CN111138436A - Ibutotinib crystal form A single crystal and preparation method thereof - Google Patents
Ibutotinib crystal form A single crystal and preparation method thereof Download PDFInfo
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- CN111138436A CN111138436A CN201811306793.4A CN201811306793A CN111138436A CN 111138436 A CN111138436 A CN 111138436A CN 201811306793 A CN201811306793 A CN 201811306793A CN 111138436 A CN111138436 A CN 111138436A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to the technical field of chemical drug preparation, and particularly discloses an ibrutinib crystal form A single crystal and a preparation method thereof. The technical scheme of the invention can be used for culturing more ibrutinib crystal form A single crystals with good shapes, and has the advantages of simple process, short single crystal culture time, stable crystal form, easy selection and difficult melting in selection at room temperature.
Description
Technical Field
The invention belongs to the technical field of chemical drug preparation, relates to a crystalline form A of ibrutinib, and particularly relates to an ibrutinib crystalline form A single crystal and a preparation method thereof.
Background
Ibrutinib or Ibrutinib (Ibrutinib) is jointly developed by pharmacy and qiangsheng company, is approved to be on the market by the U.S. food and drug administration at 11 months in 2013 with the trade name of Imbruvica and the common 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 may come from chronic lymphocytic leukemia indication (CLL), which is also currently awaiting FDA approval. The structural formula is as follows:
polymorphism is well known to occur widely in medicine. Different crystal forms of the same drug have obvious differences in the 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.
The crystal form research and solid characterization of the drug are significant in the pharmaceutical industry, because the difference of the three-dimensional structure of a plurality of complex and ordered aggregates formed by weak interaction of drug molecules leads to the change of the physicochemical properties of the drug. Different crystal forms of the same drug often have different biochemical properties, and have significant differences in the aspects of stability, solubility and the like. In addition, the crystal form of the medicine has great influence on the absorption and the transportation of the medicine, so that the bioavailability of the medicine is changed, and the curative effect is greatly influenced.
The crystal form and lattice structure of the medicine are not only related to the chemical structure of the medicine molecule, but also closely related to the solvent type, solution concentration, cooling, evaporation rate, drying method and other factors used in the preparation of the crystal. The research on the drug polymorphism plays an extremely important role in ensuring the stability in the drug production and storage process and the safety and effectiveness in clinical use, and in addition, the crystal form of the drug plays a key role in the design of the dosage form.
The ibrutinib belongs to a polymorphic compound, and a plurality of crystal forms have been reported at home and abroad at present. CN201510952168.7 discloses a method for preparing an amorphous ibrutinib. WO2013184572a1 discloses crystalline forms a, B, C of the anhydrate 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 crystalline forms D, E, F of the solvate. Only form a of the above forms is suitable for pharmaceutical formulations. CN201510980745.3 also discloses a preparation method and spectrum data of the crystal form A. Another form a (hereinafter referred to as form a') is disclosed in suzhou crystal clouds CN201410542609.1 and CN201610156820.9, and two preparation methods are provided, however, when the methods are repeated in experimental studies, the inventors find that the reproducibility is poor, and the crystal form a disclosed in WO2013/184572 can be obtained by slightly poor control.
CN201410043636.4 discloses a crystalline form of ibrutinib: anhydrous crystal forms II and VIII, hydrate crystal form III, crystal form IV is Tetrahydrofuran (THF) solvate, and crystal forms V, VI and VII are trichloromethane solvate; CN201610347177.8 and CN201610347787.8 are the same.
CN 201310616065.4 discloses a new crystal form A of PCI-32765, and CN201510246220.7 discloses XRPD data and a preparation method of new crystal form A2 and a new crystal form A3 of ibrutinib; CN201510808526.7 discloses a preparation method of ibrutinib crystal forms I and II and a conversion preparation method between the two crystal forms; cn201610497395.x discloses crystalline form III of ibrutinib; 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 WO2017029586a1 also discloses crystal forms of crystal forms S1, S2, S3, S4 and amorphous a 1. Discloses a preparation method thereof, conversion between crystal forms and the like.
