Solubility of anti-inflammatory drug lornoxicam in ten different green solvents at different temperatures

Journal of Molecular Liquids 209 (2015) 280–283

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Solubility of anti-inflammatory drug lornoxicam in ten different green solvents at different temperatures Faiyaz Shakeel a,b,⁎, Nazrul Haq a,b, Fars K. Alanazi b, Ibrahim A. Alsarra a,b a b

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

a r t i c l e

i n f o

Article history: Received 5 April 2015 Received in revised form 15 May 2015 Accepted 16 May 2015 Available online xxxx Keywords: Apelblat model Green solvent Lornoxicam Solubility Thermodynamics Van't Hoff model

a b s t r a c t In this work, the solubility of poorly water soluble anti-inflammatory drug lornoxicam (LOX) in ten different green solvents such as water, ethanol, 1-butanol, 2-butanol, ethylene glycol (EG), ethyl acetate (EA), isopropanol (IPA), propylene glycol (PG), polyethylene glycol-400 (PEG-400) and 2-(2-ethoxyethoxy) ethanol was measured at T = (298.15 to 323.15) K and p = 0.1 MPa using an isothermal method. The measured solubility data of LOX were correlated with Apelblat and Van't Hoff models with root mean square deviations in the range of 0.33 to 3.70%. The mole fraction solubility of LOX was observed highest in PEG-400 (8.55 × 10−3) followed by 2-(2ethoxyethoxy) ethanol, EG, EA, PG, 2-butanol, 1-butanol, IPA, ethanol and water at T = 298.15 K. Thermodynamic analysis indicated an endothermic and spontaneous dissolution behavior of LOX in all green solvents. © 2015 Elsevier B.V. All rights reserved.

1. Introduction The IUPAC name of lornoxicam (LOX) is 6-chloro-4-hydroxy-2methyl-N-2-pyridinyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide as shown in Fig. 1 [1,2]. It is commercially available as orange to yellow crystalline powder [2]. It is a newly launched non-steroidal anti-inflammatory drug (NSAID) which is used in the treatment of pains associated with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and postoperative dental pain [3–5]. It is marketed in the form of tablets and injections and its dose is relatively low as compared to other NSAIDs [3]. It has been reported as practically insoluble in water which results in poor in vivo absorption and bioavailability upon oral administration [1,3]. The solubility data of solid solutes in pure solvents could be useful in purification, crystallization, drug development process and formulation development [6–8]. The commonly used environmentally benign solvents (green solvents) for solubility enhancement of poorly water soluble drugs are ethanol, propylene glycol (PG) and polyethylene glycol-400 (PEG-400) [8–10]. Recently, 2-(2-ethoxyethoxy) ethanol (Transcutol) has also been investigated as a potential green solvent for solubility enhancement of various poorly water soluble drugs [11,12]. Various approaches such as cosolvency, solid dispersion and complexation have been investigated for solubility and dissolution enhancement of LOX in literature [3,13–15]. ⁎ Corresponding author at: Center of Excellence in Biotechnology Research, College of Science, King Saud University, Riyadh, Saudi Arabia. E-mail address: [email protected] (F. Shakeel).

http://dx.doi.org/10.1016/j.molliq.2015.05.035 0167-7322/© 2015 Elsevier B.V. All rights reserved.

Moreover, the solubility of LOX in various pure solvents such as water, ethanol, ethyl acetate (EA), PG and PEG-400 at 298.15 K has also been reported in literature [3]. However, the temperature dependent solubility data of LOX in water, ethanol, ethylene glycol (EG), EA, 1-butanol, 2-butanol, isopropyl alcohol (IPA), PG, PEG-400 and 2-(2-ethoxyethoxy) ethanol are not available in literature. Therefore, in this work, the solubilities of crystalline LOX were measured at T = (298.15 to 323.15) K and p = 0.1 MPa using an isothermal method. From solubility data of crystalline LOX, various thermodynamic parameters for LOX dissolution were also determined using Van't Hoff and Krug et al. analysis approaches.

