A CRYSTAL FORM OF NEPTINIB di-P-METHYLBENZENESULFONATE, PREPARATION METHOD THEREOF, AND PHARMACEUTICAL COMPOSITION CONTAINING SAME

Abstract

Provided is a composition of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2-butenamide p-toluene sulfonate 1.5 hydrate α-polymorph. The α-polymorph has a stable form, a defined melting point, a good chemical stability, and a good endurance to high temperature and light irradiation, and is suitable for pharmaceutical use.

Claims

1. A crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate represented by Formula (1), said crystal form α is (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate 1.5 hydrate, having an X-ray powder diffraction pattern with characteristic peaks at 2θ° of 5.0±0.2, 12.1±0.2, 14.5±0.2, 15.6±0.2, 17.6±0.2, 18.7±0.2, 20.1±0.2, 22.0±0.2, 25.4±0.2, 26.0±0.2 and 26.3±0.2, ##STR00002##

2. The crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate of claim 1, characterized in that, said 2θ° has an approximate relative intensity I/I.sub.0 as the following value: TABLE-US-00011 2θ° I/I.sub.0 1 5.0280  100% 2 12.1417 13.90%  3 14.5223 7.69% 4 15.6252 8.19% 5 17.6798 41.02%  6 18.7496 25.08%  7 20.1191 7.48% 8 22.0733 8.89% 9 25.4152 7.29% 10 26.0953 7.39% 11 26.3735 11.13% 

3. The crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate according to claim 1, characterized in that, said crystal form α has a maximum endothermic transition at about 133° C. in DSC scanning pattern.

4. The crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate according to claim 1, characterized in that, its thermogravimetric pattern shows a weight loss of 2.5% at 169° C.

5. The crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate according to claim 1, characterized in that, the infrared absorption spectrum using a potassium bromide disc comprises absorption peaks at about 3419, 3284, 3052, 2930, 2732, 2589, 1695, 1640, 1575, 1543, 1524, 1498, 1452, 1400, 1368, 1328, 1266, 1238, 1218, 1185, 1160, 1121, 1033, 1008, 814, 684, 568, 500 cm.sup.−1.

6. A preparation method of the crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate of claim 1, comprising the steps of: 1) adding crude product of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate into a mixed solvent of C.sub.1-C.sub.4 alkyl alcohol and water or into a mixed solvent of C.sub.3-C.sub.4 alkyl ketone and water, heating under reflux to achieve dissolution; wherein the alkyl alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol and butanol, and the volume ratio of alcohol to water is 11:1˜20:1; the alkyl ketone is selected from the group consisting of acetone, methyl ethyl ketone and butanone, and the volume ratio of ketone to water is 11:1˜20:1; and the weight volume ratio of the crude product to the solvent is 1 (g):5˜30 (ml), and the heating temperature is 50˜80° C.; and 2) cooling the clear solution to precipitate, filtrating, collecting the precipitate, and drying the collected precipitate under reduced pressure to obtain the crystal form α; wherein the precipitation is carried out for 2˜8 hours, the precipitation temperature is 0˜40° C., after the completion of precipitation and filtration, the drying temperature is 30˜60° C.

7. The preparation method of claim 6, wherein in step (1), the alkyl alcohol is ethanol, the alkyl ketone is acetone, the weight volume ratio of the crude product to the solvent is 1:12 (g/ml), the mixed solvent of alcohol and water is heated to 70° C., the mixed solvent of ketone and water is heated to 60° C.; in step (2), the precipitation is carried out for 4 hours, the precipitation temperature is 5˜15° C., and the drying temperature is 45° C.

8. A pharmaceutical composition comprising the crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide di-p-methylbenzenesulfonate of claim 1.

Description

DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 is an X-ray diffraction pattern of the α-polymorph obtained in Example 1 of the present invention;

[0024] FIG. 2 is a DSC pattern of the α-polymorph obtained in Example 1 of the present invention;

[0025] FIG. 3 is a TG pattern of the α-polymorph obtained in Example 1 of the present invention;

[0026] FIG. 4 is an IR spectrum of the α-polymorph obtained in Example 1 of the present invention;

[0027] FIG. 5 is an HPLC pattern of the α-polymorph obtained in Example 1 of the present invention;

DETAILED DESCRIPTION OF THE INVENTION

[0028] All materials and reagents were commercially available.

[0029] Preparation of crude product:

[0030] (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide(Neptinib) was prepared using N-3-chloro-4-fluorophenyl)amino]-7-fluor-6-nitro-4-quinazolinamine as a starting material with reference to method of the patent publication WO2007085638, and the salt-forming process was performed with reference to the method of the patent publication WO2012121764.

