Article pubs.acs.org/jced
Solubility of Two Polymorphs of Erlotinib Hydrochloride in Isopropanol and Acetone from (273.15 to 303.15) K Jie Lu,*,† Xiaolan Zhan,† Lianwei Chen,† Lijuan Zhang,‡ and Shimin Mao§ †
School of Chemical & Material Engineering, Jiangnan University, Wuxi 214122, P. R. China School of Chemistry & Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, P. R. China § Department of Chemical Engineering & Applied Chemistry, University of Toronto, Toronto M5S 3E5, Canada ‡
ABSTRACT: In this work the solubility of two polymorphic forms A and B of erlotinib hydrochloride in isopropanol (IPA) and acetone were determined by means of high-performance liquid chromatography (HPLC) in the temperature range from (273.15 to 303.15) K. The experimental data were correlated with the modified Apelblat equation. In particular, the effect of the surfactant Tween 80 on the solubility of both polymorphs was studied as well. The results show that the solubility of both polymorphs generally increases with the temperature, and polymorph A has a higher solubility than polymorph B which indicates that polymorph A is the metastable form. The modified Apelblat equation shows a good agreement with the experimental data with a percent error less than 3 %. Furthermore, the solubility of both polymorphs increases in a linear fashion with increasing the content of Tween 80 in organic solvents, wherein Tween 80 presents a same solubilization capacity to both polymorphs and a higher solubilization capacity in acetone than in IPA.
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INTRODUCTION Erlotinib hydrochloride which can inhibit the activity of epidermal growth factor receptor was approved as a 4aminophenylquinazoline oral anticancer drug by the Food and Drug Administration (FDA) in November 2004 to increase survival rates of patients with advanced nonsmall-cell lung cancer.1,2 The chemical structure of erlotinib hydrochloride is shown in Scheme1.
temperatures is prerequisite to crystallize the required polymorphs and to optimize the crystallization process. To date, numerous efforts on the measurement of the solubility of different polymorphs of APIs have been made.5,6 However, there are no experimental data about the solubility of different polymorphs of erlotinib hydrochloride in any solvent reported so far, though its various polymorphs have been disclosed in the literature, i.e., polymorphs A, B, E, L, M, N, and P, and among them polymorph B is currently used as a medicinal form, and polymorph A is being developed as the alternative.7 In this study, the solubility of polymorphs A and B of erlotinib hydrochloride in isopropanol and acetone was determined by high-performance liquid chromatography (HPLC) in the temperature range from (273.15 to 303.15) K under atmospheric pressure.8,9 The obtained solubility data were then validated by the modified Apelblat equation. In addition, as a nonionic surfactant, Tween 80 (C24H44O6) was studied to identify its effect on the solubility of above two polymorphic forms.
Scheme 1. Chemical Structure of Erlotinib Hydrochloride
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EXPERIMENTAL SECTION Materials and Apparatus. Polymorph B of erlotinib hydrochloride (99.5% in mass fraction) was supplied by Suzhou Lixin Pharmaceutical Company (Jiangsu, China). The procedure for the preparation of polymorph A is described in the following section. All other reagents with the purity above 99.5 % in mass were purchased from Sinopharm Chemical Reagent Company (Shanghai, China) and were used as
Pharmaceutical polymorphism can be defined as the capability of an active pharmaceutical ingredient (API) to have two or more crystalline forms which are caused by different crystal arrangements (packing polymorphism) and/or conformers (conformational polymorphism) in the crystal lattice.3 It can affect the solid-state properties of a drug such as solubility, dissolution rate, and finally bioavailability.4 It is well-recognized that crystallization is a critical step in forming different polymorphs and that the knowledge of the solubility of different polymorphs in various solvents at different © 2014 American Chemical Society
Received: May 28, 2014 Accepted: July 16, 2014 Published: July 21, 2014 2665
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measurement was operated in an isocratic elution program with the flow rate of mobile phase at 1.0 mL·min−1 at 298.15 K, and before each run, HPLC column was equilibrated with the mobile phase for 30 min at same temperature. The linear standard curve was obtained in the appropriate concentration range using pure erlotinib hydrochloride.