2. Experimental 2.1. Materials LOX, 1-butyl alcohol (IUPAC name: 1-butanol), 2-butyl alcohol (IUPAC name: 2-butanol) and ethyl alcohol (IUPAC name: ethanol) were obtained from Sigma Aldrich (St. Louis, MO). EG (IUPAC name: ethane-1,2-diol), EA (IUPAC name: ethyl acetate) and IPA (IUPAC name: 2-propanol) were obtained from Winlab Laboratory (Leicestershire, UK). PG (IUPAC name: propane-1,2-diol) and PEG-400 [IUPAC name: poly(ethylene glycol)-400] were obtained from Fluka Chemicals (Busch, Switzerland). Transctol [IUPAC name: 2-(2-ethoxyethoxy) ethanol] was obtained from Gattefosse (Lyon, France). The water used in this work was chromatographic grade/high pure deionized water which was collected from Milli-Q water purification unit (Berlin,

F. Shakeel et al. / Journal of Molecular Liquids 209 (2015) 280–283

Fig. 1. Molecular structure of LOX (molar mass: 371.81 g·mol−1).

Germany). The general information regarding all these materials is listed in Table 1. 2.2. Determination of LOX solubility The solubility of LOX in ten different green solvents was determined at T = (298.15 to 323.15) K and p = 0.1 MPa using an isothermal method [16]. The excess amount of crystalline LOX was added in known amount of each green solvent. The experiments were carried out in triplicates. The samples were shaken continuously in a biological shaker bath (Julabo, PA) equipped with a thermostatic bath which was used to control the temperature. The speed of shaker was maintained at 100 rpm and experiments were performed for 72 h [8,9]. After 72 h, the samples were taken out from the biological shaker and allowed to settle LOX particles for 2 h [11,12]. The supernatants were taken, centrifuged (at 5000 rpm for 10 min) to remove fine solid particles, diluted with 0.05 M sodium hydroxide solution and subjected for analysis of LOX content using a UV–Visible spectrophotometer at a maximum wavelength of 376 nm [13]. The proposed spectrophotometric method was found to be linear in the concentration range of 1 to 25 μg·g− 1 with correlation coefficient (R2) of 0.999. The experimental mole fraction solubility (xe) of LOX was calculated as reported in literature [6,7].

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400 and EA at T = 298.15 K was observed as 2.91 × 10−6, 8.43 × 10−6, 3.17 × 10−5, 8.55 × 10−3 and 8.39 × 10−5, respectively. These results were in accordance with previously published report. In general, the mole fraction solubility of LOX was found to be increasing with the rise in temperature in all green solvents. The mole fraction solubilities of crystalline LOX were observed highest in PEG-400 (8.55 × 10−3 at T = 298.15 K) followed by 2-(2-ethoxyethoxy) ethanol (3.17 × 10−4 at T = 298.15 K), EG (2.24 × 10−4 at T = 298.15 K), EA (8.39 × 10− 5 at T = 298.15 K), PG (3.17 × 10−5 at T = 298.15 K), 2-butanol (2.99 × 10−5 at T = 298.15 K), 1-butanol (1.36 × 10−5 at T = 298.15 K), IPA (9.05 × 10− 6 at T = 298.15 K), ethanol (8.43 × 10− 6 at T = 298.15 K) and water (2.91 × 10− 6 at T = 298.15 K) at room temperature (Table 2). The solubilities of crystalline LOX in PEG-400 were significantly higher than other green solvents investigated. This observation was possible due to higher molar mass of PEG-400.

3.2. Correlation of measured solubilities of LOX with Apelblat equation According to this equation, the solubility of crystalline LOX was calculated using Eq. (1) [17,18]:

ln xApl ¼ A þ

B þ C ln ðT Þ: T

ð1Þ

In which, xApl is the solubility of crystalline LOX calculated by Apelblat equation and T is the absolute temperature (K). The coefficients A, B and C are the Apelblat parameters and these coefficients were calculated by multivariate regression analysis of experimental solubilities of LOX [11]. The correlation between xe and xApl was made by the calculation of the root mean square deviations (RMSD) which was calculated using Eq. (2) [11]. "

