http://informahealthcare.com/phd
`ISSN: 1083-7450 (print), 1097-9867 (electronic)
`
`Pharm Dev Technol, 2014; 19(6): 702–707
`! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/10837450.2013.823992
`
`ORIGINAL ARTICLE
`
`Thermodynamics-based mathematical model for solubility prediction
`of glibenclamide in ethanol–water mixtures
`
`Faiyaz Shakeel1,2, Fars K. Alanazi2,3, Ibrahim A. Alsarra1,2, and Nazrul Haq1,2
`
`1Center of Excellence in Biotechnology Research, 2Department of Pharmaceutics, College of Pharmacy, and 3Kayyali Chair for Pharmaceutical
`Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
`
`Abstract
`
`in various ethanol–water
`Temperature-dependent solubility data of glibenclamide (GBN)
`mixtures is not reported in literature so far. Therefore, the aim of this study was to determine
`the mole fraction solubility of GBN in various ethanol–water mixtures at the temperature range
`of 293.15 to 318.15 K. The solubility of GBN was determined by reported shake flask method
`and the experimental data was fitted in thermodynamics-based modified Apelblat model. The
`solubility of GBN was found to be increased with increase in temperature and mass fraction
`of ethanol
`in ethanol–water mixtures. The experimental data of GBN was well correlated
`with the modified Apelblat model at each temperature range with correlation coefficient of
`0.9940–1.0000. The relative absolute deviation (AD) was found to be less than 0.1% except
`in pure ethanol and water. The positive values of enthalpies and entropies for GBN dissolution
`indicated that its dissolution is endothermic and an entropy-driven process.
`
`Keywords
`
`Dissolution, ethanol, glibenclamide, mole
`fraction solubility, thermodynamics
`
`History
`
`Received 17 April 2013
`Revised 5 June 2013
`Accepted 22 June 2013
`Published online 9 August 2013
`
`Introduction
`
`Glibenclamide (GBN), also known as glyburide (molecular
`formula-C23H28ClN3O5S, molecular weight-494 g/mol
`and
`CAS registry Number-10238-21-8),
`is an oral hypoglycemic
`agent which has been recommended for the management and
`treatment of type II non-insulin-dependent diabetes mellitus1.
`Physicochemical characterization of this drug indicates that it has
`very poor aqueous solubility but shows very good permeability
`through gastrointestinal mucosa2,3. The poor solubility is the main
`barrier for the drug development process of GBN especially in
`terms of liquid dosage forms where high amount of GBN is
`required to be solubilized in relatively small amounts of the
`solvents1–5. A thorough literature survey revealed that several
`thermodynamics-based mathematical models are used for predic-
`tion of solubility of various drugs/pharmaceuticals in various
`mixtures of solvents/cosolvents4–10. Nevertheless, all these math-
`ematical models do not consider the impact of temperature
`on solubility data of these drugs/pharmaceuticals due to certain
`limitations of each model4,5. Therefore,
`it
`is very important
`to measure temperature-dependent solubility data of such poorly
`soluble drugs in order to maintain complete information about the
`physicochemical parameters of such drugs4. The most recent
`research works on temperature-dependent solubility data of
`some pharmaceuticals such as 2,4-dicholrophenoxyacetic acid,
`4-acetylbenzoic acid, daidzein and succinic anhydride have shown
`that
`the modified Apelbalt model
`is the most accurate and
`commonly
`employed
`thermodynamics-based mathematical
`model for both polar as well as for nonpolar systems to predict
`temperature-dependent solubility data11–14. Although, saturated
`
`Address for correspondence: Dr Faiyaz Shakeel, Center of Excellence in
`Biotechnology Research, King Saud University, Riyadh, Kingdom of
`Saudi Arabia (KSA). Tel: +966-537507318. E-mail: faiyazs@fastmail.fm
`
`equilibrium solubility of GBN in water (0.024 mg/ml – practically
`insoluble) and ethanol (5 mg/ml – slightly soluble) at room
`temperature (298.15 K) has been reported in several pharmaco-
`peias but temperature-dependent mole fraction solubility data of
`GBN in various ethanol–water mixtures has not been reported in
`literature or any pharmacopeia so far1–3. Therefore, the attempts
`were made in the present study for measurement of the mole
`fraction solubility of GBN in various ethanol–water mixtures by
`shake flask method to correlate experimental solubility data with
`the modified Aplelblat model at the temperature range from
`293.15 to 318.15 K. These preliminary studies could be useful
`in generating temperature-dependent solubility data of various
`poorly soluble drugs as well as in preformulation studies and
`formulation development of GBN.
