CN112047978A - Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine - Google Patents
Novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a new crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine, which at least comprises the following characteristic peaks in an X-ray powder diffraction pattern measured by Cu-Ka rays: diffraction angle 2 theta values are 5.46 +/-0.2 degrees, 12.94 +/-0.2 degrees, 14.88 +/-0.2 degrees, 20.73 +/-0.2 degrees, 23.42 +/-0.2 degrees and 41.62 +/-0.2 degrees; the obtained new crystal form has the water content of 2-5%, is good in stability and is suitable for industrial production. In addition, the invention also provides a preparation method and a pharmaceutical composition of the novel crystal.
Description
Technical Field
The invention relates to a crystal form of a pharmaceutical compound, in particular to a novel crystal form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine, a preparation method and a medicinal composition thereof.
Background
US patent US201313842951 describes a phosphorus derivative as a kinase inhibitor, in particular 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine. On 28 d, 4.2017, 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine (brigatinib, trade name alunbrigitm), approved for sale in the united states as a tyrosine and enzyme inhibitor with anti-tumor properties for ALK-positive metastatic non-small cell lung cancer patients with crizotinib intolerance or post-drug disease progression.
US patent No. 9611283 describes a method of inhibiting ALK-driven cancer cell proliferation, and in particular the use of the compound 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine, for the treatment of ALK-positive metastatic non-small cell lung cancer patients with greater efficacy.
Ten polymorphs of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine and processes for their preparation are described by ariyad, usa in chinese patent application CN107108599A (publication number).
5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine is slightly soluble in water, and the solubility of different crystal forms is different, so that the dissolution and release of the pharmaceutical composition in vitro are influenced, and the bioavailability of the pharmaceutical composition in vivo is further influenced. Therefore, it is of extraordinary interest to study and prepare different morphological crystals of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine.
Disclosure of Invention
The first purpose of the invention is to provide a novel crystal of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine, which has the advantages of good water solubility, good stability, suitability for industrial scale preparation and the like.
Another object of the present invention is to provide a process for preparing said novel crystals of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine, which is low in cost, high in yield and capable of effectively controlling impurities in the product.
It is a third object of the present invention to provide a pharmaceutical composition comprising the above novel crystal.
The crystal of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine provided by the invention has diffraction peaks at 5.46 +/-0.2 °, 10.89 +/-0.2 °, 11.63 +/-0.2 °, 12.94 +/-0.2 °, 14.88 +/-0.2 °, 16.05 +/-0.2 °, 17.32 +/-0.2 °, 20.34 +/-0.2 °, 20.73 +/-0.2 °, 22.42 +/-0.2 °, 23.42 +/-0.2 ° and 41.62 +/-0.2 ° in an X-ray diffraction diagram of Cu-Ka radiation. In particular, there are also one or more (in any combination, including more than two, or all) diffraction peaks at 5.46 ± 0.2 °, 12.94 ± 0.2 °, 14.88 ± 0.2 °, 20.73 ± 0.2 °, and 23.42 ± 0.2 °; the X-ray diffraction pattern of the crystal is shown in fig. 2.
Furthermore, 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] of the present invention]-N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl]An infrared absorption spectrum of a crystal of phenyl } pyrimidine-2, 4-diamine measured with a KBr pellet, characterized by a peak at about 3426cm-1，3222cm-1，3164cm-1，3087cm-1，2933cm-1，2796cm-1，1616cm-1，1569cm-1，1513cm-1，1442cm-1，1413cm-1，1309cm-1，1232cm-1，1157cm-1，1035cm-1，933cm-1，865cm-1，773cm-1，757cm-1，709cm-1，623cm-1，476cm-1Has an absorption peak; see fig. 3.
The invention also provides a preparation method of the 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystal, which is realized by the following steps: firstly, adding 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazine-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine into methanol and water solution in a volume ratio of 1:5 to 5:1, stirring for 2 to 4 hours at the temperature of 60 to 70 ℃, cooling to room temperature, and standing until crystals are slowly precipitated; filtering and drying the obtained solid to obtain the new crystal of the 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine.
The use amount of the organic solvent is increased, the product quality is not improved, and the overall production cost is increased.
In the invention, the X-powder diffraction test instrument and the test conditions are as follows: rigaku D/max-rA type X-ray diffractometer (Japan science); a Cu target, a graphite curved crystal monochromator, a tube voltage of 40kv, a tube current of 100mA, a wavelength of 1.5406A, and a scanning range of 3-70 degrees.
