Article pubs.acs.org/jced
Solubility of Metoclopramide Hydrochloride in Six Green Solvents at (298.15 to 338.15) K Faiyaz Shakeel,1,* Gamal A. Shazly,1,2 and Nazrul Haq1 1 2
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia Department of Industrial Pharmacy, College of Pharmacy, Assiut University, Assiut, Egypt ABSTRACT: In the present investigation, the solubility of metoclopramide hydrochloride (MHCl) in six green solvents, namely water, ethanol, propylene glycol (PG), polyethylene glycol-400 (PEG-400), ethylene glycol (EG), and Transcutol from (298.15 to 338.15) K was measured using an isothermal method. The measured solubilities of MHCl were correlated with the Apelblat equation at (298.15 to 338.15) K. The root-mean-square deviations (rmsd’s) were calculated with the help of experimental and calculated solubility data of MHCl. The rmsd’s were observed in the range of (0.063 to 0.569)·10−3 in all green solvents investigated. Moreover, the correlation coefficients in all green solvents were observed in the range of 0.993 to 0.998. The data of rmsd’s and correlation coefficients indicated good fitting of experimental data with calculated values. At 298.15 K (room temperature), the solubility of MHCl was found to be highest in EG (134.93·10−3 at 298.15 K) followed by water (51.61·10−3 at 298.15 K), Transcutol (48.17·10−3 at 298.15 K), PG (45.57· 10−3 at 298.15 K), PEG-400 (41.89·10−3 at 298.15 K), and ethanol (32.88·10−3 at 298.15 K). On the basis of these results, MHCl has been considered as freely soluble in EG, PG, ethanol, and Transcutol, very soluble in water, and soluble in PEG-400.
1. INTRODUCTION The IUPAC name of metoclopramide hydrochloride (MHCl) is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-o-anisamide monohydrochloride monohydrate and its molecular structure is presented in Figure 1 (molecular formula, C14H22ClN3O2
used green solvents such as water, ethanol, EG, PG, PEG-400, and Transcutol (green solvents) were selected for measurement of MHCl solubility at (298.15 to 338.15) K. Literature survey revealed that several mathematical models/equations have been applied for the correlation of experimental solubility data with calculated data but the Apelblat equation is the most widely used equation which is applicable to both polar as well as for nonpolar systems.7−15 To date, temperature-dependent solubility data of MHCl in water, ethanol, EG, PG, PEG-400, and Transcutol have not been reported in literature or any pharmacopoeia. Therefore, the aim of present investigation was to measure and correlate the temperature-dependent solubility data of MHCl in six green solvents such as water, ethanol, EG, PG, PEG-400, and Transcutol from (298.15 to 338.15) K at an atmospheric pressure of 0.1 MPa using an isothermal method. The solubility data of MHCl in these green solvents could be extremely useful in the development of liquid dosage forms of MHCl.
