Solubility of Metoclopramide Hydrochloride in Six Green Solvents at(298.15 to 338.15) KFaiyaz Shakeel,1,* Gamal A. Shazly,1,2 and Nazrul Haq1

1Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia2Department of Industrial Pharmacy, College of Pharmacy, Assiut University, Assiut, Egypt

ABSTRACT: In the present investigation, the solubility of metoclopramidehydrochloride (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 measuredsolubilities 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 ofexperimental and calculated solubility data of MHCl. The rmsd’s were observed in therange of (0.063 to 0.569)·10−3 in all green solvents investigated. Moreover, thecorrelation coefficients in all green solvents were observed in the range of 0.993 to0.998. The data of rmsd’s and correlation coefficients indicated good fitting ofexperimental data with calculated values. At 298.15 K (room temperature), thesolubility of MHCl was found to be highest in EG (134.93·10−3 at 298.15 K) followedby 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, MHClhas been considered as freely soluble in EG, PG, ethanol, and Transcutol, very soluble in water, and soluble in PEG-400.

1. INTRODUCTIONThe IUPAC name of metoclopramide hydrochloride (MHCl)is 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-o-anisamidemonohydrochloride monohydrate and its molecular structureis presented in Figure 1 (molecular formula, C14H22ClN3O2

HCl; molecular mass, 336.26 g·mol−1).1,2 It is a dopaminereceptor antagonist which is used as an effective antiemeticdrug.1,3 It occurs as a white or almost white crystalline powderwhich has been reported as freely soluble in alcohol, verysoluble in water, and sparingly soluble in methylene chloride.2,4

However, its solubilization behavior in other green solventssuch as ethylene glycol (EG), propylene glycol (PG),polyethylene glycol-400 (PEG-400), and Transcutol has notbeen reported in literature so far. Green solvents are defined asnontoxic, nonflammable, and eco-friendly solvents such aswater.5 Commonly used green solvents for solubilization andstabilization of poorly water-soluble drugs are ethanol, PG, andPEG-400.6−8 Most recently, Transcutol has also beeninvestigated as an effective green solvent for the solubilityenhancement of several poorly water-soluble drugs such asdiclofenac sodium, paracetamol, glibenclamide, and risperidonein water.9−12 Hence, in the present investigation, the commonly

used green solvents such as water, ethanol, EG, PG, PEG-400,and Transcutol (green solvents) were selected for measurementof MHCl solubility at (298.15 to 338.15) K. Literature surveyrevealed that several mathematical models/equations have beenapplied for the correlation of experimental solubility data withcalculated data but the Apelblat equation is the most widelyused equation which is applicable to both polar as well as fornonpolar systems.7−15 To date, temperature-dependent sol-ubility data of MHCl in water, ethanol, EG, PG, PEG-400, andTranscutol have not been reported in literature or anypharmacopoeia. Therefore, the aim of present investigationwas to measure and correlate the temperature-dependentsolubility data of MHCl in six green solvents such as water,ethanol, EG, PG, PEG-400, and Transcutol from (298.15 to338.15) K at an atmospheric pressure of 0.1 MPa using anisothermal method. The solubility data of MHCl in these greensolvents could be extremely useful in the development of liquiddosage forms of MHCl.

2. EXPERIMENTAL SYSTEM AND METHODS

2.1. Materials. MHCL (mass fraction purity of 0.993) waspurchased from Alpha Aesar (Ward Hill, MA). Transcutol(IUPAC name, diethylene glycol monoethyl ether; massfraction purity of 0.999) was a kind gift sample from Gattefosse(Lyon, France). PG (IUPAC name, propane-1,2-diol; massfraction purity of 0.995) and PEG-400 [IUPAC name,

Received: February 14, 2014Accepted: April 7, 2014Published: April 16, 2014

Figure 1. Molecular structure of metoclopramide hydrochloride(molecular mass, 336.26 g·mol−1)

Article

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© 2014 American Chemical Society 1700 dx.doi.org/10.1021/je500154k | J. Chem. Eng. Data 2014, 59, 1700−1703

