CN102816145B - Methanesulfonic acid imatinib polymorphic substance and medical combination thereof - Google Patents

Abstract

The invention discloses methanesulfonic acid imatinib polymorphic substance III. In addition, the invention further discloses a preparation and medical combination of the methanesulfonic acid imatinib polymorphic substance III.

Description

Imatinib mesylate polymorph and pharmaceutical composition thereof

technical field

The present invention relates to the polymorphic form of pharmaceutical compound, more specifically, relate to a kind of novel polymorphic form of imatinib mesylate, in addition, the present invention also relates to the preparation method of this polymorphic form and its pharmaceutical composition.

Background technique

Imatinib mesylate, a tyrosinase inhibitor, is used in the treatment of gastrointestinal stromal tumors (GISTs). Its chemical name is 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino]phenyl]-benzene Formamide methanesulfonate, the chemical structure is as follows:

Chinese patent application-Application No. 98807303.X (hereinafter referred to as Patent Application No. 303) discloses two polymorphs α and β of imatinib mesylate; wherein, the α crystal form is characterized by hygroscopicity, flow Needle crystal with poor properties, its typical XRPD pattern shows that the α-form is at 4.9, 10.5, 14.9, 16.5, 17.7, 18.1, 18, 6, 19.1, 21.3, 21.6, 22.7, 23.2, 23.8, 24.9, 27.4, 28.0 And there is a peak at 28.6±0.1 degrees 2θ.

The characteristics of the β crystal form described in this patent document are: non-acicular crystals that are thermodynamically stable below 140°C, have low hygroscopicity, good fluidity, and are easy to store and process. These features are beneficial to the preparation and storage of preparations; there are peaks at 9.7, 13.9, 14.7, 17.5, 18.2, 20.0, 20.6, 21.1, 22.1, 22.7, 23.8, 29.8 and 30.8 ± 0.1 degrees 2θ; and provide more Method for the preparation of crystals. The preparation method provided in this document is as follows:

α crystal form: 98.6g (0.2mol) of free 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2 -Amino]phenyl]-benzamide (preparation see EP-A-0564409) was added to 1.4 liters of ethanol. To this beige suspension, 19.2 g (0.2 mol) of methanesulfonic acid was added dropwise over 20 minutes. The solution was heated to reflux for 20 minutes and then filtered at 65°C. The filtrate was evaporated by 50% and the residue was filtered at 25° C. (filter material A). The mother liquor was evaporated to dryness. The residue and filter material A were suspended in 2.2 liters of ethanol and dissolved by adding 30 ml of water under reflux. Cool overnight to 25°C, filter and dry at 65°C until constant weight. The light beige 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino]phenyl]-benzene Formamide mesylate crystallizes.

β crystal form:

Method 1: 11% (w/w) α-crystalline form of 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) The pyrimidine-2-amino]phenyl]-benzamide methanesulfonate suspension was macerated in methanol at about 25°C for 2 days. The crystals were isolated by filtration on a G4 glass filter and dried overnight on filter paper at room temperature.

Method 2: 50.0g (101mmol) 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino] Phenyl]-benzamide mesylate was suspended in methanol (480ml). 9.71 g (101 mmol) of methanesulfonic acid and methanol (20 ml) were added, heated to 50° C., activated charcoal (5.0) was added, the mixture was boiled at reflux for 30 minutes, filtered and concentrated by evaporation. The residue was dissolved in methanol (150ml), inoculated with 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino ]phenyl]-benzamide methanesulfonate (beta variant, several mg), resulting in crystallization of the product. Drying at 50 millibars and 60 °C gave the β variant of 4-(4-methylpiperazin-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) Pyrimidine-2-amino]phenyl]-benzamide methanesulfonate.

Method 3: 670g (1136mmol) 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino]benzene ]-benzamide methanesulfonate (α-modification) was heated in methanol (1680ml). Inoculate the solution with 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino] at 60°C Phenyl]-benzamide mesylate (beta variant, 55 mg), at which point the product began to crystallize. Drying at 50 millibars and 100 °C gave the β variant of 4-(4-methylpiperazin-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl) Pyrimidine-2-amino]phenyl]-benzamide methanesulfonate.

In addition, patents WO2006/024863, WO2005/077933, CN200680030515.X, 200680044007.7 disclose stable crystalline forms of α, α2, δ, ε, F, G, H, I and K-type imatinib mesylate .

