CN110903239A - Novel crystal form of lenvatinib mesylate and preparation method thereof - Google Patents
Novel crystal form of lenvatinib mesylate and preparation method thereof Download PDFInfo
- Publication number
- CN110903239A CN110903239A CN201910863405.0A CN201910863405A CN110903239A CN 110903239 A CN110903239 A CN 110903239A CN 201910863405 A CN201910863405 A CN 201910863405A CN 110903239 A CN110903239 A CN 110903239A
- Authority
- CN
- China
- Prior art keywords
- degrees
- crystal form
- mesylate
- preparation
- lenvatinib
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- 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
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a new crystal form of lenvatinib mesylate and a preparation method thereof. The novel mesylate crystal form provided by the invention has the advantages of good stability, obvious process purification effect, simple preparation method and low cost, and has important value for the optimization and development of the medicine in the future.
Description
Technical Field
The invention relates to the field of chemical medicine, in particular to a new crystal form of lenvatinib mesylate and a preparation method thereof.
Background
Lenvatinib is an oral multi-Receptor Tyrosine Kinase (RTK) inhibitor developed by kawasaki corporation for the treatment of aggressive, differentiated thyroid cancer, FDA approval was obtained 2/13 days 2015, EMA approval was obtained 5/28 days 2015, and lenvatinib mesylate form C was used in the marketed approved drug. The chemical name of lenvatinib is: 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide, the structural formula of which is shown in formula (I).
It is known that different crystal forms of solid chemical drugs can cause different solubility and stability, thereby affecting the absorption and bioavailability of the drugs and causing differences in clinical efficacy. Therefore, comprehensive and systematic polymorphic form screening and salt form screening are performed in drug development, and the selection of the most suitable crystal form or salt form for development is one of important research contents which cannot be ignored.
Patent CN100569753C discloses a mesylate crystal form A, B, C, F, I, wherein the crystal form I is an acetate crystal, the crystal form B is transformed to the crystal form C under high humidity or high temperature conditions, and the solubility of the crystal form a is poorer than that of the crystal form C. Patent WO2016184436a1 discloses crystalline form M mesylate, and discloses that crystalline form M mesylate is placed in an aluminum plastic bag package at 25 ℃/60% RH; 40 ℃/75% RH; the mesylate crystal form C has good stability at 60 ℃/75% RH, and the solubility in several biological media is higher than that of the mesylate crystal form C disclosed in the patent CN 100569753C. Through the research of the inventor of the application, the preparation process of the crystal form M is difficult to control and is difficult to purify.
The invention provides a new crystal form of the mesylate, which has advantages in at least one aspect of solubility, melting point, stability, dissolution rate, hygroscopicity, biological effectiveness, processing performance, purification effect and the like; particularly, the preparation process of the crystal form 6 is simple and controllable, the crystal form can be obtained by direct crystallization in a solution, no metastable crystal form is generated in the preparation process, and special control on conditions is not needed.
The crystal form 6 of the mesylate prepared by the invention has simple preparation process and low cost, and has important value for the optimization and development of the medicine in the future.
Disclosure of Invention
The present invention provides, according to an object of the present invention, crystalline form 6 of the mesylate salt of the compound of formula (I) (hereinafter referred to as "crystalline form 6").
On the one hand, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at diffraction angles 2 theta of 8.2 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees and 12.5 degrees +/-0.2 degrees by using Cu-K α radiation.
Further, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at one or more positions with diffraction angles 2 theta of 13.5 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees and 25.3 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at diffraction angles 2 theta of 13.5 degrees +/-0.2 degrees, 14.9 degrees +/-0.2 degrees and 25.3 degrees +/-0.2 degrees.
Further, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at one or more positions with diffraction angles 2 theta of 6.2 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at diffraction angles 2 theta of 6.2 degrees +/-0.2 degrees, 16.4 degrees +/-0.2 degrees and 19.2 degrees +/-0.2 degrees.
On the other hand, the X-ray powder diffraction of the crystal form 6 has characteristic peaks at any 3, or 4, or 5, or 6, or 7, or 8, or 9 of diffraction angles 2 theta of 6.2 DEG + -0.2 DEG, 8.2 DEG + -0.2 DEG, 10.9 DEG + -0.2 DEG, 12.5 DEG + -0.2 DEG, 13.5 DEG + -0.2 DEG, 14.9 DEG + -0.2 DEG, 16.4 DEG + -0.2 DEG, 19.2 DEG + -0.2 DEG, and 25.3 DEG + -0.2 DEG by using Cu-K α radiation.