received. A jacketed 100 mL glass crystallizer with a Tefloncoated stirrer was used in all experiments. The temperature of the crystallizer was controlled by a F38-EH refrigerated/heating circulator (Julabo, Seelbach, Germany) with a precision of 0.05 K. The polymorphic form of solids was characterized using a D8 Advance powder X-ray diffractometer (PXRD; Bruker AXS, Karlsruhe, Germany). Preparation of Erlotinib Base. Polymorph B of erlotinib hydrochloride was first dissolved in water at 373.15 K. Then a certain amount of NH3·H2O (28 wt %) was dropped into the solution. The solid of erlotinib base appeared immediately. After being cooled down to the room temperature, the suspension was filtered off and washed by water. The product was dried in a vacuum oven at 333.15 K for 12 h. Preparation of Polymorph A. The first erlotinib base was dissolved in acetone at 273.15 K. Then the saturated solution of HCl in methyl tert-butyl ether (MTBE) was added slowly into the base solution. Crystallization occurred immediately. The crystalline suspension was agitated for 1 h and then was filtered, rinsed with acetone, and dried in a vacuum oven at 333.15 K for 6 h. The final product was identified by PXRD as polymorph A. The diffractograms of polymorphs A and B are shown in Figure 1.
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RESULTS AND DISCUSSION Solubility in Pure Solvents. To date, a number of thermodynamic models have been developed to predict or Table 1. Measured Solubility (xAexp) and Calculated Solubility (xAcalc) of Polymorph A of Erlotinib Hydrochloride in IPA at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa T/K
106 xAexp
106 xAcalc
E/%
273.15 278.15 283.15 288.15 293.15 298.15 303.15
7.3774 9.2507 11.3661 13.5355 15.7586 18.0722 22.1184
7.7495 9.2643 11.0514 13.1556 15.6279 18.5232 21.9208
2.64 0.15 2.77 2.81 0.83 2.49 0.89
a Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
Table 2. Measured Solubility (xBexp) and Calculated Solubility (xBcal) of Polymorph B of Erlotinib Hydrochloride in IPA at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa T/K
106 xBexp
106 xBcalc
E/%
273.15 278.15 283.15 288.15 293.15 298.15 303.15
5.1631 5.8913 7.2688 8.3097 9.6323 10.9829 12.9989
5.1508 6.0365 7.0574 8.2314 9.5788 11.1219 12.8858
0.24 2.47 2.91 0.94 0.56 1.27 0.87
a
Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
Figure 1. Diffractograms of polymorph A and polymorph B of erlotinib hydrochloride.
Table 3. Measured Solubility (xAexp) and Calculated Solubility (xAcalc) of Polymorph A of Erlotinib Hydrochloride in Acetone at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa
Solubility Measurement. At first, precise weights of organic solvent and surfactant were filled into the crystallizer which was controlled at the desired temperature. Then an excess amount of polymorph A or polymorph B was added into the solvent meanwhile the stirring was started. After 1 h, the stirring was stopped to allow the suspension to stand for about 0.5 h. Next, the supernatant was quickly filtered through 0.22 μm organic membrane filters, and the filtrate was diluted for HPLC analysis. The residual solid in the suspension was finally withdrawn for checking its polymorphic purity by PXRD. Each reported solubility data point is an average of at least three measurements. HPLC Analysis. The measurement of the concentration of erlotinib hydrochloride in diluted filtrates was performed using a Zorbax SB C18 reversed-phase column (Agilent Technologies, Santa Clara, CA) with dimensions of 150 mm × 4.6 mm. The wavelength of UV detector was set at 243 nm. The mobile phase was prepared by methanol and potassium dihydrogen phosphate (0.01 mol·L−1) in a volumetric ratio of 65:35. The
T/K
106 xAexp
106 xBcalc
E/%
273.15 278.15 283.15 288.15 293.15 298.15 303.15
2.4349 2.7286 3.0435 3.3411 3.6558 3.9008 4.3257