poly(oxyethene); mass fraction purity of 0.999] were purchasedfrom 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) andWinlab 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 usingan isothermal method from (298.15 to 338.15) K at anatmospheric pressure of 0.1 MPa.11,12 For solubility measure-ments, the excess amount of MHCl was added in 5 g of eachgreen solvent in triplicate, and mixtures were equilibrated in awater shaker bath (Julabo, PA) at 100 rpm for 72 h. After 72 h,all the mixtures were taken out from the shaker bath andallowed to settle MHCl particles for the period of 2 h.12,14 Afterthe MHCl particles had completely settled (2 h), supernatantsfrom each sample were taken, diluted with respective greensolvent, and were subjected to analysis of the MHClcontent.9−11 The quantification of MHCl was performed byUV−visible spectrophotometer (SP1900, Axiom, Germany) atthe wavelength of 272 nm.1 The calibration curve was plottedbetween concentration (μg·g−1) and UV absorbance of MHCl.The proposed spectrophotometric method was found to belinear in the concentration range of (2 to 20) μg·g−1 with acorrelation coefficient of 0.997. The standard uncertainty forthe temperatures u(T) was found to be ± 0.20 K. However, therelative standard uncertainty in solubility ur(xe) was observed as1.65 %. The experimental mole fraction solubility (xe) of MHClwas then calculated as reported previously.13,14

3. RESULTS AND DISCUSSION

3.1. Solubility Data of MHCl. The experimentalsolubilities (mole fraction and mass fraction) of MHCl in sixgreen solvents (water, ethanol, EG, PG, PEG-400, andTranscutol) from (298.15 to 338.15) K and atmosphericpressure are listed in Table 1. According to the BritishPharmacopoeia, MHCl has been reported as very soluble inwater and freely soluble in ethanol.2 However, its temperature-dependent solubility data in water, ethanol, EG, PG, PEG-400,and Transcutol has not been reported in literature so far. In thepresent study, the mole fraction solubility of MHCl in waterand ethanol were observed as 51.61·10−3 at 298.15 K and32.88·10−3 at 298.15 K, respectively. These results were in goodagreement with reported solubility behavior of MHCl in BritishPharmacopoeia. Overall, the solubility of MHCl was found toincrease exponentially (nonlinearly) with an increase intemperature in all green solvents investigated at (298.15 to338.15) K. The mole fraction solubility of MHCl was found to

be highest in EG. However, the lowest one was observed inethanol at (298.15 to 338.15) K (Table 1). Good solubility ofMHCl was observed in all green solvents investigated at(298.15 to 338.15) K. On the basis of these results, MHCl hasbeen considered as freely soluble in EG, PG, ethanol, andTranscutol, 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 ofMHCl were correlated with the Apelblat equation.9,10

According to this equation, the mole fraction solubility ofMHCl can be calculated using eq 1:16,17

= + +x ABT

C Tln ln( )(1)

where x and T represents the Apelblat solubility of MHCl andabsolute 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 thefusion enthalpy as a deviation of heat capacity. The coefficientsA and B reflect the variation in the solution activity coefficientand provide an indication of the impact of solution non-idealities on the solubility of solute (MHCl).18,19 Thecoefficients A, B, and C were determined by unweightedmultivariate least-squares method with the help of eq 1.20 TheApelblat/calculated solubilities (xAc) were calculated usingApelblat coefficients A, B, and C using eq 1. The correlationbetween experimental and calculated solubilities in all greensolvents 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.

∑=−

=

⎡⎣⎢⎢

⎛⎝⎜

⎞⎠⎟

⎤⎦⎥⎥N

x xx

rsmd1

i

N z

1

Ac e

e

1/2

(2)

where N represents the number of data points in theexperiment. The values of regressed coefficients A, B, and Cand correlations coefficients (R2) along with rmsd’s of MHCl inwater, ethanol, PG, PEG-400, and Transcutol are listed in Table2. The rmsd value of MHCl was found to be lowest in ethanol(0.063·10−3). However, the highest one was observed in PEG-400 (0.569·10−3). The R2 values for MHCl were observed inthe range of 0.993 to 0.998 in all green solvents investigated(Table 2). The results of the rmsd and R2 indicated the goodfitting of experimental data.

3.3. Thermodynamic Parameters for MHCl Dissolu-tion in Green Solvents. The molar enthalpy (ΔH0) for thedissolution of MHCl in all green solvents was determined byVan’t Hoff analysis.21,22 According to the Van’t Hoff analysis,the ΔH0 for the dissolution of MHCl can be calculated using

Table 1. Experimental Mole Fraction Solubilities (xe) and Mass Fraction Solubilities (Sm) of Crystalline MetoclopramideHydrochloride in Six Green Solvents (S) at Temperatures T = (298.15 to 338.15) K and Pressure p = 0.1 MPaa

103 xe Sm/kg·kg−1

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 51.61 58.40 64.27 69.49 75.34 1.015 1.157 1.282 1.394 1.521ethanol 32.88 34.71 36.95 39.52 42.51 0.248 0.262 0.280 0.300 0.324PG 45.57 48.90 51.55 54.81 58.22 0.211 0.227 0.240 0.256 0.273PEG-400 41.89 49.39 57.44 69.53 84.43 0.036 0.043 0.051 0.062 0.077Transcutol 48.17 51.15 55.20 59.55 63.95 0.126 0.135 0.146 0.158 0.171EG 134.93 145.66 157.13 171.82 188.93 0.845 0.923 1.010 1.124 1.262

aThe standard uncertainty for the temperatures u(T) is ± 0.20 K, the relative standard uncertainty in solubility ur(xe) is 1.65 %.

