Journal of Molecular Liquids 191 (2014) 68–72

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Journal of Molecular Liquids

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Solubility of antipsychotic drug risperidone in Transcutol + waterco-solvent mixtures at 298.15 to 333.15 K

Faiyaz Shakeel a,b,⁎, Fars K. Alanazi b,c, Ibrahim A. Alsarra a,b, Nazrul Haq a,b

a Center of Excellence in Biotechnology Research (CEBR), King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabiab Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabiac Kayyali Chair for Pharmaceutical Industry, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia

⁎ Corresponding author at: Center of Excellence in BiotUniversity, Riyadh, Saudi Arabia. Tel.: +966 537507318.

E-mail address: faiyazs@fastmail.fm (F. Shakeel).

0167-7322/$ – see front matter © 2013 Elsevier B.V. All rihttp://dx.doi.org/10.1016/j.molliq.2013.11.026

a b s t r a c t

a r t i c l e i n f o

Article history:Received 4 November 2013Received in revised form 22 November 2013Accepted 25 November 2013Available online 5 December 2013

Keywords:RisperidoneSolubilityThermodynamicsTranscutol

The objective of this study was to determine the mole fraction solubility of a poorly water soluble antipsychoticdrug risperidone (RIS) in mono-solvents and various Transcutol + water co-solvent mixtures at 298.15 to333.15 K. The experimental solubility of RIS was determined using shake flask method and resulting data werecorrelated with the modified Apelblat model at 298.15 to 333.15 K. Excellent correlation existed between theexperimental data of RIS and the calculated one with absolute relative deviation in the range of 0.009–6.374%.The correlation coefficients were observed in the range of 0.996–0.999, indicating good fitting. The lowestmole fraction solubility of RIS was observed in pure water (1.100 × 10−7 at 298.15 K) whereas the highestone was observed in pure Transcutol (5.163 × 10−3 at 298.15 K). The enthalpies and entropies for RISdissolution were observed in the range of 10.005–45.723 kJ mol−1 and 33.558–137.246 J mol−1 K−1,respectively in all sample matrices, indicating that the dissolution of RIS is an endothermic and an entropy-driven process. Based on solubility data of this study, RIS was considered as practically insoluble in water andsoluble in Transcutol and most of the co-solvent mixtures. Overall, these studies indicated that Transcutolcould be used as a physiologically compatible co-solvent for solubility enhancement of RIS which could help informulation development of RIS.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

Risperidone (RIS) is 3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one [1,2]. It is a white crystalline powder with molecularmass and molecular formula of 410.48 g mol−1 and C23H27FN4O2,respectively (Fig. 1) [3,4]. It is an approved antipsychotic drugbelonging to the benzisoxazole class and commercially available asconventional tablets, disintegrating tablets and oral liquid [1]. It is apotent drug which is prescribed frequently in the treatment ofschizophrenia and bipolar mania [3]. It is practically insoluble in waterdue to which its dissolution rate is poor [4]. Poor aqueous solubilityand extensive first pass metabolism of RIS are main barriers for poorin vivo absorption/bioavailability of RIS [1]. The aqueous solubility ofRIS at 25 and 37 °C has been reported as 2.8 and 5 μg mL−1, respectively[3,4]. Various approaches such as resin-complexation, cyclodextrin-complexation, pH modifiers (benzoic acid and tartaric acid), oraldisintegrating tablets and nanoemulsion have been used to enhance

echnology Research, King Saud

ghts reserved.

solubility and bioavailability of RIS [1–9]. However, the co-solventapproach has not been used to enhance aqueous solubility of RIS inliterature so far. Co-solvent technique is generally considered as anerror free approachwhich can be applied in solubilization and stabiliza-tion of drugs/pharmaceuticals in aqueous solutions [10–12]. Solubilityof the drugs is a key parameter in the formulation developmentespecially in terms of liquid dosage forms of poorly soluble drugs[13–15]. Transcutol-HP is highly purified diethylene glycol monoethylether with molecular mass and molecular formula of 134.17 g mol−1

and C6H14O3, respectively [13]. It has been used as a co-surfactant inthe formulation development of various oil-based nanocarriers suchas nanoemulsions/microemulsions and self-nanoemulsifying (SNEDDS)/self-microemulsifying (SMEDDS) drug delivery systems [13,16–18].These oil-based nanocarriers (nanoemulsions/microemulsions andSNEDDS/SMEDDS) are known to enhance solubility/dissolution andbioavailability of poorly soluble drugs [17–21]. Nevertheless, it has notbeen used as a co-solvent to enhance solubility of RIS in co-solventmixtures in the literature so far. Therefore, the aim of the presentstudy was to measure the mole fraction solubility of RIS in mono-solvents (pure water and pure Transcutol) and various Transcutol–water co-solvent mixtures at 298.15 to 333.15 K. The experimentalsolubility data of RIS also correlated with the modified Apelblat modelat 298.15 to 333.15 K. These preliminary studies could be useful in thedevelopment of liquid and oil based nanocarriers of RIS.

