CN109053738B - Solvate of ibrutinib and preparation method thereof - Google Patents
Solvate of ibrutinib and preparation method thereof Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses an ibrutinib solvate and a preparation method thereof. The ibrutinib solvate is an isopropyl acetate mono-solvate of ibrutinib, and the preparation method comprises the following steps: adding the ibrutinib raw material into a proper amount of isopropyl acetate to form a suspension, stirring at a certain temperature, filtering, and drying to obtain an ibrutinib single solvate; or dissolving the ibrutinib raw material in isopropyl acetate under the heating condition, transferring the obtained solution to the low-temperature condition for temperature reduction and crystallization, filtering, collecting the solid, and drying to obtain the ibrutinib single solvate. The new solvate of ibrutinib provided by the invention has the solubility 2-4 times that of medicinal crystal form A under different pH conditions, is good in stability, safe and low in toxicity, simple in preparation process, easy to control conditions, high in yield, free of special requirements on equipment and has the potential of becoming medicinal crystal forms.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, relates to preparation of raw material medicines, and particularly relates to an ibrutinib solvate and a preparation method thereof.
Background
Ibrutinib (Ibrutinib), chemical name is 1- ((3R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-d ] pyrimidin-1-yl) -1-piperidinyl) -2-propen-1-one, trade name is Imbruvica, chemical structural formula is shown as formula (II):
ibrutinib is a targeted anticancer drug cooperatively developed by Johnson Johnson and pharmaceuticals, is an inhibitor of small-molecule Bruton's Tyrosine Kinase (BTK), and is suitable for treating Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) of B-cell non-Hodgkin's lymphoma (NHL). The medicine is approved by the Food and Drug Administration (FDA) to be marketed in 2013, 11/13/month.
In international patent WO2013/184572a1, which was filed by the original research corporation, six crystal forms of ibrutinib are disclosed, wherein there are three anhydrates, namely, crystal form a, crystal form B and crystal form C; there are three additional solvates, namely, methyl isobutyl ketone solvate form D, toluene solvate form E, and methanol solvate form F. The crystal form A is a medicinal crystal form of the current ibrutinib, the solubility of the crystal form A is 13.0 mu g/mL at the pH value of 8.0, and the problem of poor solubility exists, and the solubility of the crystal form B is only 9.6 mu g/mL at the pH value of 7.42, and the problem of poor solubility also exists; stability and solubility data for form C are not mentioned in this patent; among the three solvates, no solubility property is reported, and neither methyl isobutyl ketone, toluene nor methanol has toxicity, so that the three solvates are not suitable for being used as medicinal crystal forms.
Journal literature (Crystal growth Des.,2018,18:1315-1326.) reports three anhydrous hydrates of crystal form A, crystal form B and crystal form C of ibrutinib and a preparation method thereof. Form a was prepared by slowly adding water as an anti-solvent to a methanol solution of ibrutinib; the crystal form B is prepared by quickly adding water into a methanol solution of ibrutinib as an anti-solvent; the crystal form C is prepared by cooling and recrystallizing ibrutinib in methanol solution. The dissolution rate of the crystal form B and the crystal form C is about 3 times of that of the crystal form A.
Patent WO2015/081180A1 of Suzhou Jingyun application discloses another crystalline form I of ibrutinib different from the original patent and a preparation method thereof, wherein the crystalline form I is prepared by a method of cooling and crystallizing an ibrutinib solution, the crystalline form I has good stability, almost has no hygroscopicity, and the improvement of the solubility is not obvious and is about 1.2 times of that of the crystalline form A.
Forms of ibrutinib hydrochloride and processes for their preparation are disclosed in patent WO2016/050422a1, filed by Ratiopharm corporation. The ibrutinib hydrochloride has better solubility (the solubility is 410 mu g/mL when the pH value is 6.8), the preparation method is that organic solution of hydrogen chloride is dripped into the ibrutinib solution under the condition of low temperature, and impurities with the chemical structure shown in the formula (III) are easily introduced in the preparation process. There is no report in this patent regarding the stability of ibrutinib hydrochloride.