The related substance high performance liquid chromatography detection conditions and the method comprise the following steps: octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability; the mobile phase is 0.1 percent trifluoroacetic acid water solution and acetonitrile, and gradient elution is carried out (acetonitrile: 0-5-40-90-5 percent, 5-60-80-85-90 minutes); the detection wavelength is 250 nm; the theoretical plate number should not be less than 5000 as calculated from the peak of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine. The separation degree of the 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine peak and the adjacent impurity peak is in accordance with the requirement.
Dissolution rate measurement conditions and methods: measured according to the second method of 0931 of the four general rules of the pharmacopoeia 2015 year edition.
Taking tablet prepared by the product, determining by dissolution method, taking 900ml of phosphate buffer (pH adjusted to 7.2 with sodium hydroxide) as dissolution medium, rotating at 70 r/min, collecting appropriate amount of solution after 60 min, filtering, discarding primary filtrate, and taking subsequent filtrate to dilute as sample solution. An appropriate amount of a control of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine was precisely weighed, and a solution containing about 10. mu.g of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine per 1ml was prepared with water as a control solution. Taking the two solutions, measuring absorbance at 250nm wavelength by ultraviolet-visible spectrophotometry (second method of 0931, the general rule of four parts of the pharmacopoeia 2015 edition of China), and calculating the dissolution amount of each granule (or tablet) according to the absorbance by an external standard method.
Crystal characterization of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine
One, stability
Test samples: crystalline 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine as prepared in example 1.
1. Water or solvent Effect test
When 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals were mixed with an appropriate amount of auxiliary materials and subjected to wet granulation, the X-ray diffraction pattern of the obtained sample was measured, and no influence or change was found in comparison with that of the 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals before granulation. The results are shown in FIG. 4 with reference to the X-ray diffraction pattern.
2. Crushing test
A proper amount of samples are taken, a high-speed pulverizer is used for pulverization, samples are taken and measured after pulverization, indexes are tested, and results are compared with those before pulverization, and the results are shown in table 1.
TABLE 1 crush test
3. Mixing experiment with auxiliary materials
A sample of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine in a quantitative amount was weighed, mixed with an appropriate amount of the adjuvant described in claim 5, and then sieved with an 80 mesh sieve three times to prepare crystals mixed with the adjuvant. The obtained sample and the mixed auxiliary materials used in the invention are subjected to X-ray diffraction detection, and the detection result is shown in FIG. 6.
4. Illumination test (5000lxs)
A proper amount of samples were taken, placed under the condition of relative illumination intensity of 5000lxs for 30 days, sampled and measured for 30 days, and the results were compared with the appearance characteristics of 0 day, and the results are shown in Table 2.
TABLE 2 light test
5. Accelerated test (40 ℃ C.)
Taking a proper amount of samples, placing the samples at the temperature of 40 ℃ for 30 days, sampling and measuring the samples in 30 days, sampling and measuring crystal powder data, comparing the appearance, testing indexes and comparing the results with 0 day, wherein the results are shown in Table 3.
TABLE 3 accelerated test (40 ℃ C.)
6. High humidity test
5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystal raw material is evenly distributed into an open petri dish, the thickness is less than or equal to 5mm, the open petri dish is placed in a constant temperature and humidity incubator with room temperature (about 25 ℃) and relative humidity of 90 +/-5%, samples are taken on the 30 th day for determination, and the results are compared with the results of the 0 th day, and the results are shown in Table 4.
TABLE 4 high humidity test (room temperature, relative humidity, 90. + -. 5%)
Solubility
The test is carried out according to the general examples of the Chinese pharmacopoeia 2015 year edition. The method comprises the following steps: an appropriate amount of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals was weighed out precisely, a certain amount of a solvent was slowly added thereto, and the mixture was vigorously shaken every 5 minutes for 30 seconds, followed by observation of dissolution within 30 minutes, and the results are shown in Table 5.
TABLE 55 chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine Crystal solubility test
A series of tests verify that the stability under the conditions of high temperature, illumination, pressure, mechanical shearing force, action with auxiliary materials and the like is researched. It can be seen that the crystalline 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine of the present invention is suitable for preparation into a formulation.
Drawings
FIG. 1 is a NMR carbon spectrum of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention.
FIG. 2 is an X-ray diffraction pattern of the crystalline 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine of the present invention.
FIG. 3 is an infrared spectrum of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention.
FIG. 4 is an X-ray diffraction pattern of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention after granulation.
FIG. 5 is an X-ray diffraction pattern of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention after pulverization.
FIG. 6 shows the X-ray diffraction pattern of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals mixed with auxiliary materials according to the present invention.