`
`2013
`
`Materials and methods
`
`Materials
`
`Glyburide (Figure 1; purity 99.0%) was obtained as a gift sample
`from Alfa Aesar (Ward Hill, MA). Ethanol (purity 96.0%) was
`purchased from Sigma Aldrich (St. Louis, MO). Distilled water
`was obtained from distillation unit in the laboratory. Various
`ethanol–water mixtures were prepared at mass fraction of 0–1.0
`with the help of density of ethanol and water. All these chemicals
`were used without further purification and their general properties
`are listed in Table 1.
`
`Measurement of GBN solubility by shake flask method
`
`The solubility of GBN in various ethanol–water mixtures was
`measured by shake flask method reported by Higuchi et al. (1979)
`at the temperature range15 from 293.15 to 318.15 K. An excess
`amount of solid GBN was carefully added in 25 ml of each
`ethanol–water mixture in 50 ml capacity stoppered conical flasks.
`Each solid–liquid mixture was mixed thoroughly and transferred
`
`Page 1
`
`Mylan v. MonoSol
`IPR2017-00200
`MonoSol Ex. 2027
`
`

`

`DOI: 10.3109/10837450.2013.823992
`
`Thermodynamics and solubility prediction of glibenclamide
`
`703
`
`Figure 1. Molecular structure of glibenclamide.
`
`Table 1. General properties of glibenclamide, ethanol and water.
`
`Materials
`
`Molecular
`formula
`
`M.W.
`(g/mol)
`
`D
`(g/ml)
`
`Purity
`(%)
`
`CAS No.
`
`Glibenclamide C23H28ClN3O5S 494.000 1.360
`Ethanol
`C2H5OH
`46.069 0.789
`Water
`H2O
`18.015 1.000
`
`99.00 10238-21-8
`96.00
`64-17-5
`100
`7732-18-5
`
`Table 2. Experimental (Xe) and calculated mole fraction solubility (XmAc)
`data of glibenclamide in various ethanol–water mixtures (293.15 to
`318.15 K).
`
`103Xe
`
`103XmAc AD (%) K at 298.15 K
`
`T/K
`Ethanolþ W (w¼ 0.0)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.1)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.2)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.3)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.4)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.5)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.6)
`293.15
`298.15
`303.15
`
`0.0042
`0.0050
`0.0062
`0.0074
`0.0088
`0.0099
`
`2.1774
`2.1800
`2.1829
`2.1859
`2.1893
`2.1919
`
`4.3498
`4.3528
`4.3560
`4.3594
`4.3632
`4.3670
`
`6.5233
`6.5276
`6.5319
`6.5368
`6.5422
`6.5471
`
`8.6983
`8.7027
`8.7083
`8.7140
`8.7203
`8.7265
`
`10.8772
`10.8832
`10.8892
`10.8952
`10.9020
`10.9087
`
`13.0910
`13.1059
`13.1245
`
`0.0042 0.563
`0.0051 2.059
`0.0061
`2.065
`0.0072
`2.494
`0.0086
`2.218
`0.0102 3.353
`
`2.1773
`0.003
`2.1804 0.018
`2.1834 0.019
`2.1863 0.018
`2.1892
`0.004
`2.1921 0.010
`
`4.3492
`0.014
`4.3528 0.001
`4.3563 0.005
`4.3597 0.007
`4.3631
`0.001
`4.3664
`0.012
`
`6.5227
`0.0009
`6.5276 0.000
`6.5325 0.008
`6.5373 0.007
`6.5420
`0.003
`6.5466
`0.006
`
`8.6982
`0.000
`8.7041 0.016
`8.7099 0.018
`8.7156 0.018
`8.7212 0.011
`8.7268 0.002
`10.8781 0.008
`10.8846 0.012
`10.8910 0.016
`10.8973 0.018
`10.9034 0.013
`10.9095 0.007
`13.0938 0.021
`13.1107 0.036
`13.1275 0.022
`
`Table 2. Continued
`
`T/K
`
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.7)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.8)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 0.9)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`Ethanolþ W (w¼ 1.0)
`293.15