2.4511 2.7302 3.0223 3.3262 3.6407 3.9644 4.2959
0.67 0.06 0.70 0.45 0.41 1.63 0.69
a
Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
correlate the solubility of a solute with temperature and solvent composition.10 Following previous works,11−19 the modified Apelblat equation, a semiempirical model, was employed to 2666
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Table 4. Measured Solubility (xBexp) and Calculated Solubility (xBcalc) of Polymorph B of Erlotinib Hydrochloride in Acetone at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa
Table 7. Solubility (x) of Two Polymorphs as a Function of the Molar Fraction (x1) of Tween 80 in the Tween 80/IPA Mixture at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa
T/K
106 xBexp
106 xBcalc
E/%
T/K
103 x1
106 xAexp
106 xBexp
273.15 278.15 283.15 288.15 293.15 298.15 303.15
1.4298 1.6022 1.7872 1.9618 2.1468 2.2905 2.5401
1.4374 1.6028 1.7755 1.9546 2.1392 2.3282 2.5208
0.53 0.04 0.66 0.37 0.35 1.65 0.76
273.15 273.15 273.15 273.15 273.15 273.15 278.15 278.15 278.15 278.15 278.15 278.15 283.15 283.15 283.15 283.15 283.15 283.15 288.15 288.15 288.15 288.15 288.15 288.15 293.15 293.15 293.15 293.15 293.15 293.15 298.15 298.15 298.15 298.15 298.15 298.15 303.15 303.15 303.15 303.15 303.15 303.15
0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191 0 0.9638 1.9276 2.8915 3.8553 4.8191
7.3774 11.5134 15.6493 19.7854 23.9214 28.0573 9.2507 13.5319 17.8132 22.0945 26.3758 30.6571 11.3661 15.1102 20.2643 25.5602 29.3330 33.6018 13.5355 18.0941 22.6528 27.2114 31.7718 36.3286 15.7586 20.4778 25.1969 29.9161 34.6352 39.3543 18.0727 22.8909 27.7089 32.5271 37.3452 42.1633 22.1184 27.1042 32.0892 37.0757 42.0615 47.0473
5.1631 9.3511 13.5448 17.7391 21.9326 26.1267 5.8913 10.1645 14.4378 18.7111 22.9843 27.2576 7.2688 12.1444 15.8029 20.2477 24.8893 29.0498 8.3097 12.7174 17.1255 21.5334 25.9414 30.3493 9.6323 14.1339 18.6354 23.1371 27.6385 32.1401 10.9829 15.5639 20.1448 24.7257 29.3066 33.8876 12.9989 17.6814 22.3640 27.0466 31.7292 36.4117
a
Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
Table 5. Model Parameters (A, B, and C) of the Modified Apelblat Equation for Polymorph A in Pure Solventsa solvent
A
B
C
R2
102 rmsd
IPA acetone
−88.5042 42.5884
896.0483 −3700.2003
13.0937 −7.4796
0.996 0.997
2.6381 0.7958
a 2
R is the correlation coefficient, and rmsd is the root-mean-square deviation between experimental and calculated solubility.
Table 6. Model Parameters (A, B, and C) of the Modified Apelblat Equation for Polymorph B in Pure Solventsa solvent
A
B
C
R2
102 rmsd
IPA acetone
−69.4878 50.5196
343.0101 −4067.1195
9.9921 −8.7491
0.996 0.994
1.6100 0.7800
a 2
R is the correlation coefficient, and rmsd is the root-mean-square deviation between experimental and calculated solubility.
simulate the solubility of both polymorphs of erlotinib hydrochloride in different solvents as a function of temperature. ln x = A + B /T + C ln T
(1)
where x is the molar fraction of erlotinib hydrochloride; T is the absolute temperature (K); A, B, and C are model parameters acquired through fitting the experimental solubility data at all temperatures using eq 1. The measured and calculated solubility of polymorphs A and B of erlotinib hydrochloride in IPA and acetone from (273.15 to 303.15) K are listed in Tables 1 to 4, respectively. The percentage error (E) between the experimental and the calculated solubility is defined as E = |x exp − x calc| /x exp·100
(2)
exp
a Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
calc
where x is the measured solubility, and x is the calculated solubility by eq 1. Model parameters (A, B, and C), the correlation coefficients of the regression (R2), and the root-mean-square deviation (rmsd) are listed in Tables 5 and 6. The rmsd is defined as ⎡ 1 rmsd = ⎢ ⎢⎣ N
⎛ x exp − x calc ⎞2 ⎤ ⎟⎥ ∑⎜ x exp ⎠ ⎥⎦ 1 ⎝ N
