CN108727387B - Ibrutinib isopropyl acetate solvent compound and preparation method thereof - Google Patents
Ibrutinib isopropyl acetate solvent compound and preparation method thereof Download PDFInfo
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- CN108727387B CN108727387B CN201810822751.XA CN201810822751A CN108727387B CN 108727387 B CN108727387 B CN 108727387B CN 201810822751 A CN201810822751 A CN 201810822751A CN 108727387 B CN108727387 B CN 108727387B
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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 relates to an ibrutinib isopropyl acetate solvent compound and a preparation method thereof, and the compound is characterized in that characteristic peaks are shown at 7.3 +/-0.2 degrees, 7.7 +/-0.2 degrees, 8.9 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.6 +/-0.2 degrees, 15.6 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.9 +/-0.2 degrees, 27.0 +/-0.2 degrees and 27.6 +/-0.2 degrees by X-ray powder diffraction 2 theta. The bulk density of the product is 0.6584g/mL, the angle of repose is 26 degrees, the preparation method is simple, the product can be prepared by ultrasonic-assisted constant-temperature suspension crystal transformation and can also be prepared by cooling crystallization, and the obtained product has high crystallinity, complete block crystal habit, good fluidity, high bulk density and difficult agglomeration.
Description
Technical Field
The invention belongs to the technical field of medical crystallization, and particularly relates to an ibrutinib isopropyl acetate solvent compound and a preparation method thereof.
Background
Ibrutinib (Ibrutinib) is produced by the American biopharmaceuticals Inc (pharmacy Inc) and Johnson (Johnson)&Johnson) was jointly developed and was first approved by the Food and Drug Administration (FDA) of 13 japanese america in 2013 as a drug for the treatment of mantle cell lymphoma. The compound is a small molecular Bruton's Tyrosine Kinase (BTK) inhibitor, and can be covalently combined with cysteine residue of BTK active center to inhibit proliferation and survival of B cells. The chemical name of the compound is 1- [ (3R) -3- [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3,4-D]Pyrimidin-1-yl]-1-piperidinyl group]-2-propen-1-one of formula C25H24N6O2The chemical structural formula is as follows:
polymorphism refers to the presence of different molecular arrangements or conformations of the same substance in its crystal lattice, resulting in different crystal structures being formed. In the field of pharmaceutical research, the broad polymorphic forms include multicomponent crystalline forms such as solvent compounds, hydrates, and the like. Different crystal forms of the same drug have obvious differences in the aspects of color, solubility, melting point, dissolution rate, fluidity, bioavailability and the like, so that the stability, bioavailability and curative effect of the drug are influenced. Therefore, the problem of polymorphism should be thoroughly studied during the drug development process.
The irutinib has various solvent compounds and non-compound solid forms, a world patent WO 2013184572A 1 applied by original U.S. biopharmaceutical company (Pharmacyclics Inc) protects crystal forms and three solvent compounds of an irutinib non-solvent compound, wherein the crystal form A, the crystal form B and the crystal form C are crystal forms of the non-solvent compound, the crystal form D, the crystal form E and the crystal form F are a methyl isobutyl ketone solvent compound, a toluene solvent compound and a methanol solvent compound respectively, and the patent WO 2015081180A 1 protects another crystal form I of the irutinib non-solvent compound, wherein the national patent CN 103923084A protects the crystal form II, the hydrate crystal form III, the tetrahydrofuran solvent compound and the trichloromethane solvent compound of the irutinib non-solvent compound. The world patent WO 2015145415 a2 filed by PERRIGO API LTD, italy, protects an ibrutinib non-solvent compound, i.e. form VI, and six solvent compounds, i.e. 1, 4-dioxane solvent compound, form III, ethylene glycol dimethyl ether solvent compound, form IV, methanol solvent compound, form V, anisole solvent compound, form VII, chlorobenzene solvate, form VIII and anisole solvent compound, form IX. The crystal form of the currently marketed ibrutinib raw material product is consistent with the crystal form A reported in the original research, the product has small particle size, no regular shape, poor fluidity, low bulk density, easy agglomeration and difficult post-processing treatment such as filtration, refining and the like. In addition, the preparation method of the crystal form A disclosed in the patent is complex in operation, long in time consumption and not beneficial to industrial production. In the crystal forms of various ibrutinib solvent compounds reported in the prior patent, solvents used in the preparation process belong to a first type of solvent and a second type of solvent, have certain toxicity and are not suitable for being used as medicinal crystal forms.
