CN110804058B

CN110804058B - Novel ibrutinib crystal form and preparation method thereof

Info

Publication number: CN110804058B
Application number: CN201810884838.XA
Authority: CN
Inventors: 张贵民; 张朝花; 翟立海; 郭立红; 胡长恺
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2018-08-06
Filing date: 2018-08-06
Publication date: 2022-11-11
Anticipated expiration: 2038-08-06
Also published as: CN110804058A

Abstract

The invention belongs to the field of pharmaceutical chemicals, and relates to a crystal form M of ibrutinib and a preparation method thereof, wherein the X-ray powder diffraction 2 theta value of the crystal form has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees and 21.7 +/-0.2 degrees. The crystal form has high purity, good stability, simple preparation method, easy operation and suitability for industrial production.

Description

Novel ibrutinib crystal form and preparation method thereof

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a new crystal form of ibrutinib and a preparation method thereof.

Background

Ibrutinib (Ibrutinib ) is jointly developed by pharmacy and qiangsheng company, 11 months in 2013 are accelerated by the U.S. food and drug administration to be approved to the market under the trade name of Ibrutinib and under the general name of Ibrutinib. It is an innovative oral drug named as a Bruton's Tyrosine Kinase (BTK) inhibitor, and is mainly used for treating Mantle Cell Lymphoma (MCL), a rare invasive blood cancer. Previous analysts have predicted that the annual peak sales of ibbrutinib will reach around $ 50 billion for all indications, the largest share of which is likely to come from chronic lymphocytic leukemia indication (CLL), which is also currently awaiting FDA approval, and formula X is shown below:

WO2013184572A1 discloses anhydrate forms a, B and C of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4d ] pyrimidin-1-yl ] -1-piperidinyl ] -2-propen-1-one as well as solvate forms D, E and F. The X-ray diffraction pattern of the crystal form A has characteristic peaks at 2-Theta values of 5.7 +/-0.1 degrees, 13.6 +/-0.1 degrees, 16.1 +/-0.1 degrees, 18.9 +/-0.1 degrees, 21.3 +/-0.1 degrees and 21.6 +/-0.1 degrees; the X-ray diffraction pattern of the crystal form B has characteristic peaks at 2-Theta values of 5.2 +/-0.1 degrees, 10.2 +/-0.1 degrees, 16.5 +/-0.1 degrees, 18.5 +/-0.1 degrees and 20.8 +/-0.1 degrees; the X-ray diffraction pattern of the crystal form C has characteristic peaks at 2-Theta values of 7.0 +/-0.1 degrees, 14.0 +/-0.1 degrees, 15.7 +/-0.1 degrees, 18.2 +/-0.1 degrees, 19.1 +/-0.1 degrees, 19.5 +/-0.1 degrees, 20.3 +/-0.1 degrees, 22.1 +/-0.1 degrees and 22.9 +/-0.1 degrees; form D is a methyl isobutyl ketone solvate; form E is a toluene solvate; the crystal form F is a methanol solvate, the solvate does not meet the pharmaceutical requirements, and only the crystal form A is suitable for medicinal preparations. The reported crystal form A has three preparation methods, and all the preparation methods have the defects that the operation is not easy to control and the preparation methods are not suitable for industrial production; meanwhile, CN201510980745.3 also discloses a preparation method and spectrum data of the crystal form A.

CN201510952168.7 discloses a method for preparing amorphous ibrutinib. And stability studies were performed on the amorphous obtained by the method disclosed in WO 2013184572.

Suzhou crystal cloud CN201410542609.1 and CN201610156820.9 disclose another crystal form a (hereinafter referred to as crystal form a') whose reported preparation methods are three: dissolving a crude ibrutinib product in a mixed solution of isopropanol and n-heptane, and stirring at the room temperature at the speed of 750 revolutions per minute to obtain a crystal form A', wherein the industrial implementation of the stirring at the high rotating speed is difficult; dissolving the crude ibrutinib product in a mixed solvent of isopropanol and n-heptane, and reducing the temperature from 50 ℃ to 5 ℃ at a cooling speed of 0.1 ℃/min to obtain a crystal form A, wherein the precise cooling speed is difficult to control; and thirdly, dissolving the crude ibrutinib product in acetone, slowly adding n-heptane, and stirring at the rotating speed of 1000 revolutions per minute for one day to obtain the crystal form A, wherein the rotating speed required by the method is higher than that required by the method I, and industrialization is more difficult to realize. The inventors have found that when these methods are repeated, the reproducibility is poor and a slight lack of control leads to the form a disclosed in WO 2013/184572.