The crystallization methods disclosed above are the crystalline forms obtained directly by suspending imatinib in an organic solvent and forming a salt with methanesulfonic acid; or suspending imatinib mesylate in a solvent and adding or not It is obtained by adding seed crystals and turning them into crystals. These existing methods have a series of shortcomings such as cumbersome process, unstable reproducibility, technical solutions that cannot ensure the effective removal of mechanical impurities, technical solutions that will lead to the risk of genotoxic impurities remaining in the product, unsuitable for industrial production, and poor product purity.

With respect to polymorphic forms of a drug, different polymorphic forms can have different chemical and physical properties, including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can directly affect the handling or manufacture of drug substances and drug products, and can affect the stability, solubility, and bioavailability of drug products. Therefore, the polymorphic forms of drugs are of great significance to the quality, safety and effectiveness of pharmaceutical preparations.

For imatinib mesylate, there is such a demand in this field: it is suitable for industrial scale production, the product has high purity, absolutely does not contain genotoxic impurities, has excellent physical and chemical properties, and can be effectively used in drug preparation and marketing. Sales of new polymorphic forms of drugs used.

Contents of the invention

The inventor has surprisingly discovered a new polymorphic form of imatinib mesylate through a large amount of research, which successfully solves the deficiencies in the prior art, and the polymorphic form of the present invention simultaneously Possess: high purity of the product, absolutely free of genotoxic impurities, excellent physical and chemical properties, good stability, more suitable for industrial scale preparation, effective application in drug preparation and marketing of new polymorphic drugs, etc.

The object of the present invention is to provide novel imatinib mesylate polymorph III with the above-mentioned technical advantages.

Another object of the present invention is to provide a process for the preparation of the new polymorph III having the above technical advantages.

The third object of the present invention is to provide a pharmaceutical composition containing the above-mentioned novel polymorph III having the above-mentioned technical advantages.

Specifically, the present invention provides a polymorph III of imatinib mesylate substantially free of solvent (organic solvent or water).

The polymorphic form III of imatinib mesylate provided by the present invention, using Cu-Ka radiation, its multi-batch typical X-ray diffraction pattern, the 2θ expressed in degrees is at 5.9 ± 0.2, 17.1 ± There are diffraction peaks at 0.2 and 24.2±0.2, especially at 5.9±0.2, 9.5±0.2, 12.8±0.2, 14.0±0.2, 15.1±0.2, 15.5±0.2, 15.8±0.2, 17.1±0.2, 18.0±0.2, 18.6± There are diffraction peaks at 0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 23.2±0.2, 23.7±0.2, 24.2±0.2, 25.1±0.2, 28.3±0.2, see Figure 1. The polymorphic form III of imatinib mesylate provided by the present invention, using Cu-Ka radiation, its multi-batch typical X-ray diffraction pattern, the 2θ represented by degrees is at 5.9 ± 0.2, 9.5 ± 0.2, 12.8±0.2, 14.0±0.2, 15.1±0.2, 15.5±0.2, 15.8±0.2, 17.1±0.2, 18.0±0.2, 18.6±0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 23.2±0.2, There are diffraction peaks at 23.7±0.2, 24.2±0.2, 25.1±0.2, and 28.3±0.2, and the relative intensity (I/IO) of these diffraction peaks is greater than 20.

Polymorph III of imatinib mesylate

peak number 2θ Flex width d-value Strength I/IO 1 5.940 0.259 14.8665 3109 73 2 9.500 0.282 9.3020 1085 26 3 11.220 0.212 7.8796 530 13 4 11.960 0.259 7.3937 927 twenty two 5 12.780 0.259 6.9210 1763 42 6 13.440 0.235 6.5826 874 twenty one 7 13.980 0.282 6.3295 1973 47 8 15.120 0.235 5.8548 1659 39 9 15.520 0.212 5.7048 1471 35 10 15.840 0.235 5.5902 1592 38 11 17.060 0.282 5.1931 4011 94 12 18.020 0.259 4.9186 3448 81 13 18.620 0.235 4.7614 3299 78 14 19.080 0.329 4.6476 2521 59 15 19.700 0.282 4.5027 3503 82 16 20.840 0.282 4.2589 3807 89

