CN110862346A - Levatinib mesylate acetic acid compound crystal form, preparation method and application thereof - Google Patents
Levatinib mesylate acetic acid compound crystal form, preparation method and application thereof Download PDFInfo
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- CN110862346A CN110862346A CN201910034088.1A CN201910034088A CN110862346A CN 110862346 A CN110862346 A CN 110862346A CN 201910034088 A CN201910034088 A CN 201910034088A CN 110862346 A CN110862346 A CN 110862346A
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- -1 mesylate acetic acid compound Chemical class 0.000 title claims description 11
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- HWLFIUUAYLEFCT-UHFFFAOYSA-N lenvatinib mesylate Chemical compound CS(O)(=O)=O.C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 HWLFIUUAYLEFCT-UHFFFAOYSA-N 0.000 claims abstract description 100
- 229960001429 lenvatinib mesylate Drugs 0.000 claims abstract description 95
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 claims description 19
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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Abstract
The invention discloses a crystal form N of a lenvatinib mesylate acetic acid compound, a preparation method and application thereof, and provides a main diffraction peak at a diffraction angle 2 theta of 4.71 degrees and a 2 theta error range of +/-0.2 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α.
Description
Technical Field
The invention relates to a crystal form of a lenvatinib mesylate acetic acid compound, a preparation method and application.
Background
Lenvatinib (lenvatinib) is a drug developed by euonymus japonicus (Eisai) corporation for the treatment of radioiodine refractory Differentiated Thyroid Cancer (DTC). Levatinib is a multi-target tyrosine kinase (PTKs) inhibitor, and researches show that the Levatinib can selectively inhibit the activity of vascular endothelial growth factor receptors and inhibit the activities of other angiogenesis-promoting related PTKs participating in tumor proliferation, and is used for local recurrence or metastasis, aggressive treatment and radioactive iodine refractory DTC single agents of patients with Differentiated Thyroid Cancer (DTC). The mesylate salt of the drug, lenvatinib mesylate, was approved by the U.S. FDA for marketing on day 2/13 of 2015.
The chemical name of the medicine is as follows: 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide having the formula shown in formula I:
the solubility, dissolution and stability of solid chemical drugs are influenced by different crystal forms of the solid chemical drugs, so that the release, absorption, bioavailability and the like of the drugs in vivo are influenced, and the difference of clinical efficacy is caused, the lenvatinib mesylate has a plurality of crystal forms, and patent CN1890220A discloses a plurality of crystal forms of the lenvatinib mesylate, including crystal forms A, B, C, F and I. At present, a crystal form of lenvatinib which has good stability, high solubility, good dissolution effect, simple preparation method and low cost and is suitable for patent medicine needs to be found.
Disclosure of Invention
The invention aims to solve the technical problem of providing a crystal form of a Levatinib mesylate acetic acid compound completely different from the prior art, a preparation method and application. The crystal form N of the lenvatinib mesylate acetic acid compound provided by the invention has ideal physicochemical properties, good stability, good solubility, high dissolution speed and good drug forming property, and the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound provided by the invention is simple and low in cost, and the crystal form N of the lenvatinib mesylate acetic acid compound prepared by the invention has high purity, meets the requirements of raw material drugs (the HPLC purity is more than 99.50%, and the maximum single impurity is less than 0.1%), is green and environment-friendly, is suitable for industrial production and has good market prospect.
The invention provides a crystal form N of a lenvatinib mesylate acetic acid compound, which has a main diffraction peak at a diffraction angle 2 theta of 4.71 degrees in a powder X-ray diffraction spectrum using a radiation source Cu-K α, wherein the error range of the 2 theta is +/-0.2 degrees.
Crystalline form N of the lenvatinib mesylate acetic acid compound has major diffraction peaks at diffraction angles 2 θ of 4.71, 9.43, and 15.72 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α with a 2 θ error range of ± 0.2 degrees.
