CN112010857B - Crystal form of ribociclib succinate - Google Patents
Crystal form of ribociclib succinate Download PDFInfo
- Publication number
- CN112010857B CN112010857B CN201910461351.5A CN201910461351A CN112010857B CN 112010857 B CN112010857 B CN 112010857B CN 201910461351 A CN201910461351 A CN 201910461351A CN 112010857 B CN112010857 B CN 112010857B
- Authority
- CN
- China
- Prior art keywords
- degrees
- crystal form
- ribociclib
- isopropanol
- succinic acid
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- 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
Abstract
The invention relates to a crystal form of ribociclib single succinate, which has the characteristic that the X-ray powder diffraction pattern at 25 ℃ has the peak values of +/-0.0 +/-0.2 degrees, 9.5 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.9 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.9 +/-0.2 degrees, 25.9 +/-0.2 degrees, 27.9 +/-0.2 degrees, 29.2 +/-0.2 degrees, 29.9 +/-0.2 degrees, 30.5 +/-0.2 degrees, 32.0.2 degrees, 33.7 +/-0.2 degrees, 36.2 +/-0.2 degrees, 29.2 +/-0.2 degrees, 37.2 +/-0.2 degrees, 2 degrees, 2.4 +/-0.4.4.4 +/-0.2 degrees, 2 degrees. The crystal form I provided by the invention has low hygroscopicity, simplifies the preparation and post-treatment processes of medicines, and is easy for industrial production. Compared with the existing crystal form, the crystal form I has better stability, is not easy to be transformed in the storage process, thereby avoiding the change of bioavailability and drug effect, and has better powder properties and very strong economic value.
Description
Technical Field
The invention relates to a crystal form of ribociclib succinate.
Background
Cyclin-dependent kinase4/6 (cyclin-dependent kinase4/6, CDK4/6) is a class of silk/threonine kinases that, in combination with cyclin D (cyclin D), regulate the transition of cells from G1 to S phase. The 'cyclin D-CDK4/6-INK4-Rb pathway' abnormality exists in a plurality of tumors, and the change of the pathway accelerates the G1 phase process, so that the tumor cells are accelerated to proliferate and obtain survival advantage. Therefore, it is a therapeutic strategy to intervene, and CDK4/6 is one of the anti-tumor targets.
LEE011 is a small molecule inhibitor of cyclin-dependent kinase4/6, developed by noval pharmaceutical company as a drug regorafenib for the treatment of drug-resistant breast cancer and melanoma, and officially approved for marketing on 3/17/2017 under the trade name Kisqali. The active ingredient of Ribociclib is the free base and the stabilizing ingredient is succinate. The structure is shown as the following formula:
patent CN103201275A discloses a hydrate crystal form and an anhydrous crystal form of ribociclib monosuccinate. The solubility of the hydrate form is lower than 0.5mg/mL, and the solubility of the non-hydrate form is better, so that the non-hydrate form is selected as a comparative crystal form, but the non-hydrate is obtained by reaction and crystallization in isopropanol at the temperature of 80 +/-3 ℃, the risk of esterification reaction between succinic acid and isopropanol is increased at high temperature, and the risk of degradation is also increased. In addition, the non-hydrate form is easy to be transformed into a crystal, at 90% RH, up to 7.35% of the non-hydrate form can be transformed into a hydrate form, and the transformation of the drug crystal form can bring the problems of curative effect, safety and the like to the drug. In addition, the non-hydrate form has poor powder properties, and these unfavorable properties may reduce the production efficiency of tableting and filling in the formulation, while causing great difficulty in controlling the quality of the pharmaceutical product.
In order to overcome the defects of the prior art, the inventor of the application unexpectedly discovers that the crystal form I of the mono-succinate provided by the invention has advantages in the aspects of solubility, melting point, stability, hygroscopicity, adhesiveness, fluidity, preparation production and the like, and has low hygroscopicity, good stability, good fluidity, excellent compressibility and small adhesiveness, and the solubility meets the medicinal requirements, so that a new better choice is provided for the preparation of the medicament, and the preparation method has very important significance for the development of the medicament.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a crystal form of ribociclib succinate and a preparation method and application thereof.