According to the literature, the anti-cancer drug ibrutinib has a plurality of crystal forms, wherein the crystal form A is the current medicinal crystal form, the water solubility is poor, and the total bioavailability is only 3%; the crystal form B, the crystal form C and the crystal form I belong to metastable crystal forms, and the solubility is improved; the crystal form D, the crystal form E and the crystal form F belong to solvates, but the used solvents have certain toxicity and are not suitable for being used as medicinal crystal forms; the ibrutinib hydrochloride has better solubility and is beneficial to improving the bioavailability, but the stability of the salt form is not reported in the patent. Therefore, the development of a novel crystal form of ibrutinib, which is safe, low in toxicity, high in solubility and stable, is needed in the art.
Disclosure of Invention
In order to overcome the defects of low solubility, insufficient stability, poor reproducibility, complicated preparation process and the like of the conventional crystal form of ibrutinib and a preparation method thereof, the invention aims to provide a solvate of ibrutinib and a preparation method thereof. The obtained ibrutinib solvate has good stability and reproducibility, the solubility of the ibrutinib solvate is improved by 2-4 times compared with that of the ibrutinib solvate, the used solvent has low toxicity compared with the crystal form D, the crystal form E and the crystal form F, the preparation process is simple, the conditions are easy to control, the yield is high, no special requirement is required on equipment, and the ibrutinib solvate has the potential of becoming a medicinal crystal form.
The ibrutinib solvate is characterized by being an isopropyl acetate mono-solvate of ibrutinib, and the structural formula of the ibrutinib solvate is shown as the formula (I):
the mass ratio of ibrutinib to isopropyl acetate is 1: 1.
The solvate of ibrutinib is characterized in that the solvate of ibrutinib has characteristic peaks at 7.44 ° ± 0.2 °, 7.91 ° ± 0.2 °, 9.05 ° ± 0.2 °, 10.32 ° ± 0.2 °, 14.39 ° ± 0.2 °, 14.69 ° ± 0.2 °, 15.73 ° ± 0.2 °, 18.27 ° ± 0.2 °, 18.97 ° ± 0.2 °, 20.64 ° ± 0.2 °, 21.34 ° ± 0.2 °, 21.97 ° ± 0.2 °, 22.71 ° ± 0.2 °, 25.05 ° ± 0.2 °, 27.05 ° ± 0.2 °, 27.72 ° ± 0.2 ° as shown by an X-ray powder diffraction (PXRD) pattern with a diffraction angle of 2 θ.
The solvate of ibrutinib is characterized by an X-ray powder diffraction (PXRD) pattern expressed in 2 theta angles, which shows characteristic peaks and relative intensities at the following positions:
the solvate of ibrutinib is characterized in that a Differential Scanning Calorimetry (DSC) curve of the solvate of ibrutinib shows that characteristic endothermic peaks are respectively arranged at 73-77 ℃ and 155-159 ℃, and characteristic exothermic peaks are arranged at 77-82 ℃; the thermogravimetric analysis (TGA) curve of the solvate of ibrutinib shows that the weight loss is 18.0-18.9% at 50-150 ℃; the weight loss is 68.0-68.9% at 300-500 ℃.
The solvate of ibrutinib is characterized in that a Fourier infrared spectrum (FT-IR) spectrum of the solvate of ibrutinib shows that the wave number of characteristic peak positions is 3409cm-1、3115cm-1、1721cm-1、1637cm-1、1613cm-1、1519cm-1、1242cm-1、11367cm-1And 1069cm-1To (3).
The preparation method of the ibrutinib solvate is characterized by adopting a crystal slurry method or a cooling crystallization method.
The preparation method of the ibrutinib solvate is characterized in that a crystal slurry method is adopted and comprises the following steps:
1) mixing an ibrutinib raw material with an isopropyl acetate solvent to obtain a suspension;
2) stirring the suspension obtained in the step 1) at a constant temperature, filtering, collecting solids, and drying to obtain the isopropyl ibrutinib acetate mono-solvate.
The preparation method of the ibrutinib solvate is characterized in that the ibrutinib raw material in the step 1) is a crystal form C; in the suspension, the material-to-liquid ratio of the ibrutinib raw material to the isopropyl acetate solvent is preferably 10-200 mg:1mL, and preferably 50-100 mg:1 mL;
the constant temperature condition in the step 2) is 0-50 ℃, and preferably 20-30 ℃; the stirring speed is 100-1500 rpm, preferably 500-1000 rpm; the stirring time is 1 to 24 hours, preferably 5 to 12 hours.
