CN113087733A - Crystal form A, crystal form B, crystal form C, crystal form D and crystal form E of Criboboro and preparation method thereof - Google Patents
Crystal form A, crystal form B, crystal form C, crystal form D and crystal form E of Criboboro and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 38
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 15
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 13
- 150000005846 sugar alcohols Polymers 0.000 claims description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
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- 239000012046 mixed solvent Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 229920005862 polyol Polymers 0.000 claims description 7
- 150000003077 polyols Chemical class 0.000 claims description 7
- 229960004063 propylene glycol Drugs 0.000 claims description 7
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
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- 239000000203 mixture Substances 0.000 claims description 3
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 claims 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 2
- 229940035437 1,3-propanediol Drugs 0.000 claims 2
- 229940093476 ethylene glycol Drugs 0.000 claims 2
- 229960005150 glycerol Drugs 0.000 claims 2
- 229920000166 polytrimethylene carbonate Polymers 0.000 claims 2
- 235000013772 propylene glycol Nutrition 0.000 claims 2
- 239000003814 drug Substances 0.000 abstract description 17
- 238000003860 storage Methods 0.000 abstract description 5
- 230000007774 longterm Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000002474 experimental method Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 5
- 229910052796 boron Inorganic materials 0.000 description 5
- 230000005855 radiation Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 206010012438 Dermatitis atopic Diseases 0.000 description 3
- 201000008937 atopic dermatitis Diseases 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000008064 anhydrides Chemical group 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 229940090805 clavulanate Drugs 0.000 description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 2
- USZAGAREISWJDP-UHFFFAOYSA-N crisaborole Chemical compound C=1C=C2B(O)OCC2=CC=1OC1=CC=C(C#N)C=C1 USZAGAREISWJDP-UHFFFAOYSA-N 0.000 description 2
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229950008199 crisaborole Drugs 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of chemical medicine, and provides five crystal forms of Criboboro: the crystal form A, the crystal form B, the crystal form C, the crystal form D and the crystal form E, and the invention also provides preparation methods for preparing the five crystal forms. The crystal form has good solubility, good stability in the processes of high temperature, high humidity, long-term storage and the like, low hygroscopicity and easy storage, and has important significance for developing pharmaceutical Cliborol.
Description
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to a Criboborol, namely five new crystal forms of 4- [ (1, 3-dihydro-1-hydroxy-2, 1-benzoxaborolan-5-yl) oxy ] benzonitrile: crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and preparation methods thereof.
Background
Krisaborole (crisabarol), chemically known as 4- [ (1, 3-dihydro-1-hydroxy-2, 1-benzoxaborolan-5-yl) oxy ] benzonitrile, is a non-steroidal PDE4 inhibitor available from Anacor at 52 billion dollars in 5 months in 2016 as fevered. In 2016, 12 months, the product is approved by FDA to be marketed and used for treating mild to moderate atopic dermatitis in children and adults, and is sold under the brand name of Eucrisa. The composition is also approved in Canada, Australia and Israel, and can be used for treating mild to moderate atopic dermatitis (eczema) of 2 years old and above. Kerley ointment (20 mg/g) is also approved by the European Union in 3 months of 2020, under the trade name Staquis for the treatment of mild to moderate atopic dermatitis (eczema) in patients over 2 years of age and with an area of skin affliction of less than 40%, which was the first non-hormonal topical application approved for European patients in the last decade. The structure of the compound is as follows:
the crystal form of the medicine has a direct relation with the quality and the curative effect of the medicine, and the research on the polymorphism and the property of the medicine has significance and value in various aspects. The polymorphism affects the preparation, stability, dissolution and bioavailability of the bulk drug and the preparation of the drug, and further affects the prescription and preparation process of the drug. For most drugs, different crystal forms have certain differences in physical and chemical properties, and the differences inevitably affect the curative effects and toxic and side effects of the drugs.