Fig. 1.Molecular structure of risperidone.

Table 1Experimental (xe) and calculated mole fraction solubility (xmAc) of risperidone inTranscutol + water co-solvent mixtures from 298.15 to 333.15 Ka.

T/K 103 xe 103 xmAc AD (%)

Transcutol + W (m = 0.0)298.15 0.0001 0.0001 −6.374303.15 0.0001 0.0001 3.148308.15 0.0002 0.0002 2.145313.15 0.0002 0.0002 0.483318.15 0.0003 0.0003 3.055323.15 0.0004 0.0004 1.639328.15 0.0005 0.0005 0.037333.15 0.0006 0.0006 −4.369

Transcutol + W (m = 0.1)298.15 0.018 0.018 0.160303.15 0.022 0.022 −1.276308.15 0.029 0.028 2.459313.15 0.036 0.035 2.489318.15 0.046 0.044 4.184323.15 0.056 0.054 3.572328.15 0.067 0.067 −0.210333.15 0.081 0.082 −1.433

Transcutol + W (m = 0.2)298.15 0.024 0.025 −0.276303.15 0.033 0.033 1.141308.15 0.045 0.043 3.613313.15 0.058 0.056 2.455318.15 0.074 0.074 0.051323.15 0.100 0.096 4.354328.15 0.127 0.124 2.056333.15 0.159 0.160 −0.960

Transcutol + W (m = 0.3)298.15 0.039 0.039 −1.665303.15 0.050 0.051 −0.397308.15 0.065 0.065 −0.586313.15 0.082 0.083 −0.874318.15 0.106 0.106 0.243323.15 0.138 0.134 2.796328.15 0.173 0.170 2.020333.15 0.203 0.214 −5.264

Transcutol + W (m = 0.4)298.15 0.052 0.051 1.555303.15 0.067 0.067 −0.731308.15 0.087 0.088 −1.199313.15 0.119 0.114 3.883318.15 0.157 0.148 5.715323.15 0.200 0.191 4.096328.15 0.248 0.246 0.758333.15 0.308 0.315 −2.174

Transcutol + W (m = 0.5)298.15 0.239 0.235 1.664303.15 0.280 0.277 1.331308.15 0.321 0.324 −1.135313.15 0.370 0.379 −2.419318.15 0.431 0.442 −2.512323.15 0.510 0.514 −0.816328.15 0.604 0.597 1.251333.15 0.703 0.691 1.737

Transcutol + W (m = 0.6)298.15 0.465 0.461 0.933303.15 0.512 0.518 −1.144308.15 0.575 0.582 −1.318313.15 0.647 0.652 −0.765318.15 0.720 0.730 −1.321323.15 0.793 0.815 −2.756328.15 0.897 0.909 −1.300333.15 1.030 1.012 1.802

Transcutol + W (m = 0.7)298.15 0.656 0.656 0.009303.15 0.735 0.730 0.778308.15 0.809 0.810 −0.119313.15 0.890 0.897 −0.805318.15 0.968 0.992 −2.534

(continued on next page)

69F. Shakeel et al. / Journal of Molecular Liquids 191 (2014) 68–72

2. Experiment

2.1. Materials

RIS (mass fraction purity of 0.993) was purchased from SigmaAldrich (St. Louis, MO). Tarnscutol-HP (mass fraction purity of 0.999)was obtained as a gift sample from Gatefosse (Cedex, France). Distilledwater was procured from distillation unit. All other chemicals usedwere of analytical grade.

