Article pubs.acs.org/jced
Effect of Solvent Composition and Temperature on the Solubility of Ibuprofen in Aqueous Ethanol Abdur Rashid,† Edward T. White,*,† Tony Howes,† James D. Litster,‡ and Ivan Marziano§ †
School of Chemical of Engineering, The University of Queensland, Brisbane, Queensland 4072, Australia School of Chemical Engineering, Purdue University, West Lafayette, Indiana 47907-2100, United States § Material Sciences and Oral Products, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom ‡
ABSTRACT: The solubilities of ibuprofen [(R,S)-2-(4-(2-methylpropyl)phenyl)propanoic acid] in absolute ethanol and in water−ethanol mixtures were measured at temperatures from 10 °C to 40 °C, the expected range relevant to its industrial crystallization. The solubility studies were carried out by dissolution of ibuprofen crystals in stirred Schott bottles kept in a constant temperature bath. The ibuprofen concentration in the clear supernatant at equilibrium was determined by vacuum drying. An allowance was made for the small amount of sublimation from dried ibuprofen. In absolute ethanol, the experimental results showed that the solubility increased as a square law with temperature, from 0.59 g of ibuprofen/g ethanol at 10.0 °C to 2.15 g/g at 40.0 °C. The results are considered to be accurate to within ±1% (as 95% confidence). In water−ethanol mixtures, the solubility of ibuprofen (expressed as w/w ibuprofen/solvent) generally decreased with increasing water addition. At 40 °C and possibly at 25 °C, the solubility initially increased slightly to a maximum level as a small amount of water was added before then decreasing. At 40 °C, phase separation into two immiscible liquid layers was observed for solvent concentrations from 34 to 64% ethanol on an ibuprofen-free basis.
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compared with the prior data, and new data are given (at 10 °C, 25 °C, and 40 °C) for water−ethanol mixtures.
INTRODUCTION The solubility of solid active pharmaceutical ingredients (API) in solvents and solvent mixtures is an important factor in the procedures of industrial pharmaceutical crystallization for the manufacture of pharmaceutical solids in dosage forms.1,2 It is also especially necessary to measure the solubility of API in preformulation studies.3 Ibuprofen (Figure 1) belongs to the
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EXPERIMENTAL SECTION Materials. Ibuprofen USP grade (CAS Registry Number 15687-27-1) purchased from Professional Compounding Chemists of Australia Pty Ltd., Matraville, NSW (cited as ibuprofen content 100% by the supplier), was a racemate of (R,S)-2-(4-(2-methylpropyl)phenyl)propanoic acid with the empirical formula C13H18O2 and molecular weight 206.27 g/ mol. The melting point of this colorless, crystalline material is quoted as 75−77 °C.15 A recent Chinese patent16 reports a monohydrate of ibuprofen, but the material used here was the normal anhydrous form. Solubility Measurements. Solubility studies were carried out by dissolution of ibuprofen in solutions in magnetically stirred Schott bottles in a constant temperature water bath.17 The Schott bottles were filled with ethanol (absolute, AR grade) for the ethanol solubility tests and with aqueous ethanol of known water (W) to ethanol (E) fractions for the aqueous ethanol tests, together with an excess amount of ibuprofen (I). RO laboratory water was used. The bottles were stirred with Teflon-coated magnetic stirrers. The bath temperature was kept within ±0.1 °C and was checked with a calibrated glass
Figure 1. Chemical structure of ibuprofen. The asterisk (*) indicates the atom where the arrangement of the CH3 and COOH entities give the R and S isomers.14
class of nonsteroidal anti-inflammatory drugs (NSAIDs) and is used as a common analgesic. Limited and varying solubility data for this active drug are available in ethanol4−9 and less is available for water−ethanol mixtures.10 Yalkowsky and coworkers11−13 mention eight solubility data values among the over 200 materials they consider in an attempt to get a general correlation for the effect of water on the solubility of drugs in organic solvents. However, they do not appear to have published the individual values. In the present research work, further solubility data are measured for ibuprofen in ethanol (at 10 °C, 15 °C, 25 °C, 30 °C, 35 °C, and 40 °C) and these are © 2014 American Chemical Society
Received: September 9, 2013 Accepted: July 30, 2014 Published: August 14, 2014 2699
dx.doi.org/10.1021/je400819z | J. Chem. Eng. Data 2014, 59, 2699−2703
Journal of Chemical & Engineering Data
Article
believed to predict the true solubility within ±1%. This relation is only applicable over the temperature range stated, as using it below 0 °C for example would indicate solubility increasing as the temperature is decreased. The deviations of the measured points from values predicted by eq 1 are presented in Figure 3. The correlated solubilities of ibuprofen in ethanol are in good agreement with the experimental values.