From the above, dozens of crystal forms of ibrutinib have been reported in the prior art, but few single crystal structures of ibrutinib have been reported.
The single crystal structure analysis can provide data of the precise spatial positions of all atoms in a compound in a solid state, including the connection form of the atoms, molecular conformation, accurate bond length and bond angle, and the like, thereby providing wide and important information for researches of chemistry, material science, life science and the like. The method of single crystal growth is various, and cooling method, normal temperature volatilization method, diffusion method, solvothermal method, solvent gel method and the like are commonly used, but crystal growth is affected by various factors, such as temperature, solvent, concentration, impurities, pH and the like, which are very important for crystal growth. Therefore, it is difficult to grow the desired single crystal. Some drugs may not be cultured as single crystals according to the refining method, or the cultured single crystals have defects such as cracks, difficulty in picking, and easiness in melting at room temperature.
Disclosure of Invention
The invention aims to provide an ibrutinib crystal form A single crystal and a preparation method thereof, and the inventor prepares the single crystal with stable crystal form A by screening under various conditions, thereby laying a foundation for screening multiple crystal forms in drug research and development. The single crystal structure is stable, and the preparation method has simple and convenient process and is convenient to amplify.
The invention provides an ibrutinib crystal form A single crystal, a molecular structure diagram is shown in figure 1, and a single crystal molecular stacking diagram is shown in figure 2.
The characterization parameters are as follows:
-a monoclinic system;
-lattice parameter:
α＝90°，β＝96.2490(10)°，γ＝90°；
-space group: p21(1)；
The number of molecules in the unit cell: 8;
-unit cell volume:
-density: d is 1.274g/cm3。
The invention also provides a preparation method of the ibrutinib crystal form A single crystal, which comprises the following steps: dissolving the ibrutinib crystal form A in a good solvent, adding a poor solvent after completely dissolving, and filtering and crystallizing to obtain the ibrutinib crystal form A.
Preferably, the mass volume ratio of the ibrutinib to the good solvent is 20: 0.5-20; the volume ratio of the good solvent to the poor solvent is 1: 0.5-15; wherein the mass is in g and the volume is in ml.
Preferably, the good solvent is selected from one or more of acetonitrile, ethyl acetate, butyl acetate, n-butanol, butanone, isopropanol, methanol, acetone and acetone/n-hexane mixed solvent.
More preferably, when the good solvent is a mixed solution of acetone/n-hexane, the volume ratio of acetone to n-hexane is 1: 1.
Preferably, the poor solvent is n-hexane or n-heptane.
Preferably, the method comprises the steps of: adding a good solvent into the ibrutinib crystal form A, heating to 20-50 ℃, dissolving, filtering, dropwise adding a poor solvent into the filtrate, slowly cooling to 0-35 ℃, standing, and crystallizing to obtain the granular stable ibrutinib crystal form A single crystal.
The inventor proves in research that the addition temperature of the poor solvent is controlled to be 30-40 ℃, so that the growth speed of the single crystal can be improved, and the culture time of the single crystal can be shortened.
Further preferably, the method comprises the steps of: adding a good solvent into the ibrutinib crystal form A, heating to 20-50 ℃, dissolving, filtering, dropwise adding a poor solvent with the temperature of 30-40 ℃ into the filtrate, slowly cooling to 0-35 ℃, standing, and crystallizing for 3-8 days to obtain the granular stable ibrutinib crystal form A single crystal.
Still further preferably, the method comprises the steps of: adding a good solvent into the ibrutinib crystal form A, heating to 20-50 ℃, dissolving, filtering, dropwise adding a poor solvent with the temperature of 30-40 ℃ into the filtrate, slowly cooling to 0-10 ℃, standing, and crystallizing for 3-8 days to obtain the granular stable ibrutinib crystal form A single crystal.