2.2. Measurement of RIS solubility

The mole fraction solubility of RIS in Transcutol + water co-solventmixtures (mass fractionm = 0.1–0.9) including pure water (m = 0.0)and pure Transcutol (m = 1.0) was measured by the shake flaskmethod at 298.15 to 333.15 K [11,12]. The excess amount of RIS wasadded in 5 mL of each co-solvents mixture or mono-solvents in 10 mLcapacity flasks in triplicate to obtain RIS suspensions. RIS suspensionof each co-solvent mixture was then transferred to an isothermalmechanical shaker bath (Julabo, PA) at 100 rpm for 72 h to reach theequilibrium. After 72 h, all of the RIS suspensions were removed fromthe shaker and allowed to settle drug particles for 2 h at the bottom ofthe flasks [15,22]. All the samples were filtered using a 0.45 μm filterpaper; the supernatant of each sample was diluted 1000 times withthe respective solvent/co-solvent mixture and subjected for analysis ofRIS content at the wavelength of 283 nm using UV–visible spectropho-tometer (SP1900, Axiom, Germany) [4]. The proposed analyticalmethod was observed linear in the range of 2–50 μg mL−1 withcorrelation coefficient of 0.999. The experimental uncertainty intemperature was observed ±0.220 K. However, the uncertainty inexperimental solubilities was observed as 1.450%. The experimentalmole fraction solubility (xe) of RIS was calculated as reported inliterature [12,15,20,22].

3. Results and discussion

3.1. Solubility data of RIS

The experimental mole fraction solubility data of RIS in mono-solvents (pure Transcutol and pure water) and co-solvent mixtures at298.15 to 333.15 K are listed in Table 1. The solubility of RIS wasfound to be increased rapidly with increase in temperature and massfraction of Transcutol in co-solvent mixtures in all sample matrices.The mole fraction solubility of RIS was found to be lowest in purewater (m = 0.0) (1.100 × 10−7 at 298.15 K) whereas the highestone was observed in pure Transcutol (m = 1.0) (5.163 × 10−3 at298.15 K) at 298.15 to 333.15 K as shown in Table 1. The mole fractionsolubility of RIS in pure Transcutol was significantly higher than purewater at each temperature studied. The effects of mass fraction ofTranscutol on mole fraction solubility of RIS at 298.15 to 333.15 K arepresented in Fig. 2. The mole fraction solubility of RIS was found to beincreased with increase in mass fraction of Transcutol in co-solventmixtures at each temperature studied. The lowest and highest solubilityof RIS in purewater and pure Transcutolwas probably due to higher andlower polarity ofwater and Transcutol, respectively. Therefore, themole

Table 1 (continued)

T/K 103 xe 103 xmAc AD (%)

323.15 1.079 1.096 −1.570Transcutol +W (m= 0.7)328.15 1.201 1.208 −0.601333.15 1.357 1.330 1.931

Transcutol + W (m = 0.8)298.15 1.382 1.364 1.356303.15 1.511 1.491 1.299308.15 1.609 1.628 −1.173313.15 1.752 1.774 −1.251318.15 1.912 1.932 −1.043323.15 2.108 2.100 0.367328.15 2.293 2.280 0.534333.15 2.506 2.473 1.305

Transcutol + W (m = 0.9)298.15 2.675 2.694 −0.714303.15 2.893 2.885 0.254308.15 3.090 3.086 0.126313.15 3.268 3.298 −0.911318.15 3.449 3.520 −2.040323.15 3.722 3.753 −0.845328.15 3.978 3.998 −0.502333.15 4.274 4.255 0.441

Transcutol + W (m = 1.0)298.15 5.163 5.145 0.346303.15 5.987 5.901 1.441308.15 6.652 6.753 −1.510313.15 7.606 7.711 −1.374318.15 8.465 8.786 −3.790323.15 9.954 9.990 −0.369328.15 11.349 11.338 0.093333.15 13.007 12.843 1.264

a The uncertainty in temperature and experimental solubility were observed as ±0.220 K and 1.450%, respectively and experimentswere recorded at atmospheric pressureof 0.1 MPa.

70 F. Shakeel et al. / Journal of Molecular Liquids 191 (2014) 68–72

fraction solubility of solute could depend on several factors such aspolarity of co-solvent mixtures, temperature, mass fraction andmolecular masses of solutes and solvents [11,12,20]. These results

Fig. 2. Effects of mass fraction of Transcutol (m) on mole fract

were in accordance with recently published mole fraction solubilitydata of indomethacin in polyethylene glycol 400 + water andethanol + propylene glycol co-solvent mixtures and nifedipine inpolyethylene glycol + water co-solvent mixtures [12,14,15]. The molefraction solubility of RIS in pure water at 298.15 K and 310.15 K hasbeen reported as 1.230 × 10−7 and 2.190 × 10−7, respectively [3,4].However, in the present study the mole fraction solubility of RIS inpure water at 298.15 K and 308.15 K was observed as 1.180 × 10−7

and 1.670 × 10−7, respectively which were very close to reportedvalues (Table 1). Based on these results, RIS has been considered aspractically insoluble water and soluble in Transcutol. Hence, Transcutolcould be used as a physiologically compatible co-solvent in formulationdevelopment of RIS especially in terms of liquid dosage forms in futurestudies.