`298.15
`303.15
`308.15
`313.15
`318.15
`
`103Xe
`
`13.1395
`13.1562
`13.1730
`
`15.3033
`15.3256
`15.3478
`15.3676
`15.3898
`15.4121
`
`17.5606
`17.5938
`17.6270
`17.6602
`17.6934
`17.7229
`
`20.1959
`20.3426
`20.4893
`20.6360
`20.7826
`20.9293
`
`0.3441
`0.3728
`0.4109
`0.4413
`0.4784
`0.5335
`
`45.924
`
`103XmAc AD (%) K at 298.15 K
`13.1439 0.033
`13.1601 0.029
`13.1761 0.023
`15.3059 0.016
`15.3281 0.016
`15.3501 0.014
`15.3717 0.026
`15.3930 0.020
`15.4140 0.012
`
`40.518
`
`17.5593
`0.007
`17.5929
`0.005
`17.6260
`0.005
`17.6587
`0.008
`17.6908
`0.014
`17.7226
`0.001
`20.1985 0.012
`20.3480
`0.026
`20.4960
`0.032
`20.6427
`0.032
`20.7880
`0.025
`20.9321
`0.013
`
`0.3409
`0.930
`0.3726
`0.051
`0.4066
`1.039
`0.4431 0.417
`0.4823 0.814
`0.5241
`1.763
`
`35.112
`
`29.707
`
`24.300
`
`Distilled water (W), experimental mole fraction solubility of glibencla-
`mide (Xe), mole fraction solubility of glibenclamide calculated by the
`modified Apelbalt equation (XmAc), relative absolute deviation between
`experimental and calculated solubility (AD), dielectric constant at
`298.15 K (K).
`
`to an isothermal shaker bath (Julabo, PA) for the period of 24 h
`to reach equilibrium. After 24 h (enough time to reach equilib-
`rium)14, each solid–liquid mixture was removed from shaker
`bath and allowed to settle drug particles for the period of 2 h
`(it is reported time for complete settling of solute particles)12
`at the bottom of flasks. The uncertainties in temperature and
`mole fraction solubility were observed as 0.65 and 0.74%,
`the samples were filtered through 0.45 mm
`respectively. All
`membrane filters, diluted suitably with respective solvent and
`subjected for analysis of GBN content using UV-Visible spectro-
`the wavelength16,17 of 245 nm. Experimental
`photometer at
`mole fraction solubility (xe) of GBN was calculated using
`Equation (1)12–14:
`xe ¼
`
`m1=M1
`m1=M1 þ m2=M2 þ m3=M3
`where, m1 is the mass of GBN (solute), and m2 and m3 are the
`mass of ethanol and distilled water, respectively. M1 represents the
`molecular weight of GBN (g/mol) and M2 and M3 represents
`the molecular weight (g/mol) of ethanol and distilled water,
`respectively.
`
`ð1Þ
`
`78.360
`
`72.954
`
`67.548
`
`62.142
`
`56.736
`
`51.330
`
`Results and discussion
`
`Solubility data of GBN
`
`(continued )
`
`The mole fraction solubility data of GBN in various ethanol–
`water mixtures is listed in Table 2 at each temperature studied.
`The reported/calculated values of dielectric constants (K) at
`
`Page 2
`
`

`

`704
`
`F. Shakeel et al.
`
`Figure 2. Experimental mole fraction solu-
`bility (Xe) of glibenclamide in various
`ethanol–water mixtures against temperature.
`
`Pharm Dev Technol, 2014; 19(6): 702–707
`
`Figure 3. Experimental mole fraction solu-
`bility (Xe) of glibenclamide against mass
`fraction of (0–1.0) of ethanol–water mixtures
`at various temperatures (293.15 to 318.15 K).
`
`298.15 K are also listed in Table 2 for each cosolvent mixture. The
`value of K was calculated using Equation (2):
`
`K ¼ k1  w1 þ k2  w2
`
`100
`
`where, k1 and k2 represent the dielectric constant of ethanol and
`respectively and w1 and w2
`distilled water,
`represent
`the
`percentage of ethanol and distilled water,
`respectively in
`ethanol–water mixtures.