FIG. 7 is an X-ray diffraction pattern of crystals of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine according to the present invention measured in 30 days with light.
FIG. 8 is an X-ray diffraction pattern of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention accelerated for 30 days
FIG. 9 is a high humidity 30 day test X-ray diffraction pattern of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals of the present invention.
Detailed Description
The following examples and drawings are intended to describe the present invention more specifically, but the present invention is not limited to the contents of the following examples.
Example 1
Adding 20g of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine into a methanol-water solution with a volume ratio of 1:1, stirring at 65 ℃ for 3 hours, cooling to room temperature, and standing until crystals are slowly separated out; the resulting solid was filtered and dried, and the X-ray diffraction pattern of the resulting product was shown in FIG. 2.
Example 2
Adding 50g of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine into an ethanol and water solution in a volume ratio of 2:1, stirring at 68 ℃ for 4 hours, cooling to room temperature, and standing until crystals are slowly separated out; the resulting solid was filtered and dried, and the X-ray diffraction pattern of the obtained product was substantially in accordance with that of example 1.
Example 3 formulation and preparation of tablets:
the above crystals of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine were formulated into tablets containing 30mg per tablet by using several kinds of excipients in the following manner, and the results are shown in Table 6.
TABLE 6 prescription conditions
The preparation process comprises the following steps: a tablet containing 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals was produced by uniformly mixing the above-mentioned excipient with 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine crystals by an equivalent-scale-up method, dry-granulating, and tableting. The reference crystals were mixed, granulated and tabletted in the same way. The dissolution test results of the tablet formulation are shown in Table 7
TABLE 7 comparison of dissolution test results for tablet formulations
The invention is described above by way of example and is not limited to the contents of the above embodiments. Any insubstantial improvement made by adopting the technical scheme and the principle of the invention or the technical scheme and the principle of the invention can be directly applied to other occasions without improvement, and the technical scheme and the principle of the invention belong to the protection scope of the invention.
Claims (9)
1. A crystalline form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine using Cu-Ka radiation having an X-ray diffraction pattern with diffraction peaks, expressed in degrees, at 5.46 ± 0.2 °, 10.89 ± 0.2 °, 11.63 ± 0.2 °, 12.94 ± 0.2 °, 14.88 ± 0.2 °, 16.05 ± 0.2 °, 17.32 ± 0.2 °, 20.73 ± 0.2 °, 23.42 ± 0.2 ° and 41.62 ± 0.2 °.
2. The crystal of claim 1, having an infrared absorption spectrum measured by KBr pellet and characterized by a value of 3426cm-1，3222cm-1，3164cm-1，3087cm-1，2933cm-1，2796cm-1，1616cm-1，1569cm-1，1513cm-1，1442cm-1，1413cm-1，1309cm-1，1232cm-1，1157cm-1，1035cm-1，933cm-1，865cm-1，773cm-1，757cm-1，709cm-1，623cm-1，476cm-1There are absorption peaks at the positions of the above.
3. The crystal of claim 1, wherein the crystal has a solid state nmr spectrum as shown in figure 1.
4. The crystal of claims 1-3, having a crystal data that does not change after mixing with an excipient.
5. The adjuvant according to claim 4 comprises an adjuvant selected from lactose, sucrose, dextrin, mannitol, microcrystalline cellulose, silicified microcrystalline cellulose, starch, pregelatinized starch, etc. as a filler, low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, etc. as a disintegrant, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, povidone, etc. as a binder, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, etc. as a lubricant, silicon dioxide, colloidal silicon dioxide, etc. as a glidant, hydroxypropyl methyl cellulose, talc, polyethylene glycol, polyvinyl alcohol, titanium dioxide, iron oxide, etc. as a coating material, and other pharmaceutically acceptable adjuvants.
6. A method for producing the crystal according to claims 1 to 3, characterized in that: dissolving 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine in a hot alcohol solvent and water in a dosage ratio of 1: 5-5: 1(v/v) under stirring, cooling to room temperature, and standing until crystals are slowly precipitated; the resulting solid was collected.
7. The alcoholic vehicle of claim 6, comprising one of methanol, ethanol, isopropanol or any mixture thereof.
8. A pharmaceutical composition comprising the crystal of any one of claims 1 to 3.
9. A pharmaceutical composition according to claim 8 wherein the unit dosage of said pharmaceutical composition comprises from 1 to 300mg of the novel crystalline form of 5-chloro-N4- [2- (dimethylphosphoryl) phenyl ] -N2- { 2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl ] phenyl } pyrimidine-2, 4-diamine of any one of claims 1 to 3.
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