CN201410043636.4 discloses crystalline forms of ibrutinib: anhydrous crystal form II, crystal form VIII, hydrate crystal form III, crystal form IV and crystal form V are Tetrahydrofuran (THF) solvates, and all the crystal forms V, VI and VII are trichloromethane solvates; CN201610347177.8 and CN201610347787.8 are hereby incorporated by reference.

CN201510246220.7 discloses XRPD data and preparation methods of new crystal form A2 and new crystal form A3 of ibrutinib, and hygroscopicity and stability studies are performed on the two crystal forms.

CN201510808526.7 discloses a preparation method of crystal forms I and II of ibrutinib and a conversion preparation method between the two crystal forms; cn201610497395.X discloses crystalline form III of ibrutinib, which was investigated for stability and hygroscopicity.

CN201610114026.8, CN201610114027.2 and CN201610114028.7 disclose XRPD data and preparation methods of crystal form B, crystal form F and crystal form G of ibrutinib, respectively, and the crystal forms are examined for stability, solubility, dissolution rate and hygroscopicity, and the hygroscopicity of crystal form B is 0.1%, and the research data of all aspects of the three crystal forms are equivalent through research.

CN201610191829.3 discloses XRPD data and preparation method of ibrutinib crystal form 1, and researches on dissolution, hygroscopicity and stability of the crystal form are carried out.

CN201680025850.4 discloses polymorphs of ibrutinib, characterized by: an anhydrous crystalline form: form D1, form D1a, form D2a, form D9; form D3 is an acetophenone solvate, form D4 is a formamide solvate, form D5 is an acetone solvate, form D6 is a chlorobenzene solvate, form D7 is a dimethylacetamide solvate, form D8 is an acetone solvate, form D10 is a1, 2-dimethoxyethane solvate, form D11 is an anisole solvate, form D12 is a dimethyl carbonate solvate, and form D13 is a1, 4-dioxane solvate.

CN 201680026436.5-discloses solvated forms of ibrutinib: form 1 is a butyronitrile solvate, form 2 is a1, 2-dimethoxyethane solvate, form 3 is a hexafluorobenzene solvate, form 4 is a hexafluorobenzene solvate, form 5 is an acetophenone solvate, form 6 is a chlorobenzene solvate, form 7 is an acetophenone solvate, form 8 is a dimethylacetamide solvate, form 9 is a benzyl acetate solvate, form 10 is a1, 2-trichloroethane solvate.

WO2015145415A2 discloses crystalline forms of ibrutinib as: form III is a1, 4-dioxane solvate, form IV is a1, 2-dimethoxyethane solvate, form V is a methanol solvate, form VI is an anhydrous form, form VII is an anisole solvate, form VIII is a chlorobenzene solvate, form IX is a benzyl etherate; wherein the crystal form VI is formed by converting a crystal form IV1, 2-dimethoxyethane solvate, the crystal form VI is a non-solvate crystal form, and the crystal form VI can be converted into the crystal form VI by placing the crystal form IV in an environment of strictly controlling the temperature at 40 ℃ and the relative humidity at 75% for a long enough time.

WO2016025720A1 discloses crystalline forms of ibrutinib: the crystal form G is acetic acid solvate, the crystal form J is benzyl etherate and the crystal form K.

WO2016079216A1 discloses crystalline forms of ibrutinib: crystal forms of anisole solvate, chlorobenzene solvate, dichloromethane solvate, 1,4 dioxane solvate, pyridine solvate, and the like.

CN201510984875.4 also discloses a purification method of ibrutinib, and the purity of the finished products of ibrutinib is improved to 99.8% and above. The process is the same as the process for preparing the crystal form WO 2013184572A.

WO2017029586A1 also discloses crystalline forms of form S1, S2, S3, S4 and amorphous A1. Discloses a preparation method thereof, conversion between crystal forms and the like.

Polymorphism is widespread in medicine. Different crystal forms of the same drug have obvious differences in the aspects of solubility, melting point, density, thermal stability and the like, so that the stability, uniformity, bioavailability, curative effect and safety of the drug are affected to different degrees. At present, a plurality of crystal forms and solvates of ibrutinib have been developed, but the solvates do not meet the pharmaceutical requirements, and the solvates are unstable; the anhydrous and hydrate crystal forms are also few in number that can be used in medicine.

Therefore, there remains a need for alternative polymorphic forms of ibrutinib and processes for their preparation.

