Crystalline forms of afatinib monomaleate, preparation methods and pharmaceutical compositions thereof
09708301 ยท 2017-07-18
Assignee
Inventors
Cpc classification
C07D405/12
CHEMISTRY; METALLURGY
International classification
A61K31/517
HUMAN NECESSITIES
Abstract
The present invention relates to the novel solid forms of Afatinib monomaleate and preparation methods thereof; the solid forms of Afatinib monomaleate of the present invention have many improved properties as compared to the known crystalline form of Afatinib salt; and the present invention also relates to pharmaceutical compositions containing the novel solid forms of Afatinib monomaleate as well as the uses thereof for treating terminal non-small cell lung cancer (NSCLS) and HER2 positive advanced breast cancer.
Claims
1. Crystalline Form N of Afatinib monomaleate with the structural formula shown below, ##STR00004## wherein, measured using Cu-K radiation, the X-ray powder diffraction pattern of the crystalline Form N of Afatinib monomaleate, expressed as 2 angles, has the following characteristic peaks: 3.80.2, 5.10.2, 5.80.2, 10.10.2, 14.90.2 and 20.20.2.
2. The crystalline Form N of Afatinib monomaleate according to claim 1, wherein the X-ray powder diffraction pattern of the crystalline Form N of Afatinib monomaleate, expressed as 2 angles, has the following characteristic peaks: 3.80.2, 5.10.2, 5.80.2, 6.80.2, 8.30.2, 10.10.2, 11.20.2, 14.90.2, 15.70.2, 18.90.2, 20.20.2 and 25.00.2.
3. The crystalline Form N of Afatinib monomaleate according to claim 2, wherein the X-ray powder diffraction pattern of the crystalline Form N of Afatinib monomaleate, expressed as 2 angles, has the following characteristic peaks with their relative intensities: TABLE-US-00006 Diffraction angel 2 Relative intensity % 3.8 0.2 39.7 5.1 0.2 100.0 5.8 0.2 48.9 6.8 0.2 14.6 8.3 0.2 21.0 10.1 0.2 36.8 11.2 0.2 17.7 14.9 0.2 30.8 15.7 0.2 28.5 16.1 0.2 24.8 16.5 0.2 12.8 17.8 0.2 18.4 18.9 0.2 29.3 20.2 0.2 67.4 21.2 0.2 28.5 23.1 0.2 30.9 25.0 0.2 71.4 25.5 0.2 34.7 27.2 0.2 35.1.
4. Crystalline Form N of Afatinib monomaleate with the structural formula shown below, ##STR00005## Wherein, measured using Cu-K radiation, the X-ray powder diffraction pattern of the crystalline Form N of Afatinib monomaleate has the characteristic peaks as depicted in
5. A method for preparing crystalline Form N of Afatinib monomaleate according to claim 1 comprising: dissolving Afatinib free base in a solvent selected from the group consisting of tetrahydrofuran, ethanol, isopropanol, ethyl acetate, isopropyl acetate, 1,4-dioxane and 1,3-dioxolane; adding under stirring, from 1 to 1.5 times molar amount of maleic acid to the solution; slowly adding an anti-solvent to form a slurry, wherein, the anti-solvent is selected from the group consisting of methyl tert-butyl ether, n-heptane, isopropyl ether, n-hexane, diethyl ether, n-octane and propyl ether, and, wherein, the ratio of the solvent to the anti-solvent is from 1:1 to 1:5; continuing stirring for 1 to 3 days to crystallize; filtering the precipitates; and drying the precipitates to obtain the crystalline Form N of Afatinib monomaleate.
6. An amorphous form of Afatinib monomaleate with the structural formula shown below ##STR00006## wherein, measured using Cu-K radiation, the X-ray powder diffraction pattern of the amorphous form of Afatinib monomaleate has the characteristic amorphous halo in the XRPD pattern as depicted in
7. A method for preparing amorphous form of Afatinib monomaleate according to claim 6 comprising: dissolving Afatinib free base in methanol; adding under stirring, from 1 to 1.5 times molar amount of maleic acid to the solution; and concentrating the solution to obtain the amorphous form of Afatinib monomaleate.
8. A pharmaceutical composition, comprising an amount of the crystalline Form N of Afatinib monomaleate according to claim 1, and at least one pharmaceutical acceptable excipient.
9. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablet, capsule, granule, solution, syrup, suspension, dispersion, emulsion, pill and pulvis.
10. A pharmaceutical composition, comprising a therapeutically effective amount of the crystalline Form N of Afatinib monomaleate prepared according to claim 5, and at least one pharmaceutical acceptable excipient.
11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is in a dosage form selected from the group consisting of tablet, capsule, granule, solution, syrup, suspension, dispersion, emulsion, pill and pulvis.
12. A pharmaceutical composition, comprising an amount of the amorphous form of Afatinib monomaleate according to claim 6, and at least one pharmaceutical acceptable excipient.
Description
DESCRIPTION OF DRAWINGS
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(2)
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EXAMPLES
(8) The present invention refers further to the following examples. Those examples describe the preparations and applications of the solid forms of the present invention in detail. It will be apparent to those skilled in the art that various modifications can be made to materials and methods without departing from the scope of the present invention.
(9) Instruments and Methods of the Characterization:
(10) X-ray powder diffraction (XRPD) is performed on Bruker D8 Advance Diffractometer using a Cu-K X-radiation with the wavelength of 1.54 nm at 40 kV and 40 mA and equipped with -2 goniometer, Mo monochrometer and Lynxeye detector. Before sample measurement, the instrument working condition is verified by the provided standard sample. The collection software is Diffrac Plus XRD Commander. The specimen is analyzed on a SiP non-reflective plate at room temperature. The specific test condition is as the following: 2 scanning range is 340 with a step size of 0.02 and a speed of 0.2 s/step. Unless particularly specified, samples had not been grinded prior to the analysis.
(11) Dynamic vapour sorption (DVS) data is collected using TA Instruments Q5000 TGA, the instrument control software is Thermal Advantage and the analytical software is Universal Analysis. Usually, 1-10 mg of the specimen is placed in a platinum pan, weight changes of the specimen are recorded by TA software within the process of the relative humidity change from 10% to 80% to 10%. Depending on specific situations, different sorption and desorption procedures may be used. An isothermal adsorption curve can be generated by the procession of software.
(12) Polarizing microscope (PLM) image is collected using XP-500E polarizing microscope (Shanghai Changfang Optical Instrument Co., Ltd). Take some powder sample on a glass slide, drop some mineral oil to disperse the sample, cover a coverslip, then place the sample on the loading table of XP-500E polarizing microscope, observe morphology of the sample with appropriate magnification and take photos.
(13) Proton nuclear magnetic resonance spectroscopy (1H-NMR) data is collected using Bruker Ascend Tm 500. Usually full-frequency excitation is used, with spectral width of 30 PPM, single pulse, 30 angle excitation, scanning of 16 times, digital orthogonal detection and a controlled temperature at 298K.
(14) Hardness testing data is collected using hardness tester (Tianjin Xintianguang Optical Analytical Instrument Co., Ltd) and the model is YC-1. The operations are: place the test tablet on the test bench and locate it between the probe and the test bench, then slowly rotate the rotating disc counterclockwise and compress the force to the test tablet, when the test tablet is squeezed broken, the displayed value in the displaying window is the hardness of the test tablet.
(15) High performance liquid chromatography (HPLC) data is collected using Agilent HPLC 1260. The instrument control software is B.04 online of Agilent ChemStation and the analytical software is B.04 offline of Agilent ChemStation. Using a C18, 150 mm4.6 mm column, column temperature, 40 C., detection wavelength, 254 nm, flow rate, 0.3 ml/min, injection volume, 50 l, running time, 30 min. Mobile phase A is water with 0.01% trifluoroacetate, mobile phase B is acetonitrile with 0.01% trifluoroacetate. The gradient is shown below:
(16) TABLE-US-00002 Gradient of mobile phase in HPLC Time Mobile phase A Mobile phase B (min) (%) (%) 0 95 5 3 95 5 10 5 95 15 5 95 30 5 95
(17) Afatinib free base, as the starting material of the present invention, was prepared by the reference to the process in example 1 in patent document WO2002/50043A1.
(18) If no specific descriptions were provided, the reagents used in the examples were purchased commercially.
(19) The examples were operated at room temperature if no specific descriptions were provided.