According to the object of the invention, the invention provides a crystalline form I of ribociclib monosuccinate, which is characterized in that the X-ray powder diffraction pattern at 25 ℃ has the characteristic peaks at 2theta values of 9.0 ± 0.2 °, 9.5 ± 0.2 °, 11.5 ± 0.2 °, 12.9 ± 0.2 °, 13.9 ± 0.2 °, 15.1 ± 0.2 °, 15.8 ± 0.2 °, 17.7 ± 0.2 °, 18.3 ± 0.2 °, 19.0 ± 0.2 °, 20.5 ± 0.2 °, 21.9 ± 0.2 °, 23.0 ± 0.2 °, 23.9 ± 0.2 °, 24.9 ± 0.2 °, 25.9 ± 0.2 °, 27.9 ± 0.2 °, 29.2 ± 0.2 °, 29.9 ± 0.2 °, 30.5 ± 0.2 °, 32.0 ± 0.2 °, 33.7 ± 0.7 ± 0.2 °, 27.9 ± 0.2 °, 2 ± 0.7 ± 0.4 ± 0.41 ± 0 °, 2.4 ± 0.7 ± 0 °, 2 °, 2.4 ± 0.4 ± 0 °, 2 °.
According to a particular aspect, the form I has an X-ray powder diffraction pattern substantially in accordance with figure 1.
According to a particular aspect of the invention, form I is anhydrate. When differential scanning calorimetry is performed, the form I begins to show an endothermic peak when heated to about 193 ℃, and the differential scanning calorimetry diagram is shown in FIG. 3. When subjected to thermogravimetric analysis, form I has a weight loss gradient of about 4.66% when heated to 240 ℃, with a thermogravimetric analysis profile as shown in figure 4.
The invention also provides a preparation method of the crystal form I, which comprises the steps of adding isopropanol into Riboxini free alkali, mechanically stirring, heating to reflux, stirring and dissolving. Succinic acid was dissolved in isopropanol. At 80 ℃, dropwise adding the isopropanol solution of succinic acid into the isopropanol solution of Ribose free base, and preserving the temperature after dropwise adding. The heat source is removed, the temperature is slowly reduced, and solid is slowly separated out. Cooling the solution to 15 ℃, stirring for 1h, performing suction filtration, and performing vacuum drying on a wet product at 55 ℃ for 16h to obtain the Riboxini succinate.
The invention also provides application of the crystal form I of the ribociclib monosuccinate in preparing a medicament for treating cancer.
The invention also provides a medicine for treating cancer, which contains the crystal form I of the ribociclib succinate.
Due to the implementation of the technical scheme, compared with the existing crystal form, the crystal form of the invention has the following advantages:
(1) compared with the existing crystal form, the crystal form I has lower hygroscopicity, and can overcome the defects caused by high hygroscopicity. The test result shows that the water adsorption of the crystal form I at 25 ℃ and 80% relative humidity is only 1.1%, and the crystal form is unchanged before and after the hygroscopicity test, which shows that the crystal form I has excellent stability even under high humidity conditions;
hygroscopicity affects the stability of a drug, the fluidity and uniformity during processing, etc., and ultimately affects the quality of a pharmaceutical preparation. Meanwhile, hygroscopicity affects the preparation, storage and post-treatment processes of the drug. The crystal form with low hygroscopicity has no strict requirement on storage conditions, reduces the cost of material storage and quality control, and has high value;
(2) the crystal form I has good solubility in simulated biological media and pure water, and the solubility is more than 10mg/mL, thereby meeting the medicinal requirements;
the solubility is the rate-limiting factor of the bioavailability of the drug, so that the solubility of the crystal form I meets the medicinal requirement, and the Riboxini drug can realize higher bioavailability, thereby ensuring the drug potency and the drug effect of the drug.