Disclosure of Invention

The invention aims to provide a novel crystal form of 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl ] -1-piperidyl ] -2-propylene-1-ketone (ibrutinib), which is named as a crystal form M in the invention. The crystal form has simple preparation process and excellent chemical stability, and is suitable for industrial production.

The crystal form M of ibrutinib provided by the invention has characteristic diffraction peaks at the X-ray powder diffraction 2 theta values of 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees.

Furthermore, the X-ray powder diffraction 2 theta value of the crystal form M has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees and 25.4 +/-0.2 degrees.

Furthermore, the X-ray powder diffraction 2 theta value of the crystal form M has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 13.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 25.4 +/-0.2 degrees and 30.7 +/-0.2 degrees.

Furthermore, the X-ray powder diffraction 2 theta value of the crystal form M has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 10.6 +/-0.2 degrees, 10.8 +/-0.2 degrees, 12.2 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 13.6 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.1 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 21.9 +/-0.2 degrees, 22.3 +/-0.2 degrees, 25.1 +/-0.2 degrees, 25.4 +/-0.2 degrees and 30.7 +/-0.2 degrees.

The crystal form M has an X-ray powder diffraction pattern shown in figure 1 and an X-ray powder diffraction pattern integral chart shown in figure 2.

The crystal form M has a first endothermic peak with an initial temperature of 75.39 ℃ and a peak value of 83.17 ℃ and a second endothermic peak with an initial temperature of 152.74 ℃ and a peak value of 156.38 ℃ in Differential Scanning Calorimetry (DSC) analysis; having the TGA and DSC analysis profiles shown in figure 3; the crystalline forms are non-solvates or non-hydrates.

In a second aspect of the invention, there is provided a process for preparing said form M, comprising the steps of:

(1) Adding the crude ibrutinib product into an N, N-dimethylformamide solvent, and heating to 60-65 ℃;

(2) Adding activated carbon into the ibrutinib solution obtained in the step (1) for decoloring, filtering, adding a solvent B into the filtrate, and heating to reflux;

(3) Stirring the solution obtained in the step (2), cooling to-5-10 ℃ at the speed of 20-30 ℃/h, keeping the temperature, stirring and crystallizing for 4-8 h;

(4) Filtering, washing with cold ethanol-water mixed liquor, and drying in vacuum to obtain the ibrutinib crystal form M;

wherein the crude ibrutinib is selected from the following group: the crude product obtained by the preparation method in the prior art also comprises an amorphous or crystal product in the prior art.

In addition, the cooling at the speed of 20-30 ℃/h is realized by ice water bath, ice salt bath or refrigeration equipment, and the non-natural cooling can be realized.

In the step, the solvent B is one or a combination of cyclohexane, normal hexane, normal heptane, petroleum ether, methyl tertiary butyl ether, water and ethyl acetate; the mass-volume ratio of the crude ibrutinib product to N, N-dimethylformamide and the solvent B is 1; the preferred ratio is 1.

In the step, the solvent B is preferably N-heptane, and the mass-to-volume ratio of the crude ibrutinib product to N, N-dimethylformamide and N-heptane is preferably 1.

The temperature of the cold ethanol-water mixed solution in the step (4) is that the volume ratio of ethanol to water is 1; the drying temperature is 50-65 ℃.

The crystal form M is used for preparing a medicament for preventing and/or treating cancer or a medicament for inhibiting tumor cells; wherein the cancer is a B-cell malignancy selected from Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL), mantle Cell Lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma.

A pharmaceutical composition comprising (a) the crystalline form M of any one of claims 1-5, and (b) a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition which comprises the active ingredient crystal form M in a safe and effective amount range and a pharmaceutically acceptable carrier.

"safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of active ingredient per dose, more preferably, 10-200mg of active ingredient per dose. Preferably, said "dose" is a tablet.

"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

The mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and the like. The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

Many solvates are available in the prior art, such as solvates of three types of solvents, and the prior art discloses solvate crystal forms of acetophenone, chlorobenzene, benzyl acetate, acetone, methanol, toluene, anisole, dichloromethane, pyridine and the like of ibrutinib. Researches find that the ibrutinib solvate of the low-boiling point solvent is very unstable, and crystal transformation and solvent loss are easy to occur when the temperature is not proper; solvents with high boiling points also have problems of moisture absorption and generation of impurities. Moreover, the preparation method of the solvate has high requirements, and the solvated crystal form provided by the prior art is difficult to repeat. Therefore, the anhydrous crystal form and the hydrate crystal form are intensively researched by the invention.