17 22.080 0.376 4.0225 1640 39 18 22.660 0.212 3.9208 1526 36 19 23.200 0.329 3.8308 2072 49 20 23.720 0.259 3.7479 3223 76 twenty one 24.160 0.282 3.6807 4282 100 twenty two 25.120 0.282 3.5421 2518 59 twenty three 25.900 0.282 3.4372 1201 29 twenty four 28.280 0.306 3.1531 1665 39 25 28.840 0.235 3.0932 1153 27 26 29.060 0.235 3.0702 1248 30 27 30.320 0.471 2.9455 859 twenty one 28 30.880 0.212 2.8933 799 19

The imatinib mesylate polymorph III provided by the present invention has no acetone and methyl ethyl ketone detected through gas-phase organic residue detection, and the residue of methyl tert-butyl ether is less than 0.2%. Organic residues meet the limit requirements of ICH (methyl tert-butyl ether limit: 0.5%, acetone limit: 0.5%, methyl ethyl ketone limit: 0.5%); the moisture value is less than 0.5% after the Karnofsky moisture test. The above results show that the polymorph III of imatinib mesylate provided by the present invention is more suitable for pharmaceutical requirements.

In an embodiment of the present invention, the present invention provides a method for the preparation of imatinib mesylate polymorph III, the method comprising the steps in the following order:

(1) Imatinib is added to methyl tert-butyl ether and methanesulfonic acid, reacted under stirring to obtain imatinib mesylate; here, preferably, methyl tert-butyl ether and imatinib The volume-to-weight ratio is 5 to 20:1, more preferably 10 to 15:1; and the molar ratio of methanesulfonic acid to imatinib is 1:1; preferably, at any temperature from room temperature to reflux Insulation and stirring reaction for 1 to 10 hours, more preferably, insulated and stirring reaction for 2 hours under reflux conditions;

(2) stirring and lowering the temperature for crystallization for 0.5 to 10 hours; preferably, cooling to room temperature; preferably, the crystallization time is 1 to 5 hours;

(3) suction filtration;

(4) Collect the obtained filter cake and dry it under reduced pressure; preferably, dry it under reduced pressure at room temperature to 80° C. to constant weight to obtain imatinib mesylate polymorph III.

In the preparation method of the above-mentioned imatinib mesylate polymorph III provided by the present invention, wherein the imatinib used in step (1) is prepared using EP-A-0564409, preferably by the following method of:

Add the crude imatinib mesylate into water, dissolve under stirring or heat up to dissolve under stirring; filter with suction, cool the filtrate to room temperature, add an organic solvent insoluble or slightly soluble with imatinib under stirring; then, Add a base that is at least equimolar to the crude product of imatinib mesylate to completely free the imatinib; crystallize at room temperature for 1-3 hours; filter with suction, rinse the filter cake with an appropriate amount of water, take out the filter The cake was dried to obtain imatinib. Here, the imatinib-insoluble or slightly soluble organic solvent is one of acetone or methyl ethyl ketone, or a mixture thereof; moreover, the volume ratio of the organic solvent to water is 1:5-100; Said one base is alkali metal carbonate or bicarbonate, more preferably, sodium carbonate or sodium bicarbonate, most preferably, sodium bicarbonate.

In the preparation method of imatinib mesylate polymorph III of the present invention, the crude imatinib mesylate can be prepared by existing methods, for example, but not limited to the following patent CN98807303.X , obtained in WO2006/024863, WO2005/077933, CN200680030515.X, CN200680044007.7, CN201010286254.6, or their α, α2, δ, ε, F, G, H, I and K-type ima mesylate Crude Tini. These documents are hereby incorporated by reference in their entirety.

As a preferred embodiment, the present invention provides a method for preparing imatinib mesylate polymorph III, comprising the following steps:

(1) Imatinib is added to methyl tert-butyl ether and methanesulfonic acid, reacted under stirring to obtain imatinib mesylate; here, preferably, methyl tert-butyl ether and imatinib The volume-to-weight ratio is 5 to 20:1, more preferably 10 to 15:1; and the molar ratio of methanesulfonic acid to imatinib is 1:1; preferably, at any temperature from room temperature to reflux Insulation and stirring reaction for 1 to 10 hours, more preferably, insulated and stirring reaction for 2 hours under reflux conditions;

(2) stirring and lowering the temperature for crystallization for 0.5 to 10 hours; preferably, cooling to room temperature; preferably, the crystallization time is 1 to 5 hours;