The crystalline form N of lenvatinib mesylate acetate compound has main diffraction peaks at diffraction angles 2 theta of 4.71, 9.43, 15.72, 10.46, 17.50 and 21.80 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α, and the error range of 2 theta is +/-0.2 degrees.
The lenvatinib mesylate acetic acid compound has main diffraction peaks at diffraction angles of 4.71, 9.43, 10.46, 12.44, 15.72, 17.50, 21.80, 22.71, 23.74 and 25.24 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α, and the error range of 2 theta is +/-0.2 degrees.
The X-ray diffraction spectrum of the crystal form N of the lenvatinib mesylate acetic acid compound in powder using a radiation source Cu-K α is shown in figure 1.
The crystal form N of the lenvatinib mesylate acetic acid compound has a wave number of 1188.33cm in an infrared absorption spectrum-1And 1646.38cm-1Has main absorption peak and wave number error range of +/-1.
The crystal form N of the lenvatinib mesylate acetic acid compound has a wave number of 406.63cm in an infrared absorption spectrum-1、428.01cm-1、446.56cm-1、473.25cm-1、525.86cm-1、552.86 cm-1cm-1、590.00cm-1、649.73cm-1、686.52cm-1、774.42cm-1、845.98cm-1、875.72cm-1、911.85cm-1、1036.43cm-1、1088.57cm-1、1149.47cm-1、1188.33 cm-1、1223.07cm-1、3401.61cm-1、1261.23cm-1、1284.71cm-1、1350.86cm-1、 1397.20cm-1、1418.72cm-1、1453.79cm-1、1474.16cm-1、1492.08cm-1、1552.03 cm-1、1586.84cm-1、1607.57cm-1、1646.38cm-1、1682.95cm-1、1749.25cm-1、 2071.97cm-1、2788.57cm-1、3179.08cm-1、3319.11cm-1Has absorption peak and wave number error rangeIs + -1.
The crystal form N of the lenvatinib mesylate acetate compound has an infrared absorption spectrum shown in figure 3.
The DSC-TGA trace of the crystal form N of the lenvatinib mesylate acetic acid compound has the thermal weight loss of 10.17 percent within the temperature range of 20-80 ℃.
The DSC-TGA trace diagram of the crystal form N of the lenvatinib mesylate acetic acid compound is shown in figure 4.
The thermal analysis of the differential scanning calorimetry shows that the crystal form N of the lenvatinib mesylate acetic acid compound has endothermic peaks at 241.07 +/-2 ℃ and 272.91 +/-2 ℃ and exothermic peaks at 237.01 +/-2 ℃.
The thermal analysis of differential scanning calorimetry of the crystalline form N of lenvatinib mesylate acetate compound is shown in fig. 5.
The invention also provides a preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, which comprises the following steps: crystallizing a solution formed by lenvatinib, methanesulfonic acid, acetic acid and a solvent shown as a formula II to obtain a crystal form N of a lenvatinib mesylate acetic acid compound;
in the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the solvent is preferably one or more of an alcohol solvent, an ester solvent, a ketone solvent and acetic acid; further, a mixed solvent of acetic acid, an alcohol solvent and an ester solvent is preferable. The alcohol solvent is preferably n-propanol. The ester solvent is preferably isopropyl acetate. The ketone solvent is preferably acetone. The mixed solvent of acetic acid, alcohol solvent and ester solvent is preferably a mixed solvent of acetic acid, n-propanol and isopropyl acetate.
In the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the acetic acid can be used as a reaction reagent and a reaction solvent.
In the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the volume-to-mass ratio of the solvent to the lenvatinib shown as the formula II is preferably 1 mL/g-30 mL/g, more preferably 2 mL/g-10 mL/g, such as 5mL/g or 7 mL/g.
In the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the mass ratio of the methanesulfonic acid to the lenvatinib shown as the formula II is preferably 0.05-1, more preferably 0.1-0.3, such as 0.27.
In the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the mass ratio of the acetic acid to the lenvatinib as shown in the formula II is preferably 0.05-1, and further preferably 0.1-0.5.