The invention has the beneficial effects that:

the ibrutinib crystal form M provided by the invention has good solubility and high solubility in biological media, is beneficial to improving the bioavailability of a medicament, and has good clinical application value.

The ibrutinib crystal form M provided by the invention has good stability and almost no hygroscopicity, is beneficial to storage and transportation of medicines, and ensures safety in clinical application.

The preparation method of the ibrutinib crystal form M provided by the invention is simple to operate, strong in impurity removal capability and high in product purity, the yield can reach more than 96%, and the purity can reach more than 99.8; is suitable for industrial production, and also provides a purification method of ibrutinib.

Drawings

FIG. 1: an X-ray powder diffraction pattern of ibrutinib form M.

FIG. 2: an X-ray powder diffraction pattern integral chart of the ibrutinib crystal form M.

FIG. 3: TGA and DSC profiles of crystalline form M of ibrutinib.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to illustrate the present invention, not to limit the present invention, therefore, the simple modifications of the present invention in the method of the present invention are all within the scope of the present invention as claimed.

Raw materials and general procedure:

the prior art of the raw material ibrutinib used in the examples provides products obtained by the preparation method, or crystal forms or amorphous forms obtained in the prior art, or is available from commercial sources.

The X-ray powder diffraction test instrument and the test conditions are as follows: a Pasnaceae Empyrean X-ray powder diffractometer; a light source copper target, a flat plate sample stage, a BBHD incident light path, a PZXCEL diffraction light path, a voltage of 45kv, a current of 40mA, a divergence slit of 1/4 °, an anti-divergence slit of 1 °, a cable-stayed slit of 0.04rad, a counting time of 0.5s per step, and a scanning range of 3-50 °.

TGA/DSC analysis: collected on TGA/DSC3+, analytical method parameters were as follows: temperature range: the room temperature is 30-200 ℃; scanning rate: 10 ℃/min; protective gas: nitrogen 50mL/min.

Ibutinib purity detection HPLC conditions and methods: chromatography column (waters symmetry shield RP-C18.6 x 150mm 3.5 μm fraction 170), λ =260nm, flow rate: 1.0ml/min, column temperature: 40 ℃, sample: 0.6mg/ml (40% acetonitrile), injection: 10 μ L, MPA =0.1% tfa water, MPB =0.1% tfa acetonitrile. The elution gradient of the ibutinib HPLC assay is shown in Table 1.

TABLE 1 Ibrutinib HPLC detection elution gradient chart

t/min	A％	B％
			0	75	25
12	65	35
			35	50	50
40	10	90
			44	10	90
45	75	25
			50	75	25

In the examples below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the experimental equipment and reagents can be obtained by a commercially available mode.

Example 1 preparation of Ebritinib form M

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ to dissolve; adding 2g of activated carbon for decolorization, filtering, adding 750ml of n-heptane into the filtrate, and heating to reflux; stirring the obtained solution, cooling to-5-0 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol aqueous solution (the volume ratio of ethanol to water is 1: 5) at 0-5 ℃, and drying at 50-65 ℃ under a vacuum condition to constant weight to obtain the crystalline form M of ibrutinib; yield 98.3%, HPLC:99.98 percent.

Example 2 preparation of crystalline form M of ibrutinib

50g of the crude ibrutinib product (HPLC: 99.5%) is added into 150ml of N, N-dimethylformamide solvent, and heated to 60-65 ℃ for clearing; adding 2g of active carbon for decolorization, filtering, adding 1000ml of n-heptane into the filtrate, and heating to reflux; stirring the obtained solution, cooling to-5-0 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol water solution (the volume ratio of ethanol to water is 1); yield 97.0%, HPLC:99.97 percent.

Example 3 preparation of crystalline form M of ibrutinib

Adding 50g of ibutinib crude product (HPLC: 99.5%) into 25ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ to dissolve; adding 2g of activated carbon for decolorization, filtering, adding 750ml of n-heptane into the filtrate, and heating to reflux; stirring the obtained solution, cooling to-5-0 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol aqueous solution (the volume ratio of ethanol to water is 1: 5) at 0-5 ℃, and drying at 50-65 ℃ under a vacuum condition to constant weight to obtain the crystalline form M of ibrutinib; yield 98.50%, HPLC:99.87 percent.

Example 4 preparation of Ebritinib form M

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ for clearing; adding 2g of activated carbon for decolorization, filtering, adding 750ml of petroleum ether into the filtrate, and heating to reflux; stirring the obtained solution, cooling to-5-0 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, and stirring and crystallizing for 7-8 h under the temperature; filtering, washing with an ethanol aqueous solution (the volume ratio of ethanol to water is 1: 5) at 0-5 ℃, and drying at 50-65 ℃ under a vacuum condition to constant weight to obtain the crystalline form M of ibrutinib; yield 97.8%, HPLC:99.96 percent.