It should be noted that the above-mentioned step standing crystallization process, i.e., the process of growing a single crystal, is to prevent vibration so as to grow a single crystal having a good shape.
The raw material used in the invention is the ibrutinib crystal form A, the source of the ibrutinib crystal form A is not limited in the invention, and the ibrutinib crystal form A can be prepared by itself or prepared according to the methods of patents CN104736178A or CN106905320A and the like.
The single crystal sample prepared by the technical scheme of the invention is shown in figure 3, single crystal particles are picked and observed under a microscope, the particles are uniform, and a microscopic picture is shown in figure 4. Detecting the picked single crystal particles by an X-ray single crystal diffractometer under the following detection conditions: a physical xtlab Synergy X-ray powder diffractometer; the light source copper target, the temperature 293K, the voltage 50kv, the current 1mA, the collection method is monoclinic, and the scanning time is 1 min. The results are shown in Table 1.
TABLE 1 Ebritinib Crystal form A Single Crystal diffraction data
The ibrutinib crystal form A single crystal cultured by the method has the advantages of good shape, no crack in the crystal, stable crystal form and easiness in selection, and is not melted when being selected at room temperature; the technical scheme of the invention has simple process and short single crystal culture time, and can culture more single crystals of the Ibtinib crystal form A with good shape.
Drawings
FIG. 1 is a molecular structure diagram of a crystalline form A of ibrutinib;
FIG. 2 is a unit cell stacking diagram of crystalline form A of ibrutinib;
FIG. 3 is a diagram of a sample of ibrutinib form A single crystal;
FIG. 4 is a microscope picture of crystalline form A of ibrutinib;
FIG. 5 is a diagram of a single crystal sample of ibrutinib form A of comparative example 3;
FIG. 6 is a microscope photograph of a single crystal of ibrutinib form A of comparative example 3.
Detailed Description
The present invention is described in detail below by way of some specific examples, it being understood that the following examples are for illustrative purposes only and are not intended to limit the present invention.
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 starting material, crystalline form a of ibrutinib, used in the following examples was obtained by the process for the preparation of crystalline form a in patent WO2013184572A, other reagents being commercially available.
Example 1
Dissolving 20mg of solid of the Ibutotinib crystal form A in 0.5ml of ethyl acetate, heating to 50 ℃, filtering after dissolving, slowly dropwise adding 7.5ml of n-hexane at room temperature into the solution, slowly cooling to 35 ℃, standing and crystallizing for 8 days to obtain the granular stable Ibutotinib crystal form A single crystal, wherein the single crystal has good single crystal property, is easy to pick, has stable crystal form, and is not melted when being picked at normal temperature.
Example 2
Dissolving 20mg of solid of the Ibutotinib crystal form A in 20ml of methanol, controlling the temperature to be 20 ℃, filtering after dissolving, slowly dropwise adding 10ml of n-heptane at room temperature into the solution, slowly cooling to 0 ℃, standing and crystallizing for 5 days to obtain the granular stable single crystal of the Ibutotinib crystal form A, wherein the single crystal has good single crystal property, is easy to pick, has stable crystal form, and is not melted when being picked at room temperature.
Example 3
The preparation method comprises the following steps of adding 20mg of solid of the ibrutinib crystal form A into 10ml of acetonitrile, heating to 30 ℃, dissolving, filtering, slowly dropwise adding 10ml of normal hexane at room temperature into the solution, slowly cooling to 10 ℃, standing, and crystallizing for 6 days to obtain granular stable ibrutinib crystal form A single crystals, wherein the single crystals are good in single crystal property, easy to pick, stable in crystal form and incapable of melting after picking at normal temperature.
Example 4
Dissolving 20mg of solid of the Ibutotinib crystal form A in 5ml of acetone, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 25ml of 30-40 ℃ n-heptane into the solution, slowly cooling to 20 ℃, standing and crystallizing for 4 days to obtain granular stable Ibutotinib crystal form A single crystal, wherein the single crystal has good single crystal property, is easy to pick, has stable crystal form, and is not melted after being picked at normal temperature.