Currently, 4 crystal forms of kreb are published and reported (WO 2017193914a 1), and kreb is easily soluble in common organic solvents such as isopropyl alcohol and propylene glycol and is insoluble in water. Therefore, by researching the CRIBORUO polymorphism, the CRIBORUO crystal form with medicinal advantages is selected to prepare the medicine, so that the stability of the crystal form of the CRIBORUO in the process of pharmaceutical preparation and medicine storage can be ensured, the dissolution rate and bioavailability of the medicine can be improved, the treatment effect of the medicine is improved, and the toxicity is reduced. The preparation process is determined according to the advantages of the crystal form of the Criboboron, and the medicament equivalence between batches of production can be effectively ensured, so that a high-quality, high-efficiency and safe preparation is prepared.
Disclosure of Invention
The invention aims to solve the problem of research and development failure caused by crystal forms, seek a new crystal form of krebs and provide more qualitative and quantitative information for clinical medication.
The invention aims to provide five new crystal forms of Clibolol, namely a crystal form A, a crystal form B, a crystal form C, a crystal form D and a crystal form E, wherein the crystal form A is methanolate, the crystal form B is anhydride, the crystal form C and the crystal form D are polyatomic alcoholate, and the crystal form E is anhydride.
The second purpose of the invention is to provide the preparation methods of the cristobalite crystal form A, the crystal form B, the crystal form C, the crystal form D and the crystal form E.
In one aspect of the invention, there is provided a crystalline form A of Krebs of formula (I),
using Cu-ka radiation, the powder X-ray diffraction pattern of form a has diffraction peaks at diffraction angles (2 θ ± 0.2 °) of 7.6 °, 12.4 °, 14.3 °, 19.1 °, 25.7 ° and 26.9 °.
The preparation method of the crystal form A comprises the following steps: heating and dissolving the Cliboren in a mixed solvent of polyhydric alcohol and methanol, cooling, stirring, crystallizing, filtering, and drying under reduced pressure for 12-24 hours to obtain the crystal form A. Wherein the polyhydric alcohol is selected from glycerol, 1, 2-propylene glycol, 1, 3-propylene glycol and ethylene glycol, and the mixing volume ratio of the polyhydric alcohol to the methanol is selected from 1: 1-1: 10.
Preferably, the mixing volume ratio of the polyol to the methanol is selected from 1: 5.
In another aspect of the invention there is provided a crystalline form B of krebs of formula (I),
using Cu-ka radiation, the powder X-ray diffraction pattern of form B has diffraction peaks at diffraction angles (2 θ ± 0.2 °) of 6.7 °, 12.6 °, 16.8 °, 17.6 °, 22.4 ° and 25.5 °.
The preparation method of the krebs crystal form B comprises the step of drying the krebs crystal form A at high temperature for more than 12 hours in vacuum, wherein the high temperature is selected from 100-150 ℃.
The invention also provides a crystalline form C of krebs of formula (I),
the powder X-ray diffraction pattern of form C has diffraction peaks at diffraction angles (2 θ ± 0.2 °) of 4.9 °, 9.8 ° and 22.9 ° using Cu-ka radiation.
The preparation method of the krebs crystal form C comprises the following steps: heating and dissolving the Cliborel in a mixed solvent of polyhydric alcohol and methanol, cooling, stirring, crystallizing, filtering, heating, decompressing and drying, and solidifying after solid melting at high temperature to obtain a crystal form C, wherein the decompressing and drying temperature is selected from 50-100 ℃.
The invention further provides a crystalline form D of krebs of formula (I),
using Cu-ka radiation, the powder X-ray diffraction pattern of form D has diffraction peaks at diffraction angles (2 θ ± 0.2 °) of 5.7 °, 11.1 °, 15.6 °, 17.6 ° and 23.4 °.
The preparation method of the krebs crystal form D comprises the following steps: heating and dissolving the Cliboren with a mixed solvent of polyhydric alcohol and ethanol, cooling, stirring, crystallizing, filtering, drying under reduced pressure for 12-24 h, and solidifying after solid melting to obtain the crystal form D.