Example 5 preparation of Ebritinib form M

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ to dissolve; adding 2g of active carbon for decolorization, filtering, adding 150ml of methyl tert-butyl ether into the filtrate, and heating to reflux; stirring the obtained solution, cooling to 0-5 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 4-5 h; filtering, washing with an ethanol water solution (the volume ratio of ethanol to water is 1); yield 97.8%, HPLC:99.92 percent.

Example 6 preparation of crystalline form M of ibrutinib

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ to dissolve; adding 2g of activated carbon for decolorization, filtering, adding 750ml of water into the filtrate, and heating to reflux; stirring the obtained solution, cooling to 5-10 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol water solution (the volume ratio of ethanol to water is 1) at 0-5 ℃, and drying at 50-65 ℃ under a vacuum condition to constant weight to obtain the crystalline form M of ibrutinib; yield 97.1%, HPLC:99.97 percent.

Example 7 preparation of Ebritinib form M

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ to dissolve; adding 2g of activated carbon for decolorization, filtering, adding 750ml of mixed solution of ethyl acetate and cyclohexane into the filtrate, and heating to reflux; stirring the obtained solution, cooling to 0-5 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol aqueous solution (the volume ratio of ethanol to water is 1: 2) at 0-5 ℃, and drying at 50-65 ℃ under a vacuum condition to constant weight to obtain an ibrutinib crystal form M; yield 96.5%, HPLC:99.96 percent.

Example 8 preparation of Ebritinib form M

Adding 50g of crude ibrutinib (HPLC: 99.5%) into 50ml of N, N-dimethylformamide solvent, and heating to 60-65 ℃ for clearing; adding 2g of active carbon for decolorization, filtering, adding 750ml of mixed solution of n-hexane and n-heptane into the filtrate, and heating to reflux; stirring the obtained solution, cooling to-5-0 ℃ at the speed of 20-30 ℃/h by using an ice salt bath, keeping the temperature, stirring and crystallizing for 5-6 h; filtering, washing with an ethanol water solution (the volume ratio of ethanol to water is 1); yield 98.0%, HPLC:99.94 percent.

Comparative example 1

513mg of ibrutinib (PCI-32765) solid powder was dissolved in 15mL of a mixed solvent of isopropanol and n-heptane in a volume ratio of 2. And stirring the obtained solution at the room temperature for 24 hours at the speed of 750 r/min, and collecting solids to obtain the crystalline form substance of the ibrutinib.

Comparative example 2

Adding 0.20g of ibrutinib and 10mL of n-propanol into a reaction bottle, stirring, heating to 90 ℃, dissolving, transferring the reaction to room temperature (25 ℃) and stirring, slowly adding 6mL of water, separating out a solid, filtering, and drying the obtained product at 35 ℃ for 6h under vacuum to obtain the crystalline form of ibrutinib.

Comparative example 3

Adding 0.20g of ibrutinib into a reaction bottle, adding 10mL of ethanol, stirring, heating to 70 ℃ for dissolving, then dropwise adding the solution into 20mL of water at room temperature (20-25 ℃), stirring for 0.5h after separating out a solid, filtering, and drying the obtained product at 35 ℃ for 5h under vacuum to obtain the crystalline form of ibrutinib.

Comparative example 4

In a clean round bottom flask, 12.0g of ibutinib was dissolved in 120ml of methanol by heating to 45 ℃ under magnetic stirring. 72ml of water were added to the warm solution of dissolved ibrutinib over 45min maintaining the internal temperature at 45 ℃. The solution slowly became a slurry and was stirred at elevated temperature for 3h. The slurry sample was aspirated, filtered and dried. The slurry was allowed to cool to room temperature and stirred for at least 16h. Another sample of the slurry was aspirated, filtered and dried. The solid was filtered and washed with 50ml of methanol: the 3. Obtaining the required ibrutinib crystal form.

Comparative example 5

The crystalline form of ibrutinib obtained in comparative example 4 (about 500 mg) was weighed into a container and dissolved in methanol (4 ml) at 50 ℃. The solution was cooled to 25 ℃ and remained as a solution. Water was added (500. Mu.l of water added in one portion, 2ml total) until the solution became cloudy. The slurry was stirred for 10min. Removing a aliquot of the sample with a pipette to evaluate the material by XRPD while the sample is stirred at 25 ℃ for 1h; however the material has very low crystallinity. After stirring for 1h at 25 ℃, the sample was left at 5 ℃ for 3 days. After this time, another aliquot of the sample was removed with a pipette for XRPD analysis. The residue of the slurry was vacuum filtered and dried under vacuum at 25 ℃ overnight to provide the desired ibrutinib polymorph.