Without limitation, in one embodiment of the invention, form 6 has an X-ray powder diffraction pattern as shown in figure 1.
According to the purpose of the invention, the invention also provides a preparation method of the crystal form 6, which comprises the steps of adding methanesulfonic acid into a mixed system of acetonitrile and water by using lenvatinib free base, stirring the mixture at the temperature of between 10 ℃ below zero and 25 ℃, reacting and crystallizing, separating and drying the mixture to obtain the crystal form.
Further, the feeding molar ratio of the methanesulfonic acid to the lenvatinib free base is 1/1-1.5/1, and preferably 1/1;
further, the volume ratio of the acetonitrile to the water is 99.5/0.5-97/3; preferably, the volume ratio of acetonitrile to water is 99/1;
further, the temperature is 10 ℃;
further, the drying condition is preferably that the product is naturally aired at room temperature.
The stirring is carried out by adopting a conventional method in the field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, preferably 300-900 rpm.
The "separation" is accomplished by methods conventional in the art, such as centrifugation or filtration. The operation of "centrifugation" was: the sample to be separated is placed in a centrifuge tube and centrifuged at 10000 rpm until all solids settle to the bottom of the centrifuge tube.
The "drying" may be carried out at room temperature or higher. The drying temperature is from room temperature to about 60 deg.C, alternatively to 40 deg.C, alternatively to 50 deg.C. The drying time can be 2-48 hours or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
According to the present invention, the lenvatinib and/or the salt thereof as a starting material means a solid (crystalline or amorphous), semi-solid, wax or oil form thereof. Preferably, the lenvatinib and/or the salt thereof as the starting material is in the form of a solid powder.
In the present invention, "crystal" or "crystalline form" means that it is confirmed by the shown X-ray diffraction pattern characterization. One skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the instrument, sample preparation and purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly noted that the relative intensities of the X-ray diffraction patterns may also vary with the experimental conditions, so that the order of the peak intensities cannot be considered as the sole or determining factor. In addition, due to the influence of experimental factors such as sample height, an overall shift in peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of a crystalline form of the present invention need not be identical to the X-ray diffraction pattern of the examples referred to herein. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention. One skilled in the art can compare the profiles listed in the present invention with a profile of an unknown crystalline form to confirm whether the two sets of profiles reflect the same or different crystalline forms.
In some embodiments, the mesylate salt form 6 of the invention is pure, substantially free of any other forms in admixture. As used herein, "substantially free" when used in reference to a novel form means that the form contains less than 20% by weight of the other form, particularly less than 10% by weight of the other form, more particularly less than 5% by weight of the other form, and even more particularly less than 1% by weight of the other form.
It is to be understood that the numerical values and numerical ranges recited herein are not to be construed narrowly as to the numerical values or numerical ranges themselves, and those skilled in the art will appreciate that they can be varied in accordance with specific technical circumstances and that there is a limit to the specific values that can be resorted to without departing from the spirit and principles of the invention, and that such departures from the present disclosure as may be realized by the term "about".
The crystal form 6 of lenvatinib mesylate has advantages in at least one aspect of solubility, melting point, stability, dissolution rate, hygroscopicity, biological effectiveness, processing performance, purification effect and the like, and particularly has the following beneficial properties:
the crystal form 6 has good stability, high solubility, low hygroscopicity and simple process preparation.
It is another object of the present invention to provide a pharmaceutical composition comprising an effective amount of crystalline form 6 mesylate salt, together with a pharmaceutically acceptable excipient.
Further, in the pharmaceutical composition of the present invention, the mesylate crystal form 6 of the compound of formula (I) can be used for preparing a drug for treating cancer, particularly a drug preparation for treating thyroid cancer.
Drawings
FIG. 1 is an XRPD pattern for mesylate salt form 6
FIG. 2 is a DSC of mesylate salt form 6
FIG. 3 is a TGA profile of mesylate salt form 6
FIG. 4 is a mesylate salt form 61H NMR chart
FIG. 5 is a comparison XRPD of the mesylate salt form 6 stability test (top panel before standing, middle panel after 13 weeks at room temperature/22.5% relative humidity, bottom panel after 13 weeks at room temperature/43.2% relative humidity)
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 described below, the test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.