Example 5
Dissolving 20mg of ibrutinib crystal form A solid in 20ml of mixed solution of acetone and n-hexane (the volume ratio of acetone to n-hexane is 1: 1), heating to 30 ℃, filtering after dissolving, slowly dripping 10ml of n-hexane at 30-40 ℃ into the solution, slowly cooling to 10 ℃, standing and crystallizing for 3 days to obtain granular stable ibrutinib crystal form A single crystal, wherein the single crystal has good single crystal properties, is easy to pick, has stable crystal form, and is not melted after being picked at normal temperature.
Example 6
Dissolving 20mg of solid of the Ibutotinib crystal form A in 30ml of isopropanol, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of n-hexane at the temperature of 30-40 ℃ into the solution, cooling to 10 ℃, standing and crystallizing for 7 days to obtain a small amount of Ibutotinib crystal form A single crystal which has good properties, is easy to pick, has a stable crystal form, and is not melted when being picked at normal temperature.
Example 7
Dissolving 20mg of solid of the Ibutotinib crystal form A in 10ml of n-butyl alcohol, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 3ml of 30-40 ℃ n-heptane into the solution, cooling to 0 ℃, standing and crystallizing for 7 days to obtain trace Ibutotinib crystal form A single crystal, wherein the trace Ibutotinib crystal form A single crystal has good properties, is easy to pick, is stable in crystal form, and is not melted when being picked at normal temperature.
Comparative example 1
Dissolving 20mg of solid of the ibrutinib crystal form A in 10ml of ethanol, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of n-hexane at the temperature of 30-40 ℃ into the solution, cooling to 0 ℃, standing for crystallization for 7 days, and clarifying the solution to obtain the ibrutinib crystal form A single crystal.
Comparative example 2
Dissolving 20mg of solid of the ibrutinib crystal form A in 10ml of methanol, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of purified water with the temperature of 30-40 ℃ into the solution, cooling to 0 ℃, standing and crystallizing for 7 days, so that the ibrutinib crystal form A single crystal cannot be obtained.
Comparative example 3
Dissolving 100mg of solid of the Ibutotinib crystal form A in a small bottle containing 3ml of methanol, transferring the solution to a large container with a plug after the solid of the Ibutotinib crystal form A is completely dissolved, adding 30ml of purified water, sealing the bottle opening, standing for 49 days to obtain the particle Ibutotinib crystal form A single crystal with uneven properties, wherein the particle Ibutotinib crystal form A single crystal is not easy to pick and melt at room temperature, and the crystal form particle is uneven when the particle is picked and melted under a microscope as shown in figure 6.
Comparative example 4
Dissolving 20mg of solid of the ibrutinib crystal form A in 10ml of methanol, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of acetone with the temperature of 30-40 ℃ into the solution, cooling to 0 ℃, standing and crystallizing for 7 days, so that the ibrutinib crystal form A single crystal cannot be obtained.
Comparative example 5
Dissolving 20mg of solid of the ibrutinib crystal form A in 10ml of acetone, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of water with the temperature of 30-40 ℃ into the solution, cooling to 0 ℃, standing and crystallizing for 7 days, so that the ibrutinib crystal form A single crystal cannot be obtained.
Comparative example 6
Dissolving 20mg of solid of the ibrutinib crystal form A in 10ml of chloroform, heating to 40 ℃, filtering after dissolving, slowly dropwise adding 20ml of 30-40 ℃ n-heptane into the solution, cooling to 0 ℃, standing and crystallizing for 7 days, so that the ibrutinib crystal form A single crystal cannot be obtained.
Comparative example 7
Dissolving 20mg of solid of the Ibutotinib crystal form A in 30ml of mixed solvent of isopropanol and n-heptane with the volume ratio of 2: 3, heating until the Ibutotinib solid is completely dissolved, cooling to room temperature, standing for crystallization for 7 days, and thus a single crystal of the Ibutotinib crystal form A cannot be obtained.