The preparation method of the ibrutinib solvate is characterized in that the cooling crystallization method comprises the following steps:
1) dissolving an ibrutinib raw material in an isopropyl acetate solvent under the condition of heating and stirring to obtain a solution;
2) filtering the solution obtained in the step 1) while the solution is hot, and placing the filtrate in a low-temperature environment for cooling crystallization, filtration and drying to obtain the isopropyl ibrutinib acetate mono-solvate.
The preparation method of the ibrutinib solvate is characterized in that the ibrutinib raw materials in the step 1) are a crystal form A, a crystal form B, a crystal form C and an amorphous form; the heating temperature is 50-89 ℃, and the optimal temperature is 70-89 ℃;
the low-temperature environment in the step 2) is-40-25 ℃; preferably-20 to 5 ℃.
By adopting the technology, the ibrutinib solvate obtained by the invention is used as a new crystal form of ibrutinib, and has the following remarkable beneficial effects compared with the known crystal form of ibrutinib and the preparation technology:
1) the ibrutinib solvate is an isopropyl acetate mono-solvate of ibrutinib, and compared with a medicinal crystal form A of ibrutinib, the solubility of the ibrutinib solvate is improved by 2-4 times under different pH conditions; according to the solvent grading standard, isopropyl acetate belongs to a third solvent, is safe and low-toxic compared with known solvates of ibrutinib methyl isobutyl ketone, toluene and methanol, and is more suitable for a raw material crystal form of a preparation, but obtains a new crystal form of ibrutinib without influencing the treatment effect of the ibrutinib, because the isopropyl acetate is used as a targeted anticancer drug, is used as an inhibitor of small-molecule Bruton Tyrosine Kinase (BTK), and is also suitable for treating Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) of B-cell non-Hodgkin lymphoma (NHL);
2) the preparation process of the ibrutinib solvate is simple, the conditions are easy to control, the yield is high, no special requirements are required on equipment, and industrialization is easy to realize;
3) the ibrutinib solvate is stable after being placed for 2 months at room temperature, is placed for 10 days under the conditions of 25 ℃, the illumination intensity of 4500 +/-500 lx and the relative humidity of 90 +/-5 percent and is ground for 10 minutes under the conditions of 25 ℃ and 20Hz, and has no change of crystal forms, so that the ibrutinib solvate has good stability, is suitable for production and storage of medicaments, and has potential for developing into medicinal preparations.
Drawings
FIG. 1 is a PXRD pattern of an ibrutinib solvate according to the present invention;
FIG. 2 is a DSC curve of an ibrutinib solvate according to the invention;
FIG. 3 is a TGA profile of an ibrutinib solvate according to the invention;
FIG. 4 is an FT-IR spectrum of an ibrutinib solvate according to the invention;
FIG. 5 shows PXRD patterns for stability comparison of isopropyl ibrutinib acetate mono-solvate according to the present invention (a is an original pattern of isopropyl ibrutinib acetate mono-solvate, b is a pattern of isopropyl ibrutinib acetate mono-solvate after being placed under the condition of 25 ℃ and 4500 + -500 lx illumination intensity for 10 days, c is a pattern of isopropyl ibrutinib acetate mono-solvate after being placed under the condition of 25 ℃ and 90 + -5% relative humidity for 10 days, and d is a pattern of isopropyl ibrutinib acetate mono-solvate after being ground under the condition of 25 ℃ and 20Hz for 10 minutes).
Detailed Description
The present invention will be further described with reference to the following examples, which will enable those skilled in the art to more fully understand the present invention, but which are not intended to limit the scope of the present invention in any way.
The invention relates to an instrument and a method for collecting data, which comprises the following steps:
the instrument used for X-ray powder diffraction pattern was a Bruker D42 Advance diffractometer. The sample is tested under the condition of room temperature, and the detection conditions are as follows: the 2 theta angle ranges from 3 degrees to 40 degrees; step length is 0.02 degree/step; the speed is 0.2 s/step.