The abbreviations used in the present invention are explained as follows:
XRPD: powder X-ray diffraction
DSC: differential scanning calorimetry
TGA: thermogravimetric analysis
1H NMR: liquid nuclear magnetic hydrogenSpectrum
The X-ray powder diffraction pattern of the invention is collected on a Panalytical Empyrean X-ray powder diffractometer. The parameters of the X-ray powder diffraction method are as follows:
x-ray reflection parameter Cu, K α
The strength ratio of K α 2/K α 1 is 0.50
Voltage: 45 kilovolt (kV)
Current: 40 milliampere (mA)
Scanning range: from 3.0 to 40.0 degrees
Differential Scanning Calorimetry (DSC) profile according to the present invention was taken on TA Q2000. The parameters of the Differential Scanning Calorimetry (DSC) method are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Thermogravimetric analysis (TGA) profiles described herein were collected on TA Q5000. The process parameters for thermogravimetric analysis (TGA) described in the present invention are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
The lenvatinib and/or the salt thereof used in the present invention can be prepared by the methods disclosed in the prior art, for example, by the methods disclosed in CN100569753C and WO2016184436a 1.
Example 1 preparation of lenvatinib mesylate form 6
1.0733g of lenvatinib free base solid was placed in a jacketed reaction flask, 25mL of a mixed solvent of acetonitrile and water (volume ratio of acetonitrile to water: 99/1) was added, and stirring was performed at 10 ℃. 155. mu.L of methanesulfonic acid (purity > 99%) was added to 3mL of acetonitrile, and the methanesulfonic acid solution in acetonitrile was dropped into the reaction flask over 120 minutes. Stirring was continued for 22 hours at 10 ℃. After filtration, the filter cake was dried at room temperature to give a white solid.
Through detection, the white solid obtained in the experiment is the crystal form 6 of the lenvatinib mesylate. The X-ray powder diffraction data are shown in fig. 1 and table 1. The DSC of form 6 is shown in figure 2, and when heated to 71 ℃, dehydration begins. The TGA of form 6 is shown in figure 3, with about 4.3% weight loss when heated to 125 ℃.
Of form 61H NMR is shown in fig. 4, nuclear magnetic data:1H NMR(400MHz,DMSO)δ8.97(d,J＝6.5Hz,1H),8.73(s,1H),8.37(d,J＝9.1Hz,1H),8.08(s,1H),7.95(d,J＝24.1Hz,2H),7.68-7.58(m,2H),7.36(dd,J＝9.1,2.7Hz,1H),7.27(d,J＝2.7Hz,1H),6.94(d,J＝6.5Hz,1H),4.09(s,3H),2.59(dt,J＝10.1,3.3Hz,1H),2.34(s,3H),0.73-0.60(m,2H),0.48-0.37(m,2H).
TABLE 1
Example 2 stability testing of mesylate salt form 6
Samples of mesylate crystal form 6 of the invention are respectively taken and placed under the conditions of room temperature/22.5% relative humidity and room temperature/43.2% relative humidity for 13 weeks, and sampling is carried out to detect the crystal form change, and the results are shown in table 2. An XRPD pattern of mesylate form 6 before and after standing is shown in figure 5. The upper panel of FIG. 5 is before standing, the middle panel is after 13 weeks at room temperature/22.5% relative humidity, and the lower panel is after 13 weeks at room temperature/43.2% relative humidity.
TABLE 2
| Starting crystal form | Condition | Time of standing | Crystal form change |
| Mesylate salt form 6 | Room temperature/22.5% relative humidity | 13 weeks | Is kept unchanged |
| Mesylate salt form 6 | Room temperature/43.2% relative humidity | 13 weeks | Is kept unchanged |
The result shows that the crystal form 6 of the lenvatinib mesylate is stable after being placed for 13 weeks under the conditions, and meets the stability requirement of drug storage.
Stability study
The stability of the medicine is crucial, and especially in the period of validity of the medicine in the market, the better stability is kept, so that the risk of changing the dissolution rate and the bioavailability of the medicine due to the change of the crystal form can be reduced, and the medicine has important significance in ensuring the curative effect and the safety of the medicine and preventing the occurrence of adverse reaction of the medicine. The more stable crystal form is more controllable in the process of crystallization process, mixed crystals are not easy to appear, and the crystal form is not easy to be converted into other crystal forms in the process of preparation process and storage, so that the quality of the sample is ensured to be consistent and controllable, and the dissolution curve of the preparation product is ensured not to be changed along with the change of storage time.
