Solubility Measurement and Correlation of Two Erlotinib

Dec 6, 2016 - ABSTRACT: The solubility of two erlotinib hydrochloride polymorphs. (form A and form B) in methanol, ethanol, isopropanol, acetone, meth...
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Solubility Measurement and Correlation of Two Erlotinib Hydrochloride Polymorphs in Alcohols and Ketones from 273.15 to 323.15 K Jinghuan Zhai, Junrui Zhao, Zhenzhen Chen, Changwei Xiao, Xijian Liu, Lijuan Zhang, and Jie Lu* School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, People’s Republic of China ABSTRACT: The solubility of two erlotinib hydrochloride polymorphs (form A and form B) in methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, and methyl isobutyl ketone from 273.15 to 323.15 K were determined by means of high-performance liquid chromatography (HPLC). The modified Apelblat equation and the Buchowski−Ksiazczak λh equation were used to correlate the experimental solubility data. The results showed that the solubility of both forms generally increased with the temperature and at a given temperature decreased with the increase of the carbon number of alcohols; furthermore, methyl isobutyl ketone showed the largest solubility in the studied ketones. Meanwhile form A had a higher solubility than form B which demonstrated that form A was the metastable form. Furthermore, both models mentioned above gave satisfactory correlation results, in which the modified Apelblat equation worked better than the Buchowski−Ksiazczak λh equation.

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INTRODUCTION

Crystallization is an important unit operation in the chemical industry, particularly in the production of active pharmaceutical ingredients (APIs).1,2 The purity, morphology, crystal size distribution (CSD), and so forth of products are directly controlled by the design and operation of crystallization process.3,4 To develop and optimize a reliable crystallization process, it is crucial to know the thermodynamic data such as solubility,5 which are essential for the selection of crystallization conditions, the calculation of yield, and annual benefits.6 However, to date, a large number of solubility data are not available, and the experimental measurements are still the main source of them. On the other hand, it is reported that more than one-third of APIs may exist polymorphic structures if different crystallization conditions are applied.7,8 Polymorphism is defined as the ability of a compound to possess at least two distinct crystalline forms with different molecular conformations and/or packing arrangements.9 Different polymorphs usually have different physicochemical properties such as solubility, dissolution rates, and melting point, etc.10,11 Hence, it is essential to obtain the solubility data of API polymorph for the purpose of polymorph screening, separation, and purification through the crystallization process.12 Erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7bis(2-methoxyethoxy)-quinazolin-4-amine hydrochloride, formula: C22H24ClN3O4, relative molecular weight: 429.90 g· mol−1, CAS registry number: 183319-69-9, Figure 1), a 4aminophenylquinazoline oral anticancer drug which can inhibit the activity of epidermal growth factor receptor,13 has been reported to have seven polymorphs including forms A, B, E, L, M, © XXXX American Chemical Society

Figure 1. Chemical structure of erlotinib hydrochloride.

N, and P. Among these polymorphs, form B is the medicinal form, and form A is being developed as the alternative.14 From literature review, Lu et al.15 have studied the effect of the nonionic surfactant Tween 80 on the solubility of forms A and B of erlotinib hydrochloride in isopropanol and acetone from 273.15 to 303.15 K. Nevertheless, the corresponding work on the solubility of the polymorphs of erlotinib hydrochloride in series of organic solvents over an abroad temperature range has not yet been conducted. In this work, the solubilities of forms A and B of erlotinib hydrochloride in methanol, ethanol, isopropanol (IPA), acetone, methyl ethyl ketone (MEK), and methyl isobutyl ketone (MIBK) from 273.15 to 323.15 K were measured, and the modified Apelblat equation and the Buchowski−Ksiazczak λh equation were employed to correlate the experimental solubility data. Received: September 10, 2016 Accepted: November 25, 2016

A

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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EXPERIMENTAL SECTION Materials. Form B of erlotinib hydrochloride and form II of clopidogrel hydrogen sulfate (mass fraction purity ≥0.995) were purchased from Lixin Pharmaceutical Co., Ltd. (Suzhou, China). Form A of erlotinib hydrochloride and form I of clopidogrel hydrogen sulfate were prepared in-house following the procedures as described in refs 15 and 16, respectively. All organic solvents were analytical reagent grade and supplied by Sinopharm Reagent Co., Ltd. (Shanghai, China). All materials were used as received without further purification. More detailed information about the materials used in this work was listed in Table 1.

