Solubility and Thermodynamic Analysis of Tenoxicam in Different Pure

Article pubs.acs.org/jced

Solubility and Thermodynamic Analysis of Tenoxicam in Different Pure Solvents at Different Temperatures Faiyaz Shakeel,*,†,‡ Nazrul Haq,†,‡ Gamal A. Shazly,‡,§ Fars K. Alanazi,‡ and Ibrahim A. Alsarra†,‡ †

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 § Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, Egypt Downloaded by UNIV OF SOUTH DAKOTA on September 6, 2015 | http://pubs.acs.org Publication Date (Web): July 28, 2015 | doi: 10.1021/acs.jced.5b00382

S Supporting Information *

ABSTRACT: The solubility data of drugs/pharmaceuticals in aqueous and organic solvents is important in pharmaceutical industries. Therefore, in this current study, the solubility of the practically insoluble drug tenoxicam (TNX) in various pure solvents, namely, water, ethyl alcohol, 1butyl alcohol, 2-butyl alcohol, ethylene glycol (EG), ethyl acetate (EA), isopropyl alcohol (IPA), propylene glycol (PG), polyethylene glycol-400 (PEG-400) and 2-(2-ethoxyethoxy)ethanol (Transcutol) was measured at different temperatures and atmospheric pressure. The measured solubilities of TNX were correlated well with calculated ones. The mole fraction solubility of crystalline TNX was found to be the highest in PEG-400 (9.76·10−3) followed by 2-(2ethoxyethoxy)ethanol (1.83·10−3), EA (6.79·10−4), EG (2.13·10−4), PG (1.94·10−4), 1-butyl alcohol (8.13·10−5), IPA (6.27·10−5), 2-butyl alcohol (6.15·10−5), ethyl alcohol (3.71·10−5), and water (4.11·10−6) at T = 298.15 K. Thermodynamic analysis indicated an endothermic and spontaneous dissolution of TNX due to positive values of standard enthalpy and Gibbs energy in all pure solvents investigated. The values of standard entropy for TNX dissolution were also observed as positive values in most of the solvents (except ethyl alcohol, 2-(2-ethoxyethoxy)ethanol and EA), indicating an entropy-driven dissolution of TNX in most of the pure solvents investigated.

1. INTRODUCTION The IUPAC name of tenoxicam (TNX) had been proposed as 4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno(2,3-e)-1,2-thiazine-3-carboxmide-1,1-dioxide and its molecular structure is presented in Figure 1.1,2 It occurs as a yellow crystalline powder

daily dose is relatively low (20 mg) in comparison with other NSAIDs.3 It is practically insoluble in water which creates hindrances in its in vivo bioavailability and development of injection formulations.6 Temperature-dependent solubility data of poorly water-soluble drugs in pure solvents/cosolvents are extremely useful in various research areas in pharmaceutical industries.7−9 The commonly used cosolvents in the development of injection formulations and solubility enhancement of drugs are reported as propylene glycol (PG), polyethylene glycol-400 (PEG-400), and ethanol.9−11 The potential of 2-(2ethoxyethoxy)ethanol (Transcutol) as a cosolvent had also been proven in solubility enhancement of various poorly soluble drugs, and hence it could also be utilized in the development of injection formulations of these drugs.12,13 Some approaches such as fast dissolving tablets, cosolvency approach, and solid dispersions have been evaluated in solubility and dissolution improvement of TNX.2,3,6,14−16 The solubility of TNX in various pure solvents such as water (mole fraction solubility, 4.06·10−6), ethanol (mole fraction solubility, 3.60·10−5), ethyl acetate [EA] (mole fraction solubility, 6.63· 10−4), and PG (mole fraction solubility, 2.01·10−4) at T = 298.15 K is reported in the literature.3 The solubility of TNX in

Figure 1. Molecular structure of TNX (molar mass, 337.37 g·mol−1).

with molar mass and molecular formula of 337.37 g·mol−1 and C13H11N3O4S2, respectively.1 It belongs to the oxicam class of nonsteroidal anti-inflammatory drug (NSAID) which is recommended in the treatment of pains associated with periarthritis, tenditis, bursitis, rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis.3−5 It is commercially available in both tablet as well as injection dosage forms and its © 2015 American Chemical Society