Preparation Example 1
(20) Crystalline form of Afatinib dimaleate in the prior art was prepared by the reference to the process described in example 3 in patent document CN1867564B. The operating procedures are detailed as follows:
(21) 1.0 g of Afatinib free base was dissolved in 14 mL of ethanol with stirring and heated to 70 C. 0.5 g of maleic acid was dissolved in 6 mL of ethanol with stirring. The ethanol solution of maleic acid was slowly added into the ethanol solution of Afatinib free base and stirred. After the solids were precipitated, the reaction solution was cooled to 20 C. and stirred for 2 hours, then stirred for 3 hours at 0 C., filtered, washed with ethanol, dried in a vacuum oven at 40 C. overnight, and Afatinib dimaleate was obtained in 90% yield.
(22) Its X-ray powder diffraction pattern is shown in
(23) Its DVS isothermal adsorption curve is shown in
(24) Its PLM image is shown in
Example 1
(25) The Preparation of Crystalline Form N of Afatinib Monomaleate
(26) At room temperature, 5.0 g of Afatinib free base was dissolved in 20 mL of tetrahydrofuran by sonication, 1.79 g of maleic acid was added into the tetrahydrofuran solution of Afatinib free base, a solution was formed and was stirred, then 60 mL of methyl tert-butyl ether was slowly added to form a slurry, stirred for one day to crystallize, the precipitates were filtered and dried in vacuum oven at 40 C. for 8 hours, and 5.3 g of the crystalline Form N of Afatinib monomaleate was obtained in 85.6% yield.
(27) The .sup.1H-NMR (DMSO) data is shown below:
(28) 9.93 (s, 1H), 9.77 (s, 1H), 8.95 (s, 1H), 8.57 (s, 1H), 8.05-8.15 (m, 1H), 7.72-7.85 (m, 1H), 7.44 (t, J=9.0 Hz, 1H), 7.28 (s, 1H), 6.81 (s, 1H), 6.10 (s, 1H), 5.32 (s, 1H), 3.85-4.05 (m, 5H), 3.71-3.85 (m, 1H), 2.75-2.85 (m, 1H), 2.83 (s, 6H), 2.30-2.42 (m, 1H), 2.06-2.20 (m, 1H), showing that the ratio of Afatinib free base to maleic acid in the salt is about 1:1.
(29) The HPLC determines that the content of Afatinib in the salt is 78.3%, which is close to the theoretical content (80.4%) of Afatinib in Afatinib monomaleate, indicating that the salt was formed from Afatinib and maleic acid in a molar ratio of 1:1.
(30) The XRPD pattern is shown in
(31) The PLM image is shown in
(32) The DVS isothermal adsorption curve is shown in
Example 2
(33) The Preparation of Crystalline Form N of Afatinib Monomaleate
(34) At room temperature, 100 mg of Afatinib free base was dissolved in 0.5 mL of ethanol by sonication, 24 mg of maleic acid was added into the ethanol solution of Afatinib free base, a solution was formed and was stirred, then 2.5 mL of n-heptane was added and stirred for two days to crystallize, the precipitates were filtered and dried in a vacuum oven for 16 hours, and 105 mg of the crystalline Form N of Afatinib monomaleate was obtained in 84.7% yield.
Example 3
(35) The Preparation of Crystalline Form N of Afatinib Monomaleate
(36) At room temperature, 3.0 g of Afatinib free base was dissolved in 60 mL of isopropanol by sonication, 0.72 g of maleic acid was added into the isopropanol solution of Afatinib free base, a solution was formed and stirred, then 60 mL of isopropyl ether was slowly added to form a slurry, stirred for three days to crystallize, the precipitates were filtered and dried in a vacuum oven at 40 C. for 8 hours, and 3.2 g of the crystalline Form N of Afatinib monomaleate was obtained in 86.1% yield.
Example 4
(37) The Preparation of Crystalline Form N of Afatinib Monomaleate
(38) At room temperature, 0.5 g of Afatinib free base was dissolved in 5 mL of ethyl acetate by sonication, 0.12 g of maleic acid was added into the ethyl acetate solution of Afatinib free base, a solution was formed and stirred, then 20 mL of n-hexane was slowly added to form a slurry, stirred for two days to crystallize, the precipitates were filtered and dried in a vacuum oven at 40 C. for 8 hours, and 0.52 g of the crystalline Form N of Afatinib monomaleate was obtained in 83.9% yield.