Preparation of crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxy quinazolin-6-yl-4-(dimethylamino)but-2-enamide (Neptinib) di-p-methylbenzenesulfonate

Example 1

[0031] 200 g of crude Neptinib di-p-methylbenzenesulfonate was added into a reaction flask, and 2400 ml of mixture of acetone and water (V/V=12:1) was added, refluxed at 60° C. under stirring. After the solid was dissolved, the solution was stirred for 10 min, cooled to 5˜15° C. to precipitate, stirred for another 4 hours for crystallization, and filtrated. The filter cake was leached with acetone, and then subjected to air blast drying at 45° C. with the assistance of phosphorus pentoxide. 163 g of whitish solid was obtained, with a yield of 81.5%. The water content was determined to be 3.3% by Karl Fischer titrator. The obtained compound was crystal form α of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-yl)-4-(dimethylamino)but-2-enamide (Neptinib) di-p-methylbenzene sulfonate 1.5 hydrate.

[0032] The characteristics of the compound were identified as shown in FIGS. 1 to 5.

[0033] Test conditions for the samples of the example:

[0034] (1) XRD:

[0035] Detection instrument: Empyrean X-ray diffractometer

[0036] Detection conditions: Cu target Kα ray, Voltage 40 kV, Current 40 mA, Divergence slit 1/32°, Anti-scatter slit 1/16°, Anti scatter slit 7.5 mm, 2θ range: 3°-50°, Step size 0.02°, step motion time: 40 s/step.

[0037] Detection method: X-ray powder diffraction method, Appendix IX F, Pharmacopoeia of the People's Republic of China (2010 Edition, Part II)

[0038] Detection result: see FIG. 1.

[0039] (2) DSC:

[0040] Detection instrument: DSC 204F1 differential scanning calorimeter, NETZSCH Company, Germany

[0041] Detection conditions: Atmosphere: N.sub.2 (purity: ≧99.99), 20 ml/min; Scanning procedure: heating rate of 10° C./min from room temperature to 180° C., recording the temperature curve; Sample quality: Sample 1: 2.27 mg (Aluminum sample tray)

[0042] Detection method: General rules for thermal analysis JY/T 014-1996

[0043] Detection result: see FIG. 2.

[0044] (3) TG:

[0045] Detection instrument: TG209 thermal gravimetric analyzer, NETZSCH company, Germany

[0046] Detection conditions: Atmosphere: air, 20 ml/min; Scanning procedures: room temperature 700° C., heating rate: 10° C./min.

[0047] Detection method: General rules for thermal analysis JY/T 014-1996

[0048] Detection result: see FIG. 3.

[0049] (4) Infrared spectrum:

[0050] Detection instrument: FT-IR NICOLET6700 (Germany)

[0051] Detection conditions: potassium bromide disc

[0052] Detection method: General rules for infrared analysis GB/T 6040-2002

[0053] Detection result: see FIG. 4.

[0054] (5) HPLC

[0055] Detection instrument: Agilent 1260 series (U.S.)

[0056] Detection conditions: Chromatographic column: Waters C18; Mobile phase A: acetonitrile-mobile phase B (70:30); Mobile phase B: 0.05 mol/l ammonium dihydrogen phosphate solution (pH=7.3); Column temperature: 30° C.; Detection wavelength: 247 nm.

[0057] Detection method: High performance liquid chromatography method, Pharmacopoeia of the People's Republic of China, Part II Appendix VD

[0058] Detection result: see FIG. 5.

Example 2

[0059] 200 g of crude Neptinib di-p-methylbenzenesulfonate was added into a reaction flask, and 1600 ml of mixed solvent of acetone and water (V/V=10:1) was added, refluxed at 60° C. under stirring. After the solid was dissolved, the solution was stirred for 10 min, cooled to 5˜15° C. to precipitate, stirred for another 4 hours for crystallization, and filtrated. The filter cake was leached with acetone, and then subjected to air blast drying at 45° C. with the assistance of phosphorus pentoxide. 154 g of whitish solid was obtained with a yield of 77%. The water content was determined to be 4.4% by Karl Fischer titrator. The obtained compound was crystal form β of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide (Neptinib) di-p-methylbenzene sulfonate 2 hydrate.