Received: May 2, 2015 Accepted: July 15, 2015 Published: July 28, 2015 2510

DOI: 10.1021/acs.jced.5b00382 J. Chem. Eng. Data 2015, 60, 2510−2514

Journal of Chemical & Engineering Data

Article

Downloaded by UNIV OF SOUTH DAKOTA on September 6, 2015 | http://pubs.acs.org Publication Date (Web): July 28, 2015 | doi: 10.1021/acs.jced.5b00382

PG (mole fraction solubility, 2.21·10−4) and PEG-400 (mole fraction solubility, 1.45·10−3) at T = 305.15 K was also determined in the literature in order to mimic skin conditions.5 Light mineral oil and various cosolvents such as ethanol, PG, and PEG-400 have been investigated as skin penetration enhancers for transdermal delivery of TNX.5,17 The temperature-dependent solubility data and thermodynamics of TNX in various pure solvents have been poorly reported in literature. Therefore, in this work, the solubilities of TNX were determined at T = (298.15 to 323.15) K and p = 0.1 MPa by shake flask method. Various thermodynamic parameters for TNX dissolution were also determined with the help of the temperature-dependent solubility data of TNX. The solubility and thermodynamic data of this work could be useful in purification, crystallization, and formulation development of TNX.

Higuchi and Connors.18 To perform these experiments, the excess amount of TNX (approximately 700 mg) was added in 3 g of each solvent in tightly closed glass vials. The vials containing concentrated suspensions of TNX were vortex mixed for about 10 min. All the experiments were repeated three times. All the glass vials were transferred to biological shakers (Julabo, PA) for continuous shaking at 100 rpm for 48 h to reach equilibrium. The time period of 48 h was enough to reach equilibrium for TNX as reported by Yeh et al. (2009).3 After equilibrium was reached, the concentrated suspensions of TNX were taken out from the shaker. The samples were allowed to settle solute/TNX particles for 2 h as reported in literature.12,13 Approximately, 1 g of supernatants was taken from each sample, centrifuged to separate fine solute particles, diluted with respective pure solvent, and subjected for quantification of TNX content spectrophotometrically at λmax of 360 nm.15 The proposed analytical method was observed linear in the range of (1 to 20) μg·g−1 with correlation coefficient (R2) value of 0.9985. The values of experimental mole fraction solubility (xe) of TNX were calculated as reported previously.10,11

2. EXPERIMENTAL SYSTEM AND METHODS 2.1. Materials. TNX, EG (IUPAC name, ethane-1,2-diol), PG (IUPAC name, propane-1,2-diol) and PEG-400 [IUPAC name, poly(oxyethene)] were obtained from Sigma-Aldrich (St. Louis, MO). Ethyl alcohol (IUPAC name, ethanol), 1-butyl alcohol (IUPAC name, 1-butanol) and 2-butyl alcohol (IUPAC name, 2-butanol) were procured from Scharlau Chemicals (Berlin, Germany). EA (IUPAC name, ethyl acetate) and IPA (IUPAC name, 2-propanol) were obtained from Acros Organics (Hamilton, NJ). Transctol [IUPAC name, 2-(2ethoxyethoxy) ethanol] was procured as a kind gift sample from Gattefosse (Lyon, France). The water was obtained from MilliQ water purification unit (Berlin, Germany) in the laboratory. The information about drug and solvents used in this work is listed in Table 1. 2.2. Measurement of TNX Solubility. The saturated solubility of TNX in different pure organic solvents and water was measured at temperatures T = (298.15 to 323.15) K and pressure p = 0.1 MPa by the shake flask method reported by