Further, the present invention provides a crystalline form E of krebs of formula (I),
using Cu-ka radiation, the powder X-ray diffraction pattern of form E has diffraction peaks at diffraction angles (2 θ ± 0.2 °) of 7.7 °, 16.5 °, 17.0 °, 22.0 °, 22.3 ° and 23.3 °.
The preparation method of the krebs crystal form E comprises the following steps: heating and dissolving the Cliboren with a mixed solvent of polyhydric alcohol and an organic solvent, cooling, stirring, crystallizing, filtering, and drying under reduced pressure for 12-24 hours to obtain the crystal form E. Wherein the polyhydric alcohol is selected from glycerol, 1, 2-propylene glycol, 1, 3-propylene glycol and ethylene glycol, the organic solvent is selected from isopropanol, acetone and acetonitrile, and the volume ratio of the mixture of the polyhydric alcohol and the organic solvent is selected from 1: 1-1: 10.
Preferably, the polyol is mixed with the organic solvent in a volume ratio selected from 1: 5.
Compared with the prior art, the invention has the beneficial effects that: researches show that the Cliboron crystal form E provided by the invention has good solubility, good stability in the processes of high temperature, high humidity, long-term storage and the like, low hygroscopicity, stable storage, can be used as a clinical medicinal crystal form, and has excellent medicinal research value.
Drawings
Fig. 1 is an X-ray powder diffraction (XPRD) pattern of the crystalline form E of clavulanic boron with 2 theta values (degrees) on the abscissa and intensity on the ordinate.
FIG. 2 is an X-ray powder diffraction (XPRD) plot of crystalline form E of krebs crystal dried at 80 ℃ for 24 hours with 2 θ values (degrees) on the abscissa and intensity on the ordinate.
Fig. 3 is an X-ray powder diffraction (XPRD) plot of crystalline form E of clavulanate boron in degrees 2 theta on the abscissa and intensity on the ordinate, after 30 days at 75% humidity.
FIG. 4 is an X-ray powder diffraction (XPRD) plot of crystalline form E of Clarithromium boron in degrees 2 θ on the abscissa and intensity on the ordinate, after standing at room temperature for 90 days.
Figure 5 is a TGA profile of crystalline form E of clavulanate.
Figure 6 is a DSC diagram of cristobramo form E.
Fig. 7 is an X-ray powder diffraction (XPRD) pattern of the crystalline form a of clavulanic boron with 2 theta values (degrees) on the abscissa and intensity on the ordinate.
Figure 8 is a TGA profile of crystalline form a of krebs.
Figure 9 is a DSC diagram of cristobalite form a.
Fig. 10 is an X-ray powder diffraction (XPRD) pattern of the crystalline form B of ceribronate, wherein the abscissa is the 2 θ value (degrees) and the ordinate is the intensity.
Fig. 11 is an X-ray powder diffraction (XPRD) pattern of the crystalline form C of clavulanic boron with 2 theta values (degrees) on the abscissa and intensity on the ordinate.
Fig. 12 is an X-ray powder diffraction (XPRD) pattern of the crystalline form D of ceribronate, wherein the abscissa is the 2 θ value (degrees) and the ordinate is the intensity.
Detailed Description
The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention. The skilled person can make modifications to the preparation method and the apparatus used within the scope of the claims, and such modifications should also be considered as the protection scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
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 raw materials and reagents shown in the figure can be obtained by a commercially available mode.
The X-ray powder diffraction (XPRD) diagram of the invention is collected on a Bruker D8 advanced diffraction instrument X-ray powder Diffractometer, and the parameters of the measuring method are as follows:
x-ray reflectance parameters: cu K (λ =1.54056 Ȧ)
Voltage: 40 kilovolt (kV)
Current: 40 milliampere (mA)
Detecting an angle: 3-40 deg. 2 theta/3-30 deg. 2 theta (hot table XRD)
Scanning speed: 0.2 sec/step
Step length: 0.02 degree 2 theta
Non-reflective sample plate: 24.6mm diameter × 1.0mm Thickness (available from MTI corporation)
Temperature-changing hot stage sample plate: a copper plate.