3. Results and discussion RMSD ¼

3.1. Solubility data of LOX The solubility data of LOX in ten different green solvents at T = (298.15 to 323.15) K and p = 0.1 MPa are presented in Table 2. Temperature-dependent solubility data of LOX in water, ethanol, 1butanol, 2-butanol, EG, EA, IPA, PG, PEG-400 and 2-(2-ethoxyethoxy) ethanol have not been reported in literature. Nevertheless, the solubility of LOX in many of these solvents such as water, ethanol, PG, PEG-400 and EA at T = 298.15 K has been reported in literature [3]. The mole fraction solubility of LOX in water, ethanol, PG, PEG-400 and EA at T = 298.15 K has been reported as 2.74 × 10−6, 8.18 × 10− 6, 3.27 × 10− 5, 8.64 × 10− 3 and 8.79 × 10−5, respectively [3]. In this work, the mole fraction solubility of LOX in water, ethanol, PG, PEG-

2 #12 N  Apl 1X x −xe xe N i¼1

ð2Þ

In which, the symbol N is the number of data points used in the experiment. The graphical correlation between x e and xApl in ten different green solvents at T = (298.15 to 323.15) K is presented in Fig. S1. The resulting data of Apelblat correlation in ten different green solvents are listed in Table S1. The RMSD values in ten different green solvents were recorded in the range of 0.26 to 1.88% (Table S1). The R2 values for crystalline LOX in ten different green solvents were recorded in the range of 0.9981 to 0.9999. These results indicated good correlation of experimental solubility data of crystalline LOX with Apelblat model.

Table 1 General information regarding LOX and green solvents. Material

Molecular formula

Molar mass (g·mol−1)

Purity (mass fraction)

Analysis method

Source

LOX Ethanol Ethylene glycol Ethyl acetate Propylene glycol Polyethylene glycol-400 2-Propanol 1-Butanol 2-Butanol 2-(2-Ethoxyethoxy) ethanol Water

C13H10ClN3O4S2 C2H5OH C2H6O2 C4H8O2 C3H8O2 H(OCH2CH2)nOH C3H8O C4H10O C4H10O C6H14O3 H2O

371.82 46.07 62.07 88.11 76.09 400 60.10 74.12 74.12 134.17 18.01

N0.980 0.999 0.996 0.998 0.995 0.999 0.997 0.990 0.990 0.999 –

HPLC GC GC GC GC GC GC HPLC HPLC GC –

Sigma Aldrich Sigma Aldrich Winlab Laboratory Winlab Laboratory Fluka Chemicals Fluka Chemicals Winlab Laboratory Sigma Aldrich Sigma Aldrich Gattefosse Milli-Q Purification Unit

High performance liquid chromatography (HPLC); gas chromatography (GC).

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F. Shakeel et al. / Journal of Molecular Liquids 209 (2015) 280–283

Table 2 Experimental solubility (xe) data of crystalline LOX in ten different green solvents (S) at temperatures T = (298.15 to 323.15) K and pressure p = 0.1 MPaa. S

xe

Water Ethanol PG PEG-400 2-(2-Ethoxyethoxy) ethanol EG IPA EA 1-Butanol 2-Butanol a

T = 298.15 K

T = 303.15 K

T = 308.15 K

T = 313.15 K

T = 323.15 K

2.91 × 10−6 8.43 × 10−6 3.17 × 10−5 8.55 × 10−3 3.17 × 10−4 2.24 × 10−4 9.05 × 10−6 8.39 × 10−5 1.36 × 10−5 2.99 × 10−5

4.12 × 10−6 1.16 × 10−5 3.60 × 10−5 1.01 × 10−2 3.82 × 10−4 3.34 × 10−4 1.16 × 10−5 9.08 × 10−5 1.55 × 10−5 3.59 × 10−5

5.52 × 10−6 1.45 × 10−5 4.05 × 10−5 1.14 × 10−2 4.62 × 10−4 4.74 × 10−4 1.45 × 10−5 9.86 × 10−5 1.75 × 10−5 4.19 × 10−5

7.27 × 10−6 1.98 × 10−5 4.50 × 10−5 1.29 × 10−2 5.52 × 10−4 6.34 × 10−4 1.81 × 10−5 1.07 × 10−4 1.99 × 10−5 4.78 × 10−5

1.19 × 10−5 3.22 × 10−5 5.40 × 10−5 1.69 × 10−2 7.43 × 10−4 1.08 × 10−3 2.67 × 10−5 1.21 × 10−4 2.39 × 10−5 6.58 × 10−5

The standard uncertainties u are u(T) = 0.18 K, u(p) = 0.003 MPa and ur(xe) = 1.24%.