Figure 1. Molecular structure of metoclopramide hydrochloride (molecular mass, 336.26 g·mol−1)
HCl; molecular mass, 336.26 g·mol−1).1,2 It is a dopamine receptor antagonist which is used as an effective antiemetic drug.1,3 It occurs as a white or almost white crystalline powder which has been reported as freely soluble in alcohol, very soluble in water, and sparingly soluble in methylene chloride.2,4 However, its solubilization behavior in other green solvents such as ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), and Transcutol has not been reported in literature so far. Green solvents are defined as nontoxic, nonflammable, and eco-friendly solvents such as water.5 Commonly used green solvents for solubilization and stabilization of poorly water-soluble drugs are ethanol, PG, and PEG-400.6−8 Most recently, Transcutol has also been investigated as an effective green solvent for the solubility enhancement of several poorly water-soluble drugs such as diclofenac sodium, paracetamol, glibenclamide, and risperidone in water.9−12 Hence, in the present investigation, the commonly © 2014 American Chemical Society
2. EXPERIMENTAL SYSTEM AND METHODS 2.1. Materials. MHCL (mass fraction purity of 0.993) was purchased from Alpha Aesar (Ward Hill, MA). Transcutol (IUPAC name, diethylene glycol monoethyl ether; mass fraction purity of 0.999) was a kind gift sample from Gattefosse (Lyon, France). PG (IUPAC name, propane-1,2-diol; mass fraction purity of 0.995) and PEG-400 [IUPAC name, Received: February 14, 2014 Accepted: April 7, 2014 Published: April 16, 2014 1700
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Table 1. Experimental Mole Fraction Solubilities (xe) and Mass Fraction Solubilities (Sm) of Crystalline Metoclopramide Hydrochloride in Six Green Solvents (S) at Temperatures T = (298.15 to 338.15) K and Pressure p = 0.1 MPaa Sm/kg·kg−1
103 xe
a
S
T = 298.15
T = 308.15
T = 318.15
T = 328.15
T = 338.15
T = 298.15
T = 308.15
T = 318.15
T = 328.15
T = 338.15
water ethanol PG PEG-400 Transcutol EG
51.61 32.88 45.57 41.89 48.17 134.93
58.40 34.71 48.90 49.39 51.15 145.66
64.27 36.95 51.55 57.44 55.20 157.13
69.49 39.52 54.81 69.53 59.55 171.82
75.34 42.51 58.22 84.43 63.95 188.93
1.015 0.248 0.211 0.036 0.126 0.845
1.157 0.262 0.227 0.043 0.135 0.923
1.282 0.280 0.240 0.051 0.146 1.010
1.394 0.300 0.256 0.062 0.158 1.124
1.521 0.324 0.273 0.077 0.171 1.262
The standard uncertainty for the temperatures u(T) is ± 0.20 K, the relative standard uncertainty in solubility ur(xe) is 1.65 %.
be highest in EG. However, the lowest one was observed in ethanol at (298.15 to 338.15) K (Table 1). Good solubility of MHCl was observed in all green solvents investigated at (298.15 to 338.15) K. On the basis of these results, MHCl has been considered as freely soluble in EG, PG, ethanol, and Transcutol, very soluble in water, and soluble in PEG-400. 3.2. Correlation and Curve Fitting of MHCl Solubility. In the present investigation, the experimental solubilities of MHCl were correlated with the Apelblat equation.9,10 According to this equation, the mole fraction solubility of MHCl can be calculated using eq 1:16,17
poly(oxyethene); mass fraction purity of 0.999] were purchased from Fluka Chemicals (Bucsh, Switzerland). Ethyl alcohol (IUPAC name, ethanol; mass fraction purity of 0.999) and EG (IUPAC name, ethane-1,2-diol; mass fraction purity of 0.997) were purchased from Sigma Aldrich (St. Louis, MO) and Winlab Laboratory (Leicestershire, UK), respectively. 2.2. Measurement of MHCl Solubility Using an Isothermal Method. The solubility of MHCl in water, ethanol, EG, PG, PEG-400, and Transcutol was measured using an isothermal method from (298.15 to 338.15) K at an atmospheric pressure of 0.1 MPa.11,12 For solubility measurements, the excess amount of MHCl was added in 5 g of each green solvent in triplicate, and mixtures were equilibrated in a water shaker bath (Julabo, PA) at 100 rpm for 72 h. After 72 h, all the mixtures were taken out from the shaker bath and allowed to settle MHCl particles for the period of 2 h.12,14 After the MHCl particles had completely settled (2 h), supernatants from each sample were taken, diluted with respective green solvent, and were subjected to analysis of the MHCl content.9−11 The quantification of MHCl was performed by UV−visible spectrophotometer (SP1900, Axiom, Germany) at the wavelength of 272 nm.1 The calibration curve was plotted between concentration (μg·g−1) and UV absorbance of MHCl. The proposed spectrophotometric method was found to be linear in the concentration range of (2 to 20) μg·g−1 with a correlation coefficient of 0.997. The standard uncertainty for the temperatures u(T) was found to be ± 0.20 K. However, the relative standard uncertainty in solubility ur(xe) was observed as 1.65 %. The experimental mole fraction solubility (xe) of MHCl was then calculated as reported previously.13,14