Disclosure of Invention
In order to overcome the defects of the prior art and solve the problems of poor flowability and easy agglomeration of the current commercial product, the influence of different crystallization modes, ultrasonic assistance, single solvent and mixed solvent, different temperatures and stirring conditions on the crystal form of the final product is inspected by a high-throughput crystal form sample screening means, and a simple, controllable, safe and low-toxicity process technical route is developed by combining various analysis and test methods such as powder diffraction, single crystal diffraction, thermal weight loss analysis, differential scanning calorimetry analysis and the like, so that new crystal forms and solvent compounds with excellent performance are prepared and discovered, and the subsequent drug development is facilitated.
The invention provides an ibrutinib solvent compound with block crystal habit and difficult agglomeration and a preparation method thereof.
The Ibrutinib isopropyl acetate solvent compound is characterized in that an X-ray powder diffraction pattern obtained by Cu-Kalpha ray measurement is shown in figure 1, and characteristic peaks are shown at 7.3 +/-0.2 degrees, 7.7 +/-0.2 degrees, 8.9 +/-0.2 degrees, 10.2 +/-0.2 degrees, 14.6 +/-0.2 degrees, 15.6 +/-0.2 degrees, 17.1 +/-0.2 degrees, 18.2 +/-0.2 degrees, 18.9 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.2 +/-0.2 degrees, 21.8 +/-0.2 degrees, 22.6 +/-0.2 degrees, 24.9 +/-0.2 degrees, 27.0 +/-0.2 degrees and 27.6 +/-0.2 degrees by the diffraction angle 2 theta, wherein the relative intensity of the characteristic peaks at 18.9 +/-0.2 degrees is 100 percent.
The crystal form of the ibrutinib isopropyl acetate solvent compound provided by the invention is a triclinic crystal system, the space group is P1, and the unit cell parameter is
α is 81.21(3) °, β is 69.22(3) °, γ is 69.88(3) °, and the unit cell volume is
The Ibrutinib isopropyl acetate solvent compound provided by the invention has the molar ratio of Ibrutinib to isopropyl acetate solvent molecules of 1:1, the theoretical weight loss of 18.8%, and the molecular formula of C25H24N6O2·C5H10O2In thermogravimetric analysis, 16.9-18.2% of weight loss exists before the temperature is 200 ℃, and the actual weight loss is identical with the theoretical weight loss. The specific weight loss depends on the drying temperature and drying time.
The preparation method of the ibrutinib isopropyl acetate solvent compound provided by the invention is realized by ultrasonic-assisted constant-temperature suspension crystal transformation: adding an ibrutinib raw material into an isopropyl acetate solvent at 25-40 ℃, wherein the mass ratio of the ibrutinib solid raw material to the isopropyl acetate solvent is 1: 50-60, carrying out ultrasonic treatment for 20-30 min, then stirring for 20-24 h, filtering, and drying to obtain an ibrutinib isopropyl acetate solvent compound.
The ultrasonic frequency is 20-40 KHz, and the ultrasonic power is 100-300W/mL.
The drying condition is that the drying is carried out for 7-10 hours at the temperature of 20-30 ℃ and under the normal pressure condition.
The preparation method of the ibrutinib isopropyl acetate solvent compound provided by the invention changes the arrangement mode and conformation of internal molecules of the crystal under the combined action of an external ultrasonic field and constant-temperature suspension crystal transformation, and a local high-temperature, high-pressure and high-shear state is formed by utilizing the cavitation effect generated by ultrasonic, so that the nucleation and growth of the ibrutinib isopropyl acetate solvent compound are promoted. Under the conventional constant-temperature suspension crystal transformation experimental conditions, the isopropyl ibrutinib acetate solvent compound cannot be successfully prepared. Comparative experiments show that the addition of an external ultrasonic field is necessary for the preparation of the new crystal form.
The ibrutinib isopropyl acetate solvent compound provided by the invention can also be prepared by a cooling crystallization method, and is prepared by dissolving an ibrutinib solid raw material in an isopropyl acetate solvent at 40-50 ℃, wherein the mass ratio of the ibrutinib raw material to isopropyl acetate is 1: 70-90, cooling to-10 ℃ at a cooling rate of 1-5 ℃/min, precipitating crystals, filtering to obtain a white solid, and drying at 25-30 ℃ for 5-10 h under normal pressure to obtain the ibrutinib isopropyl acetate solvent compound.