Preferably, the crystalline form I of the present invention also has the following beneficial effects:
(1) compared with the crystal form in the prior art, the crystal form I has better fluidity. In a particular flow
In the evaluation experiment, the experimental result shows that the crystal form I has good fluidity, but the non-hydrate form has poor fluidity;
the crystal form has better fluidity, so that the production speed of tabletting and filling can be effectively increased, and the production efficiency is improved; in addition, the feasibility of direct tabletting and direct powder filling can be improved, the production process is greatly simplified, and the production cost is reduced. The better flow property of the crystal form I ensures the mixing uniformity and the content uniformity of the preparation, reduces the weight difference of the dosage form and improves the product quality;
(2) compared with the crystal form in the prior art, the crystal form I has better compressibility; in a specific compressibility evaluation experiment, the tensile strength of the crystal form I is 4.18MPa which is far higher than that of the crystal form in the prior art;
the crystal form I has good compressibility, can effectively improve the problems of unqualified hardness/friability and the like in the processing process of raw material medicines, reduces the requirements on the process treatment of the prior products, ensures that the process is more stable, improves the appearance of the products and improves the quality of the products. In addition, the process feasibility of directly processing the crystal form I preparation is high, the preparation process is greatly simplified, and the research, development and production costs are reduced;
(3) the crystal form I of the present invention can have less adhesiveness than the crystal forms of the prior art. In a particular adhesion evaluation experiment, the average amount of adhesion of form I was 0.025mg, whereas the average amount of adsorption of the non-hydrate form was 0.095 mg, which is about four times as much as form I of the present invention.
The low adhesion of the crystal form I can effectively improve or avoid the phenomena of sticking, sticking and punching and the like caused by links such as dry granulation, tablet tabletting and the like, and is beneficial to improving the appearance, the weight difference and the like of products. Therefore, the crystal form I is low in adhesion, the agglomeration phenomena of raw materials and the like can be effectively reduced, the adsorption between the materials and an appliance is reduced, the dispersion of the raw materials and the mixing of other auxiliary materials are facilitated, and the mixing uniformity of the materials during mixing and the uniformity of the dosage of the raw materials in a final product are improved.
Drawings
Figure 1 is an XRPD pattern of form I;
FIG. 2 is a 1H-NMR chart of form I;
FIG. 3 is a DSC chart of form I;
figure 4 is a TGA profile of form I;
FIGS. 5-1,5-2 are comparison graphs of hygroscopicity experiments XRPD of form I: fig. 5-1 is the XRPD pattern before the experiment, and fig. 5-2 is the XRPD pattern after the experiment (form-unchanged).
Detailed Description
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples. Conditions not noted in the examples are conventional conditions.
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: x-ray powder diffraction;
DSC: differential scanning calorimetry analysis;
TGA: thermogravimetric analysis;
1H-NMR: nuclear magnetic resonance hydrogen spectroscopy;
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 reflectance parameters: cu, Ka;
Kα11.540598；Kα21.544426 ；
the K alpha 2/K alpha 1 intensity ratio: 0.50;
voltage: 45 kilovolts (kV);
current: 40 milliamperes (mA);
scanning range: from 3.0 to 40.0 degrees;
differential Scanning Calorimetry (DSC) profile according to the invention was taken on a PerkinElmer Pyrs 1 DSC. 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 Netzsch TG209F 3. The process parameters for thermogravimetric analysis (TGA) described in the present invention are as follows:
scanning rate: 10 ℃/min;
protective gas: nitrogen gas.
Example 1
152g of Ribociclib free base is weighed into a 5L reaction bottle, 2.5L of isopropanol is added, mechanical stirring is carried out, heating is carried out till reflux, and stirring is carried out to dissolve out. 43.37g of succinic acid was weighed out and added to 450mL of isopropyl alcohol and dissolved out under reflux. At 80 ℃, dropwise adding the isopropanol solution of succinic acid into the isopropanol solution of Ribosinic free base for about 15min, clarifying, changing the color from light yellow to yellow, and keeping the temperature at 80 ℃ for 15 min. The heat source is removed, the temperature is slowly reduced, and solid is slowly separated out. Cooling the solution to 15 ℃, stirring for 1h, performing suction filtration, and performing vacuum drying on wet products at 55 ℃ for 16h to obtain 179g of Ribociclib succinate. The yield thereof was found to be 92.7%.
The X-ray powder diffraction data of form I obtained in this example are shown in table 1. The XRPD pattern is shown in table 1:
TABLE 1
The nuclear magnetic spectrum of the crystal form I is shown in figure 2, and nuclear magnetic data show that the obtained crystal form I is ribociclib monosuccinate.