thermometer. After equilibrium was reached (24 h), excess solid solute was allowed to settle with the agitation off. A mass of clear supernatant solution was then transferred quickly with a pipet to a previously weighed 70 mm square plastic drying tray, weighed, evaporated to dryness in a vacuum oven at 50 °C for 18 h and reweighed to determine the ibuprofen concentration in solution. The solubility was expressed in gram of solute (I) per gram of ethanol (E). An allowance was made for the small amount of sublimation from the dried ibuprofen, a loss of 6.0 mg of ibuprofen over 18 h for the procedure used.17
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RESULTS AND DISCUSSION Solubility in Absolute Ethanol. Solubilities of ibuprofen were measured in replicate at six temperatures between 10 °C to 40 °C. The values are given in Table 1 and plotted in Figure Table 1. Mean Solubility in Ethanola at Atmospheric Pressure with 95% Uncertainties on Mean at Various Temperatures temp.
solubility
solubility I*/E
°C
x*I
w/w
10 15 20 25 30 40
0.370 0.427 0.476 0.531 0.588 0.681
0.588 0.745 0.907 1.132 1.425 2.139
num. data
95% eub as I*/E
5 6 7 10 6 3
0.003 0.001 0.008 0.011 0.016 0.016
w/w
Figure 3. Difference ([I*/E] − [I*/E]pred) between the experimental solubility values of ibuprofen in ethanol at different temperatures [I*/ E], mass ratio ibuprofen to ethanol) and the fitting eq 1 at the same temperature [I*/E]pred. Symbols ○, 10 °C;▲, 20 °C; dark blue ■, 25 °C; yellow ■, 30 °C;light blue ■, 40 °C. Dotted line represents perfect agreement.
a
As mass fraction x*I and mass ratio ibuprofen to ethanol, I*/E. b95% expanded uncertainty, as per JCGM.18
Figure 4 shows the comparison of the measured value with the published data for ibuprofen in ethanol. The results of
Figure 4. Comparison of ibuprofen solubility values (I*/E, mass ratio ibuprofen to ethanol) in ethanol at different temperatures with published data showing chosen fitting correlation (eq 1).
Figure 2. Solubility of ibuprofen as mass ratio ibuprofen to ethanol (I*/E); ■, results; , fitting correlation of eq 1. Error bars are smaller than the symbols for the points.
Gracin and Rasmuson6 and Jouyban et al.9 are in good agreement with our results in the temperature range 10 to 40 °C, and the data of Wang et al.4 are close. The data of Cano et al.7 are about 10% higher than the prediction equation, the recent data of Domanska et al.8 are about 15% lower and the values of Manrique and Martinez5 are about 25% higher. Solubility in Water−Ethanol Mixtures. Solubility measurements were made over a range of water concentrations [expressed as XW = W / (E + W), by weight, where W = water and E = ethanol] for three temperatures (10 °C, 25 °C, and 40 °C). The results are given in Table 2. Figure 5 plots the ibuprofen solubility values (expressed as ibuprofen/ethanol, w/ w) in water−ethanol mixtures. The chosen concentration units
2. The results show that the ibuprofen solubility increases dramatically with temperature from 0.59 g of ibuprofen per g of ethanol at 10 °C to 2.14 g/g at 40 °C. The overall results are considered to be accurate to within ±1% (as 95% confidence) and are correlated empirically by I */E = 0.497(± 0.008) + 0.001026(± 0.000012)T 2
(1)
where T is temperature in °C, I*/E is the solubility mass ratio of ibuprofen to ethanol in solution and the values in brackets are the 95% confidence intervals on the parameters This correlation fits 95% of the data within ±0.03 I*/E units and is 2700
dx.doi.org/10.1021/je400819z | J. Chem. Eng. Data 2014, 59, 2699−2703
Journal of Chemical & Engineering Data
Article
Table 2. Mean Solubility Values in Aqueous Ethanola with Water Concentration As XW = W/(E + W), by Weight, at Three Temperatures and Atmospheric Pressure 10 °C
a
25 °C
95% eub on I*/E,
40 °C
95% eub on I*/E,
95% eub on I*/E,
XW
x*I
I*/E
w/w
XW
x*I
I*/E
w/w
XW
x*I
I*/E
w/w
0 0.105 0.203 0.299 0.4 0.498 0.594 0.645
0.370 0.301 0.217 0.122 0.059 0.019 0.003
