1908
J. Chem. Eng. Data 2007, 52, 1908-1910
Solubility of Clindamycin Phosphate in Binary Water-Ethanol Solvent Yi Chen and Jing-Kang Wang* School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, People’s Republic of China
The solubilities of clindamycin phosphate in different solvents were measured using a static method. The RPHPLC was used to determine the concentration of clindamycin phosphate in the liquid phase. The solubility data were correlated with the combined nearly ideal binary solvent (CNIBS)/Redlich-Kister equation which provided an accurate mathematical representation of the experimental data.
Introduction Clindamycin phosphate is (2S-trans)-methyl 7-chloro-6,7,8trideoxy-6-(1-methyl-trans-4-propyl-L-2-pyrrolidinecarboxamido)1-thio-L-threo-R-D-galacto-octopyranoside-2-(dihydrogen phosphate), (CAS No. 24729-96-2). It is a white or almost white crystalline powder, and Figure 1 shows the chemical structure. Clindamycin phosphate is the third generation product of lincomycin and has a lot of advantages relative to these two products, and as a semisynthetic antibiotic drug of Gram-positive and Gram-negative bacteria, it is widely used in clinical applications. In industrial manufacture, the purification step includes ion-change resin adsorption and crystallization from solution.1 To determine the proper solvent and to design an optimized separation process, it is necessary to know its solubility in different solvents.2 However, no experimental solubility data on clindamycin phosphate in aqueous + organic solvents have been reported. In this work, solubility data of clindamycin phosphate in water, ethanol, and different water + ethanol mixtures were experimentally determined using an analytical method. Analytical and synthetic methods are two ways of measuring the solubility.3,4 The advantage of the synthetic method is the short time for measurement, but its disadvantage is lower precision. To obtain more precise solubility data, an analytical method was used, using high-performance liquid chromatography (HPLC).
Experimental Section A. Reagents and Apparatus. A crystalline powder of clindamycin phosphate (C18H34ClN2O8PS, relative mole mass 504.96) was obtained from North China Pharmaceutical Co., Ltd., China. Its mass fraction was better than 99.0 %, determined by HPLC. It was dried in a vacuum at 80 °C for 24 h and stored in a desiccator. Ethanol was analytical purity grade from Tianjin Chemical Reagent Co., and distilled deionized water was used. The concentration measurements were carried out on HPLC (Agilent Technologies 1200, USA) with an XDB C18 reversephase column (4.6 mm × 150 mm, 5 µm) eluted ahead with methanol + water. The masses of the samples and solvents were determined by an analytical balance (Mettler Toledo AB204N, Switzerland) with an accuracy of 0.0001 g. * Corresponding author. E-mail:
[email protected]. Fax: 86-2227374971. Supported by the Programme of Introducing Talents of Discipline to Universities, No.:B06006.
Figure 1. Molecular structure of clindamycin phosphate.
B. Sample Preparation. An excess amount of clindamycin phosphate was added to the solvents in a jacketed glass vessel. Between the outer and inner walls of the vessel, water at a desired temperature was circulated from a water bath with a thermoelectric controller within 0.05 K (type 501A, China). A condenser was connected with the vessel to prevent solvent evaporation. A mercury-in-glass thermometer which had an uncertainty of 0.05 K was inserted into the inner wall of the vessels for temperature measuring. The solution was stirred by a magnetic stirrer continuously. To confirm the exact time consumed of attaining equilibrium, the concentrations of clindamycin phosphate in pure ethanol at 283.15 K with different stirring times were measured, and the concentrations kept almost identical after nearly 1 h. The stirrer was turned off to let the solution settle for 0.5 h. Then the quantitative upper portion was taken by a heated piette with an accuracy of 0.01 mL into 100 mL of distilled deionized aqueous solution to prepare the samples for HPLC analysis. All the measurements were repeated three times. C. Sample Analysis. HPLC analysis5,6 was performed by an external standard method. More than 20 µL of clindamycin phosphate dilution that was extracted from the samples was injected into an HPLC for quantity analysis. The mobile phase was acetonitrile (1) + water (2) with a volume fraction, Φ1, of 0.3, containing potassium dihydrogen phosphate (10.54 g‚L-1). The HPLC conditions were set as follows: wavelength of determination, 210 nm; column temperature, 303.15 K; flow rate of the mobile phase, 1.0 mL‚min-1; retention time, 8 min. The calibration curve for the estimation of clindamycin phosphate was prepared by using the standard solutions in the concentration range of (0.01 to 4.0) mg‚mol-1 (at room temperature). The uncertainty in the measurement of the concentration of clindamycin phosphate was less than 2 %.