Differential scanning calorimetry data was collected from TA DSC 250. The detection process comprises the following steps: taking 1-10 mg of sample, taking 30 ℃ as equilibrium temperature, and heating the sample from 30 ℃ to 200 ℃ at a heating rate of 10 ℃/min under the protection of 200mL/min dry nitrogen atmosphere.
Thermogravimetric analysis data was collected from TGA Q500. The detection process comprises the following steps: taking 5-10 mg of sample, and heating the sample from 30 ℃ to 500 ℃ at a heating rate of 20 ℃/min under the protection of 40mL/min dry nitrogen atmosphere.
The infrared spectrum was obtained from the Burker Tensor 27 FT-IR. The test method comprises the following steps: and preparing a sample tablet and a KBr blank tablet, and detecting to obtain an infrared spectrogram.
The solubility data is from a UV-2550 UV spectrophotometer at a detection wavelength of 260nm at which the isopropyl acetate solvent contained in the solvate does not interfere with the detection.
Example 1
Weighing 1000mg of ibrutinib crystal form C raw material, adding the raw material into a 20mL penicillin bottle, weighing 10mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, stirring at 10 ℃ and a rotation speed of 1000 rpm for 12 hours, filtering, and placing a filter cake at room temperature for air drying for 24 hours to obtain an ibrutinib isopropyl acetate mono-solvate 1121mg with a yield of 91%. The complete crystallization of the raw material can be judged to be an ibrutinib solvate through powder X-ray diffraction analysis, the obtained solvate can be judged to be an isopropyl acetate single solvate through TGA analysis, the obtained isopropyl acetate single solvate of ibrutinib has an X-ray powder diffraction pattern shown in figure 1, the DSC curve is shown in figure 2, the TGA curve is shown in figure 3, and the FT-IR spectrum is shown in figure 4.
Example 2
Weighing 500mg of ibrutinib crystal form C raw material, adding the raw material into a 20mL penicillin bottle, weighing 10mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, stirring for 5 hours at 25 ℃ at a rotating speed of 1000 rpm, filtering, and placing a filter cake at room temperature for vacuum drying for 2 hours to obtain 524mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 85%.
Example 3
Weighing 1000mg of ibrutinib crystal form C raw material, adding the raw material into a 20mL penicillin bottle, weighing 15mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, stirring at the temperature of 30 ℃ and the rotating speed of 500 r/min for 10 hours, filtering, and placing a filter cake in a room-temperature environment for vacuum drying for 2 hours to obtain 1059mg of ibrutinib isopropyl acetate mono-solvate with the yield of 86%.
Example 4
Weighing 1000mg of ibrutinib crystal form C raw material, adding the raw material into a 20mL penicillin bottle, weighing 7mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, stirring at the temperature of 0 ℃ and the rotating speed of 1200 rpm for 24 hours, filtering, and placing a filter cake at room temperature for air drying for 24 hours to obtain an ibrutinib isopropyl acetate mono-solvate 1146mg with the yield of 93%.
Example 5
Weighing 100mg of ibrutinib crystal form A raw material, adding the raw material into a 4mL penicillin bottle, weighing 3mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating to 89 ℃ while stirring, filtering while the solution is hot, and placing the filtrate in an environment with the temperature of-20 ℃ for cooling and crystallizing for 3 days to obtain 100mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 81%.
Example 6
Weighing 100mg of ibrutinib crystal form B raw material, adding the raw material into a 4mL penicillin bottle, weighing 3mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating the mixture to 80 ℃ while stirring, filtering the mixture while the mixture is hot, and placing the filtrate in an environment with the temperature of-30 ℃ for cooling and crystallizing for 5 days to obtain 102mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 83%.
Example 7
Weighing 100mg of ibrutinib crystal form C raw material, adding the raw material into a 4mL penicillin bottle, weighing 4mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating the mixture to 50 ℃ while stirring, filtering the mixture while the mixture is hot, and placing the filtrate in an environment with the temperature of-40 ℃ for cooling and crystallizing for 7 days to obtain 95mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 77%.
Example 8
Weighing 100mg of ibrutinib amorphous raw material, adding the ibrutinib amorphous raw material into a 4mL penicillin bottle, weighing 4mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating the mixture to 80 ℃ while stirring, filtering the mixture while the mixture is hot, and placing the filtrate in an environment with the temperature of 0 ℃ for cooling and crystallizing the filtrate for 3 days to obtain 97mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 79%.