Compared with other preparation processes, the preparation method of the ibrutinib isopropyl acetate solvent compound by ultrasonic-assisted constant-temperature suspension crystal transformation and cooling crystallization has mild conditions and is easy to prepare; the selected solvent is three solvents, namely isopropyl acetate, and the toxicity is low.
The crystal habit of the ibrutinib isopropyl acetate solvent compound product is inspected, the obtained product is blocky, the crystal habit is complete, the surface of a crystal is smooth and clean, the agglomeration phenomenon is avoided, a scanning electron microscope image of the crystal form is shown in figure 2, the bulk density of the crystal form product is 0.6584g/mL, and the angle of repose is 26 degrees. The bulk density of the commercial product is 0.5248g/mL, the angle of repose is 37 degrees, and the scanning electron micrograph thereof is shown in figure 3. Compared with the commercial product, the crystal product provided by the invention has the advantage that the bulk density and the flowability of the product are improved to a certain extent.
According to the invention, the stability of the isopropyl acetate solvent compound of ibrutinib is inspected, the isopropyl acetate solvent compound product is uniformly distributed in an open culture dish, the temperature is controlled at 25 ℃, the humidity is 50%, the thickness of the sample is less than 5mm, the isopropyl acetate solvent compound product is hermetically placed in a dryer for 30 days, then XRD detection is respectively carried out on the samples placed for 7 days, 14 days and 30 days, and the detection result is compared with the detection result of the day 0. The specific spectrum is shown in figure 4, and the result shows that the XRD spectrum is not obviously changed, which proves that the stability of the isopropyl acetate ibrutinib solvate compound is better.
Drawings
FIG. 1 is an X-ray diffraction pattern of an isopropyl ibrutinib acetate solvent compound of the present invention.
FIG. 2 is a scanning electron micrograph of isopropyl ibrutinib acetate solvate of the present invention.
FIG. 3 scanning electron micrograph of commercially available ibrutinib product.
FIG. 4 is a comparison of stability test patterns of isopropyl acetate solvate of ibrutinib, wherein the XRD patterns of samples placed for 0 day, 7 days, 14 days and 30 days are from bottom to top.
Figure 5 thermogravimetric analysis of the isopropyl ibrutinib acetate solvate prepared in example 1.
Figure 6 thermogravimetric analysis of the isopropyl ibrutinib acetate solvate prepared in example 4.
Figure 7 thermogravimetric analysis of the isopropyl ibrutinib acetate solvate prepared in example 6.
Detailed Description
The foregoing and other objects of the present invention will be more fully understood from the following detailed description of the embodiments, taken in conjunction with the accompanying drawings, which are included to illustrate, but are not to be construed as the limit of the invention. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 1
Putting 0.08g of ibrutinib raw material into a 4mL sample bottle, adding 4g of isopropyl acetate, starting an ultrasonic instrument, adjusting the ultrasonic frequency to be 20KHz, the ultrasonic power to be 100W/mL solution, carrying out ultrasonic treatment for 20min to enable the solution to be dissolved and in a supersaturated state, stirring for 24h at 25 ℃, filtering the suspension to obtain a white solid, and drying for 7h at 30 ℃ under normal pressure to obtain the product. The X-ray powder diffraction pattern of the product is expressed by 2 theta, characteristic peaks exist at 7.3 degrees, 7.7 degrees, 8.9 degrees, 10.2 degrees, 14.6 degrees, 15.6 degrees, 17.1 degrees, 18.2 degrees, 18.9 degrees, 20.5 degrees, 21.2 degrees, 21.8 degrees, 22.6 degrees, 24.9 degrees, 27.0 degrees and 27.6 degrees, TGA thermogravimetric analysis is carried out on the product, a Switzerland Mullerley TG A/DSC 1 type thermogravimetric analyzer is adopted, the atmosphere is nitrogen, the temperature rising rate is 10 ℃/min, the analysis result is shown in figure 5, an obvious desolvation peak is existed, the desolvation loss weight ratio is 16.95 percent, the product is blocky, and similar to figure 2, the bulk density is 0.6578g/ml, and the angle of repose is 26.5 degrees.