Other Examples

[0060] 20 g of Neptinib di-p-methylbenzenesulfonate was respectively added into a reaction flask, and the experiments were carried out with reference to the experiment operations of Examples 1˜2:

TABLE-US-00003 Crude product/ Solvent/ mixed Heat Dry Organic water solvent temp. Precipitation Precipitation temp. Yield Water No. solvent (V/V) (g/ml) (° C.) temp. (° C.) time (h) (° C.) (%) (%) 3 Ethanol  1:1 1 g:5 ml 50 0~5 2 45 52 4.6 4 Ethanol  5:1 1 g:18 ml 65  5~15 3 30 58.3 4.5 5 Ethanol 10:1 1 g:30 ml 70 15~25 4 60 60.7 4.4 6 Ethanol 12:1 1 g:5 ml 70 15~25 4 60 65 3.4 7 Ethanol 15:1 1 g:18 ml 75 25~40 6 30 47.8 3.3 8 Ethanol 20:1 1 g:30 ml 80 15~25 8 45 56.1 3.2 9 Methanol  5:1 1 g:15 ml 65 0~5 2 60 52.7 4.5 10 Methanol 10:1 1 g:18 ml 70 15~25 4 45 52 4.4 11 Methanol 15:1 1 g:25 ml 75  5~15 6 50 60.3 3.3 12 Methanol 20:1 1 g:30 ml 80 25~40 8 50 51.6 3.2 13 Isopropyl  6:1 1 g:15 ml 70 0~5 4 45 45.3 4.4 alcohol 14 Butanol 12:1 1 g:20 ml 80 15~25 5 55 42.8 3.3 15 Propanol 18:1 1 g:12 ml 75 25~40 6 60 44.7 3.2 16 Acetone  1:1 1 g:5 ml 80 0~5 4 60 70 4.5 17 Acetone  5:1 1 g:5 ml 70 25~40 5 45 71.3 4.3 18 Acetone  8:1 1 g:8 ml 75 15~25 6 50 74.5 4.6 19 Acetone 10:1 1 g:11 ml 60  5~15 4 45 89 4.4 20 Acetone 12:1 1 g:12 ml 60 15~25 8 45 85.6 3.3 21 Acetone 15:1 1 g:30 ml 50 0~5 4 40 74 3.2 22 Butanone  1:1 1 g:5 ml 50 0~5 2 30 43.8 4.4 23 Methyl 20:1 1 g:30 ml 80 25~40 8 60 49.6 3.1 ethyl ketone

Stability studies on crystal forms of (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-dimethylamino)but-2-enamide (Neptinib) di-p-methylbenzene sulfonate

Example 3

[0061] The stability studies of crystal forms α and β (accelerated test for 10 days) were performed respectively under the conditions of 40° C., 60° C., relative humidity 75%, 92.5%, and light irradiation, to compare the data of water content, purity, maximum single impurity and total impurities of the new crystal form with that on the day 0, and the results showed that the obtained crystal form is stable. The free base (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-4-(dimethylamino)but-2-enamide was obviously degraded under the condition of 60° C., indicating that high temperature has an effect on the stability of the free base.

TABLE-US-00004 TABLE 1 Results of stress testing on crystal form α Stress testing on crystal form α Sample No: 1 (prepared in Example 1) Maximum Total Water Purity single impurities (%) (%) impurity (%) (%) Day 0 1 3.3 99.98 0.021 (RRT: 1.22) 0.02 Day 5 1-40° C. 3.3 99.98 0.022 (RRT: 1.22) 0.02 1-60° C. 3.3 99.96 0.022 (RRT: 1.22) 0.04 1-75% 3.1 99.98 0.021 (RRT: 1.22) 0.02 1-92.5% 3.2 99.98 0.021 (RRT: 1.22) 0.02 1-light 3.1 99.93 0.051 (RRT: 0.93) 0.07 irradiation Day 10 1 3.2 99.98 0.022 (RRT: 1.22) 0.02 1-40° C. 3.3 99.98 0.022 (RRT: 1.22) 0.02 1-60° C. 3.3 99.96 0.020 (RRT: 1.22) 0.04 1-75% 3.1 99.98 0.022 (RRT: 1.22) 0.02 1-92.5% 3.2 99.98 0.022 (RRT: 1.22) 0.02 1-light 3.1 99.91 0.055 (RRT: 0.93) 0.09 irradiation