In the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the temperature of the solution formed by the lenvatinib as shown in the formula II, acetic acid and a solvent is preferably 0-80 ℃, more preferably 5-40 ℃, for example 30-35 ℃.
In the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the crystallization is preferably performed by stirring.
In the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the crystallization temperature is preferably 0-80 ℃, more preferably 5-40 ℃, for example 30-35 ℃.
In the method for preparing the crystal form N of the lenvatinib mesylate acetic acid compound, the crystallization time is preferably 1 to 24 hours, more preferably 2 to 10 hours, for example 3 to 4 hours.
The preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound preferably adopts the following steps: and mixing a solution formed by lenvatinib, methanesulfonic acid, acetic acid and a solvent shown as a formula II with a seed crystal, and crystallizing to obtain the crystal form N of the lenvatinib mesylate acetate compound.
The preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound preferably adopts the following post-treatment steps: and after stirring and crystallization, removing the solvent, and drying to obtain the crystal form N of the lenvatinib mesylate acetate compound. The solvent is removed by filtration or centrifugation. The filtration or centrifugation can be carried out by methods conventional in the art for such procedures. The drying is preferably atmospheric forced air drying or reduced pressure drying. The drying temperature is preferably from 30 ℃ to 80 ℃, more preferably from 40 ℃ to 50 ℃, for example, 35 ℃. The drying time is preferably 10 hours to 30 hours, more preferably 11 hours to 20 hours, for example, 15 hours.
The invention also provides a crystal form N of the lenvatinib mesylate acetic acid compound prepared by the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound.
The invention also provides application of the crystal form N of the lenvatinib mesylate acetic acid compound in preparing medicaments for treating and/or preventing tumors, cancer metastasis diseases, retinal angiogenesis, diabetic retinopathy, atherosclerosis, inflammatory diseases and diseases which can be effectively treated through angiogenesis inhibition. The tumor comprises thyroid cancer, intestinal cancer, breast cancer, prostatic cancer, lung cancer, renal cancer, pancreatic cancer, gastric cancer, brain tumor, leukemia, hemangioma and ovarian cancer. The inflammatory diseases include osteoarthritis, rheumatoid arthritis, psoriasis and delayed hypersensitivity reactions.
The invention also provides a pharmaceutical composition, which comprises the crystal form N of the lenvatinib mesylate acetic acid compound.
The pharmaceutical composition preferably further comprises pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable auxiliary materials are selected from one or more of diluents, fillers, disintegrants, glidants, lubricants, binders and coloring agents.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating and/or preventing tumors, cancer metastasis diseases, retinal angiogenesis, diabetic retinopathy, atherosclerosis, inflammatory diseases and diseases which can be effectively treated through angiogenesis inhibition. The tumor comprises thyroid cancer, intestinal cancer, breast cancer, prostatic cancer, lung cancer, renal cancer, pancreatic cancer, gastric cancer, brain tumor, leukemia, hemangioma and ovarian cancer. The inflammatory diseases include osteoarthritis, rheumatoid arthritis, psoriasis and delayed hypersensitivity reactions.
The crystal form N of the lenvatinib mesylate acetic acid compound prepared by the method does not contain or only contains a lower content of residual solvent, and meets the limit requirement of the residual solvent of related medical products specified by national formulary, so that the crystal of the invention can be better used as a medical active ingredient.
Researches show that the crystal form N of the Levatinib mesylate prepared by the invention has good crystal form stability under the conditions of grinding, pressure and the like, can meet the medicinal requirements of production, transportation and storage, has stable, repeatable and controllable production process, and can be suitable for industrial production. And the Levatinib mesylate acetic acid compound crystal form N prepared by the invention has high dissolution speed, is more suitable for preparing quick release medicaments, and has good marketization prospect.