3. RESULTS AND DISCUSSION 3.1. Solubility Data of TNX and Its Comparison with Literature Values. Table 2 presents the solubility data of TNX in various pure solvents at T = (298.15 to 323.15) K and p = 0.1 MPa. The solubility data of TNX in all these pure solvents (listed in Table 2) with respect to temperature are not available in the literature. Nevertheless, the solubility of TNX in various pure solvents such as EA, ethanol, water, and PG at T = 298.15 K has been reported.3 Moreover, the solubility of TNX in PG and PEG-400 has also been reported at T = 305.15 K in order to mimic skin conditions.5 The xe value of TNX in water, ethanol, EA, and PG at T = 298.15 K has been reported as 4.05· 10−6, 3.60·10−5, 6.63·10−4, and 2.01·10−4, respectively.3 The xe value of TNX in PG and PEG-400 at T = 305.15 K has been reported as 2.21·10−4 and 1.45·10−2, respectively.5 In this work, the xe value of TNX in water, ethanol, EA, and PG at T = 298.15 K was recorded as 4.11·10−6, 3.71·10−5, 6.79·10−4, and 1.94·10−4, respectively. The xe value of TNX in PG and PEG400 at T = 305.15 K was not measured directly in this work. However, these values were determined by interpolation of a graph plotted between ln xe and T/K. The xe value of TNX in PG and PEG-400 at T = 305.15 K was recorded as 2.48·10−4 and 1.44·10−2, respectively, by the interpolation method. Overall, all these data of TNX solubility were in good agreement with literature values of TNX. From T = (298.15 to 323.15) K, the xe values of TNX were found to be increasing with increase in temperature in all pure solvents investigated. The xe values of TNX were recorded highest in PEG-400 (9.76·10 −3 ) followed by 2-(2ethoxyethoxy)ethanol (1.83·10−3), EA (6.79·10−4), EG (2.13· 10−4), PG (1.94·10−4), 1-butyl alcohol (8.13·10−5), IPA (6.27· 10−5), 2-butyl alcohol (6.15·10−5), ethyl alcohol (3.71·10−5) and water (4.11·10−6) at T = 298.15 K. The xe values of TNX in PEG-400 were sufficiently higher than in water which could be due to higher molar mass and low polarity of PEG-400 as compared to lower molar mass and higher polarity of water.10 On the basis of the solubility data obtained in this work, TNX has been considered as practically insoluble in water, slightly soluble in EA, EG, 2-(2-ethoxyethoxy)ethanol, and PEG-400, and very slightly soluble in ethanol, IPA, PG, 1-butanol, and 2butanol according to the USP and BP classification of solubility.

Table 1. A Sample Table for Drug (TNX) and Pure Solvents Used in This Work materials

mass fraction purity

purification method

analysis method a

source

TNX ethanol

> 0.990 0.999

none none

HPLC GCb

ethylene glycol ethyl acetate

> 0.990 0.998

none none

GCb GCb

propylene glycol polyethylene glycol-400 2-propanol

0.995

none

GCb

Sigma-Aldrich Scharlau Laboratory Sigma-Aldrich Acros Organics Sigma-Aldrich

0.999

none

GCb

Sigma-Aldrich

0.997

none

GCb

1-butanol

> 0.990

none

GCb

2-butanol

> 0.990

none

GCb

Transcutol water

0.999 1.000

none none

GCb conductivity < 1 μS·cm−1

Acros Organics Scharlau Laboratory Scharlau Laboratory Gattefosse Milli-Q purification unit

a

High performance liquid chromatography (HPLC). bGas chromatography (GC). 2511



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Table 2. Experimental Mole Fraction Solubility (xe) Data of Crystalline TNX in Different Pure Solvents (S) at Temperatures T = (298.15 to 323.15) K and Pressure p = 0.1 MPaa xe


a

S

T/K = 298.15

T/K = 303.15

T/K = 308.15

T/K = 313.15

T/K = 323.15

water ethanol PG PEG-400 Transcutol EG IPA EA 1-butanol 2-butanol

4.11·10−6 3.71·10−5 1.94·10−4 9.76·10−3 1.83·10−3 2.13·10−4 6.27·10−5 6.79·10−4 8.13·10−5 6.15·10−5

5.07·10−6 4.11·10−5 2.35·10−4 1.31·10−2 2.02·10−3 2.46·10−4 8.91·10−5 7.46·10−4 1.05·10−4 8.79·10−5

6.46·10−6 4.56·10−5 2.75·10−4 1.75·10−2 2.22·10−3 2.83·10−4 1.25·10−4 8.25·10−4 1.34·10−4 1.23·10−4

8.33·10−6 4.98·10−5 3.27·10−4 2.27·10−2 2.41·10−3 3.24·10−4 1.64·10−4 9.08·10−4 1.63·10−4 1.63·10−4

1.38·10−5 5.84·10−5 4.37·10−4 3.45·10−2 2.86·10−3 4.41·10−4 2.67·10−4 1.06·10−3 2.39·10−4 2.72·10−4

The standard uncertainties u are u(T) = 0.10 K, u(p) = 0.003 MPa and ur(xe) = 1.1%.

curve fitting of xe values of TNX with the modified Apelblat model. Van’t Hoff model solubility/calculated solubility (xVan’t) of TNX was calculated using eq 2:21