TABLE-US-00005 TABLE 2 Results of stress testing on crystal form β Stress testing on crystal form β Sample No. 2 (prepared in Example 2) Maximum Total Water Purity single impurities (%) (%) impurity (%) (%) Day 0 2 4.4 99.97 0.017 (RRT: 1.22) 0.03 Day 5 2-40° C. 4.4 99.97 0.020 (RRT: 1.22) 0.03 2-60° C. 4.3 99.83 0.151 (RRT: 0.93) 0.17 2-75% 4.4 99.97 0.019 (RRT: 1.22) 0.03 2-92.5% 4.5 99.97 0.018 (RRT: 1.22) 0.03 2- light 4.4 99.94 0.032 (RRT: 1.17) 0.06 irradiation Day 10 2 4.3 99.98 0.022 (RRT: 1.22) 0.02 2-40° C. 4.5 99.98 0.020 (RRT: 122) 0.02 2-60° C. 4.4 99.94 0.020 (RRT: 1.22) 0.06 2-75% 4.4 99.98 0.022 (RRT: 1.22) 0.02 2-92.5% 4.5 99.98 0.021 (RRT: 1.22) 0.02 2- light 4.5 99.80 0.177 (RRT: 0.93) 0.20 irradiation

TABLE-US-00006 TABLE 3 Results of stress testing on free base Maximum single Study Content impurity Sample condition (%) (%) Free base, Sample Day 0 99.37 0.45 (RRT: 1.11) No. 3 60° C., Day 5 96.77 2.14 (RRT: 0.44) (self-prepared) 40° C., Day 5 98.96 0.46 (RRT: 1.11) 60° C., Day 10 95.15 2.88 (RRT: 0.43) 40° C., Day 10 98.59 0.71 (RRT: 0.43)

[0062] Preparation of free base: The free base was prepared using N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine as a starting material with reference to method of the patent publication WO2007085638.

Preparation of Solid Pharmaceutical Preparations

[Example 4] Preparation of Solid Pharmaceutical Preparations

[0063] Formulation 1:

TABLE-US-00007 Ingredient Amount Crystal form α of Neptinib di-p-methylbenzenesulfonate 10 mg  1.5 hydrate (Example 1) Mannitol 126 mg  Lactose 50 mg  Crospovidone 8 mg Powder Silica gel 2 mg Glyceryl behenate 4 mg Total 200 mg 

[0064] Method: The above ingredients were mixed and directly compressed in accordance with the conventional preparation methods.

[0065] Formulation 2:

TABLE-US-00008 Ingredient Amount Crystal form α of Neptinib di-p-methylbenzenesulfonate 10 g 1.5 hydrate (Example 1) Mannitol 80 g Lactose 74 g Crospovidone 20 g Powder Silica gel  6 g Glyceryl behenate 10 g 3% HPMC suitable amount Total 200 g 

[0066] Method: Crystal form α of Neptinib p-methylbenzenesulfonate 1.5 hydrate, mannitol, lactose, crospovidone were mixed well by equal quantity increment method, then added with the prepared HPMC solution to make soft material, granulated through a 20 mesh sieve, dried at 60° C. for 30 minutes, granulated with an 18 mesh sieve, added with powder silica gel and mixed well, and then packed into 2# capsules.

[0067] Formulation 3:

TABLE-US-00009 Ingredient Amount Free base of Neptinib (self-prepared) 10 mg  Mannitol 126 mg  Lactose 50 mg  Crospovidone 8 mg Powder Silica gel 2 mg Glyceryl behenate 4 mg Total 200 mg 

[0068] Method: The above ingredients were mixed and directly compressed in accordance with the conventional preparation methods.

[Example 5] Control Stress Testing

[0069] Three batches of samples were prepared according to the process of Formulations 1˜3 in Example 4. After the basic items were checked to be qualified, the samples were tested under the conditions of light irradiation, high temperature and high humidity to examine the appearance, content and dissolution of the samples. The results of stress testing showed that the samples are stable under the conditions of high temperature and light irradiation, and can be used as reference formulation and process. However, Formulation 3 is prone to absorb moisture under the conditions of 25° C., RH75% and 25° C., RH92.5%, and is easily degraded under the condition of light irradiation.

TABLE-US-00010 TABLE 4 Tested item Formulation 1 Formulation 2 Formulation 3 Dissolution good good poor Compressibility good / medium Disintegration good medium poor

[0070] The purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution rate. The dissolution test results according to the 2010 edition of the Pharmacopoeia showed that both Formulations 1 and 2 have a dissolution rate of more than 80% within 15 minutes, while Formulation 3 has a dissolution rate of less than 70% within 15 minutes. Based on the same excipients, each tested item of Formulation 1 is better than that of Formulation 3. The crystal form α and free base product have differences not only in melting point, solubility, crystal solubility, but also in stability, preparation dissolution, compressibility, disintegration, and so on. The latter has poor properties compared to the crystal form α of Neptinib di-p-methylbenzenesulfonate 1.5 hydrate of the invention.

[0071] While the description above refers to the preferred embodiments of the invention, various changes or modifications may be made by the persons skilled in the art without departing from the spirit of the invention, and should belong to the scope of the appended claims of the present invention.