Since the diffraction angle (2 θ) in the powder X-ray diffraction generally has an error in the range of ± 0.20 degrees (°), the value of the diffraction angle needs to be understood to include values in the range of about ± 0.20 degrees. Therefore, the present invention includes not only crystals having a diffraction angle completely uniform in powder X-ray diffraction but also crystals having a diffraction angle uniform within an error range of. + -. 0.2 degrees. For example, in the present specification, "having diffraction peaks at diffraction angles of 4.71, 9.43, and 15.72 degrees" means "having diffraction peaks at diffraction angles of 4.51 to 4.91 degrees, 9.23 to 9.63 degrees, and 15.52 to 15.92 degrees.
In the present specification, the "wave numbers" are 1188.33 and 1646.38cm-1Has absorption peaks at wavenumbers of 1187.33-1189.33 and 1645.38-1647.38cm-1Has an absorption peak.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
The positive progress effects of the invention are as follows: the crystal form N of the lenvatinib mesylate acetate compound provided by the invention has ideal physicochemical properties, good stability, good solubility, high dissolution speed and good drug forming property, and the new crystal form provided by the invention has the advantages of simple preparation method and low cost, and the prepared product has good stability and high purity, meets the requirements of raw material drugs (the HPLC purity is more than 99.50%, and the maximum single impurity is less than 0.1%), is green and environment-friendly, is suitable for industrial production and has good marketization prospect.
Drawings
Figure 1 is an X-ray powder diffraction pattern (XRPD pattern) of crystalline form N of lenvatinib mesylate acetic acid compound prepared in example 1.
Figure 2 is a dissolution profile of lenvatinib mesylate acetic acid compound form N and lenvatinib mesylate form C, prepared in example 1.
Fig. 3 is an infrared spectrum of crystal form N of lenvatinib mesylate acetate compound prepared in example 1.
Figure 4 is a DSC-TGA trace plot of crystalline form N of lenvatinib mesylate acetate prepared in example 1.
Fig. 5 is a differential scanning calorimetry thermogram of crystalline form N of lenvatinib mesylate acetate compound prepared in example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
Adding 25g of lenvatinib shown as a formula II into a 1000ml reaction bottle, adding 175ml of acetic acid, mechanically stirring, adding 6.75g of methanesulfonic acid at 30-35 ℃, stirring to dissolve, adding 200ml of N-propanol, adding 125ml of isopropyl acetate, stirring for 10 minutes, adding 10mg of crystal form N of lenvatinib mesylate acetate, stirring for 3 hours, filtering, leaching with isopropyl acetate, and drying at 35 ℃ under normal pressure for 15 hours to obtain 29g of crystal form N of solid lenvatinib mesylate acetate, wherein the yield is 94.7%, the HPLC purity is 99.74%, and the maximum single impurity content is 0.09%. The XPRD spectrum is shown in FIG. 1, and the specific data of XPRD are shown in Table 1. Solubility data for lenvatinib mesylate, form C, and lenvatinib mesylate, acetic acid compound, form N, prepared in example 1 are shown in table 2. Dissolution data for lenvatinib mesylate, form C, and lenvatinib mesylate, acetic acid compound, form N, prepared in example 1 are shown in table 3, and the dissolution profile is shown in fig. 2. The infrared data of the crystalline form N of the lenvatinib mesylate acetate compound prepared in example 1 are shown in table 4, and the infrared spectrum is shown in fig. 3. The DSC-TGA trace of the crystal form N of the lenvatinib mesylate acetic acid compound has the thermal weight loss of 10.17% in the range of 20-80 ℃, and the DSC-TGA trace is shown as figure 4. The thermal analysis of the crystal form N of the lenvatinib mesylate acetic acid compound by differential scanning calorimetry shows that endothermic peaks exist at 241.07 +/-2 ℃ and 272.91 +/-2 ℃, exothermic peaks exist at 237.01 +/-2 ℃, and the thermal analysis of the differential scanning calorimetry is shown in figure 5.