Example 5
(39) The Preparation of Crystalline Form N of Afatinib Monomaleate
(40) At room temperature, 0.5 g of Afatinib free base was dissolved in 8 mL of isopropyl acetate by sonication, 0.12 g of maleic acid was added into the isopropyl acetate solution of Afatinib free base, a solution was formed and stirred, then 24 mL of diethyl ether was slowly added to form a slurry, stirred for two days to crystallize, the precipitates were filtered and dried in vacuum oven at 40 C. for 8 hours, and 0.44 g of the crystalline Form N of Afatinib monomaleate was obtained in 71% yield.
Example 6
(41) The Preparation of Crystalline Form N of Afatinib Monomaleate
(42) At room temperature, 1.0 g of Afatinib free base was dissolved in 4 mL of 1,4-dioxane by sonication, 0.24 g of maleic acid was added into the 1,4-dioxane solution of Afatinib free base, a solution was formed and stirred, then 4 mL of n-octane was slowly added to form a slurry, stirred for one day to crystallize, the precipitates were filtered and dried in a vacuum oven at 40 C. for 8 hours, and 0.92 g of the crystalline Form N of Afatinib monomaleate was obtained in 74.3% yield.
Example 7
(43) The Preparation of Crystalline Form N of Afatinib Monomaleate
(44) At room temperature, 0.5 g of Afatinib free base was dissolved in 5 mL of 1,3-dioxolane by sonication, 0.12 g of maleic acid was added into the 1,3-dioxolane solution of Afatinib free base, a solution was formed and stirred, then 5 mL of propyl ether was slowly added to form a slurry, stirred for one day to crystallize, the precipitates were filtered and dried in a vacuum oven at 40 C. for 8 hours, and 0.39 g of the crystalline Form N of Afatinib monomaleate was obtained in 63.0% yield.
(45) The .sup.1H-NMR data, HPLC chromatograms, XRPD patterns, PLM images and DVS isothermal adsorption curves of the samples prepared in examples 27 were similar to those of the sample prepared in example 1, indicating that the crystalline forms obtained in examples 27 were the same as that of example 1.
Example 8
(46) The Preparation of the Amorphous Form of Afatinib Monomaleate
(47) 500 mg of Afatinib free base was dissolved in 10 mL of methanol by sonication, 120 mg of maleic acid was added into the methanol solution of Afatinib free base, a solution was formed, stirred, and concentrated to dry under reduced pressure, and 610 mg of the solid was obtained. The solid was confirmed by the .sup.1H-NMR to be Afatinib monomaleate, and the yield is 98.5%.
(48) The XRPD pattern is shown in
Example 9
(49) According to tablet formulas of Table 1, tablets A, B, C, D and E were prepared with different dosages containing the crystalline Form N or the amorphous form of Afatinib monomaleate of the present invention.
(50) TABLE-US-00003 TABLE 1 Tablet Formulas Weight percentage A Dosage B Dosage C Dosage D Dosage E Dosage Ingredients (%/tablet) (mg/table) (mg/table) (mg/table) (mg/table) (mg/table) the crystalline Form N or 13.63 24.78 37.16 49.55 61.94 86.72 the amorphous form of Afatinib monomaleate Afatinib free base 11 20 30 40 50 70 (equivalent to crystalline Form N or the amorphous form of Afatinib monomaleate) Lactose monohydrate 71.60 128.64 192.97 257.29 321.61 450.25 Microcrystalline cellulose 10.27 18.48 27.72 36.96 46.20 64.68 Crospovidone 2.00 3.6 5.4 7.2 9.0 12.6 Anhydrous colloidal 0.50 0.90 1.35 1.80 2.25 3.15 silica Magnesium stearate 2.00 3.6 5.4 7.2 9.0 12.6 Total 100 180 270 360 450 630
(51) The tablets are prepared by the following procedures: pass microcrystalline cellulose, crospovidone, the unmilled crystalline form N or amorphous form of Afatinib monomaleate through a 30-mesh sieve (about 430 m to 655 m). Load crospovidone into a bivalve tumble mixer with three cubic feet, add microcrystalline cellulose and lactose monohydrate, mix for five minutes, then add the crystalline Form N or the amorphous form of Afatinib monomaleate of the present invention, mix for twenty-five minutes. Pass the premix through a roller compactor with a hammer mill at the discharge point and bring it back to the tumble mixer. Add magnesium stearate and anhydrous colloidal silica into the tumble mixer, mix for about three minutes. Press the final mixture on the rotary tablet press and the batch is 200,000 tablets.