3.2. Thermodynamic modeling of RIS solubility

In the present study, the experimental data of RIS were correlatedwith the modified Apelblat model because of its frequent applica-tions for both polar as well as for nonpolar systems [11,15,22].According to the modified Apelblat model, the mole fractionsolubility of drug/solute is temperature-dependent which canbe expressed using Eq. (1) to describe solid–liquid equilibrium[22,23]:

ln xe ¼ Αþ BTþ C ln Tð Þ ð1Þ

Where xe is the experimentalmole fraction solubility of RIS at 298.15to 333.15 K. T represents the absolute temperature and A, B and C arethe adjustable model parameters. Apelbalt model parameters (A, Band C) were calculated by regression analysis of experimental datawith the help of Eq. (1). The calculated/modified Apelblat solubilities(xmAc) were calculated using these model parameters. The absoluterelative deviation (%AD)was calculated using Eq. (2). The experimental

ion solubility (xe) of risperidone at various temperatures.

Table 2The modified Apelblat parameters (A, B and C) and correlation coefficients (R2) forrisperidone in Transcutol + water co-solvent mixtures.

m Apelblat parameters

A B C R2

0.0 −94.112 74.800 14.910 0.9960.1 −81.947 71.700 13.640 0.9980.2 −99.451 84.300 16.760 0.9990.3 −89.839 75.400 15.160 0.9980.4 −96.212 82.600 16.320 0.9970.5 −56.881 69.800 9.691 0.9970.6 −41.267 43.400 7.083 0.9970.7 −36.790 34.700 6.364 0.9960.8 −30.329 28.200 5.362 0.9960.9 −22.535 23.800 4.116 0.9971.0 −45.521 66.700 8.240 0.997

m, mass fraction of Transcutol in co-solvent mixtures.

71F. Shakeel et al. / Journal of Molecular Liquids 191 (2014) 68–72

and calculated solubility data alongwith % AD in all co-solventmixturesare listed in Table 1.

AD %ð Þ ¼ xe−xCð Þxe

� 100 ð2Þ

Where, xc is the calculated solubility of RIS. The%ADwas observed inthe range of 0.093–6.374% in mono-solvents at 298.15 to 333.15 K asshown in Table 1. However, the % AD was found to be 0.009–5.215% invarious co-solvent mixtures at 298.15 to 333.15 K. Overall, the AD wasfound to be less than 7.000% in all sample matrices, indicating goodcorrelation between experimental and calculated solubility data of RIS.

Table 3Thermodynamic parameters (ΔH0 and ΔS0) for risperidone dissolution in various Transcutol +

m T/K

298.15 303.15 308.15 3

0.0ΔH0 (kJ mol−1) 36.339 36.959 37.579ΔS0 (J mol−1 K−1) 121.882 121.917 121.950 10.1ΔH0 (kJ mol−1) 33.216 33.783 34.350ΔS0 (J mol−1 K−1) 111.409 111.442 111.447 10.2ΔH0 (kJ mol−1) 40.846 41.543 42.239ΔS0 (J mol−1 K−1) 136.999 137.038 137.075 10.3ΔH0 (kJ mol−1) 36.954 37.584 38.214ΔS0 (J mol−1 K−1) 123.944 123.979 124.012 10.4ΔH0 (kJ mol−1) 39.769 40.448 41.126ΔS0 (J mol−1 K−1) 133.388 133.426 133.463 10.5ΔH0 (kJ mol−1) 23.443 23.846 24.248ΔS0 (J mol−1 K−1) 78.628 78.661 78.6920.6ΔH0 (kJ mol−1) 17.197 17.492 17.786ΔS0 (J mol−1 K−1) 57.681 57.701 57.7200.7ΔH0 (kJ mol−1) 15.487 15.752 16.016ΔS0 (J mol−1 K−1) 51.945 51.961 51.9760.8ΔH0 (kJ mol−1) 13.057 13.280 13.503ΔS0 (J mol−1 K−1) 43.795 43.808 43.8210.9ΔH0 (kJ mol−1) 10.005 10.176 10.347ΔS0 (J mol−1 K−1) 33.558 33.569 33.5801.0ΔH0 (kJ mol−1) 19.872 20.214 20.557ΔS0 (J mol−1 K−1) 66.651 66.681 66.711

m, mass fraction of Transcutol in co-solvent mixtures.