The parameters of the X-ray powder diffraction method are as follows:
x-ray reflection parameters Cu, Ka, K α 1(A): 1.54056;
voltage 40 kilovolt (kV)
Current 40 milliampere (mA)
Scanning: 3.0 degrees to 44.9933 degrees; step size 0.01973; time spent 24.78 (seconds); cu (40kV,40mA), i (max) 8783.
Number of peaks: 35/parabola, threshold 3.0, cutoff 0.1%, BG 3/1.0, and peak top.
Note: for calculating the lattice spacing d, by counting the intensity and by 0.0(°) 2T (0)
Table 1 XPRD data for lenvatinib mesylate acetate compound form N prepared as example 1
Table 2 solubility data table for lenvatinib mesylate acetate compound crystalline form N and lenvatinib mesylate salt crystalline form C prepared in example 1
It can be seen that the solubility of form N of the lenvatinib mesylate acetate compound prepared in example 1 in acetic acid is significantly better than that of form C of lenvatinib mesylate.
Table 3 dissolution data table for crystal form N of lenvatinib mesylate acetate compound and crystal form C of lenvatinib mesylate salt prepared in example 1
As can be seen, the dissolution rate of the crystal form N of the lenvatinib mesylate acetic acid compound prepared in example 1 is higher, and the effect is better.
Table 4 infrared data table for lenvatinib mesylate acetate compound crystalline form N and lenvatinib mesylate salt crystalline form C prepared in example 1
The range is as follows: 4000.00-400.00
(absolute) threshold 97.007; sensitivity 50
| Peak position | Strength of | Peak position | Strength of |
| 406.63 | 76.565 | 1261.23 | 16.974 |
| 428.01 | 73.113 | 1284.71 | 31.343 |
| 446.56 | 70.943 | 1350.86 | 32.668 |
| 473.25 | 70.293 | 1397.20 | 24.507 |
| 525.86 | 46.964 | 1418.72 | 25.281 |
| 552.86 | 39.295 | 1453.79 | 20.060 |
| 590.00 | 60.003 | 1474.16 | 36.190 |
| 649.73 | 63.660 | 1492.08 | 41.819 |
| 686.52 | 64.650 | 1552.03 | 28.708 |
| 774.42 | 59.844 | 1586.84 | 25.836 |
| 845.98 | 58.424 | 1607.57 | 25.565 |
| 875.72 | 72.712 | 1646.38 | 20.533 |
| 911.85 | 53.607 | 1682.95 | 17.520 |
| 1036.43 | 23.724 | 1749.25 | 70.930 |
| 1088.57 | 56.751 | 2071.97 | 94.715 |
| 1149.47 | 23.764 | 2788.57 | 71.616 |
| 1188.33 | 15.633 | 3179.08 | 46.602 |
| 1223.07 | 17.532 | 3319.11 | 47.069 |
| 3401.61 | 49.318 |
Table 5 stability data for crystalline form N of lenvatinib mesylate acetate compound prepared in example 1 remained stable for 12 months at 5 ℃ ± 2 ℃ and 60% ± 5% relative humidity.
| HPLC purity | Maximum single hetero | |
| Before placing | 99.83％ | 0.05％ |
| After 12 months of standing | 99.82％ | 0.05％ |
Example 2:
adding 25g of lenvatinib shown as a formula II into a 1000ml reaction bottle, adding 175ml of acetic acid, mechanically stirring, adding 6.75g of methanesulfonic acid at 30-35 ℃, stirring to dissolve, adding 200ml of N-propanol, adding 125ml of isopropyl acetate, stirring for 10 minutes, adding 25mg of crystal form N of lenvatinib mesylate acetate, stirring for 3 hours, filtering, eluting with isopropyl acetate, and drying at 35 ℃ under normal pressure for 15 hours to obtain 29.2g of crystal form N of solid lenvatinib mesylate acetate, wherein the yield is 95.4%, the HPLC purity is 99.85%, and the maximum single impurity content is 0.06%.