Example 1 preparation of Clibororock form E
Dissolving 10.0g of clironic by heating with a mixed solvent of 10mL of ethylene glycol and 50mL of isopropanol, cooling, stirring, crystallizing for 12h, filtering, and drying at 50 ℃ under reduced pressure for 12h to obtain 7.5g of crystalline form E clironic, wherein the X-ray powder diffraction pattern (XPRD) of the crystalline form E clironic is shown in figure 1 and is characterized by having characteristic peaks at 2 theta values of 7.7 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.0 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.3 +/-0.2 degrees and 23.3 +/-0.2 degrees.
Example 2 preparation of Clibororock form A
Dissolving 10.0g of clironic by a mixed solvent of 10mL of ethylene glycol and 50mL of methanol under heating, cooling, stirring, crystallizing for 12h, filtering, and drying under reduced pressure at 40 ℃ for 12h to obtain 7.8g of crystal form A clironic, wherein an X-ray powder diffraction pattern (XPRD) of the crystal form A clironic is shown in figure 2, and the crystal form A clironic is characterized by having characteristic peaks at 2 theta values of 7.6 +/-0.2 degrees, 12.4 +/-0.2 degrees, 14.1 +/-0.2 degrees, 19.1 +/-0.2 degrees, 25.7 +/-0.2 degrees and 26.9 +/-0.2 degrees.
Example 3 preparation of Clibororock form B
Vacuum drying 2.0g of Cribobromide of Crystal form A at 70 deg.C for 15h to obtain Cribobromide of Crystal form B, wherein the X-ray powder diffraction pattern (XPRD) is shown in FIG. 3, and is characterized by having characteristic peaks at 2 theta values of 6.7 + -0.2 °, 12.6 + -0.2 °, 16.8 + -0.2 °, 17.6 + -0.2 °, 22.4 + -0.2 °, and 25.5 + -0.2 °.
Example 4 preparation of Clibororock form C
Heating and dissolving 10.0g of clironic with a mixed solvent of 10mL of ethylene glycol and 50mL of methanol, cooling, stirring, crystallizing for 12h, filtering, vacuum drying at 80 ℃, and solidifying after solid melting to obtain 7.0g of crystal form C clironic, wherein an X-ray powder diffraction pattern (XPRD) of the crystal form C clironic is shown in figure 4, and the crystal form C clironic is characterized by having characteristic peaks at 2 theta values of 4.9 +/-0.2 degrees, 9.8 +/-0.2 degrees and 22.9 +/-0.2 degrees.
Example 5 preparation of Clibororock form D
Heating and dissolving 10.0g of clironic with a mixed solvent of 10mL of ethylene glycol and 50mL of ethanol, cooling, stirring, crystallizing for 12h, filtering, vacuum drying at 80 ℃, and solidifying after solid melting to obtain 6.6g of crystal form D clironic, wherein an X-ray powder diffraction pattern (XPRD) of the crystal form D clironic is shown in figure 5, and the crystal form D clironic is characterized by having characteristic peaks at 2 theta values of 5.7 +/-0.2 degrees, 11.1 +/-0.2 degrees, 15.6 +/-0.2 degrees, 17.6 +/-0.2 degrees and 23.4 +/-0.2 degrees.
Experimental part
Experiment I, crystal form E high-temperature stability experiment
The crystal form E of the invention is placed at the temperature of 80 ℃ for 24h, and the characteristic 2 theta values are compared as follows:
TABLE 1 Crystal form E standing at 80 deg.C for 24h characteristic 2 theta value comparison
The result shows that the crystal form E of the invention is stable and has no obvious change when being placed for 24 hours at the temperature of 80 ℃.
Experiment II, crystal form E hygroscopicity experiment
The crystal form E of the present invention was left at 75% humidity for 30 days, and the characteristic 2 θ values were compared as follows:
table 2 form E is placed at 75% humidity for 30 days characteristic 2 theta value comparison
The results show that the crystal form E of the invention is stable and has no obvious change when being placed for 30 days under 75% humidity.