The crystal form prepared by the method is respectively placed in an open place under the conditions of 25 ℃/60% relative humidity, 40 ℃/75% relative humidity and 60 ℃/75% relative humidity. The result shows that the crystal form is kept unchanged after being placed, and the crystal form has good stability.
Dynamic solubility study
Solubility is one of the key properties of a drug and directly affects the absorption of the drug in the human body. The solubility of different crystal-form drugs may have obvious difference, and the absorption dynamics in vivo also changes, so that the difference of bioavailability is caused, and the clinical safety and curative effect of the drugs are finally influenced.
Especially for a poorly soluble drug, it is more important to improve the solubility. The improvement of the solubility is beneficial to improving the bioavailability of the medicament, thereby improving the medicament forming property of the medicament. In addition, the difficulty of the development of a preparation process is reduced due to the improvement of the solubility, a crystal form with high enough solubility can be developed by adopting the traditional preparation process, and a more complex preparation process is required for achieving the ideal bioavailability for a crystal form with lower solubility. In addition, the solubility is increased, so that the curative effect of the medicine can be ensured, and the dosage of the medicine can be reduced, thereby reducing the side effect of the medicine and improving the safety of the medicine.
Referring to solubility determination method in appendix of Chinese pharmacopoeia; combined with the change of pH value of different organ parts in the organism. According to the two reference evidences, the invention is provided with a solvent system with 4 pH values, such as 1.2-7.5. The method specifically comprises the following steps: SGF at pH 1.8 (simulated gastric fluid), FeSSIF at pH 5.0 (simulated fed artificial intestinal fluid), FaSSIF at pH 6.5 (simulated fasting artificial intestinal fluid) and water.
5mg of the crystal form of the invention are precisely weighed and placed in a vial, and mixed with SGF (simulated gastric fluid) having a pH of 1.8, FeSSIF (simulated fed state artificial intestinal fluid) having a pH of 5.0, FaSSIF (simulated fasting state artificial intestinal fluid) having a pH of 6.5 and water, respectively. The samples were taken at 1 hour, 4 hours and 24 hours, respectively, with rotation at 25 rpm on a rotator, and after centrifugation using a 0.45 μm Polytetrafluoroethylene (PTFE) filter, the filtrate was collected for HPLC analysis.
The result shows that the solubility of the crystal form meets the medicinal requirement, and provides favorable conditions for drug development.
Purity test
The purity of the crystalline forms of the invention was determined by HPLC. The result shows that the crystal form has better purity and is suitable for medicinal use.
Test of purification Effect
A certain amount of crude levovatinib mesylate is taken, and the crude levovatinib mesylate is purified by the crystallization method of the crystal form. The result shows that the crystal form has a good purification effect and a good industrial value.
Morphological testing
The crystal form is shot by a polarizing microscope, and the shooting picture of the polarizing microscope shows that the crystal form is suitable for developing pharmaceutical preparations.
Particle size distribution test
Respectively taking 10-30mg of the crystal form of the invention, adding 10mL of Isopar G (containing 0.2% of lecithin), fully and uniformly mixing the samples to be tested, adding the samples into an SDC sampling system, enabling the sample amount indication diagram to reach a proper position, starting an experiment, and testing the particle size distribution, thereby obtaining the average particle size calculated according to the volume, the particle size corresponding to 10% in the particle size distribution (volume distribution), and the particle size corresponding to 50% in the particle size distribution (volume distribution). The particle size distribution (volume distribution) accounts for 90% of the corresponding particle size and crystal form particle size distribution diagram.
The experimental result shows that the crystal form obtained by the invention has narrower particle size distribution.
Fluidity evaluation test
The crystalline forms of the present invention were evaluated by compressibility factor according to USP <1174> and, after determining their bulk and tap densities, compressibility factor was calculated according to the following formula.
Compressibility factor (%) - (tap density-bulk density)/tap density × 100%
The result shows that the crystal form has better fluidity.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (6)
1. Levatinib mesylate crystal form 6 is characterized in that an X-ray powder diffraction pattern thereof has characteristic peaks at diffraction angles 2 theta of 8.2 degrees +/-0.2 degrees, 10.9 degrees +/-0.2 degrees and 12.5 degrees +/-0.2 degrees.