Comparative example 6

In a clean round bottom flask, 2.0g of ibrutinib was suspended in 25ml of methanol and heated to 50 ℃. The warm solution of dissolved ibrutinib was filtered into a clean round bottom flask. The refined solution was allowed to cool to room temperature under magnetic stirring. The solution slowly became a slurry and stirred over 14h. The solid was filtered, washed with 5ml of methanol and dried on the filter for 20h and then in a vacuum oven at 50 ℃ for 8h; obtaining the required ibrutinib crystal form.

Comparative example 7

Ibutinib amorphous (10.0 g, prepared in reference to WO 2008/039218) was added to 50ml of isopropanol and heated to reflux to dissolve. Stirring for 30min after dissolving. The heating was stopped and the temperature was reduced at a rate of about 1 c/min, and solids gradually precipitated. And cooling to room temperature, keeping the temperature, stirring for 2 hours, filtering, leaching the filtrate with acetone, and drying the filter cake at 50 ℃ in vacuum to obtain the crystalline ibrutinib substance.

Comparative example 8

And (2) adding the crystalline form of ibrutinib (10.0 g) obtained in comparative example 4 into 50ml of ethyl acetate, heating and refluxing for dissolving, cooling to room temperature at the speed of 1 ℃/minute after dissolving, stirring for 4 hours at room temperature, filtering, leaching a filter cake by using an ethyl acetate mixed solvent, and performing vacuum drying at 50 ℃ to obtain a crystalline substance.

Comparative example 9

And adding 10g of the ibutinib amorphous substance into 100ml of mixed solution of isopropanol and methanol (the volume ratio of the isopropanol to the methanol is 2.

Comparative example 10

And adding 10g of the amorphous substance of the ibrutinib to 100ml of a mixed solution of ethyl acetate and methanol (the volume ratio of the ethyl acetate to the methanol is 2.

Comparative example 11

Ibutotinib powder 500mg was added to 4ml methanol, heated to 60 ℃ and stirred for 1h to obtain a clear solution. Cooling the solution to 25 ℃, dropwise adding 2ml of water, stirring at 25 ℃ for 1h, cooling to 5 ℃ within 1h, continuously stirring for 48h, filtering, collecting solids, and carrying out vacuum at 50 ℃ for 18h to obtain the ibrutinib crystal form.

Comparative example 12

Adding 50g of ibrutinib crude product (HPLC: 99.5%) into 200ml of N, N-dimethylformamide solvent, and heating to 50-55 ℃ to dissolve; adding 3g of activated carbon for decolorization, filtering, adding 1500ml of n-octane into the filtrate, and heating until reflux; stirring the obtained solution, cooling to-15 to-12 ℃ at the speed of 10-15 ℃/h by using an ice salt bath, and stirring and crystallizing for 2-3 h at the temperature; filtering, washing with a methanol solution at 0-5 ℃, and drying at 70-80 ℃ under a vacuum condition to constant weight to obtain an ibrutinib crystal form M; yield 91.25%, HPLC:99.87 percent.

Comparative example 13

Dissolving 99.9mg of ibrutinib powder in 0.6mL of a methanol/water mixed solvent with the volume ratio of 2 to obtain a suspension, and stirring for 5h at room temperature to obtain an ibrutinib crystal form.

Comparative example 14

Dissolving 101.1mg of ibrutinib powder in 1mL of ethanol/water mixed solvent with the volume ratio of 1.

Comparative example 15

Ibutinib amorphous (5.0 g) was added to 50ml of n-propanol and heated to reflux to dissolve. Stirring for 30min after dissolving. Stopping heating, cooling at the speed of about 1 ℃/min, cooling to 50 ℃, separating out solids, keeping the temperature, stirring for 2h, filtering, leaching the filtrate with ethyl acetate, and drying the filter cake at the temperature of 50 ℃ in vacuum to obtain the ibrutinib crystal form substance.