Example 10
(52) According to single dosage formula and batch formula of capsules in table 2, the capsules containing the crystalline Form N or the amorphous form of Afatinib monomaleate of the present invention were prepared.
(53) TABLE-US-00004 TABLE 2 Capsule Formulas Weight percent Single dosage Batch Ingredients (%/capsule) (mg/capsule) (kg/batch) the crystalline Form N or 14.87 74.33 6.24 the amorphous form of Afatinib monomaleate Lactose monohydrate 72.54 362.72 30.47 Microcrystalline cellulose 10.53 52.65 4.42 Magnesium stearate 2.06 10.3 0.87 Total 100.0 500 42.00
(54) The capsules are prepared by the following procedures: passlactose monohydrate, microcrystalline cellulose and the crystalline Form N or the amorphous form of Afatinib monomaleate through a 710 m sieve, load into a diffusion mixer with baffles insert and mix for fifteen minutes. Pass magnesium stearate through a 210 m sieve, add it into the diffusion mixer, and then fill the mixture into number 0# capsules using Dosator-capsule filling machine. The weight of obtained capsule is 500 mg per capsule and the batch is 84000 capsules.
Comparative Example 1
(55) Take 5 mg of the crystalline form of Afatinib dimaleate in the prior art prepared in preparation example 1 and the crystalline Form N of Afatinib monomaleate prepared in example 1 as the sample respectively, pure water was added into each sample progressively at 25 C. until the sample completely dissolved, then calculate the solubility of the sample according to the weight of the sample and water. The results are shown in Table 3.
(56) TABLE-US-00005 TABLE 3 Results of the solubility solubility Crystalline forms of Afatinib salts (mg/mL) The crystalline form of Afatinib dimaleate 7.5 salt in the prior art The crystalline Form N of Afatinib monomaleate 126.9
(57) The results of the solubility in Table 3 show that the solubility of the crystalline Form N of Afatinib monomaleate of the present invention is significantly higher than that of the crystalline form of Afatinib dimaleate in the prior art, indicating that the crystalline Form N of Afatinib monomaleate has better solubility at room temperature.
Comparative Example 2
(58) According to the tablet formula C and its preparation process described in example 9, prepare 100 tablets containing the crystalline form of Afatinib dimaleate in the prior art or containing the crystalline Form N of Afatinib monomaleate of the present invention respectively. Observe the tableting processes and tablet shapes.
(59) The result shows that during the tableting process, the tablets containing the crystalline form of Afatinib dimaleate in the prior art have obvious sticking phenomenon and the tablets containing the crystalline Form N of Afatinib monomaleate of the present invention have no sticking phenomenon. The result indicates that in terms of processibility of the tablets, granular crystal morphology of the crystalline Form N of Afatinib monomaleate of the present invention is superior to fine needle morphology of the crystalline form of Afatinib dimaleate in the prior art.
Comparative Example 3
(60) Take 20 intact tablets containing the crystalline form of Afatinib dimaleate in the prior art and 20 intact tablets containing the crystalline Form N of Afatinib monomaleate of the present invention prepared in comparative example 2, and test their hardness.
(61) The result shows that the average hardness of tablets containing the crystalline Form N of Afatinib monomaleate is higher than that of tablets containing the crystalline form of Afatinib dimaleate in the prior art. The result indicates that in terms of tablet compressibility, granular crystal morphology of the crystalline Form N of Afatinib monomaleate of the present invention is superior to fine needle morphology of the crystalline form of Afatinib dimaleate in the prior art.
(62) The described above are only specific embodiments of the present invention, but not limitations to the scope of the present invention. Any changes or replacements without creative work, which made by those skilled in the art within the technical scope disclosed by the present invention, should be fallen within the scope of the present invention.