ln x = A +
B + C ln(T ) T
(1)
where x and T represents the Apelblat solubility of MHCl and absolute temperature (K), respectively. The coefficients A, B, and C are adjustable parameters (empirical constants) of eq 1. The coefficient C represents the impact of temperature on the fusion enthalpy as a deviation of heat capacity. The coefficients A and B reflect the variation in the solution activity coefficient and provide an indication of the impact of solution nonidealities on the solubility of solute (MHCl).18,19 The coefficients A, B, and C were determined by unweighted multivariate least-squares method with the help of eq 1.20 The Apelblat/calculated solubilities (xAc) were calculated using Apelblat coefficients A, B, and C using eq 1. The correlation between experimental and calculated solubilities in all green solvents at (298.15 to 338.15) K is presented Figure 2. The root-mean-square deviations (rmsd’s) between xe and xAc of MHCl were calculated using eq 2. ⎡1 rsmd = ⎢ ⎢⎣ N
3. RESULTS AND DISCUSSION 3.1. Solubility Data of MHCl. The experimental solubilities (mole fraction and mass fraction) of MHCl in six green solvents (water, ethanol, EG, PG, PEG-400, and Transcutol) from (298.15 to 338.15) K and atmospheric pressure are listed in Table 1. According to the British Pharmacopoeia, MHCl has been reported as very soluble in water and freely soluble in ethanol.2 However, its temperaturedependent solubility data in water, ethanol, EG, PG, PEG-400, and Transcutol has not been reported in literature so far. In the present study, the mole fraction solubility of MHCl in water and ethanol were observed as 51.61·10−3 at 298.15 K and 32.88·10−3 at 298.15 K, respectively. These results were in good agreement with reported solubility behavior of MHCl in British Pharmacopoeia. Overall, the solubility of MHCl was found to increase exponentially (nonlinearly) with an increase in temperature in all green solvents investigated at (298.15 to 338.15) K. The mole fraction solubility of MHCl was found to
1/2 ⎛ xAc − xe ⎞ z ⎤ ⎥ ⎟ ∑⎜ xe ⎠ ⎥⎦ i=1 ⎝ N
(2)
where N represents the number of data points in the experiment. The values of regressed coefficients A, B, and C and correlations coefficients (R2) along with rmsd’s of MHCl in water, ethanol, PG, PEG-400, and Transcutol are listed in Table 2. The rmsd value of MHCl was found to be lowest in ethanol (0.063·10−3). However, the highest one was observed in PEG400 (0.569·10−3). The R2 values for MHCl were observed in the range of 0.993 to 0.998 in all green solvents investigated (Table 2). The results of the rmsd and R2 indicated the good fitting of experimental data. 3.3. Thermodynamic Parameters for MHCl Dissolution in Green Solvents. The molar enthalpy (ΔH0) for the dissolution of MHCl in all green solvents was determined by Van’t Hoff analysis.21,22 According to the Van’t Hoff analysis, the ΔH0 for the dissolution of MHCl can be calculated using 1701
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ΔG0 = −RThm × intercept
(4)
in which the intercept was obtained by plotting ln x against 1/T − 1/Thm using eq 3. The molar entropy (ΔS0) for the dissolution of MHCl was calculated using eq 5: ΔS0 =
Table 2. The Apelblat Coefficients (A, B, and C) along with R2 and rmsd’s for Metoclopramide Hydrochloride in Six Different Green Solventsa S
A
water ethanol PG PEG-400 Transcutol EG
62.29 −70.07 −14.46 −168.07 −53.95 −83.84
2
4. CONCLUSION In the present investigation, the solubility of antiemetic drug MHCl in six green solvents (water, ethanol, EG, PG, PEG-400, and Transcutol) was measured at (298.15 to 338.15) K using an isothermal method. The solubility of MHCl was found to increase exponentially (nonlinearly) with an increase in temperature. The experimental solubilities of MHCl were correlated well with Apelblat equation in all green solvents investigated at (298.15 to 338.15) K with correlation coefficients in the range of 0.993 to 0.998. The rmsd values between experimental and calculated solubilities were observed in the range of (0.063 to 0.569)·10−3 in all green solvents investigated. The results of correlation coefficients and rmsd’s indicated the good fitting of experimental solubility data. On the basis of solubility data of the present investigation, MHCl has been considered as freely soluble in EG, PG, ethanol, and Transcutol, very soluble in water, and soluble in PEG-400. These data could be extremely useful in the development of liquid dosage forms of MHCl.