(3) suction filtration;

(4) Collect the obtained filter cake and dry it under reduced pressure; preferably, dry it under reduced pressure at room temperature to 80° C. to constant weight to obtain imatinib mesylate polymorph III;

Here, the imatinib used in the step (1) is prepared by the following method: adding the crude product of imatinib mesylate into water, dissolving under stirring or heating up to dissolve under stirring; to room temperature, adding an organic solvent insoluble or slightly soluble with imatinib under stirring; then, adding a base at least equimolar to the crude product of imatinib mesylate to completely free imatinib; and Crystallize at room temperature for 1-3 hours; filter with suction, rinse the filter cake with an appropriate amount of water, take out the filter cake and dry to obtain imatinib. Here, the imatinib-insoluble or slightly soluble organic solvent is one of acetone or methyl ethyl ketone, or a mixture thereof; and the volume ratio of the organic solvent to water is greater than 1:5; the One of the bases is an alkali metal carbonate or bicarbonate, more preferably, sodium carbonate or sodium bicarbonate, most preferably, sodium bicarbonate.

As a particularly preferred embodiment, the present invention provides a method for preparing imatinib mesylate polymorph III, comprising the following steps:

(1) Imatinib is added in methyl tert-butyl ether and methanesulfonic acid, under reflux condition, keep stirring and react for 1-10 hours, more preferably react for 2 hours, so as to obtain imatinib mesylate; here The volume-to-weight ratio of methyl tert-butyl ether to imatinib is 5-20:1, more preferably 10-15:1; and the molar ratio of methanesulfonic acid to imatinib is 1:1 ;

(2) Stir and cool down to room temperature, and crystallize for 1 to 5 hours;

(3) suction filtration;

(4) Collect the filter cake obtained, and dry it under reduced pressure at room temperature to 80°C to constant weight to obtain imatinib mesylate polymorph III;

Here, the imatinib used in the step (1) is prepared by the following method: adding the crude product of imatinib mesylate into water, dissolving under stirring or heating up to dissolve under stirring; to room temperature, add acetone or methyl ethyl ketone or a mixture thereof under stirring; then, add at least an equimolar amount of sodium bicarbonate with the crude product of imatinib mesylate, so that imatinib is completely free; and at room temperature Crystallize for 1-3 hours; filter with suction, rinse the filter cake with an appropriate amount of water, take out the filter cake and dry to obtain imatinib. Here, the volume ratio of acetone or methyl ethyl ketone or their mixture to water is greater than 1:5.

In the present invention, the X-powder diffraction test instrument and test conditions involved in the present invention are: an anode transfer target X-ray diffractometer D/max-2500/PC type (Japan Rigaku); copper target, graphite monochromator, The tube voltage is 40kv, the tube current is 100mA, the divergence slit and the anti-scatter slit are both 1°, the receiving slit is 0.3mm, the scanning speed is 5°/min, and the scanning range is 3-40°. The instrument was calibrated with a silica standard.

Content of imatinib mesylate involved in the present invention and related substance detection conditions: measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2005 edition two appendix VD).

Conditions for high performance liquid chromatography:

Chromatographic column: Modified octadecylsilane bonded silica gel is used as filler.

Eluent (gradient): 0% b) in a) for 20 minutes, then 0% → 30% b) in a) for 10 minutes, then 30% b) in a) for 5 minutes.

Eluent a): 1% sodium octane sulfonate solution (pH2.5): methanol (42:58)

Eluent b): 1% sodium octane sulfonate solution (pH2.5): methanol (4:96)

Detection wavelength: 267nm

Flow rate: 1.2ml/min

Column temperature: 25°C.

Properties of Imatinib Mesylate Polymorph III

1. Solubility experiment:

Method: Accurately weigh an appropriate amount of imatinib mesylate polymorph III, slowly add a certain amount of dissolution medium, shake vigorously for 30 seconds every 5 minutes, and observe the dissolution within 30 minutes. The results are shown in Table 1.

The solubility test of table 1 imatinib mesylate polymorph III

The marketed Gleevec raw material adopts the β crystal form, and the solubility of imatinib mesylate is described in its marketing instructions: "Imatinib mesylate is dissolved in a buffer solution with a pH ≤ 5.5 ; very slightly soluble to insoluble in neutral/alkaline aqueous buffer solutions; readily soluble to slightly soluble in dimethyl sulfoxide, methanol and ethanol; insoluble in n-octanol, acetone and acetonitrile". The above solubility experiments show that the solubility of imatinib mesylate polymorph III in various solvents is obviously better than that of the listed crystal form.