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mean harmonic temperature (Thm was 317.52 K in the presentinvestigation) using eq 3:

∂∂ −

= − Λ⎛⎝⎜

⎞⎠⎟

xT T

HR

ln(1/ 1/ )

phm (3)

where R is the universal gas constant. The ΔH0 value wasobtained 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 Thmusing eq 4:23

Δ = − ×G RT intercept0 hm (4)

in which the intercept was obtained by plotting ln x against 1/T− 1/Thm using eq 3. The molar entropy (ΔS0) for thedissolution of MHCl was calculated using eq 5:

Δ =Δ − Δ

SH G

T00 0

hm (5)

The values of these thermodynamic parameters in all greensolvents are listed in Table 3. The ΔH0 value for MHCldissolution was observed as positive value in all green solvents,indicating endothermic dissolution of MHCl. The ΔH0 value inwater, ethanol, EG, PG, PEG-400 and Transcutol was observedas 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). TheΔG0 value was also observed as positive value in all greensolvents, indicating that the dissolution of MHCl wasspontaneous. The ΔS0 value for MHCl dissolution in water,PEG-400, and EG was observed as positive value, indicatingthat the dissolution of MHCl was an entropy-driven process inwater, 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 MHCldissolution in all green solvents indicated that low energy isrequired for solubilization of MHCl in water, ethanol, EG, PG,PEG-400, and Transcutol. These results indicated that MHClwas not slightly soluble/insoluble in any of the green solventinvestigated.

4. CONCLUSIONIn the present investigation, the solubility of antiemetic drugMHCl in six green solvents (water, ethanol, EG, PG, PEG-400,and Transcutol) was measured at (298.15 to 338.15) K usingan isothermal method. The solubility of MHCl was found toincrease exponentially (nonlinearly) with an increase intemperature. The experimental solubilities of MHCl werecorrelated well with Apelblat equation in all green solventsinvestigated at (298.15 to 338.15) K with correlationcoefficients in the range of 0.993 to 0.998. The rmsd valuesbetween experimental and calculated solubilities were observedin the range of (0.063 to 0.569)·10−3 in all green solventsinvestigated. The results of correlation coefficients and rmsd’sindicated the good fitting of experimental solubility data. Onthe basis of solubility data of the present investigation, MHClhas been considered as freely soluble in EG, PG, ethanol, andTranscutol, very soluble in water, and soluble in PEG-400.These data could be extremely useful in the development ofliquid dosage forms of MHCl.

■ AUTHOR INFORMATIONCorresponding Author*Tel.: +966-537507318. E-mail: faiyazs@fastmail.fm.FundingThe authors would like to extend their sincere appreciation tothe Deanship of Scientific Research at King Saud University for

Figure 2. The correlation and curve fitting of experimental molefraction solubilities (xe) with Apelblat solubilities for metoclopramidehydrochloride in blue ◆, water; red ■, ethanol; green ▲, PG, ×, PEG-400, ∗, Transcutol, and gold ●, EG from (298.15 to 338.15) K atatmospheric pressure of 0.1 MPa (solid lines represent the solubilitiescalculated by Apelblat equation).

Table 2. The Apelblat Coefficients (A, B, and C) along withR2 and rmsd’s for Metoclopramide Hydrochloride in SixDifferent Green Solventsa

S Ab B C R2 103 rmsd

water 62.29 −3854.38 −9.18 0.993 0.377ethanol −70.07 2582.16 10.17 0.994 0.063PG −14.46 20.56 1.98 0.998 0.241PEG-400 −168.07 6258.13 25.25 0.995 0.569Transcutol −53.95 1779.20 7.88 0.997 0.318EG −83.84 3129.12 12.52 0.995 0.257

aAbbreviations: pure green solvents, S; propylene glycol, PG;polyethylene glycol-400, PEG-400; ethylene glycol, EG; correlationcoefficient, R2; root-mean-square deviation, rmsd. bApelblat coef-ficients were determined by unweighted multivariate least-squaresmethod.

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 7.82 5.38 5.06 14.59 6.01 7.01ΔG0/kJ·mol−1 7.28 8.69 7.82 7.48 7.63 4.85ΔS0/J·mol−1·K−1 1.71 −10.41 −8.67 22.39 −5.10 6.78

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its funding the work through the research group Project No.RGP-VPP-139.

NotesThe authors declare no competing financial interest.

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