`
`ð2Þ
`
`It was observed that the mole fraction solubility of GBN was
`found to be increased exponentially with increase in temperature
`in each mixture of ethanol and water. The mole fraction solubility
`of GBN was found to be highest and lowest in ethanol–water
`mixture (w¼ 0.9) and distilled water,
`respectively at each
`temperature studied (Figure 2). Mole fraction solubility of GBN
`(w¼ 1.0) was observed as 3.728 10
`4 at
`in pure ethanol
`298.15 K (room temperature) as compared to 5 10
`7 in distilled
`water which was significantly higher in pure ethanol than pure
`
`Page 3
`
`

`

`DOI: 10.3109/10837450.2013.823992
`
`Thermodynamics and solubility prediction of glibenclamide
`
`705
`
`Figure 4. Impact of dielectric constant (K) on
`experimental mole fraction solubility (Xe) of
`glibenclamide at room temperature
`(298.15 K).
`
`as a green and environmentally benign cosolvent in preformula-
`tion studies and formulation development especially for liquid
`dosage forms of GBN.
`
`Thermodynamic modeling of GBN solubility
`
`According to the modified Apelblat model, the mole fraction
`solubility of solutes/drugs depends mainly on absolute tempera-
`ture (T)11–14. At an equilibrium, the temperature-dependent mole
`fraction solubility (xe) of GBN can be represented by Equation (3)
`(modified Apelblat equation)12:
`ln xe ¼ A þ B
`T
`
`þ C lnðTÞ
`
`ð3Þ
`
`distilled water (Table 2). The effect of mass fraction of ethanol on
`mole fraction solubility of GBN at various temperatures is
`depicted in Figure 3. It was observed that the mole fraction
`solubility of GBN was found to be increased with increase in mass
`fraction of ethanol (up to 0.9 in ethanol–water mixtures) and
`started to decrease at mass fraction of 1.0 (pure ethanol) at each
`temperature studied (Figure 3). The highest value of mole fraction
`solubility was obtained at mass fraction of 0.9 at each temperature
`studied. The results of mole fraction solubility of GBN have also
`been correlated with dielectric constant/polarity and molecular
`weight of cosolvents. The effect of dielectric constant/polarity
`of various ethanol–water mixtures on mole fraction solubility of
`GBN is presented in Figure 4. It has been reported in literature
`that the dielectric constant (K) of pure water (78.36) is much
`higher than pure ethanol18 (24.30) at 298.15 K. Therefore, the
`lowest mole fraction solubility of GBN in distilled water was
`probably due to its highest polarity19. It has also been reported
`in literature that the solubility of solutes could be increased
`by decreasing the dielectric constants of solvents or cosolvent
`mixtures20. The solubility of GBN in ethanol–water mixtures was
`increased significantly by increasing the mass fraction of ethanol
`in cosolvent mixtures (except in case of pure ethanol) that could
`be due to reduced polarities in ethanol–water mixtures18–20.
`As stated previously that the mole fraction solubility of GBN
`was found to be highest at mass fraction 0.9 of ethanol in ethanol–
`water mixtures (Figure 3). The dielectric constant of mass fraction
`0.9 was observed as 29.707 (Table 2) which was greater than pure
`ethanol (24.30). Therefore, we can conclude that mole fraction
`solubility could depend not only on polarity/dielectric constant
`but also on molecular structure and molecular weight of the
`solutes and solvents. The highest mole fraction solubility of GBN
`at 0.9 mass fraction of ethanol in ethanol–water mixture was
`probably due to the lower molecular weight of ethanol (46.069)
`because it is inversely proportional to the molecular weight of
`cosolvents. Based on the solubility data of GBN in pure distilled
`water and pure ethanol, it was considered as practically insoluble
`in water and slightly soluble in ethanol as reported previously1–3.
`Overall, ethanol was found to be efficient in enhancing the mole
`fraction solubility of GBN in cosolvent mixtures, it could be used
`
`where, A, B and C are adjustable parameters of the modified
`Apelblat equation. In the present study, these adjustable param-
`eters were determined by regression analysis of the experimental
`solubility data. The modified Aplelblat/calculated solubility
`(xmAc) at each temperature was calculated using equation
`parameters A, B and C. The modified Apelblat solubility was
`correlated with experimental solubility of GBN (Figure 5). The
`percent of absolute relative deviation (%AD) was also calculated
`using Equation (4) to evaluate the differences between experi-
`mental (xe) and calculated (xc) solubility of GBN. The data of
`all these parameters is listed in Table 2.