Comparative example 8
Dissolving 20mg of solid of the Ibutotinib crystal form A in 30ml of mixed solvent of ethyl acetate and n-heptane with the volume ratio of 1: 1, heating until the Ibutotinib solid is completely dissolved, cooling to room temperature, standing for crystallization for 7 days, and thus obtaining the Ibutotinib crystal form A single crystal.
Comparative example 9
Dissolving 20mg of solid of the crystalline form A of the ibrutinib in 30ml of mixed solvent of chloroform and n-heptane with the volume ratio of 1: 1, heating to 50 ℃ until the solid of the ibrutinib is completely dissolved, stopping stirring, standing at 50 ℃ for 1h until the solution is clear, placing the obtained clear solution at-20 ℃, standing and crystallizing for 7 days, and thus obtaining the crystalline form A of the ibrutinib.
Claims (10)
1. An ibutinib crystal form A single crystal is characterized in that a molecular structure diagram is shown in figure 1, and the characteristic parameters are as follows:
-a monoclinic system;
-lattice parameter:
α＝90°，β＝96.2490(10)°，γ＝90°；
-space group: p21(1)；
The number of molecules in the unit cell: 8;
-unit cell volume:
-density: d is 1.274g/cm3。
2. The preparation method of the ibrutinib crystal form A single crystal is characterized by comprising the following steps: dissolving the ibrutinib crystal form A in a good solvent, adding a poor solvent after completely dissolving, and filtering and crystallizing to obtain the ibrutinib crystal form A.
3. The method according to claim 2, wherein the mass-to-volume ratio of ibrutinib to the good solvent is 20: 0.5-20; wherein the mass is in g and the volume is in ml.
4. The method according to claim 2, wherein the volume ratio of the good solvent to the poor solvent is 1: 0.5-15.
5. The method according to claim 2, wherein the good solvent is selected from one or more of acetonitrile, ethyl acetate, butyl acetate, n-butanol, butanone, isopropanol, methanol, acetone, and acetone/n-hexane mixed solvent.
6. The method according to claim 5, wherein the good solvent is an acetone/n-hexane mixed solvent.
7. The method of claim 5, wherein the volume ratio of acetone to n-hexane is 1: 1.
8. The method according to claim 7, wherein the poor solvent is n-hexane or n-heptane.
9. Method according to claim 2, characterized in that it comprises the following steps: adding a good solvent into the ibrutinib crystal form A, heating to 20-50 ℃, dissolving, filtering, dropwise adding a poor solvent into the filtrate, slowly cooling to 0-35 ℃, standing, and crystallizing for 3-8 days to obtain the ibrutinib crystal form A single crystal.
10. Method according to claim 2, characterized in that it comprises the following steps: adding a good solvent into the ibrutinib crystal form A, heating to 20-50 ℃, dissolving, filtering, dropwise adding a poor solvent with the temperature of 30-40 ℃ into the filtrate, slowly cooling to 0-35 ℃, standing, and crystallizing for 3-8 days to obtain the ibrutinib crystal form A single crystal.
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| WO2018000250A1 (en) * | 2016-06-29 | 2018-01-04 | 上海创诺医药集团有限公司 | New ibrutinib crystal form and preparation method therefor |
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| CN104736178A (en) * | 2012-06-04 | 2015-06-24 | 药品循环公司 | Crystalline forms of a Bruton's tyrosine kinase inhibitor |
| CN103694241A (en) * | 2013-11-27 | 2014-04-02 | 苏州晶云药物科技有限公司 | Novel crystal form A of PCI-32765 and preparation method thereof |
| US20170226114A1 (en) * | 2014-08-14 | 2017-08-10 | Assia Chemical Industries Ltd. | Solid state forms of ibrutinib |
| WO2018000250A1 (en) * | 2016-06-29 | 2018-01-04 | 上海创诺医药集团有限公司 | New ibrutinib crystal form and preparation method therefor |
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