3.2. Correlation of Experimental Solubilities of TNX with Calculated Solubilities. The xe values of TNX were correlated with the solubilities calculated by the modified Apelblat and Van’t Hoff models because these models are frequently used for this purpose.19−21 The modified Apelblat solubility/calculated solubility (xApl) of TNX was calculated using eq 1:19,20 B ln x Apl = A + + C ln(T ) (1) T in which T is the absolute temperature (K) and the parameters A, B, and C are the model parameters of the Apelblat model. The parameters of eq 1 were calculated by regression analysis of xe values of TNX presented in Table 2.12 To correlate xe values of TNX with xApl values, the root-mean-square deviations (RMSD) were calculated as per the formula presented in the literature.12 The curve fitting and graphical correlation of xe values of TNX with xApl values in all pure solvents over the entire temperature range are presented in Supporting Information, Figure 1 (Figure S1). The resulting data of this correlation in all pure solvents are listed in Table 3. The values of RMSD in

b (2) T in which the parameters a and b are the model parameters of eq 2 which were calculated by plotting ln xe values of TNX against reciprocal of absolute temperature (1/T). To correlate the xe values of TNX with xVan’t values, the RMSD values were calculated again as reported previously.12 The curve fitting and graphical correlation of xe values of TNX with xVan’t values in all pure solvents are presented in Supporting Information, Figure S2. The resulting data of this correlation in all pure solvents are listed in Table 4. The values ln x Van ′ t = a +

Table 4. Parameters of eq 2 for Crystalline TNX in Different Pure Solvents (S)

Table 3. Parameters of eq 1 for Crystalline TNX in Different Pure Solvents (S) S

A

B

C

R2

RMSD (%)


−365.22 91.93 91.96 427.87 29.14 −200.36 499.78 88.40 895.27 427.90

12290.75 −6190.99 −7279.72 −24077.00 −3086.68 6484.74 −28204.30 −5869.53 −44975.50 −25009.40

54.68 −14.28 −13.35 −61.73 −4.40 29.86 −72.81 −13.34 −132.31 −62.08

0.9995 0.9999 0.9996 0.9999 0.9997 0.9997 0.9997 0.9997 0.9997 0.9996

0.89 0.23 0.62 0.82 0.48 0.41 1.00 0.51 3.77 0.98

S

a

b

R2

RMSD (%)


3.32 −4.31 1.95 11.79 −0.54 0.90 9.05 −1.51 4.47 9.50

−4698.20 −1751.70 −3127.40 −4889.60 −1716.80 −2793.10 −5574.50 −1722.30 −4134.10 −5714.10

0.9968 0.9983 0.9992 0.9962 0.9995 0.9976 0.9958 0.9981 0.9977 0.9969

2.38 1.21 0.85 2.77 0.40 1.23 3.40 0.75 1.80 2.83

of RMSD in various pure solvents were recorded as (0.40 to 3.40) %. For Van’t Hoff correlation, the highest value of RMSD was observed in IPA (3.40%) followed by 2-butanol, PEG-400, water, 1-butanol, EG, ethanol, PG, EA, and 2-(2-ethoxyethoxy)ethanol. However, the R2 values for TNX in various pure solvents were recorded as 0.9958 to 0.9995 (Table 4). The low values of RMSD and higher values of R2 again indicated good correlation and curve fitting of xe values of TNX with the Van’t Hoff model. 3.3. Thermodynamic Studies for TNX Dissolution. Thermodynamic studies were performed to evaluate the dissolution behavior TNX in various pure solvents via calculation of standard enthalpy (ΔsolH0), standard Gibbs energy (ΔsolG0), and standard entropy (ΔsolS0). The ΔsolH0

various pure solvents were recorded as (0.23 to 3.77) %. For Apelblat correlation, the highest value of RMSD was observed in 1-butanol (3.77 %) followed by IPA, 2-butanol, water, PEG400, PG, EA, 2-(2-ethoxyethoxy)ethanol, EG, and ethanol. However, the R2 values for TNX in various pure solvents were recorded as 0.9995 to 0.9999 (Table 3). The low values of the RMSD and higher values of R2 indicated good correlation and 2512