`ADð%Þ ¼ xe xcð
`Þ
` 100
`
`
`
`xe
`
`ð4Þ
`
`It was observed that the %AD was found to be less than
`0.1% in most of the ethanol–water mixtures at each temperature
`studied (Table 2). The values of equation parameters A, B and C
`in various ethanol–water mixtures are listed in Table 3. The
`correlation between the experimental and modified Apelblat
`solubility data in various ethanol–water mixtures is presented
`in Figure 5. The values of correlation coefficient (R2) for GBN in
`pure water (w¼ 0.0) and pure ethanol (w¼ 1.0) were found to be
`0.9940 and 0.9963, respectively (Table 3). However, R2 values for
`GBN in various ethanol–water mixtures (w¼ 0.1–0.9) were
`observed in the range of 0.9954–1.0000. The lower values of
`
`Page 4
`
`

`

`706
`
`F. Shakeel et al.
`
`Figure 5. The correlation of experimental
`mole fraction solubilities (Xe) with the
`modified Aplelblat model for glibenclamide
`in various ethanol–water mixtures at tem-
`perature range from 293.15 to 318.15 K
`(mApl denotes the modified Apelblat
`solubilities).
`
`Pharm Dev Technol, 2014; 19(6): 702–707
`
`Table 3. The modified Apelblat model parameters (A, B and C) for
`glibenclamide in various ethanol–water mixtures.
`
`Modified Aplelblat model
`
`Sample
`Ethanolþ W (w¼ 0.0)
`Ethanolþ W (w¼ 0.1)
`Ethanolþ W (w¼ 0.2)
`Ethanolþ W (w¼ 0.3)
`Ethanolþ W (w¼ 0.4)
`Ethanolþ W (w¼ 0.5)
`Ethanolþ W (w¼ 0.6)
`Ethanolþ W (w¼ 0.7)
`Ethanolþ W (w¼ 0.8)
`Ethanolþ W (w¼ 0.9)
`Ethanolþ W (w¼ 1.0)
`
`A
`66.64
`0.302
`1.190
`1.615
`1.907
`2.181
`2.130
`2.232
`2.215
`0.5117
`31.53
`
`B
`
`35.30
`2.00
`1.68
`1.62
`1.58
`1.55
`1.96
`2.20
`2.36
`5.40
`68.90
`
`C
`
`10.7510
`0.0826
`0.0482
`0.0448
`0.0400
`0.0352
`0.0766
`0.0860
`0.1131
`0.4359
`5.2550
`
`R2
`
`0.9940
`0.9980
`0.9961
`0.9972
`0.9954
`0.9983
`0.9992
`0.9996
`0.9999
`1.0000
`0.9963
`
`Distilled water (W), mass fraction of ethanol in cosolvent mixtures (w).
`
`%AD and higher values of R2 clearly indicated a good fitting
`of the experimental data with the modified Apelblat model.
`
`Thermodynamic parameters for GBN dissolution
`
`
`
`According to thermodynamics principles, the process of GBN
`dissolution into a liquid or cosolvent mixtures can be expressed as:
`Solid þ liquid ¼ solid liquid at solid liquid equilibrium
`The molar enthalpy (DsolH) and entropy (DsolS) for GBN
`
`dissolution can be calculated with the help of Equations (5) and
`(6), respectively21–23:
`DsolH ¼ RT C B
`
`
`T
`DsolS ¼ R C B
`T
`
`ð5Þ
`
`ð6Þ
`
`The results of these thermodynamic parameters in various
`ethanol–water mixtures at the temperature range of 293.15 to
`318.15 K are listed in Table 4. The DsolH for GBN dissolution
`in pure water and pure ethanol ranged from 25.910–28.145 and
`1, respectively at various temperatures.
`12.235–13.327 kJ mol
`However, the DsolH for GBN dissolution in various ethanol-water
`1 at same temperature
`mixtures ranged from 0.072–3.483 kJ mol
`range which was significantly lower than pure solvents (Table 4).
`The DsolH for GBN dissolution in pure water was observed as
`highest as compared to pure ethanol and various ethanol–water
`mixtures which clearly indicated that high input of energy is
`required for complete dissolution/solubilization of GBN in pure
`water as compared to pure ethanol and various ethanol–water
`mixtures. However, the lower values of DsolH for GBN dissol-
`ution in pure ethanol and various ethanol–water mixtures
`indicated that relatively low input of energy is required for
`complete dissolution/solubilization of GBN in pure ethanol and
`various ethanol–water mixtures. Overall, the positive values of
`DsolH in pure water, pure ethanol and various ethanol–water
`mixtures indicated that
`the dissolution process of GBN is
`endothermic in each case12. The DsolS values for GBN dissol-
`ution in pure water, pure ethanol and various ethanol–water
`mixtures were also observed as positive values at each tempera-
`ture studied which also indicated the possibility of GBN
`dissolution as an endothermic and an entropy-driven process
`(Table 4).