Finally, the standard dissolution entropy (ΔsolS0) for LOX dissolution in ten different green solvents was calculated using Eq. (6):

3.3. Correlation of measured solubilities of LOX with Van't Hoff model According to this model, the solubility of crystalline LOX can be calculated using Eq. (3) [19]: b 0 ln xVan t ¼ a þ : T

ð3Þ

In which, xVan't is the solubility of crystalline LOX calculated by Van't Hoff model. The parameters a and b are Van't Hoff model parameters. The parameters a and b were determined by plotting ln xe values of LOX as a function of 1/T. For correlation of experimental solubilities of LOX with Van't Hoff model, the RMSD values were calculated again using Eq. (2). The graphical correlation between xe and xVan't in ten different green solvents at T = (298.15 to 323.15) K is presented in Fig. S2. The resulting data of Van't Hoff correlation in ten different green solvents are listed in Table S2. The RMSD values in ten different green solvents were recorded in the range of 0.63 to 3.70% (Table S2). The R2 values for crystalline LOX in ten different green solvents were recorded in the range of 0.9950 to 0.9990. These results again indicated good correlation of experimental solubilities of LOX with Van't Hoff model. 3.4. Thermodynamic analysis for LOX dissolution

Δsol S0 ¼

Δsol H 0 −Δsol G0 : T hm

ð6Þ

The resulting data of ΔsolH0, ΔsolG0 and ΔsolS0 along with R2 values for LOX dissolution in ten different green solvents are listed in Table 3. The ΔsolH0 values for LOX dissolution in ten different green solvents were observed as positive values in the range of 11.90 to 50.21 kJ·mol−1. The ΔsolH0 value for LOX dissolution in water, ethanol, 1-butanol, 2-butanol, EG, EA, IPA, PG, PEG-400 and 2-(2-ethoxyethoxy) ethanol was found to be 44.80 kJ·mol− 1, 42.76 kJ·mol−1, 18.27 kJ·mol− 1, 24.97 kJ·mol− 1, 50.21 kJ·mol− 1, 11.90 kJ·mol−1, 34.55 kJ·mol−1, 17.04 kJ·mol−1, 21.49 kJ·mol−1 and 27.40 kJ·mol−1, respectively. The ΔsolG0 values for LOX dissolution in ten different green solvents were also recorded as positive values in the range of 11.42 to 31.03 kJ·mol− 1. The ΔsolG0 value for LOX dissolution in water, ethanol, 1-butanol, 2-butanol, EG, EA, IPA, PG, PEG-400 and 2(2-ethoxyethoxy) ethanol was found to be 31.03 kJ·mol−1, 28.43 kJ·mol− 1, 28.09 kJ·mol− 1, 25.84 kJ·mol− 1, 19.64 kJ·mol−1, 23.66 kJ·mol−1, 28.53 kJ·mol−1, 25.95 kJ·mol−1, 11.42 kJ·mol−1 and 19.67 kJ·mol−1, respectively. The positive values of ΔsolH0 and ΔsolG0 for LOX dissolution indicated an endothermic and spontaneous dissolution of LOX in all green solvents investigated. The ΔsolS0 values for LOX

The standard enthalpy (ΔsolH 0) for dissolution of crystalline LOX in ten different green solvents was measured by Van't Hoff analysis [20, 21]. The ΔsolH 0 values for LOX dissolution were calculated at mean harmonic temperature (Thm) of 308.91 K using Eq. (4): 