0.99 which indicates that the modified Apelblat equation can be used to simulate the solubility of both polymorphs of erlotinib hydrochloride in IPA and acetone with a function of the temperature. In general, the solubility of both polymorphs of erlotinib hydrochloride increases with the increase of temperature in both IPA and acetone. But the solubility in IPA is higher than that in acetone. It can be explained by the different properties of two solvents such as polarity, viscosity, dipole moments, Hildebrand solubility parameters, and dielectric constants.20 In addition, the solubility of polymorph A is far higher than that of polymorph B in both IPA and acetone,
1/2
(3)
where N represents the number of experimental points. From the data listed in Tables 1 to 4, it is observed that the calculated solubility shows a good agreement with the experimental values. Meanwhile, all correlation coefficients of the regression (R2) listed in Tables 5 and 6 are greater than 2667
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Table 8. Solubility (x) of Two Polymorphs as a Function of the Molar Fraction (x1) of Tween 80 in the Tween 80/ Acetone Mixture at Temperature T = (273.15 to 303.15) K and Pressure p = 0.1 MPaa T/K
103 x1
106 xAexp
106 xBexp
273.15 273.15 273.15 273.15 273.15 273.15 278.15 278.15 278.15 278.15 278.15 278.15 283.15 283.15 283.15 283.15 283.15 283.15 288.15 288.15 288.15 288.15 288.15 288.15 293.15 293.15 293.15 293.15 293.15 293.15 298.15 298.15 298.15 298.15 298.15 298.15 303.15 303.15 303.15 303.15 303.15 303.15
0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191 0 0.9286 1.9276 2.8915 3.8553 4.8191
2.4349 7.9491 13.4631 18.9775 24.4915 30.0057 2.7286 8.2951 13.8617 19.4283 24.9948 30.5614 3.0435 9.2791 13.6568 19.8797 25.4921 30.5887 3.3409 9..0079 14.6716 20.3369 26.0022 31.6675 3.6557 9.3932 15.1306 20.8681 26.6055 32.3429 3.9008 9.9171 15.5335 21.3499 27.1665 32.9829 4.3257 10.2434 16.1611 22.0789 27.9966 33.9144
1.4298 6.3498 11.2698 16.1898 21.1096 26.0296 1.6022 6.5743 11.5466 16.5169 21.4889 26.4607 1.7872 7.3694 11.8333 16.4435 21.8793 27.1017 1.9618 7.0424 12.1229 17.2035 22.2841 27.3647 2.1468 7.2854 12.4242 17.5628 22.7016 27.8402 2.2905 7.4612 12.6319 17.8025 22.9734 28.1443 2.5401 7.7863 13.0326 18.2792 23.5259 28.7715
Figure 2. Effect of the Tween 80 content in mixed solvent on the solubility of polymorphs A and B of erlotinib hydrochloride at 283.15 K: △, polymorph A in IPA/Tween 80; □, polymorph B in IPA/ Tween 80; ◆, polymorph A in acetone/Tween 80; ■, polymorph B in acetone/Tween 80.
Figure 3. Schematic illustration of the solubilization of the surfactant to forms A and B in organic solvents.
8, respectively. The solubility of both polymorphs as a function of x1 at 283.15 K is schematically plotted in Figure 2. As shown in Tables 7 and 8 as well as Figure 2, it is obvious that the solubility of both polymorphs increases linearly with the increase in the content of Tween 80 in mixed solvents. As shown in Figure 3, the solubilization effect of Tween 80 can be attributed to the fact that Tween 80 can form reverse micelles in organic solvents and the core of micelles can solubilize hydrophobic organic compounds such as erlotinib hydrochloride.9,21,22 The higher the surfactant concentration is, the more the micelles form.23 That is, the solubilization of the surfactant to a solute is controlled by the amounts of the micelles formed. Therefore, the solubilization capacity of Tween 80 to erlotinib hydrochloride is dependent upon solvent type and temperature instead of its solid forms.24 In short, Tween 80 has the almost same solubilization capacity to both polymorphs of erlotinib hydrochloride and can present a higher solubilization capacity to both polymorphs in acetone and a lower solubilization capacity in IPA.
a
Relative uncertainties ur are ur(T) = 0.002, ur(x) = 0.02, and ur(p) = 0.05.