amount of form A or form B was added into the solvents followed by vigorous stirring. It was found that the saturation can be closely approached within 30 min through powder dissolution experiments and the induction time for the transformation from form A to form B generally took more than 2 h in the studied temperature range and solvents in this work through slurry experiments. Thus, after 1 h, the stirring was stopped to allow the suspension to stand for about 0.5 h.15,17 The supernatant in equilibrium with solids was quickly filtered through 0.22 μm membrane filters, and the filtrate was diluted for HPLC analysis. The polymorphic form of the residual solids in the suspension was determined by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). Each reported solubility data were an average of six independent measurements. To date, the solubility data of forms A and B of erlotinib hydrochloride in the solvents used in this work such as methanol, ethanol, MIBK, and MEK have not been reported yet; therefore, the reliability of the method of solubility measurement employed was validated through comparing the solubility of forms I and II of clopidogrel hydrogen sulfate in 1-butanol at atmospheric pressure obtained by the method with those reported in refs 16 and 18, respectively. As shown in Table 2, the solubility data of forms I and II of clopidogrel hydrogen sulfate in 1-butanol obtained in this work are in good agreement with those reported in refs 16 and 18, respectively, with the relative deviation (RD) of less than 3.6%. HPLC Analysis. 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 measurement was operated in an isocratic elution program with the 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 the same temperature. The linear standard curve was obtained in the appropriate concentration range using pure erlotinib hydrochloride. PXRD Analysis. PXRD was performed on a D8 Advance powder X-ray diffractometer (Bruker AXS, Karlsruhe, Germany) with Cu Kα radiation (λ = 1.5418 Å) at 40 mA and 40 kV. The samples were scanned from 4° to 40° (2θ) at a scanning rate of 0.01 deg·s−1. The diffractograms of pure forms A and B of

Table 1. Chemicals Used in This Study chemical name erlotinib hydrochloride clopidogrel hydrogen sulfate methanol ethanol isopropanol acetone methyl ethyl ketone methyl isobutyl ketone 1-butanol

source Lixin Pharmaceutical Co., Ltd. Lixin Pharmaceutical Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd. Sinopharm Reagent Co., Ltd.

mass fraction purity

purification method

analysis method

≥0.995

none

HPLCa, PXRDb

≥0.995

none

HPLCa, PXRDb

≥0.995

none

GCc

≥0.995

none

GCc

≥0.995

none

GCc

≥0.995

none

GCc

≥0.995

none

GCc

≥0.995

none

GCc

≥0.995

none

GCc

a

High-performance liquid chromatography for determining chemical purity. bPowder X-ray diffraction for determining polymorphic purity. c Gas chromatography.

Solubility Measurement. The solubility was measured by dissolution method as described in our previous work.15 Organic solvents were first precisely weighted and filled into jacketed 200 mL glass crystallizers which were controlled at the desired temperatures by Julabo F12-ME refrigerated/heating circulators (Seelbach, Germany) with a precision of 0.01 K. Then an excess

Table 2. Comparison of the Experimental Solubility of Forms I and II of Clopidogrel Hydrogen Sulfate (xexp) with the Solubility of 16 18 a Form I of Ref 16 (xref ) and the Solubility of Form II of Ref 18 (xref I II ) in 1-Butanol under p = 101.3 kPa form I T/K 273.15 278.15 283.15 288.15 292.85 298.35 303.35 308.50 313.25 318.15

a

4

10

xexp I

17.59 19.21 22.39 25.76 29.70 34.58 39.52 45.13 51.82 59.93

form II 4

10

16 xref I

18.12 18.78 21.99 24.91 28.77 33.34 38.73 43.73 52.23 61.67

2

10 RD

T/K

−3.01 2.24 1.79 3.30 3.13 3.59 2.00 3.10 −0.79 −2.90

293.15 295.65 298.15 300.65 303.15 305.65 308.15 310.65 313.15 315.65 318.15

4

10

xexp II

12.50 14.24 16.32 18.42 20.87 23.60 26.64 30.00 33.23 37.85 42.40

18 104 xref II

102RD

12.62 14.29 16.20 18.34 20.76 23.47 26.51 29.91 33.73 37.99 42.76

−0.96 −0.35 0.74 0.43 0.53 0.55 0.49 0.30 −1.50 −0.37 −0.85

Standard uncertainties u are u(T) = 0.01 K, u(p) = 0.5 kPa. The relative standard uncertainty ur is ur(x) = 0.05. B