The differential scanning calorimetry pattern of form I is shown in FIG. 3, which indicates that form I begins to show an endothermic peak when heated to about 193 ℃. Form I is anhydrous.
The thermogravimetric analysis of form I is shown in figure 4 and shows a gradient of about 4.66% weight loss when heated to 240 ℃.
Example 2
The stability of the crystal form I and the anhydrous crystal form of the mono succinate of patent CN103201275A under high humidity condition is researched:
1. placing a dried glass weighing bottle with a plug (the outer diameter is 50mm, the height is 15 mm) in a proper constant temperature drier with the temperature of 25 +/-1 ℃ on the previous day (the lower part is placed with saturated solution of ammonium chloride or ammonium sulfate) or a climatic chamber (the set temperature is 25 +/-1 ℃, and the relative humidity is 80% +/-2%), and precisely weighing (m 1);
2. taking a proper amount of a test article, placing the test article in the weighing bottle, and spreading the test article in the weighing bottle, wherein the thickness of the test article is about 1mm generally, and precisely weighing (m 2);
3. opening the weighing bottle, and placing the weighing bottle and the bottle cap under the constant temperature and humidity condition for 24 hours;
4. The weighing bottle cap was closed and precision weighed (m 3).
Percent weight gain = (m3-m2)/(m2-m1) × 100%
Taking about 100mg of the form I of the present invention, hygroscopicity was measured according to the above-mentioned method. And XRPD was measured before and after testing for hygroscopicity. A comparison graph of XRPD before and after the hygroscopicity test is shown in fig. 5, and the results show that the moisture adsorption of the crystal form I at 25 ℃ and 80% relative humidity is only 1.1%, and the crystal form before and after the hygroscopicity test is unchanged, which shows that the crystal form I has excellent stability even under high humidity conditions, while according to the report of the special CN103201275A, the water adsorption of the anhydrous crystal form of the mono succinate salt at 25 ℃ and 90% relative humidity is 2% and 7.35% of the compound is converted into a hydrate form from a non-hydrate form, and 0.52% of the compound is converted into a hydrate form at 25 ℃ and 80% relative humidity. Therefore, the crystal form of the comparative patent is easy to generate crystal form transformation and relatively poor in stability.
Example 3
Solubility study of form I:
the mono-succinate crystal form I prepared by the invention is respectively prepared into solution by SGF (simulated artificial gastric juice) with pH of 1.8, artificial intestinal juice with pH of 6.5FaSSIF (fasting state) and artificial intestinal juice with pH of 5.0FeSSIF (feeding state), and the phenomenon is observed after 1 hour, 4 hours and 24 hours, and the solutions are found to be uniformly dissolved. The results of the experiment are shown in table 2:
TABLE 2
The experiment shows that the solubility of the crystal form I in a simulated biological medium is more than 10mg/mL, and the crystal form I meets the medicinal requirement.
Example 4: flowability of form I
The flowability of the crystalline form I prepared according to the invention was investigated by compressibility factor according to the united states pharmacopeia, the bulk density and tap density of crystalline form I and the prior art non-hydrate form were determined separately and the compressibility factor was calculated according to the following company.
Compressibility factor (%) = (tap density-bulk density)/tap density × 100%
The results of the measurements of form I and the non-hydrate form are shown in table 3.
TABLE 3
The result shows that the compressibility coefficient of the crystal form I is 14.2%, the fluidity is good, the pressure stability coefficient of the non-hydrate form is 33.8%, the fluidity is poor, and the crystal form I has better fluidity compared with the crystal form in the prior art.
Example 5: compressibility of form I
And (3) tabletting by adopting a manual tablet press, and selecting circular flat punch capable of pressing into a cylindrical tablet (ensuring the isotropy of the tablet) during tabletting. Respectively taking a certain amount of non-hydrate form and crystal form I, pressing into round tablets by adopting a certain pressure, placing in a dryer for 24h, and testing the radial crushing force (hardness, N) of the tablets by adopting a tablet hardness tester after complete elastic recovery. The diameter (D) and the thickness (L) of the tablet are measured by a vernier caliper, and the tensile strength of the powder under different hardness is calculated by using a formula T = 2N/pi DL. The higher the tensile strength at a certain pressure, the better the compressibility. When the amount of the sample is small in the screening stage, the test can be performed by using the recommended parameters in the following table.