Example 2
Putting 0.24g of ibrutinib raw material into a 20mL sample bottle, adding 14.4g of isopropyl acetate, starting an ultrasonic instrument, adjusting the ultrasonic frequency to be 30KHz, the ultrasonic power to be 200W/mL, carrying out ultrasonic treatment for 25min to enable the raw material to be dissolved and in a supersaturated state, stirring for 20h at 40 ℃, filtering the suspension to obtain a white solid, and drying for 8h at 25 ℃ under normal pressure to obtain the product. The X-ray powder diffraction pattern of the product is expressed by 2 theta, characteristic peaks are arranged at 7.3 degrees, 7.6 degrees, 8.8 degrees, 10.1 degrees, 14.5 degrees, 15.5 degrees, 17.0 degrees, 18.1 degrees, 19.0 degrees, 20.5 degrees, 21.2 degrees, 21.8 degrees, 22.5 degrees, 24.8 degrees, 26.9 degrees and 27.6 degrees, TGA thermogravimetric analysis is carried out on the product, the weight loss ratio of the desolventizing agent is 17.12 percent, the product is blocky, and similar to the attached figure 2, the bulk density is 0.6579g/ml, and the angle of repose is 26.5 degrees.
Example 3
And (4) amplifying the experiment. Weighing 0.50g of ibrutinib raw material into a 100mL crystallizer, adding 28g of isopropyl acetate, starting an ultrasonic instrument, adjusting the ultrasonic frequency to be 40KHz, the ultrasonic power to be 300W/mL, and performing ultrasonic treatment for 30min to enable the ibrutinib raw material to be dissolved and in a supersaturated state, controlling the stirring speed to be 250rpm by using mechanical stirring, stirring for 22h at the temperature of 30 ℃, filtering, and drying for 10h at the temperature of 20 ℃ under normal pressure to obtain the product. The X-ray powder diffraction pattern of the product is expressed by 2 theta, characteristic peaks are arranged at 7.3 degrees, 7.7 degrees, 8.9 degrees, 10.2 degrees, 14.4 degrees, 15.6 degrees, 17.2 degrees, 18.2 degrees, 18.8 degrees, 20.5 degrees, 21.2 degrees, 21.7 degrees, 22.6 degrees, 24.9 degrees, 26.9 degrees and 27.6 degrees, TGA thermogravimetric analysis is carried out on the product, the weight loss ratio of the desolventizing agent is 17.36 percent, the product is blocky, and similar to the attached figure 2, the bulk density is 0.6581g/ml, and the angle of repose is 26 degrees.
Example 4
Weighing 0.3g of ibrutinib raw material, adding the raw material into 21g of isopropyl acetate, stirring at 40 ℃ until the mixture is clear, cooling to 10 ℃ at a cooling rate of 1 ℃/min, filtering, drying at 30 ℃ under normal pressure for 8 hours, wherein the X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 7.3 degrees, 7.8 degrees, 8.9 degrees, 10.2 degrees, 14.5 degrees, 15.5 degrees, 17.2 degrees, 18.0 degrees, 18.7 degrees, 20.4 degrees, 21.2 degrees, 21.9 degrees, 22.8 degrees, 24.9 degrees, 26.9 degrees and 27.5 degrees, and the TGA thermogravimetric analysis is carried out on the product, wherein the analysis result is shown in figure 6, the obvious desolvation peak is formed, the desolvation weight loss ratio is 18.15 percent, the product is blocky and is similar to figure 2, the bulk density is 0.6580g/ml, and the angle of repose.
Example 5
Weighing 0.5g of ibrutinib raw material, adding the raw material into 40g of isopropyl acetate, stirring at 45 ℃ until the mixture is clear, cooling to 5 ℃ at a cooling rate of 5 ℃/min, filtering, drying at 28 ℃ under normal pressure for 10 hours, wherein the X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 7.3 degrees, 7.7 degrees, 8.9 degrees, 10.2 degrees, 14.5 degrees, 15.8 degrees, 17.2 degrees, 18.2 degrees, 18.9 degrees, 20.6 degrees, 21.4 degrees, 21.8 degrees, 22.6 degrees, 24.8 degrees, 27.0 degrees and 27.6 degrees, performing TGA thermogravimetric analysis on the product, wherein the weight loss ratio of a desolventizing agent is 18.20 percent, the product is blocky, and is similar to the attached figure 2, the bulk density is 0.6582g/ml, and the angle of repose is 26.