2. Stability

1. Illumination test

Evenly distribute the imatinib mesylate polymorph III to an open petri dish with a thickness of ≤5mm, adjust the distance so that the light intensity is 4500±500Lx, take samples for detection on day 5 and 10 respectively, and compare with day 0 The results are compared. The results are shown in Table 2.

Table 2 Lighting test (4500±500lx)

Note: The temperature range is 23-26°C; the relative humidity range is 58%-63%

2. High temperature test

The polymorph III raw material of imatinib mesylate was placed in a sealed clean glass bottle and placed in a constant temperature drying oven at 60°C. Samples were taken for testing on day 5 and day 10 respectively, and compared with the results on day 0. The results are shown in Table 3.

Table 3 High temperature test (60°C)

Note: Relative humidity ranges from 53% to 61%

3. Accelerated test

The raw material of imatinib mesylate polymorph III is sealed and packed in a polyethylene film plastic bag, placed in a constant temperature and humidity incubator at 40±2°C and a relative humidity of 75±5%, and placed for six months , samples were taken at the end of 1, 2, 3, and 6 months for testing, and compared with the results of 0 months. The results are shown in Table 4.

Table 4 Accelerated Test (40°C, Relative Humidity 75%)

As can be seen from the above results, the imatinib mesylate polymorph III obtained by the present invention has no obvious change in its appearance, related substances and content in the light test and high temperature test (60° C.), indicating that its physicochemical properties are relatively stable. Stable; no change in the crystal form of this product was observed in the long-term retention sample observation test.

The above experiments show that the crystal form of the polymorph III of the present invention is relatively stable, and is suitable for making medicines and preparations thereof.

In another embodiment of the present invention, the present invention provides a pharmaceutical composition containing the above-mentioned imatinib mesylate polymorph III and pharmaceutical excipients, preferably, the pharmaceutical composition unit The formulation contains 1-1000 mg of imatinib mesylate polymorph III, particularly preferably, about 50, 100, 200, 400 mg of the above-mentioned imatinib mesylate polymorph III. According to the teaching of the prior art in the field and referring to the patents cited in the present invention, the pharmaceutical composition of the present invention can be made into various dosage forms, and suitable pharmaceutical excipients can be selected. For example, according to the disease to be treated and the object, the pharmaceutical composition of the present invention can be administered orally, parenterally (such as intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or infusion), inhalation spray, Nasal, vaginal, rectal, sublingual or topical routes of administration, preferably, parenteral (e.g. intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or infusion) formulations, e.g. frozen Dosage forms such as dry preparations and injections.

The pharmaceutical composition of the present invention comprises imatinib mesylate polymorph III, and may also contain other therapeutic components as required.

The pharmaceutical composition of the present invention is administered in one or more daily doses of about 1-2500 mg/day, more preferably about 1-1000 mg/day.

Examples of diseases and conditions in which polymorph III of imatinib mesylate of the present invention can be used to treat include but are not limited to: treatment of myeloproliferative disease, myelodysplastic syndrome, angiogenesis, cancer, pain, macular degeneration, Myelodysplastic syndrome, asbestosis, anemia, nervous system disease, poor sleep, skin disease, pulmonary hypertension, immunodeficiency disease, parasitic disease, central nervous system injury and other diseases.

The beneficial technical effect of the present invention is embodied in: although the prior art-patent application No. 303 discloses imatinib mesylate α and β crystal forms and preparation methods thereof, the preparation of imatinib mesylate taught by patent application No. 303 The method for the polymorphic form of matinib is not suitable for the needs of large-scale stable production.

The preparation method of patent application No. 303 is to suspend and immerse the methanesulfonic acid addition salt raw material of another crystalline or amorphous compound of formula I in a suitable polar solvent at a temperature of 20°C to 50°C, Alternatively, another crystal form of imatinib mesylate is dissolved in a polar solvent at a suitable temperature of 25°C to reflux temperature of the reaction mixture, and then β- The crystalline form acts as a seed to initiate crystallization.

1. Although the β-crystal form provided in Patent Application No. 303 is suitable for medicinal use in terms of physical and chemical properties, the preparation method is complicated, requiring the addition of seed crystals for initiation, or the use of solvents that can cause genotoxic impurities.