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Figure 2. Diffractograms of forms A and B of erlotinib hydrochloride.

Figure 3. DSC thermograms of forms A and B of erlotinib hydrochloride.

erlotinib hydrochloride are shown in Figure 2. The characteristic peaks of form A were at 5.64°, 18.93°, 23.57°, 25.51°, 26.18°,

26.54°, and 29.30°, which were in accordance with those reported in ref 14. The characteristic peaks of form B were at C

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 3. Experimental Solubility (xexp), Calculated Solubility (xApel) by the Modified Apelblat Equation, Calculated Solubility (xλh) by the λh Equation of Form A in Various Solvents under p = 101.3 kPaa T/K

xexp

xApel

102 RD

xλh

102 RD

Methanol 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

1.678 2.151 2.733 3.443 4.304 5.339 6.578 8.048 9.784 1.182 1.420

× × × × × × × × × × ×

10−05 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−4 10−4

1.681 2.154 2.737 3.448 4.310 5.347 6.587 8.060 9.799 1.184 1.422

× × × × × × × × × × ×

10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−4 10−4

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

8.363 1.016 1.226 1.470 1.751 2.074 2.442 2.861 3.335 3.869 4.468

× × × × × × × × × × ×

10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

8.354 1.015 1.224 1.468 1.749 2.071 2.439 2.857 3.331 3.864 4.462

× × × × × × × × × × ×

10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

7.562 9.179 1.111 1.331 1.573 1.864 2.187 2.574 2.995 3.499 4.045

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

7.634 9.228 1.109 1.326 1.577 1.866 2.198 2.577 3.010 3.500 4.054

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

2.439 2.739 3.022 3.314 3.635 3.973 4.331 4.707 5.103 5.518 5.952

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

2.455 2.726 3.015 3.321 3.645 3.987 4.346 4.722 5.116 5.527 5.955

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

1.386 1.625 1.895 2.199 2.538 2.915 3.333 3.795 4.302 4.859 5.466

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

1.374 1.617 1.891 2.198 2.541 2.921 3.340 3.802 4.306 4.857 5.455

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

−0.179 −0.139 −0.146 −0.145 −0.139 −0.150 −0.137 −0.149 −0.153 −0.169 −0.141

1.691 2.162 2.741 3.445 4.302 5.332 6.564 8.031 9.767 1.181 1.421

× × × × × × × × × × ×

10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−4 10−4

−0.775 −0.511 −0.293 −0.058 0.047 0.131 0.213 0.211 0.174 0.085 −0.070

0.108 0.098 0.163 0.136 0.114 0.145 0.123 0.140 0.120 0.129 0.134

8.467 1.024 1.232 1.472 1.749 2.069 2.435 2.853 3.328 3.868 4.481

× × × × × × × × × × ×

10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

−1.244 −0.787 −0.489 −0.136 0.114 0.241 0.287 0.280 0.210 0.026 −0.291

−0.952 −0.534 0.180 0.376 −0.254 −0.107 −0.503 −0.117 −0.501 −0.029 −0.222

7.610 9.213 1.107 1.324 1.577 1.866 2.197 2.572 3.006 3.492 4.050

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

−0.635 −0.370 0.360 0.526 −0.254 −0.107 −0.457 0.078 −0.367 0.200 −0.124

−0.656 0.475 0.232 −0.211 −0.275 −0.352 −0.346 −0.319 −0.255 −0.163 −0.050

2.383 2.646 2.993 3.240 3.573 3.933 4.323 4.644 5.095 5.583 6.111

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

2.296 3.395 0.960 2.233 1.706 1.007 0.185 1.338 0.157 −1.178 −2.671

0.866 0.492 0.211 0.045 −0.118 −0.206 −0.210 −0.184 −0.093 0.041 0.201

1.374 1.640 1.904 2.200 2.532 2.904 3.318 3.779 4.291 4.860 5.490

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.866 −0.923 −0.475 −0.046 0.236 0.377 0.451 0.422 0.256 −0.021 −0.439