Example 9
Weighing 100mg of ibrutinib crystal form A raw material, adding the raw material into a 4mL penicillin bottle, weighing 2mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating to 89 ℃ while stirring, filtering while the solution is hot, and placing the filtrate in an environment at 0 ℃ for cooling and crystallizing for 7 days to obtain 106mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 86%.
Example 10
Weighing 100mg of ibrutinib crystal form C raw material, adding the raw material into a 20mL penicillin bottle, weighing 1mL isopropyl acetate, adding the isopropyl acetate into the penicillin bottle, heating to 89 ℃ while stirring, filtering while the solution is hot, and placing the filtrate in an environment with the temperature of 25 ℃ for cooling and crystallizing for 7 days to obtain 108mg of ibrutinib isopropyl acetate mono-solvate, wherein the yield is 88%.
Examples 2-10 samples have the same or similar PXRD pattern, DSC curve, TGA curve, and FT-IR pattern as example 1; the samples of examples 2-10 and example 1 are in the same crystal form.
The isopropyl ibrutinib acetate mono-solvate is basically pure and single, and is basically not mixed with other crystal forms or amorphous states. The "crystal form" in the invention is confirmed by an X-ray powder diffraction pattern. It is well known to those skilled in the art that experimental errors therein depend on sample preparation, sample purity, instrument conditions, etc. The 2 θ angles in a PXRD pattern will typically vary slightly from sample to sample and instrument to instrument. The difference of the diffraction peak 2 theta angles may be different by 1 deg., 0.8 deg., 0.5 deg., 0.3 deg., 0.2 deg., 0.1 deg., etc., and the allowable error is usually + -0.2 deg., depending on different samples, different instruments, etc., so the diffraction peak 2 theta angle cannot be used as the unique standard. The relative intensities of the diffraction peaks may vary depending on the amount of sample, sample preparation and other experimental conditions, so the relative intensities of the diffraction peaks cannot be used as the only criterion. Thus, it is considered that any crystalline form having characteristic peaks identical or similar to those of the X-ray powder diffraction pattern of the present invention falls within the scope of the present invention. The 'single crystal form' means that the crystal form is detected to be the single crystal form through X-ray powder diffraction.
Comparative example 1
Solubility experiments and stability experiments were performed on ibrutinib form a and ibrutinib isopropyl acetate mono-solvate.
1. Room temperature solubility test: 25mg of each of the isopropyl acetate mono-solvate of ibrutinib and the crystal form A of ibrutinib are respectively placed in 20mL penicillin bottles, 15mL of 0.05M phosphate buffer solution with the pH values of 2.0, 2.5, 3.5, 4.5, 5.5, 6.8 and 8.0 is respectively added, the mixture is stirred for 24 hours at the temperature of 25 ℃ and the rotation speed of 400 rpm/min, the mixture is filtered, the filtrate is detected by an ultraviolet spectrophotometer, and the result is shown in Table 1.
Table 1 solubility of isopropyl ibrutinib acetate mono-solvate and form a
The results shown in table 1 show that the solubility of the isopropyl ibrutinib acetate mono-solvate in phosphoric acid buffer solutions with different pH values is improved by 2-4 times compared with that of the crystal form A.
2. Stability test: the isopropyl ibrutinib acetate mono-solvate is uniformly distributed in an open culture dish, the thickness of a sample is less than 5mm, the sample is respectively placed at 25 ℃, the illumination intensity is 4500 +/-500 lx and the relative humidity is 90 +/-5%, samples are taken on the 0 th day, the 5 th day and the 10 th day for PXRD detection, and the results are shown in table 2 and figure 5, and the crystal form of the isopropyl ibrutinib acetate mono-solvate is not changed.
Grinding stability test: 100mg of each of the isopropyl acetate mono-solvate of ibrutinib and the crystal form A of ibrutinib are respectively put into a ball mill, ground for 10 minutes at 25 ℃ and 20Hz, subjected to PXRD detection, and compared with the detection before grinding, and the results are shown in Table 2 and figure 5.