2. All technical solutions provided by patent application No. 303 cannot effectively remove impurities, and the product has low purity.

In short, the polymorphic form of imatinib mesylate in patent application 303 and the prior art has disadvantages such as: unavoidable genotoxic impurities, poor stability, poor crystal fluidity, etc., which are not conducive to medicinal use; or the process is complicated, The operation is complex, the repeatability is poor, and the process defects such as low product purity, so, the existing imatinib mesylate polymorph or its preparation process are not ideal enough.

However, the polymorphic form III of imatinib mesylate provided by the present invention has a simple preparation process, high purity of the prepared product, absolute avoidance of genotoxic impurities, good stability of physical and chemical properties, and is suitable for industrial production. The polymorphic form of imatinib acid and the preparation method overcome various defects existing in the prior art.

The present invention is to the polymorph of imatinib mesylate, its crystallization condition fully takes into account the deficiency of the above-mentioned existing method, has adopted more reasonable and scientific preparation method:

1. The present invention has simple preparation process, simple operation, controllable quality, high yield, good process parallelism and reproducibility, and is suitable for process production;

2. The polymorphic form prepared by the preparation process of the present invention has excellent solubility, stability, and physical and chemical properties and is suitable for medicinal use;

3. The preparation method of the polymorph of the present invention can effectively remove mechanical impurities.

4. Selectively use three types of solvents with low toxicity, non-alcohols and esters, in the preparation method of the polymorph of the present invention. Avoid the formation of genotoxic impurities such as alkyl sulfonates. This has played success or failure and decisive effect to the actual medicinal use of the present invention.

5. The preparation method of the polymorph of the present invention selectively uses three types of solvents with low toxicity. Due to the structural properties of the compound of this structure, it is easy to form a solvate, and the organic solvent selected in the present invention can effectively avoid forming a solvate with the compound of this structure. more suitable for medicinal use.

6. The preparation method of the polymorph of the present invention can effectively remove impurities, especially strong polar impurities, and can obtain high-purity imatinib mesylate up to 99.9%.

7. Tablets and capsules prepared from the polymorphic form of the present invention have better dissolution rate than the comparison crystal form (beta form), and are more suitable for pharmaceutical use.

The above advantages show that the present invention is beneficial to significantly improve the quality of products and is more suitable for industrial production.

Description of drawings

Fig. 1 is a typical XRPD pattern of imatinib mesylate polymorph III of the present invention.

Fig. 2 is a chromatogram of imatinib mesylate polymorph III prepared in Example 1 of the present invention.

peak# keep time Area % 1 2.930 0.009 2 4.866 0.023 3 10.783 0.055 4 14.093 99.867 5 23.216 0.010 6 29.365 0.036

Detailed ways

The preparation of embodiment 1 imatinib mesylate crude product

Add imatinib (2Kg), methanesulfonic acid (390g) and acetone (20L) into the reaction flask, heat up to reflux for 2.5 hours under stirring. Cool down to room temperature, stir and crystallize for 3 hours. After suction filtration, the obtained filter cake was collected and dried under reduced pressure at 70°C to constant weight to obtain 2.2Kg of crude imatinib mesylate. Yield, 92.1%.

Purity: 98.7%.

The preparation of embodiment 2 polymorph III

Preparation of imatinib free base

The crude imatinib mesylate obtained in Example 1 (1.5 Kg) was added into water (15 L), heated to 60° C., and stirred to dissolve. Suction to remove impurities. The filtrate was cooled to room temperature, and acetone (4.5 L) was added with stirring. Sodium bicarbonate (214 g) was added and crystallized at room temperature for 3 hours. After suction filtration, the filter cake was washed with water and dried to constant weight to obtain 1.17Kg of imatinib. Yield: 92.9%.

Preparation of imatinib mesylate

The imatinib (80g) obtained above, methanesulfonic acid (15.6g) and methyl tert-butyl ether (800ml) were added into the reaction flask, and the temperature was raised to reflux for 2 hours under stirring. Cool down to room temperature, stir and crystallize for 1 hour. After suction filtration, the obtained filter cake was collected and dried under reduced pressure at 70°C to constant weight to obtain 87.6 g of imatinib mesylate polymorph III, with a yield of 91.6%.