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4. CONCLUSION The solubilities of the practically insoluble drug TNX in various pure solvents were measured at various temperatures and atmospheric pressure using a well-established shake flask method. With the rise in temperature, the solubility of TNX was found to be increased in all pure solvents investigated. The measured solubilities of TNX were correlated well with calculated ones with RMSD values in the range of (0.23 to 3.77) %. The mole fraction solubility of TNX was observed highest in PEG-400 (9.76·10 −3 ) followed by 2-(2ethoxyethoxy)ethanol, EA, EG, PG, 1-butanol, IPA, 2-butanol, ethanol, and water at T = 298.15 K. Thermodynamic studies indicated an endothermic and spontaneous dissolution behavior of TNX in all pure solvents. On the basis of the solubility data obtained in this work, TNX has been considered as practically insoluble in water, slightly soluble in EA, EG, 2(2-ethoxyethoxy)ethanol, and PEG-400, and very slightly soluble in ethanol, IPA, PG, 1-butanol, and 2-butanol.

values for dissolution of TNX in various pure solvents were determined at mean harmonic temperature (Thm) using eq 3:22,23


⎞ ⎛ ∂ ln xe Δ H0 ⎟ = − sol ⎜ R ⎝ ∂(1/T − 1/Thm) ⎠ P

(3)

For the determination of ΔsolH0 values, the ln xe values of TNX were plotted as a function of 1/T − 1/Thm (Figure S3). Van’t Hoff plots in all pure solvents were observed linear with R2 values of 0.9950 to 0.9990. The ΔsolG0 values for TNX dissolution in various pure solvents were also calculated at Thm by using the approach of Krug et al. analysis.24 Finally, the ΔsolS0 values for TNX dissolution in various pure solvents were determined by using the combined approach of Van’t Hoff and Krug et al. analysis. The results of the thermodynamic studies in terms of ΔsolH0, ΔsolG0, and ΔsolS0 along with R2 values for TNX dissolution in various pure substances are presented in Table 5.

■

Table 5. Standard Dissolution Enthalpy (ΔsolH0), Standard Dissolution Entropy (ΔsolS0), Standard Gibbs Energy (ΔsolG0) and R2 Values for Dissolution of TNX in Different Pure Solvents Determined by Van’t Hoff and Krug et al. Analysis ΔsolH0 −1


ΔsolG0 −1

kJ mol

kJ mol

39 14.5 26 40.6 14.2 23.2 46.3 14.3 34.3 47.5

30.5 25.6 20.9 10.3 15.6 20.9 22.8 18.2 22.8 23

Figures showing curve fitting of ln xe values of TNX in different pure solvents as a function of T/K and Van’t Hoff plots of experimental solubilities of TNX in different pure solvents. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.5b00382.

■

ΔsolS0 J mol−1·K−1

R2

27.7 −35.8 16.2 98.1 −4.5 7.5 76.1 −12.5 37.2 79

0.996 0.998 0.999 0.996 0.999 0.997 0.995 0.998 0.9970 0.9960

ASSOCIATED CONTENT

S Supporting Information *

AUTHOR INFORMATION

Corresponding Author

*Tel.: +966-537507318. E-mail: [email protected]. Funding

The project was financially supported by King Saud University, Vice Deanship of Research Chairs, Kayyali Chair for Pharmaceutical Industry (Grant no. FN-2015). Notes

The authors declare no competing financial interest.

■

REFERENCES

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It was observed that the ΔsolH0 values for TNX dissolution in all pure solvents were found to be positive values in the range of (14.2 to 47.5) kJ mol−1. The ΔsolH0 value was found to be highest in 2-butanol (47.5 kJ mol−1) followed by IPA, PEG400, water, 1-butanol, PG, EG, ethanol, EA, and 2-(2ethoxyethoxy)ethanol. The ΔsolG0 values for TNX dissolution in all pure solvents were also found to be positive values in the range of (10.3 to 30.5) kJ mol−1. The ΔsolG0 value was found to be highest in water (30.5 kJ mol−1) followed by ethanol, 2butanol, 1-butanol, IPA, EG, PG, EA, 2-(2-ethoxyethoxy)ethanol, and PEG-400 (Table 5). The thermodynamic data in terms of ΔsolH0 and ΔsolG0 indicated an endothermic and spontaneous dissolution behavior of TNX in all pure solvents. The ΔsolS0 values for TNX dissolution in seven pure solvents, namely, water, PEG-400, EG, IPA, PG, 1-butanol, and 2butanol were observed as positive values, indicating an entropydriven dissolution behavior of TNX in seven pure solvents. However, the ΔsolS0 values in the remainder of three pure solvents (ethanol, EA, and 2-(2-ethoxyethoxy)ethanol) were observed as negative values, indicating that TNX dissolution was not entropy-driven in these solvents. 2513




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Solubility and Thermodynamic Analysis of Tenoxicam in Different Pure

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