`
`Conclusions
`
`In the present study, the mole fraction solubility of GBN in
`various ethanol–water mixtures was measured by shake flask
`method at various temperatures. The solubility data of GBN was
`found to be temperature-dependent in all ethanol–water mixtures
`(solubility was found to be increased exponentially with increase
`in temperature). The lower values of % AD and higher values of
`R2 clearly indicated a good correlation between experimental
`solubility data and the modified Apelblat model. Results of
`
`Page 5
`
`

`

`DOI: 10.3109/10837450.2013.823992
`
`Thermodynamics and solubility prediction of glibenclamide
`
`707
`
`(DsolH and DsolS)
`parameters
`4. Thermodynamic
`Table
`glibenclamide in various ethanol–water mixtures.
`
`for
`
`Sample
`Ethanolþ W (w¼ 0.0)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.1)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.2)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.3)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.4)
`1)
`DsolH (kJ mol
`1K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.5)
`1)
`DsolH (kJ mol
`1K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.6)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.7)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.8)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 0.9)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`Ethanolþ W (w¼ 1.0)
`1)
`DsolH (kJ mol
`1 K
`1)
`DsolS (J mol
`
`T/K
`
`293.15 2938.15 303.15 308.15 313.15 318.15
`
`25.910
`88.387
`
`26.357
`88.404
`
`26.804 27.251 27.698 28.145
`88.420 88.436 88.451 88.466
`
`0.184
`0.630
`
`0.103
`0.353
`
`0.095
`0.326
`
`0.084
`0.287
`
`0.072
`0.248
`
`0.170
`0.581
`
`0.191
`0.652
`
`0.256
`0.873
`
`1.017
`3.471
`
`0.188
`0.631
`
`0.105
`0.353
`
`0.097
`0.327
`
`0.086
`0.288
`
`0.074
`0.249
`
`0.173
`0.582
`
`0.194
`0.653
`
`0.260
`0.874
`
`1.035
`3.473
`
`0.191
`0.631
`
`0.195
`0.632
`
`0.198
`0.633
`
`0.201
`0.634
`
`0.107
`0.354
`
`0.109
`0.354
`
`0.111
`0.356
`
`0.113
`0.356
`
`0.099
`0.328
`
`0.101
`0.328
`
`0.103
`0.329
`
`0.105
`0.330
`
`0.087
`0.289
`
`0.089
`0.289
`
`0.091
`0.290
`
`0.092
`0.291
`
`0.075
`0.250
`
`0.077
`0.250
`
`0.078
`0.251
`
`0.080
`0.252
`
`0.176
`0.583
`
`0.179
`0.584
`
`0.183
`0.584
`
`0.186
`0.585
`
`0.198
`0.654
`
`0.202
`0.655
`
`0.205
`0.656
`
`0.209
`0.657
`
`0.265
`0.875
`
`0.270
`0.876
`
`0.274
`0.877
`
`0.279
`0.878
`
`1.053
`3.476
`
`1.071
`3.478
`
`1.090
`3.480
`
`1.108
`3.483
`
`12.235
`41.738
`
`12.454
`41.771
`
`12.672 12.890 13.109 13.327
`41.802 41.833 41.563 41.891
`
`Distilled water (W), mass fraction of ethanol in cosolvent mixtures (w).
`
`thermodynamic parameters indicated that GBN dissolution is
`endothermic in pure water, pure ethanol and various ethanol–
`water mixtures. Overall, these preliminary studies indicated that
`ethanol could be used as a green and environmentally benign
`cosolvent in preformulation studies and formulation development
`especially for liquid dosage forms of GBN.
`
`Acknowledgements
`
`to Center of Excellence in Biotechnology
`The authors are grateful
`Research (CEBR) and Department of Pharmaceutics, College of
`Pharmacy, King Saud University, Riyadh, Saudi Arabia for providing
`necessary facilities to carry out these studies.
`
`Declaration of interest
`
`The authors report no declaration of interest. The authors alone are
`responsible for the content and writing of the paper.
`
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