Table 2 crystal form stability experiment of isopropyl ibrutinib acetate mono-solvate
From the results shown in table 2 and fig. 5, it can be seen that the crystal form of isopropyl ibrutinib acetate mono-solvate obtained by the present invention is not changed under different conditions.
Claims (7)
1. A preparation method of an ibrutinib solvate, namely an isopropyl acetate mono-solvate of ibrutinib, has a structural formula shown in a formula (I):
the mass ratio of the ibrutinib to the isopropyl acetate is 1:1, and the preparation method is characterized by being prepared by adopting a crystal slurry method or a cooling crystallization method;
the crystal slurry method comprises the following steps:
1) mixing an ibrutinib raw material with an isopropyl acetate solvent to obtain a suspension, wherein the ibrutinib raw material is a crystal form C; in the suspension, the material-to-liquid ratio of the ibrutinib raw material to the isopropyl acetate solvent is preferably 10-200 mg:1 mL;
2) stirring the suspension obtained in the step 1) at a constant temperature, filtering, collecting solids, and drying to obtain an ibrutinib isopropyl acetate mono-solvate, wherein the constant temperature is 0-30 ℃; the stirring speed is 100-1500 rpm; stirring for 1-24 hours;
the cooling crystallization method comprises the following steps:
a) dissolving an ibrutinib raw material in an isopropyl acetate solvent under the condition of heating and stirring to obtain a solution, wherein the ibrutinib raw material is a crystal form A, a crystal form B, a crystal form C and an amorphous form; the heating temperature is 50-89 ℃;
b) filtering the solution obtained in the step a) while the solution is hot, and placing the filtrate in a low-temperature environment for cooling crystallization, filtration and drying to obtain the isopropyl ibrutinib acetate mono-solvate, wherein the low-temperature environment is-40-25 ℃.
2. The preparation method of the solvate of ibrutinib according to claim 1, characterized in that in the suspension in step 1), the ratio of the raw material of ibrutinib to the solvent of isopropyl acetate is 50-100 mg:1 mL;
the constant temperature condition in the step 2) is 10-25 ℃; the stirring speed is 500-1000 rpm; the stirring time is 5-12 hours.
3. The process for the preparation of the solvate of ibrutinib according to claim 1, characterized in that the heating temperature in step a) is 70-89 ℃; the low-temperature environment in the step b) is-20-5 ℃.
4. The process for preparing a solvate of ibrutinib according to claim 1, characterized in that the solvate of ibrutinib exhibits characteristic peaks at 7.44 ° ± 0.2 °, 7.91 ° ± 0.2 °, 9.05 ° ± 0.2 °, 10.32 ° ± 0.2 °, 14.39 ° ± 0.2 °, 14.69 ° ± 0.2 °, 15.73 ° ± 0.2 °, 18.27 ° ± 0.2 °, 18.97 ° ± 0.2 °, 20.64 ° ± 0.2 °, 21.34 ° ± 0.2 °, 21.97 ° ± 0.2 °, 22.71 ° ± 0.2 °, 25.05 ° ± 0.2 °, 27.05 ° ± 0.2 °, 27.72 ° ± 0.2 ° in an X-ray powder diffraction pattern with a diffraction angle of 2 θ.
5. The process for the preparation of a solvate of ibrutinib according to claim 1 characterized in that the X-ray powder diffraction pattern expressed in terms of 2 Θ angles shows characteristic peaks and relative intensities at the following positions:
6. the preparation method of the solvate of ibrutinib according to claim 1, characterized in that the differential scanning calorimetry curve of the solvate of ibrutinib shows characteristic endothermic peaks at 73-77 ℃ and 155-159 ℃ and characteristic exothermic peaks at 77-82 ℃ respectively; the thermogravimetric analysis curve of the solvate of ibrutinib shows that the weight loss is 18.0-18.9% at 50-150 ℃; the weight loss is 68.0-68.9% at 300-500 ℃.
7. The process for preparing the solvate of ibrutinib according to claim 1, wherein the Fourier transform infrared spectroscopy of the solvate of ibrutinib shows characteristic peak positions at a wave number of 3409cm-1、3115cm-1、1721cm-1、1637cm-1、1613cm-1、1519cm-1、1242cm-1、11367cm-1And 1069cm-1To (3).
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