quickly convert to dl-NBP in vitro and in vivo and showed equal or better efficacy to an equal amount of dl-NBP.5,6,8,9 Research in the last several years has shown that dl-PHPB may protect neurons against H2O2-induced apoptosis by modulating apoptosis-related proteins and reduce white matter rarefaction.6,8 Therefore, dl-PHPB has therapeutic potential for the treatment of dementia caused by a decrease of cerebral blood flow. The solubility of solid drugs often directly affects drugs activities.10 Since dl-PHPB is a type of potassium salt, it dissolves well in water. dl-PHPB can be dissolved in polar solvents such as methanol and ethanol, but its solubility in nonpolar solvents is poor. However, until now, there is no experimental data for solubility of dl-PHPB available in the © 2014 American Chemical Society
Received: Revised: Accepted: Published: 14892
July 14, 2014 September 5, 2014 September 9, 2014 September 9, 2014 dx.doi.org/10.1021/ie5028149 | Ind. Eng. Chem. Res. 2014, 53, 14892−14895
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Research Note
solubility of dl-PHPB x in different solvents can be obtained as follows (eq 1): x=
(m3 − m1)/M1 (m3 − m1)/M1 + (m2 − m3)/M 2
(1)
where M1 and M2 are the molecular weight of the solute (dlPHPB) and solvent, respectively. All experiments were repeated three times at each temperature. The uncertainty of the mole fractions in the solubility values was established to be ±4.0%.
3. RESULTS AND DISCUSSION 3.1. Solubility Data of dl-PHPB. The solubility data of dlPHPB in methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone in the range of (298.15 to 333.15) K are available in the Supporting Information. The mole fraction solubility of dl-PHPB at 298.15 K in methanol (6.22 × 10−2), ethanol (2.58 × 10−2), n-propanol (2.39 × 10−2), and isopropyl alcohol (6.72 × 10−3) was far greater than in acetone (2.58 × 10−4) and ethyl acetate (8.02 × 10−5). The solubility of dlPHPB increased with the increase of temperature, and the highest solubility of dl-PHPB was in methanol followed by ethanol, n-propanol, isopropyl alcohol, acetone, and ethyl acetate. It was also noted that the solubility in ethyl acetate grew gradually with temperature. The higher solubilities in methanol and ethanol were perhaps due to their higher polarities compared to other solvents. Furthermore, the formation of hydrogen bonds between the solute and solvent has also increased its solubility in methanol and ethanol. On the basis of the above conclusions, dl-PHPB is believed to be slightly soluble in ethyl acetate and acetone and soluble in methanol, ethanol, n-propanol, and isopropyl alcohol. 3.2. Correlation Data of dl-PHPB. The experiment solubility values were fitted with the modified Apelblat equation, which was described as follows (eq 2):16−18 ln(x) = A + B /(T /K) + C ln(T /K)
(2) Figure 2. Mole fraction solubility of dl-PHPB (x1) in (a) methanol, ethanol, n-propanol, and isopropyl alcohol, and (b) ethyl acetate, and acetone from 298.15 K to 333.15 K.
where x is the mole fraction of dl-PHPB; T is the corresponding absolute temperature (K); and A, B, and C are the adjustable empirical parameters. The calculated Apelblat solubilities (xcalcd) were calculated by these three parameters which are given in the Supporting Information. The relationship between experimental solubility (x1) and xcalcd from 298.15 K to 333.15 K in six solvents is graphically displayed in Figure 2. The relative deviation (δ) is defined as (x − x calcd) δ= 1 x1
dissolution enthalpy and entropy could be different. The enthalpy of dissolution (ΔsolH) and entropy (ΔsolS) of dlPHPB in six solvents (methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone) can be expressed as12,19,20
(3)
calcd
where x represents the calculated value of the solubility. The values of parameters A, B, and C and the root-meansquare deviations (rmsd) are listed in Table 1. The rmsd is defined as ⎛ ∑N (x − x calcd)2 ⎞1/2 i i ⎟ rmsd = ⎜⎜ i = 1 ⎟ N ⎝ ⎠
⎛ B⎞ Δsol H = RT ⎜C − ⎟ ⎝ T⎠
(5)
⎛ B⎞ Δsol S = R ⎜C − ⎟ ⎝ T⎠
(6)
where R is the gas constant and coefficients B and C were calculated by the Apelblat equation (eq 2.). Equations 5 and 6 are derived equations of eq 2.19 The enthalpy and entropy of dissolution are presented in the Supporting Information. Compared to the other five solvents, ΔsolH and ΔsolS for dlPBPB in methanol had the lowest values, indicating that less energy was required for the solid to dissolve. Positive values for ΔsolH indicate the endothermic nature of the dissolving process for dl-PHPB, shining light on the direct correlation of solubility and temperature. It is likely that the positive values of ΔsolH are due to the molecular bond energy between the solvent and the solute not being sufficient enough to disrupt the initial intermolecular forces of solvent−solvent and solute−solute.
(4)
xicalcd
where N is the number of experimental points, xi and represent the experimental and calculated values of the solubility, respectively. The values of R2 in six solvents were found to be 0.993−0.998 (Table 1), indicating a good fit. 3.3. Thermodynamic Properties for dl-PHPB Dissolution. When a solute dissolves in different solvents, the
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dx.doi.org/10.1021/ie5028149 | Ind. Eng. Chem. Res. 2014, 53, 14892−14895
Industrial & Engineering Chemistry Research
Research Note
Table 1. Parameters of Apelblat Parameter Equation for dl-PHPB in Different Solvents Apelblat parameters solvent
A
B
C
R2
100rsmd
methanol ethanol n-propanol isopropyl alcohol ethyl acetate acetone
42.94 −3.88 9.14 −85.58 −99.98 −110.56
−4063.82 −4381.92 −3993.55 −2175.76 206.53 679.82
−5.63 2.61 0.10 15.42 15.76 17.54
0.993 0.995 0.997 0.998 0.998 0.996
0.172 0.236 0.106 0.074 3.163 × 10−4 1.679 × 10−3
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An entropy greater than zero (ΔsolS > 0) indicates that the dissolution is an entropy-driven process.
4. CONCLUSIONS In the present study, the solubility of dl-PHPB in methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, and acetone from 298.15 K to 333.15 K were measured by the equilibrium method. The mole fraction solubility of dl-PHPB in methanol, ethanol, n-propanol, and isopropyl alcohol was far greater than in ethyl acetate and acetone, and the solubilities of dl-PHPB in six solvents were found to be increased with the increasing temperature with the changes being less prominent in ethyl acetate. In a word, the solubility of dl-PHPB can be represented as methanol > ethanol > n-propanol > isopropyl alcohol > acetone > ethyl acetate. The experimental data were correlated and fit well with the modified Apelblat model in six solvents. Moreover, the root-mean-square deviation (rmsd) among these values does not exceed 0.24% and the relative deviation (δ) did not exceed 5.55%. On the basis of the results, dl-PHPB is considered to have a good solubility in methanol and ethanol, be soluble in n-propanol and isopropyl alcohol, and be slightly soluble in ethyl acetate and acetone.
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ASSOCIATED CONTENT
S Supporting Information *
Tables listing information on chemicals used, solubility data of dl-PHPB, and the dissolution enthalpy and entropy. This material is available free of charge via the Internet at http:// pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Tel./Fax: 86-10-68913065. Notes
The authors declare no competing financial interest.
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REFERENCES
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(20) Williamson, A. T. The exact calculations of heats of solutions from solubility data. Trans. Faraday Soc. 1944, 40, 421−436.
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