10.1021/je700216w CCC: $37.00 © 2007 American Chemical Society Published on Web 08/14/2007
Journal of Chemical and Engineering Data, Vol. 52, No. 5, 2007 1909 Table 1. Experimental Solubilities (xA) and Calculated Solubilities (xAcalcd) of Clindamycin Phosphate in Binary Ethanol + Water Solvent Mixtures from T ) (278.15 to 343.15) K x0C 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000 0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
103xA T ) 278.15 K 0.006 1.37 1.7 3.8 5.81 18.48 176.08 T ) 288.15 K 0.09 1.71 3.61 5.19 7.53 34.33 185.89 T ) 298.15 K 0.14 3.22 4.1 8.76 13.6 43.2 202.92 T ) 308.15 K 0.31 4.57 6.16 12.99 19.49 51.27 216.65 T ) 318.15 K 0.42 5.44 7.98 17.28 25.74 60.87 227.87 T ) 328.15 K 0.47 6.73 14.73 25.58 37.64 66.81 234.95 T ) 338.15 K 0.74 8.72 19.74 28.97 42.91 76.5 251.87
103xAcalcd
x0C
0.47 1.48 2.08 2.76 6.09 18.49 176.1
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
1.01 1.74 2.15 3.34 9.78 33.86 185.88
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
1.25 3.07 4.39 6.46 15.32 42.84 202.93
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
1.20 4.22 7.16 10.45 21.4 50.80 216.66
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
1.04 4.96 9.69 14.34 27.6 60.43 227.89
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
0.67 5.92 16.00 24.27 38.32 66.65 234.95
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
1.39 8.80 19.83 28.19 43.83 76.18 251.87
0.0000 0.1499 0.3085 0.4502 0.6150 0.7518 1.0000
103xA T ) 283.15 K 0.09 1.48 2.57 4.54 6.78 21.42 179.86 T ) 293.15 K 0.11 2.84 3.74 6.08 9.4 36.93 199.57 T ) 303.15 K 0.24 4.18 5.72 9.17 15.12 50.89 209.42 T ) 313.15 K 0.34 5 7.37 14.07 20.86 53.43 222.86 T ) 323.15 K 0.45 5.55 11.03 24.52 35.61 63.74 231.77 T ) 333.15 K 0.56 7.62 16.12 27.23 39.82 69.05 240.71 T ) 343.15 K 1.12 11.4 21.79 34.51 50.63 91.47 292.39
103xAcalcd 0.59 1.69 2.5 3.49 7.59 21.27 179.87 1.24 2.61 3.15 4.37 11.24 36.55 199.53 1.82 3.79 4.93 7.14 17.51 50.32 209.42 1.24 4.8 8.2 11.6 22.81 52.95 222.85 0.36 4.09 13.37 22.29 36.57 63.56 231.79 0.99 6.9 17.29 25.95 40.54 68.87 240.72 1.78 10.62 23.17 32.79 51.71 91.18 292.4
Figure 2. Correlation of clindamycin phosphate solubilities in binary ethanol + water with the (CNIBS)/Redlich-Kister mode: 9, T ) 278.15 K; b, T ) 293.15 K; 2, T ) 308.15 K; [, T ) 323.15 K; f, T ) 333.15 K; *, T ) 343.15 K. Table 2. Curve Fitting Parameters of Clindamycin Phosphate in Binary Ethanol + Water in the Temperature Range from T ) (278.15 to 343.15) K T/K
B0
B1
B2
B3
B4
10 % deva
278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 328.15 333.15 338.15 343.15
-7.652 -7.433 -6.893 -6.691 -6.685 -6.306 -6.723 -6.689 -6.865 -7.941 -7.303 -6.920 -6.580 -6.332
12.617 11.130 6.625 9.119 9.766 8.396 12.762 13.812 15.452 22.574 20.527 18.174 17.700 17.225
-42.386 -34.872 -27.878 -36.745 -32.691 -31.219 -36.678 -39.965 -41.536 -49.298 -47.604 -41.138 -42.9150 -42.447
63.843 52.278 55.276 64.922 54.233 55.411 52.910 56.352 55.612 51.868 52.611 44.951 49.66 50.173
-28.159 -22.819 -28.812 -32.217 -26.219 -27.845 -23.800 -25.011 -24.141 -18.667 -19.679 -16.491 -19.248 -19.848
0.3299 0.39889 0.99838 0.84432 0.84859 1.10897 1.02417 0.97771 1.15232 1.04042 0.63339 0.64442 0.40424 0.84723
composition, Acree and co-workers8-10 suggested a mathematical representation for isothermal solubility data based on the combined nearly ideal binary solvent (CNIBS)/Redlich-Kister model N
ln xA ) x0B ln(xA)B + x0C ln(xA)C + x0Bx0C
∑ S (x i
0 B
- x0C)i (2)
i)0
Here Si is the model constant and N can be equal to 0, 1, 2, and 3, respectively. Depending on the values of N, four equations can be obtained from eq 2. x0B and x0C refer to the initial mole fraction of the solvent mixture when the solute (A) was not present. For x0B ) (1 - x0C) in eq 1, N ) 2 and subsequent rearrangements result in eq 3
Results and Discussion The solubility data for clindamycin phosphate in ethanol (B) + water (C) mixtures at different temperatures are listed in Table 1. The mole fraction solubility is given by7 mA/MA xA ) mA/MA + mB/MB + mC/MC