Ethanol

IPA

Acetone

MEK

D

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 3. continued T/K

xexp

xApel

xλh

102 RD

102 RD

MIBK 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 a

2.660 3.071 3.528 4.032 4.588 5.198 5.865 6.592 7.381 8.235 9.157

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

2.647 3.061 3.520 4.027 4.586 5.197 5.864 6.590 7.375 8.223 9.136

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.489 0.326 0.227 0.124 0.044 0.019 0.017 0.030 0.081 0.146 0.229

2.703 3.100 3.542 4.063 4.574 5.173 5.833 6.560 7.360 8.240 9.206

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

−1.617 −0.944 −0.397 −0.769 0.305 0.481 0.546 0.485 0.285 −0.061 −0.535

Standard uncertainties u are u(T) = 0.01 K, u(p) = 0.5 kPa; The relative standard uncertainty ur is ur(x) = 0.05.

oxygen atom in ketones, which can lead to the solubility of erlotinib hydrochloride in alcohols higher than that in ketones. The sequence in the studied alcohols is consistent with the polarity and the solubility parameter order: methanol > ethanol > IPA.20 That is, the polarity of the selected alcohols may be the dominated factor that determines the solubility of two forms of erlotinib hydrochloride. The solubility order of both forms in ketones is not consistent with the polarity. The solubility in MIBK is largest in the studied ketones may be attributed to that the polarity of MIBK is similar to the polarity of erlotinib hydrochloride. But, compared to MEK, the higher solubility of both forms in acetone may be owed to that hydrogen bonds between the oxygen atom in acetone and the hydrogen atom of imino group in erlotinib hydrochloride are more easily set up. Solubility Correlation. The modified Apelblat equation, deduced from the Clausius−Clapeyron equation,21 can be written as the following expression22,23

6.27°, 7.88°, 13.41°, 14.78°, 15.72°, 16.96°, 17.60°, 20.22°, 21.14°, 22.50°, 23.9°, 25.14°, 26.84°, 28.64°, 29.76°, and 34.76°. No detectable polymorphic transformation was found within 1.5 h in the studied solvents and temperature range. DSC Analysis. DSC was conducted on a SDT Q600 thermal analyzer (TA Instruments, Leatherhead, UK). The temperature and enthalpy calibration was performed using high-purity indium (mass fraction purity ≥0.99999; onset temperature, 429.75 K; enthalpy of fusion, 3.2723 kJ·mol−1) as the standard material and an empty pan as the reference. All measurements for the calibration were repeated at least 3 times. After the calibration, accurately weighed samples (5−8 mg) were placed in alumina crucibles and scanned at 10 K·min−1 under a nitrogen purge. The obtained DSC thermograms of forms A and B of erlotinib hydrochloride are shown in Figure 3. The onset temperature as the melting point (Tm) of form A was obtained at 479.6 K and that of form B was 502.1 K; meanwhile the enthalpy of fusion (ΔHfus) of form A was calculated as 52.8 kJ·mol−1, and that of form B was 61.8 kJ·mol−1. The standard uncertainties were evaluated to be 0.5 K for temperature and 0.6 kJ·mol−1 for the enthalpy of fusion. In ref 14, the onset temperatures of forms A and B of erlotinib hydrochloride were obtained at 479.6 and 506.0 K, respectively. The difference between the reported onset temperature of form B in this work and that in the ref 14 may be resulted from the source of sample (chemical and/or polymorphic purity, crystallinity, etc.) and sample preparation (particle size, stacking mode, weight, etc.). Thermograms also confirmed that there were no solvation and polymorphic transformation during the solubility measurements.