Comparative example 16

5.0g of ibrutinib was charged into a round-bottom flask at 25-30 ℃. 200mL of methanol was charged to the flask and the contents were heated to 50-60 ℃. The solution was made particle free and cooled to 5-10 ℃. 200mL of demineralized water precooled to 2-10 ℃ were slowly added to the above flask. The contents of the flask were maintained at 5-15 ℃ for 1-3 hours and filtered using a vacuum pump to obtain an undried crystal. Drying the crystals at 50-60 ℃ under vacuum for 4-6 hours to obtain the crystalline form of ibrutinib.

Comparative example 17

1.5g of ibrutinib were charged to a round-bottom flask at 25-30 ℃ and cooled to-18 ℃. 4.6mL of an ethanol-water mixture (80). The contents were held at-15 to-20 ℃ for 15-18h. The contents were distilled under reduced pressure at 0 ℃ for 2-4h. The distilled compound was dried at 52 ℃ under reduced pressure for 4-6h to obtain ibrutinib polymorph.

Comparative example 18

Dissolving 1.0g of the ibutinib crystal form substance in comparative example 4 in 5ml of ethylene glycol dimethyl ether, refluxing at about 80 ℃, then cooling to 10 ℃ within 5h, filtering, and vacuum drying at 40 ℃ for 16h to obtain a crystal form substance; the crystal was placed in an open small reaction flask in an incubator with a temperature of 40 ℃ and an RH of 75% for 48h. Collecting the solid to obtain the ibrutinib crystal form substance.

Comparative example 19

Dissolving 10g of ibrutinib amorphous substance into a mixed solution of 50ml of toluene and 30ml of Dimethylformamide (DMA) at room temperature, heating the solution to 50 ℃, and then dropwise adding 30ml of water; phase separation is carried out, and 30ml of methyl tert-butyl ether (MTBE) is added into the organic phase dropwise; and cooling by using an ice bath, adding amorphous ibrutinib seed crystal, continuously stirring, crystallizing, filtering, and drying in vacuum to obtain an ibrutinib crystal form substance.

According to the guiding principle of crystal form research and crystal form quality control of the drug of the fourth general rule 9015 in the 2015 edition of Chinese pharmacopoeia. The following investigations were carried out on the crystal forms of the present invention and the crystal forms related to the prior art which are close to the present invention:

1. stability test

The specific stability investigation method can refer to the guidance principle of 9001 raw material medicaments and preparation stability tests in the fourth guideline of the pharmacopoeia 2015 edition; the HPLC method for detecting the purity of the ibrutinib can be carried out under the conditions and the method for detecting the purity of the ibrutinib in the general method, and can also refer to the high performance liquid chromatography 0512 in the general rule of Chinese pharmacopoeia 2015 edition.

Influence factor test: the crystal form M obtained in example 1 and the various crystal forms obtained or accumulated in the comparative examples were placed in a petri dish and spread into a thin layer with a thickness of 10mm or less, and the following experiments were performed:

1) High temperature test, placing the sample in a clean container at 60 deg.C for 10 days, sampling at 5 th and 10 th days, and inspecting the purity of the product according to stability.

2) And (3) high humidity test, namely opening the test sample, placing the test sample in a constant humidity closed container at 25 ℃ for 10 days under the condition that the relative humidity is 90% and 5%, sampling on the 5 th day and the 10 th day, and detecting the purity of the project according to the emphasis on stability.

3) In the strong light irradiation test, the opening of a test article is placed in a lighting box or other suitable lighting devices provided with fluorescent lamps, the test article is placed for 10 days under the condition of the illumination of 4500lx and 500lx, samples are taken on the 5 th day and the 10 th day, the purity of the project is inspected according to the emphasis of stability, and the appearance change of the test article is particularly noticed. The stability results are shown in Table 2.

Table 2 stability test results

Compared with the prior art, the crystal form M provided by the invention has good stability. Can better avoid crystal transformation and impurity generation in the process of medicine storage and development, thereby avoiding the change of bioavailability and efficacy.

2. Hygroscopicity test

The method and conditions of the hygroscopicity test refer to the guiding principle of the hygroscopicity test of medicaments 9103 in the fourth part of the pharmacopoeia 2015 edition:

wherein, the characterization of hygroscopicity and the definition of hygroscopicity increase are as follows:

deliquescence: sufficient water is absorbed to form a liquid.

Has very moisture-wicking property: the moisture-guiding weight gain is not less than 15%.

Moisture absorption: the moisture-inducing weight gain is less than 15% but not less than 2%.

Slightly hygroscopic: the moisture-inducing weight gain is less than 2% but not less than 0.2%.

No or almost no hygroscopicity: the moisture-guiding weight gain is less than 0.2%.

The results of the hygroscopicity examination are shown in Table 3.