Example 3:
adding 100g of lenvatinib shown as a formula II into a 2000ml reaction bottle, adding 500ml of acetic acid, mechanically stirring, adding 27g of methanesulfonic acid at 30-35 ℃, stirring to dissolve, adding 500ml of N-propanol, adding 400ml of isopropyl acetate, stirring for 10 minutes, adding 100mg of crystal form N of lenvatinib mesylate acetate, stirring for 4 hours, filtering, leaching with isopropyl acetate, drying at 35 ℃ under normal pressure for 15 hours to obtain 115.4g of crystal form N of solid lenvatinib mesylate acetate, wherein the yield is 94.2%, the HPLC purity is 99.87%, and the maximum single impurity content is 0.06%.
Claims (10)
1. Crystalline form N of lenvatinib mesylate acetate compound is characterized by having a major diffraction peak at a diffraction angle 2 θ of 4.71 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α with a 2 θ error range of ± 0.2 degrees.
2. Crystalline form N of lenvatinib mesylate acetic acid compound of claim 1, having major diffraction peaks at diffraction angles 2 Θ of 4.71, 9.43 and 15.72 degrees, with a 2 Θ error range of ± 0.2 degrees, in a powder X-ray diffraction spectrum using a radiation source of Cu-K α;
and/or the presence of a gas in the gas,
which has main diffraction peaks at diffraction angles 2 theta of 4.71, 9.43, 15.72, 10.46, 17.50 and 21.80 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α, and has an error range of +/-0.2 degrees in 2 theta;
and/or the presence of a gas in the gas,
which has main diffraction peaks at diffraction angles 2 theta of 4.71, 9.43, 10.46, 12.44, 15.72, 17.50, 21.80, 22.71, 23.74 and 25.24 degrees in a powder X-ray diffraction spectrum using a radiation source of Cu-K α, and has an error range of +/-0.2 degrees in 2 theta;
and/or the presence of a gas in the gas,
the powder X-ray diffraction spectrum of Cu-K α used as the radiation source is shown in FIG. 1.
3. Crystalline form N of lenvatinib mesylate acetate compound of claim 1, wherein: it has a wave number of 1188.33cm in infrared absorption spectrum-1And 1646.38cm-1Has main absorption peak and wave numberThe error range is +/-1;
and/or the presence of a gas in the gas,
it has a wave number of 406.63cm in infrared absorption spectrum-1、428.01cm-1、446.56cm-1、473.25cm-1、525.86cm-1、552.86cm-1cm-1、590.00cm-1、649.73cm-1、686.52cm-1、774.42cm-1、845.98cm-1、875.72cm-1、911.85cm-1、1036.43cm-1、1088.57cm-1、1149.47cm-1、1188.33cm-1、1223.07cm-1、3401.61cm-1、1261.23cm-1、1284.71cm-1、1350.86cm-1、1397.20cm-1、1418.72cm-1、1453.79cm-1、1474.16cm-1、1492.08cm-1、1552.03cm-1、1586.84cm-1、1607.57cm-1、1646.38cm-1、1682.95cm-1、1749.25cm-1、2071.97cm-1、2788.57cm-1、3179.08cm-1、3319.11cm-1An absorption peak exists, and the wave number error range is +/-1;
and/or the presence of a gas in the gas,
the crystal form N of the lenvatinib mesylate acetate compound has an infrared absorption spectrum shown in figure 3.
4. Crystalline form N of lenvatinib mesylate acetate compound of claim 1, wherein: the DSC-TGA trace of the crystal form N of the lenvatinib mesylate acetic acid compound has the thermal weight loss of 10.17 percent within the range of 20-80 ℃;
and/or the presence of a gas in the gas,
the DSC-TGA trace of the crystal form N of the lenvatinib mesylate acetic acid compound is shown in figure 4.