ln x = a +

b T + c ln T /K K

(1)

where x represents the mole fraction solubility of erlotinib hydrochloride polymorphs at the temperature T; a, b, and c are the equation parameters acquired through the regression of experimental solubility data. To an extent, a and b reflect the effect of solution nonideality on the solubility of the solute, and c reveals the relationship between temperature and the enthalpy of fusion of the solute.24 The optimized parameters a, b, and c with the root-mean-square deviations (RMSD) of forms A and B of erlotinib hydrochloride in various pure solvents are listed in Tables 5 and 6, respectively. The λh equation, developed by Buchowski et al. in 1981, can be expressed as follows25,26

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RESULTS AND DISCUSSION Solubility Data. The solubilities of forms A and B of erlotinib hydrochloride in methanol, ethanol, IPA, acetone, MEK, and MIBK, as a function of temperature (T), are listed in Tables 3 and 4, respectively. From Tables 3 and 4, it is found that the solubility of both forms generally increases with the temperature, and form A has a higher solubility than form B which demonstrates that form A is the metastable form. According to the solubility rule as well as the heat-of-fusion rule,19 two forms of A and B are monotropically related. The order of the solubility of both forms in the studied solvents is methanol > ethanol > IPA > MIBK > acetone > MEK. In other words, the solubility of two forms of erlotinib hydrochloride at a given temperature decreases with the increase of the carbon number of alcohols. In general, the hydrogen atom of imino group in erlotinib hydrochloride is more easily bonded with the oxygen atom in alcohols than with the

⎛1 ⎡ ⎛ 1 − x ⎞⎤ 1 ⎞ ⎟ = λh⎜ ln⎢1 + λ⎜ − ⎟ ⎝ x ⎠⎥⎦ ⎣ Tm ⎠ ⎝T

(2)

where T and Tm are the system temperature and the melting point of the solute, respectively. The λ and h are the two equation parameters evaluated by regressing experimental solubility data. The λh equation has been widely employed to correlate the experimental solubility data because it avoids the calculation of activity coefficients and thus simplifies the correlation process.27 The optimized parameters λ and h with the root-mean-square deviations (RMSD) of forms A and B of erlotinib hydrochloride in various pure solvents are listed in Tables 5 and 6, respectively. E

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Table 4. Experimental Solubility (xexp), Calculated Solubility (xApel) by the Modified Apelblat Equation, and Calculated Solubility (xλh) by the λh Equation of Form B in Various Solvents under p = 101.3 kPaa T/K

xexp

xApel

xλh

102 RD

102 RD

Methanol 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

7.348 9.440 1.202 1.518 1.901 2.364 2.918 3.578 4.391 5.265 6.347

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

7.308 9.407 1.200 1.517 1.902 2.366 2.921 3.581 4.360 5.274 6.340

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

5.174 6.246 7.491 8.927 1.058 1.246 1.459 1.701 1.973 2.278 2.618

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5

5.181 6.254 7.499 8.935 1.060 1.247 1.460 1.702 1.975 2.280 2.620

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

5.104 6.017 7.112 8.294 9.647 1.115 1.280 1.474 1.689 1.919 2.159

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5

5.105 6.042 7.107 8.313 9.672 1.119 1.289 1.478 1.687 1.917 2.170

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

1.450 1.613 1.775 1.950 2.126 2.322 2.535 2.760 3.005 3.255 3.507

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

1.452 1.606 1.771 1.946 2.134 2.332 2.543 2.766 3.001 3.249 3.510

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15

9.220 1.069 1.232 1.414 1.614 1.835 2.078 2.343 2.632 2.945 3.285

× × × × × × × × × × ×

10−07 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

9.213 1.067 1.231 1.412 1.612 1.832 2.074 2.339 2.627 2.941 3.280

× × × × × × × × × × ×

10−07 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.544 0.350 0.166 0.066 −0.053 −0.085 −0.103 −0.084 0.706 −0.171 0.110