3
B
C
R
−3854.38 2582.16 20.56 6258.13 1779.20 3129.12
−9.18 10.17 1.98 25.25 7.88 12.52
0.993 0.994 0.998 0.995 0.997 0.995
10 rmsd 0.377 0.063 0.241 0.569 0.318 0.257
a
Abbreviations: pure green solvents, S; propylene glycol, PG; polyethylene glycol-400, PEG-400; ethylene glycol, EG; correlation coefficient, R2; root-mean-square deviation, rmsd. bApelblat coefficients were determined by unweighted multivariate least-squares method.
mean harmonic temperature (Thm was 317.52 K in the present investigation) using eq 3: ⎞ ⎛ ∂ ln x ΛH ⎟ =− ⎜ R ⎝ ∂(1/T − 1/Thm) ⎠ p
(5)
The values of these thermodynamic parameters in all green solvents are listed in Table 3. The ΔH0 value for MHCl dissolution was observed as positive value in all green solvents, indicating endothermic dissolution of MHCl. The ΔH0 value in water, ethanol, EG, PG, PEG-400 and Transcutol was observed as 7.82 kJ.mol−1, 5.38 kJ.mol−1, 7.01 kJ.mol−1, 5.06 kJ.mol−1, 14.59 kJ.mol−1 and 6.01 kJ.mol−1, respectively (Table 3). The ΔG0 value was also observed as positive value in all green solvents, indicating that the dissolution of MHCl was spontaneous. The ΔS0 value for MHCl dissolution in water, PEG-400, and EG was observed as positive value, indicating that the dissolution of MHCl was an entropy-driven process in water, PEG-400, and EG. However, the ΔS0 value in ethanol, PG, and Transcutol was observed as negative value (Table 3). Moreover, the lower values of ΔH0, ΔG0, and ΔS0 for MHCl dissolution in all green solvents indicated that low energy is required for solubilization of MHCl in water, ethanol, EG, PG, PEG-400, and Transcutol. These results indicated that MHCl was not slightly soluble/insoluble in any of the green solvent investigated.
Figure 2. The correlation and curve fitting of experimental mole fraction solubilities (xe) with Apelblat solubilities for metoclopramide hydrochloride in blue ◆, water; red ■, ethanol; green ▲, PG, ×, PEG400, ∗, Transcutol, and gold ●, EG from (298.15 to 338.15) K at atmospheric pressure of 0.1 MPa (solid lines represent the solubilities calculated by Apelblat equation).
b
ΔH0 − ΔG0 Thm
■
(3)
where R is the universal gas constant. The ΔH value was obtained from the slope of graph plotted between ln x and 1/T − 1/Thm using eq 3. The Gibbs function (ΔG0) for the dissolution of MHCl was determined by adopting the Approach of Krug et al. at Thm using eq 4:23 0
AUTHOR INFORMATION
Corresponding Author
*Tel.: +966-537507318. E-mail:
[email protected]. Funding
The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for
Table 3. Thermodynamic Parameters for Dissolution of Metoclopramide Hydrochloride in Six Different Green Solvents parameters
water
ethanol
PG
PEG-400
Transcutol
EG
ΔH0/kJ·mol−1 ΔG0/kJ·mol−1 ΔS0/J·mol−1·K−1
7.82 7.28 1.71
5.38 8.69 −10.41
5.06 7.82 −8.67
14.59 7.48 22.39
6.01 7.63 −5.10
7.01 4.85 6.78
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its funding the work through the research group Project No. RGP-VPP-139. Notes
The authors declare no competing financial interest.
■
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