Purity: 99.87% (see Figure 2).

Organic residues: acetone - not detected (limit: 0.50%); methyl tert-butyl ether - 0.15% (limit: 0.50%).

The preparation of embodiment 3 polymorph III

According to the existing method, we used different crystal forms of imatinib mesylate prepared by different processes as raw materials, and used the scheme of Example 2 to prepare the data list of polymorph III as follows:

It can be seen from the above test data that the crude product of imatinib mesylate in any crystal form can be converted into the crystal form of the present invention. At the same time, impurities can be effectively removed to obtain high-purity imatinib mesylate up to 99.9%.

The preparation of embodiment 4 polymorph III

Preparation of imatinib free base

Add crude imatinib mesylate (100 g) into water (1 L), heat up to 60° C., and stir to dissolve. Suction to remove impurities. The filtrate was cooled to room temperature, and methyl ethyl ketone (450ml) was added with stirring. Sodium bicarbonate (14.2 g) was added and crystallized at room temperature for 2.5 hours. After suction filtration, the filter cake was washed with water and dried to constant weight to obtain 75.6 g of imatinib. Yield: 90.3%.

Preparation of imatinib mesylate

The above-obtained imatinib (20 g), methanesulfonic acid (3.9 g) and methyl tert-butyl ether (250 mL) were added into the reaction flask, and the temperature was raised to reflux for 2 hours under stirring. Cool down to room temperature, stir and crystallize for 1 hour. After suction filtration, the obtained filter cake was collected and dried under reduced pressure at 70°C to constant weight to obtain 21.6 g of imatinib mesylate polymorph III, with a yield of 90.4%.

Purity: 99.89%.

Organic residues: acetone - not detected (limit: 0.5%), methyl ethyl ketone - not detected (limit: 0.5%), methyl tert-butyl ether - 0.12%.

The preparation of embodiment 5 polymorph III

According to the existing method, we used different crystal forms of imatinib mesylate prepared by different processes as raw materials, and used the scheme of Example 4 to prepare the data list of polymorph III as follows:

It can be seen from the above test data that the crude product of imatinib mesylate in any crystal form can be converted into the crystal form of the present invention. At the same time, impurities can be effectively removed to obtain high-purity imatinib mesylate up to 99.9%.

The prescription and preparation technology of embodiment 6 imatinib mesylate tablet:

The above-mentioned imatinib mesylate polymorph III was formulated into tablets containing 100 mg with several excipients as follows.

Imatinib mesylate (calculated as imatinib) 100g   Microcrystalline Cellulose 40g Hypromellose 2g crospovidone 15g Micronized silica gel 13g Magnesium stearate 1.5g suppression 1000 pieces

Weigh the microcrystalline cellulose, hypromellose and crospovidone according to the prescription, mix them uniformly to obtain auxiliary material powder, and set aside. Weigh the imatinib mesylate according to the prescription, and mix it evenly with the auxiliary material powder to obtain the drug-containing mixed powder. Add appropriate amount of water to the drug-containing mixed powder, make wet granules, dry and granulate, add micropowder silica gel and magnesium stearate, mix with dry granules, and press into tablets.

According to the above-mentioned prescription and process, the raw material drug of β crystal form of patent application No. 303 was also prepared into tablets and the dissolution rate was measured.

Dissolution test method: use 0.1mol/L hydrochloric acid solution as the dissolution medium, and measure according to the dissolution test method (the second method of Appendix XC of the Chinese Pharmacopoeia 2010 edition).

Dissolution Data Comparison:

Dissolution time Dissolution of Form III  Dissolution of β-crystal of patent application No. 303 10 minutes 84% 73% 15 minutes 92% 82%

The prescription and preparation technology of embodiment 7 imatinib mesylate capsules:

The above-mentioned imatinib mesylate polymorph III was formulated into capsules containing 100 mg with several excipients as follows.

Imatinib mesylate (calculated as imatinib) 100g   Microcrystalline Cellulose 40g crospovidone 15g Micronized silica gel 15g Magnesium stearate 1.5g filling 1000 capsules

Weigh microcrystalline cellulose, crospovidone, micropowder silica gel and magnesium stearate according to the prescription, and mix them uniformly to obtain auxiliary material powder. Weigh the imatinib mesylate according to the prescription, and mix it evenly with the auxiliary material powder to obtain the drug-containing mixed powder. The drug-containing mixed powder is filled into No. 00 hard capsules to prepare capsules.