7.401 9.491 1.207 1.522 1.904 2.365 2.919 3.577 4.357 5.277 6.356

× × × × × × × × × × ×

10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5 10−5

−0.721 −0.540 −0.416 −0.264 −0.158 −0.042 −0.034 0.028 0.774 −0.228 −0.142

−0.135 −0.128 −0.107 −0.090 −0.189 −0.080 −0.069 −0.059 −0.101 −0.088 −0.076

5.223 6.284 7.516 8.936 1.057 1.243 1.456 1.697 1.965 2.273 2.624

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5 10−5

−0.947 −0.608 −0.334 −0.101 0.095 0.241 0.206 0.235 0.406 0.220 −0.229

−0.020 −0.415 0.070 −0.229 −0.259 −0.359 −0.703 −0.271 0.118 0.104 −0.509

5.064 5.984 7.032 8.222 9.569 1.109 1.279 1.470 1.683 1.921 2.186

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−5 10−5 10−5 10−5 10−5 10−5

0.784 0.548 1.125 0.868 0.809 0.538 0.078 0.271 0.355 −0.104 −1.251

−0.138 0.434 0.225 0.205 −0.376 −0.431 −0.316 −0.217 0.133 0.184 −0.086

1.433 1.584 1.747 1.920 2.110 2.312 2.529 2.763 3.013 3.282 3.570

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

1.172 1.798 1.578 1.539 0.753 0.431 0.237 −0.109 −0.266 −0.830 −1.796

0.076 0.187 0.081 0.141 0.124 0.163 0.192 0.171 0.190 0.136 0.152

9.208 1.075 1.249 1.434 1.640 1.869 2.109 2.358 2.668 2.972 3.347

× × × × × × × × × × ×

10−07 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.130 −0.561 −1.380 −1.414 −1.611 −1.853 −1.492 −0.640 −1.368 −0.917 −1.887

Ethanol

IPA

Acetone

MEK

F

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Table 4. continued xexp

T/K

xApel

xλh

102 RD

102 RD

MIBK 273.15 278.15 283.15 288.15 293.15 298.15 303.15 308.15 313.15 318.15 323.15 a

1.915 2.168 2.445 2.745 3.069 3.420 3.796 4.200 4.632 5.093 5.583

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−06 10−6 10−6 10−6

1.900 2.162 2.445 2.753 3.083 3.438 3.818 4.221 4.649 5.102 5.579

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.783 0.277 0.204 −0.291 −0.456 −0.526 −0.580 −0.500 −0.367 −0.177 0.072

1.897 2.147 2.421 2.721 3.049 3.408 3.771 4.194 4.655 5.155 5.699

× × × × × × × × × × ×

10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6 10−6

0.940 0.969 1.184 0.874 0.652 0.351 0.659 0.143 −0.497 −1.217 −2.078

Standard uncertainties u are u(T) = 0.01 K, u(p) = 0.5 kPa; The relative standard uncertainty ur is ur(x) = 0.05.

Table 5. Parameters and Root-Mean-Square Deviations of Modified Apelblat Equation and λh Equation for Form A in Various Solvents λh equation

Apelblat equation solvent

a

methanol ethanol IPA acetone MEK MIBK

2.928 −1.146 −22.326 1.574 8.485 1.580

−3

10

c

4

10 RMSD

3

10 λ

10−6 h

104 RMSD

−0.018 0.042 3.186 −1.309 −1.952 −0.958

1.125 0.337 0.715 0.118 0.068 0.095

5.942 0.759 0.694 0.020 0.049 0.059

0.626 3.768 4.136 71.928 46.641 33.550

1.140 0.341 0.710 0.118 0.067 0.095

b

−3.775 −2.945 −2.002 −1.952 −3.013 −2.471

Table 6. Parameters and Root-Mean-Square Deviations of the Modified Apelblat Equation and λh Equation for Form B in Various Solvents λh equation