5. Crystalline form N of lenvatinib mesylate acetate compound of claim 1, wherein:
the thermal analysis of the crystal form N of the lenvatinib mesylate acetate compound by differential scanning calorimetry shows that endothermic peaks exist at 241.07 +/-2 ℃ and 272.91 +/-2 ℃, and exothermic peaks exist at 237.01 +/-2 ℃;
and/or the presence of a gas in the gas,
the thermal analysis of differential scanning calorimetry of the crystalline form N of lenvatinib mesylate acetate compound is shown in fig. 5.
6. A preparation method of a crystal form N of a lenvatinib mesylate acetic acid compound is characterized by comprising the following steps: crystallizing a solution formed by lenvatinib, methanesulfonic acid, acetic acid and a solvent shown as a formula II to obtain a crystal form N of a lenvatinib mesylate acetic acid compound;
7. a process for preparing lenvatinib mesylate acetic acid compound of claim 6, wherein:
in the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the solvent is one or more of an alcohol solvent, an ester solvent, a ketone solvent and acetic acid;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the volume-mass ratio of the solvent to the lenvatinib shown as the formula II is 1 mL/g-30 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the mass ratio of the methanesulfonic acid to the lenvatinib shown as the formula II is 0.05-1;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the mass ratio of the acetic acid to the lenvatinib shown as the formula II is 0.05-1;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the temperature of the solution formed by the lenvatinib, acetic acid and a solvent as shown in a formula II is 0-80 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the crystallization is stirring crystallization;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetate compound, the crystallization temperature is 0-80 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound, the crystallization time is 1-24 hours;
and/or the presence of a gas in the gas,
the preparation method of the crystal form N of the lenvatinib mesylate acetate compound comprises the following steps: mixing a solution formed by lenvatinib, methanesulfonic acid, acetic acid and a solvent shown as a formula II with a seed crystal, and crystallizing to obtain a crystal form N of a lenvatinib mesylate acetate compound;
and/or the presence of a gas in the gas,
the preparation method of the crystal form N of the lenvatinib mesylate acetic acid compound adopts the following post-treatment steps: and after stirring and crystallization, removing the solvent, and drying to obtain the crystal form N of the lenvatinib mesylate acetate compound.
8. Levatinib mesylate acetic acid compound, crystalline form N, prepared by the process for preparing crystalline form N of the compound according to claim 6 or 7.
9. A pharmaceutical composition characterized in that it comprises the crystalline form N of lenvatinib mesylate acetic acid compound of any one of claims 1-5 or claim 8.
10. Use of crystalline form N of lenvatinib mesylate acetic acid compound of any one of claims 1-5 or claim 8 for the preparation of a medicament for the treatment and/or prevention of tumors, cancer metastasis diseases, retinal angiogenesis, diabetic retinopathy, atherosclerosis, inflammatory diseases and diseases which can be effectively treated by angiogenesis inhibition;
and/or the presence of a gas in the gas,
use of a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment and/or prevention of tumors, cancer metastatic diseases, retinal angiogenesis, diabetic retinopathy, atherosclerosis, inflammatory diseases and diseases effectively treatable by angiogenesis inhibition.
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| WO2006137474A1 (en) * | 2005-06-23 | 2006-12-28 | Eisai R & D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for producing the same |
| CN101337931A (en) * | 2003-12-25 | 2009-01-07 | 卫材R&D管理有限公司 | Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these |
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| CN101337931A (en) * | 2003-12-25 | 2009-01-07 | 卫材R&D管理有限公司 | Crystal of salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)amino-phenoxy)-7-methoxy-6-quinolinecarboxamide or of solvate thereof and processes for producing these |
| WO2006137474A1 (en) * | 2005-06-23 | 2006-12-28 | Eisai R & D Management Co., Ltd. | Amorphous salt of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide and process for producing the same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114174264A (en) * | 2020-04-24 | 2022-03-11 | 成都苑东生物制药股份有限公司 | Crystal form XI of varlitinib mesylate and preparation method thereof |
| CN114174264B (en) * | 2020-04-24 | 2024-02-27 | 成都苑东生物制药股份有限公司 | Crystal form XI of lenvatinib mesylate and preparation method thereof |
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