TABLE 3 examination of hygroscopicity

And (4) conclusion: the crystal form M obtained by the invention has no or almost no hygroscopicity, is not easy to deliquesce under the influence of high humidity, and is convenient for long-term storage and placement of the medicine.

3. Solubility determination

Taking the crystal form M product obtained in example 1 as an example, the solubility of the crystal form or amorphous sample related in the prior art is measured and compared.

The crystal form M of the invention and a sample prepared by the prior art are dissolved by FeSSIF (artificial intestinal juice under a feeding state) with pH of 5.0, SGF (artificial gastric juice) with pH of 1.8, water and 0.01mol/L HCl solution respectively at room temperature, and the concentration of ibrutinib in the solution is measured by High Performance Liquid Chromatography (HPLC) after 24 hours. The results of the experiment are shown in table 4.

TABLE 4 determination of solubility

After 24 hours, the solubilities of the crystal form M prepared in the examples 1,2 and 3 at 25 ℃ in FeSSIF (fed artificial intestinal juice) with pH5.0, SGF (artificial gastric juice) with pH1.8, water and 0.01mol/L HCl solution are all superior to the solubilities of the crystal form M prepared in the comparative example under the conditions, so that the crystal form M is beneficial to the absorption of the medicine in a human body and is convenient to widely apply clinically. Unexpected results were obtained with the solubility of the crystalline form of the present invention being higher than that of the prior art.

Claims

1. The crystal form M of ibrutinib is characterized in that the X-ray powder diffraction 2 theta value of the crystal form has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees and 21.7 +/-0.2 degrees.

2. A crystal form M of ibrutinib is characterized in that the X-ray powder diffraction 2 theta value of the crystal form has characteristic diffraction peaks at 5.1 +/-0.2 degrees, 5.7 +/-0.2 degrees, 12.2 +/-0.2 degrees, 13.4 +/-0.2 degrees, 15.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.3 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees and 25.4 +/-0.2 degrees.

3. Form M according to claim 1, characterized in that it has characteristic diffraction peaks at X-ray powder diffraction 2 θ values of 5.1 ± 0.2 °, 5.7 ± 0.2 °, 12.2 ± 0.2 °, 13.2 ± 0.2 °, 13.4 ± 0.2 °, 13.6 ± 0.2 °, 15.2 ± 0.2 °, 18.9 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °, 21.7 ± 0.2 °, 21.9 ± 0.2 °, 22.3 ± 0.2 °, 25.4 ± 0.2 °, 30.7 ± 0.2 °.

4. Form M according to claim 1, characterized in that it has characteristic diffraction peaks at 5.1 ± 0.2 °, 5.7 ± 0.2 °, 10.6 ± 0.2 °, 10.8 ± 0.2 °, 12.2 ± 0.2 °, 12.4 ± 0.2 °, 13.2 ± 0.2 °, 13.4 ± 0.2 °, 13.6 ± 0.2 °, 15.2 ± 0.2 °, 16.1 ± 0.2 °, 18.9 ± 0.2 °, 19.7 ± 0.2 °, 20.3 ± 0.2 °, 21.3 ± 0.2 °, 21.7 ± 0.2 °, 21.9 ± 0.2 °, 22.3 ± 0.2 °, 25.1 ± 0.2 °, 25.4 ± 0.2 °, 30.7 ± 0.2 ° in X-ray powder diffraction 2 θ.

5. The crystalline form M according to claim 1, characterized in that it has an X-ray powder diffraction pattern as shown in figure 1; the crystalline form M has a TGA and DSC analysis shown in figure 3.

6. A method for preparing the crystal form M of any one of claims 1 to 5, which is characterized by comprising the following steps:

(2) Adding activated carbon into the ibrutinib solution obtained in the step (1) for decolorization, filtering, adding a solvent B into the filtrate, and heating to reflux;

(4) Filtering, washing with a cold ethanol-water mixed solution, and drying in vacuum to obtain the ibrutinib crystal form M;

wherein the crude ibrutinib is selected from the following group: amorphous or existing crystal products.

7. A preparation method of the crystal form M of claim 6, characterized in that in the step, the solvent B is one or a combination of cyclohexane, n-hexane, n-heptane, petroleum ether, methyl tert-butyl ether, water and ethyl acetate; the mass volume ratio of the crude ibrutinib product to N, N-dimethylformamide and solvent B is 1.

8. A process for preparing form M according to claim 7, wherein in said step, solvent B is n-heptane; the mass-to-volume ratio of the crude ibrutinib product to N, N-dimethylformamide and N-heptane is 1.