Recommended tensile Strength test parameters
The results of the experimental determination of form I and the non-hydrate form are shown in Table 4
TABLE 4
The result shows that the tensile strength of the crystal form I is 4.18MPa, the tensile strength of the non-hydrate form is 2.75MPa, and the compressibility of the crystal form I has obvious advantages compared with the non-hydrate form.
Example 6: adhesion of Crystal form I
Adding a proper amount of the crystal form I and the non-hydrate form into a proper die, tabletting by adopting a certain pressure, staying for about half a minute after tabletting, and weighing the powder amount absorbed by the punch. After the method is adopted to continuously carry out pressing for a plurality of times, the accumulated final adsorption amount of the punch, the highest adsorption amount and the average adsorption amount in the pressing process are recorded. The experimental data are shown in Table 5.
TABLE 5
The result shows that compared with the non-hydrate form, the average adsorption amount of the crystal form I is only 0.025mg, which is far lower than that of the non-hydrate form, and the crystal form I has obvious adhesion advantage.
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 (2)
1. A preparation method of crystal form I of ribociclib monosuccinate comprises the steps of weighing 152g of ribociclib free alkali in a 5L reaction bottle, adding 2.5L of isopropanol, mechanically stirring, heating to reflux, stirring to dissolve, weighing 43.37g of succinic acid, adding into 450mL of isopropanol, refluxing to dissolve, dripping an isopropanol solution of succinic acid into the isopropanol solution of the ribociclib free alkali at 80 ℃, clarifying after about 15min, changing the color from light yellow to yellow, keeping the temperature at 80 ℃ for 15min, removing a heat source, slowly cooling, slowly separating out solids, cooling the solution to 15 ℃, stirring for 1h, performing suction filtration, and drying wet products at 55 ℃ in vacuum for 16h to obtain 179g of ribociclib succinic acid salt with the yield of 92.7%;
wherein the X-ray powder diffraction pattern of the crystal form I at 25 ℃ has the characteristic peaks at the 2theta values of 9.5 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.9 +/-0.2 degrees, 15.1 +/-0.2 degrees, 15.8 +/-0.2 degrees, 17.7 +/-0.2 degrees, 18.3 +/-0.2 degrees, 19.0 +/-0.2 degrees, 20.5 +/-0.2 degrees, 21.9 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.9 +/-0.2 degrees, 24.9 +/-0.2 degrees, 25.9 +/-0.2 degrees, 27.9 +/-0.2 degrees, 29.2 +/-0.2 degrees, 29.9 +/-0.2 degrees, 30.5 +/-0.2 degrees, 32.0 +/-0.2 degrees, 33.7 +/-0.2 degrees, 36.2 +/-0.2 degrees, 37.4 +/-0.2 degrees, 39.5 +/-0.2 degrees, 41.0.2 degrees and 0.44.2 degrees.
2. A process for preparing form I according to claim 1, characterized in that: the crystal form I is an anhydrate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910461351.5A CN112010857B (en) | 2019-05-30 | 2019-05-30 | Crystal form of ribociclib succinate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910461351.5A CN112010857B (en) | 2019-05-30 | 2019-05-30 | Crystal form of ribociclib succinate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112010857A CN112010857A (en) | 2020-12-01 |
| CN112010857B true CN112010857B (en) | 2021-11-05 |
Family
ID=73501484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910461351.5A Active CN112010857B (en) | 2019-05-30 | 2019-05-30 | Crystal form of ribociclib succinate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112010857B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN105085533A (en) * | 2014-12-12 | 2015-11-25 | 苏州晶云药物科技有限公司 | Novel crystal form of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridine-2-yl amino)-7H-pyrrolo [2,3-D] pyrimidine-6-carboxylic acid dimethylamide single succinate |
| WO2018051280A1 (en) * | 2016-09-15 | 2018-03-22 | Dr. Reddy’S Laboratories Limited | Process for preparation of ribociclib, its acid addition salts |
| IN201741000072A (en) * | 2017-12-29 | 2018-07-06 | ||