which refers to the latter as the stable form whereas the former is the metastable form. Solubilization of Tween 80. The nonionic surfactant Tween 80, containing an active substance with a low aqueous solubility, is a popular excipient in drug formulation. Since different polymorphs have different bioavailabilities, the influence of Tween 80 on the solubility of polymorphs has been studied. In the temperature range from (273.15 to 303.15) K, the solubility of polymorphs A and B in two types of mixed solvent, IPA/Tween 80 and acetone/Tween 80, with various molar fractions x1 of Tween 80 is listed in Tables 7 and
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CONCLUSIONS The solubility of both polymorph A and polymorph B of erlotinib hydrochloride generally increases with the increase in temperature, which can be simulated by the modified Apelblat equation with a good agreement. In addition, the solubility of both polymorphs in IPA is higher than that in acetone, and the solubility of polymorph A is higher than that of polymorph B, 2668
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(13) Xu, H.; Zhang, B.; Yang, Z. P.; Yao, G. B.; Zhao, H. K. Solubility of dichloronitrobenzene in eight organic solvents from T= (278.15 to 303.15) K: measurement and thermodynamic modeling. J. Chem. Eng. Data 2014, 59, 1281−1287. (14) El-Badry, M.; Haq, N.; Fetih, G.; Shakeel, F. Measurement and correlation of tadalafil solubility in five pure solvents at (298.15 to 333.15) K. J. Chem. Eng. Data 2014, 59, 839−843. (15) Qian, C.; Wang, Y. Y.; Chen, X. Z. Solubility of 1-fluoro-4(methylsulfonyl)benzene in five pure organic solvents at temperatures from (288.40 to 331.50) K. J. Chem. Eng. Data 2014, 59, 1254−1256. (16) Wang, X. M.; Qin, Y. N.; Zhang, T. W.; Tang, W. W.; Ma, B. A.; Gong, J. B. Measurement and correlation of solubility of azithromycin monohydrate in five pure solvents. J. Chem. Eng. Data 2014, 59, 784− 791. (17) Jiang, P. P.; Wang, Z. Z. Solubility of p-aminobenzenesulfonamide in different solvents from (283.15 to 323.15) K. J. Chem. Eng. Data 2009, 54, 1945−1946. (18) Hou, G. Y.; Yin, Q. X.; Zhang, M. J.; Su, W. Y.; Mao, H. L.; Wang, J. K. Solubility of indinavir sulfate in different solvents from (278.35 to 314.15) K. J. Chem. Eng. Data 2009, 54, 2106−2108. (19) Dang, L. P.; Du, W. W.; Black, S.; Wei, H. Y. Solubility of fumaric acid in propan-2-ol, ethanol, acetone, propan-1-ol, and water. J. Chem. Eng. Data 2009, 54, 3112−3113. (20) Liu, J. Q.; Cao, X. X.; Ji, B. M.; Zhao, B. T. Measurement and correlation of solubilities of indole-2-carboxylic acid in ten different pure solvents from (278.15 to 360.15) K. J. Chem. Eng. Data 2013, 58, 3309−3313. (21) Zhang, H. L.; Kong, C. Q.; Yang, S. J.; Bi, H. Y.; Li, J. Microcalorimetric studies on the CMC and thermodynamic functions of a nonionic surfactant (Tween80) in DMF/long-chain alcohol systems from T = 298.15 to T = 313.15 K. J. Solution Chem. 2011, 40, 632−642. (22) Zeng, Q. H.; Peng, S.; Liu, M.; Song, Z. J.; Wang, X. K.; Zhang, X.; Hong, S. Solubilization and adsorption behaviors of 2,4,6trichlorophenol in the presence of surfactants. Chem. Eng. J. 2013, 230, 202−209. (23) Manorama, P.; Kabir, D. Solubilization of polycyclic aromatic hydrocarbons by gemini-conventional mixed surfactant systems. J. Mol. Liq. 2013, 187, 106−113. (24) Mbah, C. J.; Ozuo, C. O. Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin. Pharmazie 2011, 66, 192−194.
indicating that polymorph A is the metastable form and polymorph B is the stable form. Moreover, Tween 80 can enhance the solubility of both polymorphs in the tested solvents to almost the same extent and has a higher solubilization capacity in acetone and a lower solubilization capacity in IPA. The solubility of both polymorphs of erlotinib hydrochloride increases linearly with the concentration of Tween 80 in mixed solvents at a certain temperature.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Fax: +86 510 85917763. Funding
The grants from the National Natural Science Foundation of China (Nos. 21176102 & 21176215), the Natural Science & Environmental Protection Foundations of Jiangsu Province (No. BK20131100 & 2012004), City Level Subjects of Shanghai University of Engineering and Technology (No. 14XKCZ04), and the Sino-German Center for Research Promotion (No. GZ935) are sincerely acknowledged. Notes
The authors declare no competing financial interest.
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