ln xA ) ln(xA)B + [ln(xA)C - ln(xA)B + S0 + S1 + S2]x0C + [-S0 + 3S1 + 5S2]x0C2 + [-2S1 - 8S2]x0C3 + [-4S2]x0C4 (3) This can be simplified as
(1)
xAcalcd is a calculated value; xAi is the saturated mole fraction solubility of the solute in pure solvent i; and x0C refers to the initial mole fraction of the solvent mixture when the solute (A) was not present. For describing how the experimental solubility of solute dissolved in a binary solvent mixture varies with binary solvent
ln xA ) B0 + B1x0C + B2x0C2 + B3x0C3 + B4x0C4
(4)
Correlated experimental solubility data (xA) with eq 4 and the calculated solubilities (xAcalcd) are listed in Table 1. For comparing the experimental points with calculated values by the (CNIBS)/Redlich-Kister model, the solubility data of clindamycin phosphate in binary ethanol + water solvent from temperatures (278.15 to 343.15) K are presented in Figure 2
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Journal of Chemical and Engineering Data, Vol. 52, No. 5, 2007
partly. The values of the five parameters, B0, B1, B2, B3, and B4, and average percent deviations (% deva) in absolute form are listed in Table 2. The % deva is expressed in absolute form as |∆xi %| )
100 n
n
∑ i)1
[
]
|xicalcd - xi| xi
(5)
Here, n is the number of experimental points and xicalcd and xi represent the solubility values of calculated results from eq 4 and experiments, respectively. From Figure 2, Table 1, and Table 2, it is easy to conclude the following: (i) With an increase in temperature, the solubility of clindamycin phosphate in binary ethanol + water solvent mixtures increases. (ii) The solubility decreases with the proportion of the increase of ethanol, and the lowest solubility happens in pure ethanol. (iii) By the correct correlation with the proper model, the calculated solubility values show good agreement with the experimental values; this could be used as essential data and models in the purification process of clindamycin phosphate. Acknowledgment The authors are very grateful to North China Pharmaceutical Co., Ltd., for supplying the experimental material of clindamycin phosphate.
Literature Cited (1) Martin, T.; Spring, V.; Simon, D.; Lalitha, K. Clindamycin phosphate synthesis. U. S. Patent 5182374, 1993.
(2) Mulin, J. W. Crystallization, 3rd ed.; Butterworth-Heinemann: Oxford, England, 2000. (3) Brandani, S.; Brandano, V.; Flammi, D. Solubility of Trioxane in Water. J. Chem. Eng. Data 1994, 39, 201-202. (4) Hao, H.-X.; Wang, J.-K.; Wang, Y.-L. Solubility of Dexamethasone Sodium Phosphate in Different Solvents. J. Chem. Eng. Data 2004, 49, 1697-1698. (5) United States pharmacopoeia; 24, 432-433. (6) Zhan, D.-C; Li, X.-N; Ge, X.; Li, Q.-S. Determination of Dissolution of Clindamycin Phosphate Tablets by HPLC. Chin. Pharm. 2004, 13 (6), 32-33. (7) Wu, J.-H.; Wang, J.-K. Solubility of Cefazolin Sodium Pentahydrate in Aqueous 2-Propanol Mixtures. J. Chem. Eng. Data 2005, 50, 980982. (8) Acree, W. E., Jr. Mathematical Representation of Thermodynamic Properties. Part 2. Derivation of the Comined Nearly Ideal Binary Solvent (NIBS)/Redlich-Kister Mathematical Representation from a Two-Body and Three-Body Interactional Mixting Model. Thermochim. Acta 1992, 198, 71-79. (9) Acree, W. E., Jr.; McCargar, J. W.; Zvaigzne, A. L.; Teng, L.-L. Mathematical Representation of Thermodynamic Properties. Carbazole Solubilities in Binary Alkane + Dibutyl Ether and Alkane + Tetrahydropyran Solvent Mixture. Phys. Chem. Liq. 1991, 23, 2735. (10) Acree, W. E., Jr.; Zvaigzne, A. L. Thermodynamic Properties of Nonelectrolyte Solutions. Part 4. Estimination and Mathematical Representation of Solute Activity Coefficients and Solubilities in Binary Solvents Using the NIBS and Modified Wilson Equation. J. Thermochim. Acta 1991, 178, 151-167.
Received for review April 25, 2007. Accepted July 9, 2007. The authors are grateful for the financial support from the Programme of Introducing Talents of Discipline to Universities, No. B06006.
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