The values of model parameters (A, B and C) along with correlationcoefficients (R2) in all sample matrices are listed in Table 2. The R2

values for RIS in mono-solvents were observed in the range of0.996–0.997 (Table 2). However, R2 values for RIS in co-solventmixtures were observed in the range of 0.996–0.999. These resultsindicated the good fitting of experimental data with the modifiedApelblat model.

3.3. Thermodynamic parameters for RIS dissolution

The dissolution of RIS into a solvent/co-solvent mixture can beexpressed as [20,22,24]

Solidþ liquid ¼ solid� liquid at the equilibrium

The molar enthalpies (ΔH0) and entropies (ΔS0) of RIS dissolutioncan be calculated using Eqs. (3) and (4), respectively:

ΔH0 ¼ RT C− BT

� �ð3Þ

ΔS0 ¼ R C− BT

� �ð4Þ

where, R represents the universal gas constant. The results ofthermodynamic investigations in terms of ΔH0 and ΔS0 in all samplematrices are listed in Table 3. The ΔH0 values for RIS dissolutionin mono-solvents (water and Transcutol) were ranged from36.339–40.678 and 19.872–22.269 kJ mol−1, respectively at 298.15 to333.15 K (Table 3). However, the ΔH0 values for RIS dissolution in

water co-solvent mixtures.

13.15 318.15 323.15 328.15 333.15

38.198 38.818 39.438 40.058 40.67821.982 122.013 122.044 122.073 122.101

34.917 35.485 36.052 36.619 37.18611.505 111.535 111.564 111.592 111.619

42.936 43.633 44.330 45.026 45.72337.112 137.147 137.181 137.214 137.246

38.844 39.475 40.105 40.735 41.36524.045 124.076 124.107 124.136 124.165

41.805 42.483 43.162 43.843 44.51933.498 133.533 133.566 133.599 133.630

24.651 25.054 25.457 25.860 26.26378.722 78.751 78.779 78.806 78.833

18.080 18.375 18.669 18.964 19.25857.739 57.757 57.774 57.791 57.808

16.281 16.545 16.810 17.074 17.33951.991 52.006 52.020 52.030 52.047

13.726 13.949 14.172 14.395 14.61843.833 43.845 43.856 43.867 43.878

10.518 10.689 10.861 11.032 11.20333.590 33.600 33.609 33.619 33.628

20.899 21.242 21.584 21.927 22.26966.740 66.768 66.795 66.821 66.846

72 F. Shakeel et al. / Journal of Molecular Liquids 191 (2014) 68–72

various co-solvent mixtures were observed in the range of 10.005–45.723 kJ mol−1 at 298.15 to 333.15 K (Table 3). The ΔH0 values forRIS dissolution in pure Transcutol were significantly lower as comparedto pure water, indicating that relatively low energy is required forsolubilization of RIS in pure Transcutol as compared to pure water[11]. Because of positive values of ΔH0 in all sample matrices the disso-lution of RISwas assumed to be endothermic [12,20]. Moreover, theΔS0

values for RIS dissolution were also observed as positive values(33.558–137.246 J mol−1 K−1) in all sample matrices at 298.15 to333.15 K which also indicated that RIS dissolution is an endothermicand an entropy-driven process. The positive values of ΔH0 and ΔS0 forRIS dissolution in all co-solvent mixtures were possible due to theattraction between solute and solvent molecules as reported inliterature [11,12,15,22].

4. Conclusion

In the present study, the mole fraction solubility of practicallyinsoluble drug risperidone in pure water, pure Transcutol and vari-ous co-solvent mixtures at 298.15 to 333.15 K was determined. Themole fraction solubility of risperidone was found to be increasedwith increase in temperature and mass fraction of Transcutol inall co-solvent mixtures. The solubility of risperidone was significantlyenhanced in pure Transcutol as compared to pure water. Theexperimental solubility data of risperidone were correlated andfitted well with the modified Apelblat model in all co-solvent mix-tures. Based on solubility data of this study, risperidone has beenconsidered as soluble in pure Transcutol and practically insolublein pure water. These studies indicated that Transcutol could beused as a physiologically compatible co-solvent in formulationdevelopment especially in terms of liquid dosage forms ofrisperidone.

Conflict of interest

The authors report no declaration of interest. The authors alone areresponsible for the content and writing of the paper.

Acknowledgements

The authors are highly thankful to the Center of Excellence inBiotechnology Research (CEBR) and the Department of Pharmaceutics,College of Pharmacy, King Saud University, Riyadh, Saudi Arabia fortheir funding and support.

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