Experiment III, Long-term stability experiment of crystal form E
When form E of the present invention is left at room temperature for 90 days, the characteristic 2 θ values are compared as follows:
TABLE 3 characteristic 2 theta values of form E after standing at room temperature for 90 days
The result shows that the crystal form E of the invention is stable and has no obvious change after being placed at room temperature for 90 days.
Experiment four, crystal form E dynamic solubility experiment
Dissolving the Cliboron crystal form E and the disclosed crystal form I with propylene glycol and ethylene glycol respectively to prepare saturated solutions, and adopting High Performance Liquid Chromatography (HPLC) to measure the drug content in the solutions for 48 hours respectively, wherein the results are as follows:
table 4 solubility of crystalline form E and form I of krebs in solution for 48h
Research results show that the solubility of the Clibororock crystal form E in propylene glycol is obviously higher than that of the Clibororock crystal form I, and the solubility of the Clibororock crystal form E in ethylene glycol has no obvious difference.
Claims (18)
1. A crystalline form A of krebs of formula (I),
the crystal form A is characterized in that a powder X-ray diffraction pattern of the crystal form A has diffraction peaks at diffraction angles (2 theta +/-0.2 degrees) of 7.6 degrees, 12.4 degrees, 14.3 degrees, 19.1 degrees, 25.7 degrees and 26.9 degrees.
2. The crystal form A as claimed in claim 1, wherein the preparation method of the crystal form A comprises the following steps: heating and dissolving the Cliboren in a mixed solvent of polyhydric alcohol and methanol, cooling, stirring, crystallizing, filtering, and drying under reduced pressure for 12-24 hours to obtain the crystal form A.
3. A process according to claim 2, wherein the polyol is selected from glycerol, 1, 2-propanediol, 1, 3-propanediol, and ethylene glycol.
4. The preparation method of the crystal form A as claimed in claim 2, characterized in that the mixing volume ratio of the polyalcohol and the methanol in the preparation method of the crystal form A is selected from 1: 1-1: 10.
5. The process for preparing form A according to claim 4, wherein the mixing volume ratio of the polyol to the methanol is selected from 1: 5.
6. A crystalline form B of krebs of formula (I),
the crystal form B is characterized in that a powder X-ray diffraction pattern of the crystal form B has diffraction peaks at diffraction angles (2 theta +/-0.2 degrees) of 6.7 degrees, 12.6 degrees, 16.8 degrees, 17.6 degrees, 22.4 degrees and 25.5 degrees.
7. The crystalline form B of krebs-n according to claim 6, wherein the process for preparing the crystalline form B comprises vacuum drying the crystalline form a of krebs-n at elevated temperature for a period of more than 12 hours.
8. The method for preparing the krebs crystal form B according to claim 7, wherein the high temperature in the method for preparing the krebs crystal form B is selected from 100-150 ℃.
9. A crystalline form C of krebs of formula (I),
the crystal form C is characterized in that a powder X-ray diffraction pattern of the crystal form C has diffraction peaks at diffraction angles (2 theta +/-0.2 degrees) of 4.9 degrees, 9.8 degrees and 22.9 degrees.
10. The crystalline form C of krebs-l according to claim 9, wherein the process for preparing the crystalline form C of krebs-l comprises: heating and dissolving the Cliboren with a mixed solvent of polyhydric alcohol and methanol, cooling, stirring, crystallizing, filtering, heating, decompressing and drying, and solidifying after solid melting at high temperature to obtain the crystal form C.
11. The method for preparing a crystalline form C of krebs-n according to claim 10, wherein the temperature of reduced pressure drying and heating is selected from 50-100 ℃.
12. A crystalline form D of krebs of formula (I),
the crystal form D is characterized in that a powder X-ray diffraction pattern of the crystal form D has diffraction peaks at diffraction angles (2 theta +/-0.2 degrees) of 5.7 degrees, 11.1 degrees, 15.6 degrees, 17.6 degrees and 23.4 degrees.