According to the above-mentioned prescription and process, the bulk drug of β crystal form of patent application No. 303 was also prepared into capsules and the dissolution rate was measured.

Dissolution test method: use 0.1mol/L hydrochloric acid solution as the dissolution medium, and measure according to the dissolution test method (the second method of Appendix XC of the Chinese Pharmacopoeia 2010 edition).

Dissolution Data Comparison:

Dissolution time Dissolution of Form III Capsules Dissolution rate of β crystal form capsules for patent application No. 303 10 minutes 80% 73% 15 minutes 89% 82% 20 minutes 93% 85%

Although the dissolution rate of the β crystal form capsules of the patent application No. 303 and the dissolution rate of the crystal form capsules of the present invention meet the requirements, it can be seen from the above comparative data that the crystalline form of the present invention is obviously better than the β crystal form in terms of medicinal properties, and is more suitable for for medicinal purposes.

Claims (13)

1. A polymorphic form III of imatinib mesylate, using Cu-Ka radiation, its X-ray diffraction pattern, the 2θ expressed in degrees is at 5.9 ± 0.2, 9.5 ± 0.2, 12.8 ± 0.2, 14.0 ±0.2, 15.1±0.2, 15.5±0.2, 15.8±0.2, 17.1±0.2, 18.0±0.2, 18.6±0.2, 19.1±0.2, 19.7±0.2, 20.8±0.2, 23.2±0.2, 23.7±0.2, 24.2±0.2 , 25.1±0.2, and 28.3±0.2 have diffraction peaks; moreover, the relative intensity of the diffraction peaks is greater than 20. 2. The polymorph III according to claim 1, whose X-ray diffraction pattern has the following diffraction peaks: 3. The polymorph III according to claim 1, whose X-ray diffraction pattern is as shown in Figure 1 . 4. A pharmaceutical composition comprising polymorph III according to any one of claims 1 to 3. 5. The method for preparing polymorph III according to any one of claims 1 to 3, the method comprising the steps in the following order: (1) Imatinib is added in methyl tert-butyl ether and methanesulfonic acid, reacts under stirring, obtains imatinib mesylate; Here, the mol ratio of methanesulfonic acid and imatinib is 1: 1; (2) stirring and lowering the temperature for crystallization for 0.5 to 10 hours; (3) suction filtration; (4) Collect the filter cake obtained, and dry under reduced pressure to obtain imatinib mesylate polymorph III. 6. The preparation method according to claim 5, wherein in step (1), the volume-to-weight ratio of methyl tert-butyl ether to imatinib is 5-20:1. 7. The preparation method according to claim 5, wherein the volume-to-weight ratio of methyl tert-butyl ether to imatinib in step (1) is 10-15:1. 8 . The preparation method according to claim 5 , wherein, in step (1), the reaction is carried out with insulation and stirring at any temperature from room temperature to reflux for 1 to 10 hours. 9. The preparation method according to claim 5, wherein, in the step (1), the reaction was incubated and stirred for 2 hours under reflux conditions. 10 . The preparation method according to claim 5 , wherein, step (2) is cooled down to room temperature with stirring, and the crystallization time is 1 to 5 hours; step (4) is dried under reduced pressure at room temperature to 80° C. to constant weight. 11 . 11. The preparation method according to any one of claims 5 to 10, wherein the imatinib used in step (1) is prepared in the following manner: Add the crude imatinib mesylate into water, dissolve under stirring or heat up to dissolve under stirring; filter with suction, cool the filtrate to room temperature, add an organic solvent insoluble or slightly soluble with imatinib under stirring; then, Add a base that is at least equimolar to the crude product of imatinib mesylate to completely free the imatinib; crystallize at room temperature for 1-3 hours; filter with suction, rinse the filter cake with an appropriate amount of water, take out the filter The cake is dried to obtain imatinib; here, the insoluble or slightly soluble organic solvent with imatinib is one of acetone or methyl ethyl ketone, or a mixture thereof; and the volume of the organic solvent and water The ratio is 1:5-100; the alkali is alkali metal carbonate or bicarbonate. 12. preparation method according to claim 11, wherein, a kind of described alkali is sodium carbonate or sodium bicarbonate. 13. The preparation method according to claim 12, wherein said a kind of alkali is sodium bicarbonate.