Example 6
Weighing 0.8g of ibrutinib raw material, adding the raw material into 72g of isopropyl acetate, stirring at 45 ℃ until the mixture is clear, cooling to 10 ℃ at a cooling rate of 1 ℃/min, filtering, drying at 25 ℃ under normal pressure for 5 hours, wherein an X-ray powder diffraction pattern of a product is expressed by 2 theta, and has characteristic peaks at 7.3 degrees, 7.7 degrees, 8.7 degrees, 10.2 degrees, 14.6 degrees, 15.6 degrees, 17.1 degrees, 18.2 degrees, 18.9 degrees, 20.5 degrees, 21.2 degrees, 21.9 degrees, 22.6 degrees, 24.9 degrees, 26.9 degrees and 27.7 degrees, and performing TGA thermogravimetric analysis on the product, wherein an analysis result is shown in a figure 7, an obvious desolvation peak is formed, the desolvation loss-weight ratio is 17.74 percent, the product is blocky and is similar to figure 2, the bulk density is 0.6582g/ml, and the angle of repose is 25..
Example 7
Weighing 1g of ibrutinib raw material, adding the raw material into 85g of isopropyl acetate, stirring at 50 ℃ until the mixture is clear, cooling to-10 ℃ at a cooling rate of 2 ℃/min, filtering, drying at 25 ℃ under normal pressure for 7h, wherein the X-ray powder diffraction pattern of the product is expressed by 2 theta, and has characteristic peaks at 7.3 degrees, 7.7 degrees, 8.8 degrees, 10.2 degrees, 14.6 degrees, 15.6 degrees, 17.1 degrees, 18.3 degrees, 18.9 degrees, 20.5 degrees, 21.3 degrees, 21.8 degrees, 22.6 degrees, 24.8 degrees, 26.9 degrees and 27.7 degrees, performing TGA thermogravimetric analysis on the product, wherein the weight loss ratio of a desolventizing agent is 17.84 percent, the product is blocky, is similar to the attached figure 2, the bulk density is 0.6584g/ml, and the angle of repose is 26 degrees.
Claims (4)
1. An isopropyl acetate solvate of ibrutinib, characterized in that the diffraction angle of the X-ray powder diffraction pattern measured by Cu-K α ray expressed as 2 θ angle has characteristic peaks at 7.3 ± 0.2 °, 7.7 ± 0.2 °, 8.9 ± 0.2 °, 10.2 ± 0.2 °, 14.6 ± 0.2 °, 15.6 ± 0.2 °, 17.1 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ± 0.2 °, 20.5 ± 0.2 °, 21.2 ± 0.2 °, 21.8 ± 0.2 °, 22.6 ± 0.2 °, 24.9 ± 0.2 °, 27.0 ± 0.2 °, and 27.6 ± 0.2 °, wherein the relative intensity of the characteristic peak at 18.9 ± 0.2 ° is 100%; the crystal form is a triclinic crystal system, the space group is P1, and the unit cell parameter is
α is 81.21(3) °, β is 69.22(3) °, γ is 69.88(3) °, and the unit cell volume is
2. The isopropyl ibrutinib acetate solvate according to claim 1, wherein the molar ratio of ibrutinib to isopropyl acetate solvate molecules is 1:1, the molecular formula is C25H24N6O 2-C5H 10O2, and the weight loss is 16.9-18.2% before 200 ℃ in thermogravimetric analysis.
3. The preparation method of isopropyl ibrutinib acetate solvate according to claim 2, characterized in that the preparation is carried out by ultrasound-assisted isothermal suspension crystallization: adding an ibrutinib raw material into an isopropyl acetate solvent with a constant temperature of 25-40 ℃, wherein the mass ratio of the ibrutinib raw material to the isopropyl acetate is 1: 50-60, the ultrasonic frequency of ultrasonic-assisted constant-temperature suspension crystal transformation is 20-40 KHz, the ultrasonic power is 100-300W/mL, the ultrasonic time is 20-30 min, stirring is carried out for 20-24 h after ultrasonic treatment, filtering is carried out, and drying is carried out at the temperature of 20-30 ℃ for 7-10 h under normal pressure to obtain the ibrutinib isopropyl acetate solvent compound.
4. The process for the preparation of isopropyl ibrutinib acetate solvate according to claim 2, characterized by the fact that it is prepared by cooling crystallization: dissolving an ibrutinib raw material in an isopropyl acetate solvent at 40-50 ℃, wherein the mass ratio of the ibrutinib raw material to the isopropyl acetate is 1: 70-90, cooling to-10 ℃ at a cooling rate of 1-5 ℃/min, precipitating crystals, filtering to obtain a white solid, and drying at 25-30 ℃ for 5-10 h under normal pressure to obtain the isopropyl acetate solvent compound of ibrutinib.
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| CN105820138A (en) * | 2009-09-20 | 2016-08-03 | Abbvie 公司 | ABT-263 crystalline forms and solvates for use in treating BCL-2 protein related diseases |
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