Apelblat equation solvent

a

methanol ethanol IPA acetone MEK MIBK

9.644 −2.485 −1.151 −15.799 −7.083 11.586

10

−3

b

−4.147 −2.826 −2.629 −1.201 −2.180 −2.690

c

4

10 RMSD

3

10 λ

10−6 h

104 RMSD

−1.121 0.118 −0.251 1.204 0.208 −2.658

1.021 0.140 0.485 0.061 0.033 0.141

4.009 0.539 0.319 0.012 0.053 0.035

0.941 5.168 7.797 109.621 47.702 50.798

1.029 0.128 0.496 0.061 0.032 0.141

modified Apelblat equation, 2.256 × 10−3; the λh equation, 6.457 × 10−3. That is, after using the experimental solubility data at different temperatures to optimize the model parameters, both modified Apelblat equation and λh equation could well correlate the solubility of two forms of erlotinib hydrochloride in alcohols and ketones over the studied temperature range, and the modified Apelblat equation performed better. In addition, the experimental solubility data of forms A and B of erlotinib hydrochloride in acetone and IPA were compared with those in ref 15, as shown in Figures 4 and 5. In general, the solubility data of forms A and B of erlotinib hydrochloride in acetone reported in this work were quite close to those in the ref 15, giving average relative deviations of 6.555 × 10−3 and 8.416 × 10−3, respectively, whereas there existed large deviations between the solubility in IPA reported in this work and in the ref 15, giving average relative deviations of 1.655 × 10−2 for form A and 1.264 × 10−2 for form B, respectively. The deviation between the reported solubility data in this work and those in the ref 15 of erlotinib hydrochloride in isopropanol and acetone may be attributed to random errors, personal error, and so forth.

In this work, the correlation performance of the selected thermodynamic models was evaluated using the root-meansquare deviations (RMSD), the relative deviation (RD), and the average relative deviation (ARD) between experimental and calculated solubility ⎡ ∑N (x exp − x cal)2 ⎤1/2 ⎥ RMSD = ⎢ 1 ⎢⎣ ⎥⎦ N RD =

x exp − x cal x exp

ARD = exp

1 N

N

∑ 1

x exp − x cal x exp

(3)

(4)

(5)

cal

where x and x are the experimental and calculated solubility data, respectively; N is the number of experimental points acquired in each set. The values of RD between experimental and calculated solubility of forms A and B are listed in Tables 3 and 4, respectively. As shown in Tables 3 and 4, the comparison of the correlated results of two models in terms of the average relative deviation (ARD) from all experimental points is as follows: the G

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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Figure 4. Comparison of the solubility data of forms A and B in acetone. Experimental solubility data: , form B; ---, form A. Ref 15, solubility data: ●, form B; ○, form A. Calculated solubility data: (form B: ▲, calculated by the modified Apelblat equation; ⧫, calculated by the λh equation), (form A: △, calculated by the modified Apelblat equation; ◊, calculated by the λh equation).

Figure 5. Comparison of the solubility data of forms A and B in IPA. Experimental solubility data: , form B; ---, form A. Ref 15, solubility data: ●, form B; ○, form A. Calculated solubility data: (form B: ▲, calculated by the modified Apelblat equation; ⧫, calculated by the λh equation), (form A: △, calculated by the modified Apelblat equation; ◊, calculated by the λh equation).

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CONCLUSIONS

temperature, and meanwhile form A had a higher solubility than form B which demonstrated that form A was the metastable form. The order of solubility of both forms in the studied solvents is methanol > ethanol > IPA > MIBK > acetone > MEK. Furthermore, the modified Apelblat equation and the λh

The solubilities of monotropically related forms A and B of erlotinib hydrochloride in selected alcohols and ketones were measured at temperatures from 273.15 to 323.15 K at 5 K intervals. The solubility of both forms increased with the H

DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

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equation were evaluated to correlate the experimental solubility data and the calculated results showed that both equations could give satisfactory correlation results, in which the modified Apelblat equation stood out to have a higher accuracy than the λh equation.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +86 21 6779 1214. Tel.: +86 21 6779 1216. ORCID

Jie Lu: 0000-0002-4581-2032 Funding

This research work was financially supported by the National Natural Science Foundation of China (Nos. 21176102, 21176215, and 21476136), the Natural Science Foundation of Jiangsu Province (No. BK20131100), the Connotation Construction Project of SUES (No. Nhky-2015-05), Science and Technology Commission of Shanghai Municipality (No. 15430501200), and the Sino-German Center for Research Promotion (No. GZ935). Notes

The authors declare no competing financial interest.

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DOI: 10.1021/acs.jced.6b00796 J. Chem. Eng. Data XXXX, XXX, XXX−XXX