 ∂ln xe Δ H0 ¼ − sol : R ∂ð1=T−1=T hm Þ P

ð4Þ

In which, R is the universal gas constant and other parameters are already defined in the previous text. The graphs between ln xe values of LOX and 1/T − 1/Thm were plotted. The ΔsolH 0 values of crystalline LOX in ten different green solvents were calculated from the slope of each plot. These plots were found to be linear with R2 values in the range of 0.9954 to 0.9991 as shown in Fig. 2. The standard Gibbs function (ΔsolG0) for LOX dissolution in ten different green solvents was determined at Thm of 308.91 K by Krug et al. analysis approach using Eq. (5) [22]: Δsol G0 ¼ −RT hm  intercept:

ð5Þ

In which, the intercept values for each green solvent were determined from Fig. 2.

Fig. 2. Van't Hoff plots for crystalline LOX in ten different green solvents at mean harmonic temperature of 308.91 K; water, ethanol, IPA, EG, EA, PG, PEG-400, 2-(2-ethoxyethoxy) ethanol, 1-butanol and 2-butanol.

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Table 3 Thermodynamic data and R2 values for dissolution of crystalline LOX in ten different green solvents at mean harmonic temperature of 308.91 Ka. Parameters

Water

Ethanol

PG

PEG-400

2-(2-Ethoxyethoxy) ethanol

EG

IPA

EA

1-Butanol

2-Butanol

ΔsolH0/kJ·mol−1 ΔsolG0/kJ·mol−1 ΔsolS0/J·mol−1·K−1 R2

44.80 31.03 44.69 0.9975

42.76 28.43 46.54 0.9980

17.04 25.95 −28.93 0.9973

21.49 11.42 32.70 0.9983

27.40 19.67 25.07 0.9987

50.21 19.64 99.24 0.9954

34.55 28.53 18.93 0.9991

11.90 23.66 −38.20 0.9974

18.27 28.09 −31.87 0.9957

24.91 25.84 −3.01 0.9986

a

The average uncertainties are u(ΔsolH0) = 0.28 kJ·mol−1, u(ΔsolG0) = 0.16 kJ·mol−1 and u(ΔsolS0) = 0.32 kJ·mol−1·K−1.

dissolution in six green solvents such as water, ethanol, PEG-400, 2-(2ethoxyethoxy) ethanol, EG and IPA were also observed as positive values in the range of 18.93 to 99.24 J·mol−1·K− 1, indicating an entropy-driven dissolution of LOX in these solvents. However, the ΔsolS0 values for LOX dissolution in remaining four solvents such as PG, EA, 1-butanol and 2-butanol were observed as negative values, indicating that the dissolution of LOX in these solvents was not an entropydriven dissolution. The ΔsolG0 values for LOX dissolution in PEG-400 were significantly lower as compared to water. These results indicated that low energy is required for the solubilization of LOX in PEG-400 as compared to water. The positive values of ΔsolH0 for LOX dissolution were probably due to the stronger molecular interactions between the molecules of LOX and the molecules of solvent as compared to those between the molecules of solvent–solvent and the molecules of LOX– LOX [11,12]. 4. Conclusion The solubilities of poorly water soluble anti-inflammatory drug LOX in ten different green solvents were measured at T = (298.15 to 323.15) K and p = 0.1 MPa using an isothermal method. The solubility of crystalline LOX was found to be increasing with the rise in temperature in all green solvents. The mole fraction solubility of crystalline LOX was found to be highest in PEG-400 followed by 2-(2-ethoxyethoxy) ethanol, EG, EA, PG, 2-butanol, 1-butanol, IPA, ethanol and water at room temperature. The measured solubility data of LOX were correlated well with the Apelblat and Van't Hoff models in all green solvents investigated. Thermodynamic analysis indicated an endothermic and spontaneous dissolution of LOX in all green solvents investigated. Conflict of interest The authors report no conflict of interest related with this manuscript. Acknowledgment The project was financially supported by King Saud University, Vice Deanship of Research Chairs, Kayyali Chair for Pharmaceutical Industry (Grant no. FN-2015).

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.molliq.2015.05.035.

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