13. The crystalline form D of krebs-l according to claim 12, wherein the process for preparing the crystalline form D of krebs-l comprises: heating and dissolving the Cliboren with a mixed solvent of polyhydric alcohol and ethanol, cooling, stirring, crystallizing, filtering, drying under reduced pressure for 12-24 h, and solidifying after solid melting to obtain the crystal form D.
14. A crystalline form E of krebs of formula (I),
the crystal form E is characterized in that a powder X-ray diffraction pattern of the crystal form E has diffraction peaks at diffraction angles (2 theta +/-0.2 degrees) of 7.7 degrees, 16.5 degrees, 17.0 degrees, 22.0 degrees, 22.3 degrees and 23.3 degrees.
15. The crystalline form E of krebs crystal of claim 14, wherein the process for preparing the crystalline form E of krebs crystal comprises: heating and dissolving the Cliboren with a mixed solvent of polyhydric alcohol and an organic solvent, cooling, stirring, crystallizing, filtering, and drying under reduced pressure for 12-24 hours to obtain the crystal form E.
16. The process of claim 15, wherein the polyol is selected from the group consisting of glycerol, 1, 2-propanediol, 1, 3-propanediol, and ethylene glycol, and the organic solvent is selected from the group consisting of isopropanol, acetone, and acetonitrile.
17. The method for preparing cristoboro form E according to claim 15, wherein the volume ratio of the polyol to the organic solvent in the preparation method of cristoboro form E is selected from 1:1 to 1: 10.
18. The process according to claim 17, wherein the ratio of polyol to organic solvent in the mixture is selected from 1: 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110366012.6A CN113087733A (en) | 2021-04-06 | 2021-04-06 | Crystal form A, crystal form B, crystal form C, crystal form D and crystal form E of Criboboro and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115417890A (en) * | 2022-09-24 | 2022-12-02 | 中山万远新药研发有限公司 | Novel crystal form of cliobromide and preparation method and application thereof |
| WO2024047571A1 (en) * | 2022-09-01 | 2024-03-07 | Savoi Guilherme | Crisaborole cocrystal derivatives |
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| US20170305936A1 (en) * | 2016-07-12 | 2017-10-26 | Pliva Hrvatska D.O.O. | Solid state forms of crisaborole |
| WO2017193914A1 (en) * | 2016-05-09 | 2017-11-16 | 苏州科睿思制药有限公司 | Crystal forms of crisaborole in free form and preparation method and use thereof |
| WO2017203514A1 (en) * | 2016-05-26 | 2017-11-30 | Perrigo Api Ltd | Polymorphs of crisaborole and production processes therefor |
| WO2018150327A1 (en) * | 2017-02-14 | 2018-08-23 | Wavelength Enterprises Ltd | Crisaborole production process |
| CN112375093A (en) * | 2020-11-13 | 2021-02-19 | 江苏知原药业股份有限公司 | Keliboro crystal form compound and preparation method thereof |
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| WO2017193914A1 (en) * | 2016-05-09 | 2017-11-16 | 苏州科睿思制药有限公司 | Crystal forms of crisaborole in free form and preparation method and use thereof |
| WO2017203514A1 (en) * | 2016-05-26 | 2017-11-30 | Perrigo Api Ltd | Polymorphs of crisaborole and production processes therefor |
| US20170305936A1 (en) * | 2016-07-12 | 2017-10-26 | Pliva Hrvatska D.O.O. | Solid state forms of crisaborole |
| WO2018150327A1 (en) * | 2017-02-14 | 2018-08-23 | Wavelength Enterprises Ltd | Crisaborole production process |
| CN112375093A (en) * | 2020-11-13 | 2021-02-19 | 江苏知原药业股份有限公司 | Keliboro crystal form compound and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2024047571A1 (en) * | 2022-09-01 | 2024-03-07 | Savoi Guilherme | Crisaborole cocrystal derivatives |
| CN115417890A (en) * | 2022-09-24 | 2022-12-02 | 中山万远新药研发有限公司 | Novel crystal form of cliobromide and preparation method and application thereof |
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Application publication date: 20210709 |