2. Crystalline mesylate salt form 6 according to claim 1, further characterized by an X-ray powder diffraction pattern having characteristic peaks at one or more of diffraction angles 2 Θ of 13.5 ° ± 0.2 °, 14.9 ° ± 0.2 °, 25.3 ° ± 0.2 °.
3. Crystalline mesylate salt form 6 according to claim 1, further characterized by an X-ray powder diffraction pattern having characteristic peaks at one or more of diffraction angles 2 Θ of 6.2 ° ± 0.2 °, 16.4 ° ± 0.2 °, 19.2 ° ± 0.2 °.
4. A method of preparing lenvatinib mesylate crystalline form 6 of claim 1, comprising: adding methanesulfonic acid into a mixed system with the volume ratio of acetonitrile to water being 99.5/0.5-97/3 by using Levatinib free alkali, stirring the mixed system at the temperature of-10-25 ℃, reacting, crystallizing, separating and drying the mixture to obtain the compound; wherein the feeding molar ratio of the methanesulfonic acid to the lenvatinib free base is 1/1-1.5/1.
5. A pharmaceutical composition comprising an effective amount of the mesylate salt form 6 of any one of claims 1-3 and a pharmaceutically acceptable excipient.
6. The pharmaceutical composition according to claim 5, wherein the mesylate salt form 6 is for use in the preparation of a medicament for the treatment of cancer, in particular a thyroid cancer medicament.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018110894494 | 2018-09-18 | ||
| CN201811089449 | 2018-09-18 | ||
| CN201811244028 | 2018-10-24 | ||
| CN2018112440284 | 2018-10-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110903239A true CN110903239A (en) | 2020-03-24 |
Family
ID=69814582
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910863405.0A Pending CN110903239A (en) | 2018-09-18 | 2019-09-12 | Novel crystal form of lenvatinib mesylate and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110903239A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
| 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 |
-
2019
- 2019-09-12 CN CN201910863405.0A patent/CN110903239A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110494423B (en) | Novel crystal form of lenvatinib mesylate and preparation method thereof | |
| CN113527203B (en) | Crystal form of lenvatinib mesylate as well as preparation method and application thereof | |
| DK1937642T3 (en) | Crystals of sodium laquinimod and the process for its preparation | |
| EP3549932B1 (en) | Novel crystalline forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid and processes for preparation thereof | |
| WO2011115066A1 (en) | Crystal of diamine derivative and method of producing same | |
| EP3508481A1 (en) | Crystal form of ozanimod hydrochloride, and preparation method therefor | |
| CN114957157A (en) | Crystal form of ozapimod hydrochloride and preparation method thereof | |
| CN106459091B (en) | C-Met inhibitor crystal type free alkali or its crystal type acid salt and its preparation method and application | |
| JP2023553930A (en) | Crystalline forms of trebrutinib, methods of its production, and its uses | |
| CN114605406B (en) | Crystal form of AMG510 compound, preparation method and application thereof | |
| CN114773342A (en) | Crystal form of MRTX849 compound, preparation method and application thereof | |
| CN110903239A (en) | Novel crystal form of lenvatinib mesylate and preparation method thereof | |
| CN114746412A (en) | Novel crystal form of KD-025 and preparation method thereof | |
| CN114920739A (en) | Crystal form of MRTX849 compound and preparation method and application thereof | |
| CN104918937A (en) | Crystalline forms of trametinib and solvate thereof, preparation method therefor, pharmaceutical composition comprising same and use thereof | |
| JP2022525125A (en) | E crystal form of braiaconitine A and its manufacturing method and application | |
| KR20210138670A (en) | Briaconitin D crystals, preparation method thereof, and application examples thereof | |
| CN112125910A (en) | Alvatinib crystal form and preparation method thereof | |
| CN108948018B (en) | Benzodiazepine derivatives, their salts and related crystalline forms, preparation and use | |
| CN113045554A (en) | Fexotinib crystal form and preparation method thereof | |
| CN110730785B (en) | Crystal form of fatty acid bile acid conjugate and preparation method and application thereof | |
| CN117886783A (en) | Hydrate crystal form C of taxane compound and preparation method and application thereof | |
| CN113717111A (en) | Crystal form of quinazoline compound and preparation method thereof | |
| CN116199668A (en) | Evobretinib compound salt and preparation method thereof | |
| CN115650955A (en) | Eutectic crystal form of Evibrutinib compound and saccharin and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200324 |