| WO2019019959A1 (en) * | 2017-07-27 | 2019-01-31 | 苏州晶云药物科技股份有限公司 | Crystal form of monosuccinate of ribociclib and preparation method and use thereof |
| WO2019040567A1 (en) * | 2017-08-25 | 2019-02-28 | Teva Pharmaceuticals Usa, Inc. | Ribociclib salts and solid state forms thereof |
| CN109400612A (en) * | 2018-12-24 | 2019-03-01 | 重庆三圣实业股份有限公司 | A kind of preparation method of Rui Boxini and products thereof and purposes |
| WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of ribociclib and its salts |
-
2019
- 2019-05-30 CN CN201910461351.5A patent/CN112010857B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103201275A (en) * | 2010-11-10 | 2013-07-10 | 诺华有限公司 | Salt(s) of 7-cyclopentyl-2 -(5-piperazin-1-yl-pyridin-2-ylamino)-7h-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and processes of making thereof |
| CN105085533A (en) * | 2014-12-12 | 2015-11-25 | 苏州晶云药物科技有限公司 | Novel crystal form of 7-cyclopentyl-2-(5-piperazin-1-yl-pyridine-2-yl amino)-7H-pyrrolo [2,3-D] pyrimidine-6-carboxylic acid dimethylamide single succinate |
| CN105111215A (en) * | 2014-12-12 | 2015-12-02 | 苏州晶云药物科技有限公司 | Crystal form and preparation method of cyclin-dependent kinase inhibitor |
| WO2018051280A1 (en) * | 2016-09-15 | 2018-03-22 | Dr. Reddy’S Laboratories Limited | Process for preparation of ribociclib, its acid addition salts |
| WO2019019959A1 (en) * | 2017-07-27 | 2019-01-31 | 苏州晶云药物科技股份有限公司 | Crystal form of monosuccinate of ribociclib and preparation method and use thereof |
| WO2019040567A1 (en) * | 2017-08-25 | 2019-02-28 | Teva Pharmaceuticals Usa, Inc. | Ribociclib salts and solid state forms thereof |
| WO2019082143A1 (en) * | 2017-10-27 | 2019-05-02 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of ribociclib and its salts |
| IN201741000072A (en) * | 2017-12-29 | 2018-07-06 | ||
| CN109400612A (en) * | 2018-12-24 | 2019-03-01 | 重庆三圣实业股份有限公司 | A kind of preparation method of Rui Boxini and products thereof and purposes |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112010857A (en) | 2020-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111094290B (en) | Crystal form of mono succinate of Ribociclib, preparation method and application thereof | |
| RU2603138C1 (en) | Crystalline form of hidamide, method of its production and use | |
| EP3763703A2 (en) | Novel crystalline forms of {[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino}acetic acid and processes for preparation thereof | |
| Tong et al. | Process‐induced phase transformation of berberine chloride hydrates | |
| EP3156406A1 (en) | Crystalline forms of ribociclib free base | |
| JP2023025000A (en) | Crystalline fumarate salt of (s)-[3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl] [3-hydroxy-3-(piperidin-2-yl) azetidin-1-yl]-methanone | |
| CN106795159B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| RU2716260C2 (en) | Crystalline form of bisulphate jak-kinase inhibitor and a method for production thereof | |
| CN101723844A (en) | Agomelatine crystal form B, preparation method thereof and medicinal composition containing same | |
| CN112010857B (en) | Crystal form of ribociclib succinate | |
| CN110650960B (en) | Novel crystal form of Acaraburtinib and preparation method and application thereof | |
| CN103864690B (en) | S crystal formation, its preparation method and the pharmaceutical composition of Ivabradine hydrochloride | |
| KR101710922B1 (en) | Method for preparing crystalline form I of Clopidogrel hydrogen sulfate | |
| CN110105307B (en) | Trimetazidine oxalate and preparation method and application thereof | |
| WO2021135346A1 (en) | New crystal form of acalabrutinib, preparation method therefor and use thereof | |
| CN111527089A (en) | Novel crystal form of Acaraburtinib and preparation method and application thereof | |
| CN110054599B (en) | Trimetazidine oxalate and preparation method and application thereof | |
| CN110183398B (en) | Trimetazidine oxalate and preparation method and application thereof | |
| WO2014193887A1 (en) | Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihydroimidazo[4,5 d]fy rrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| KR20190017310A (en) | Salts of L-Carnitine Compound with Improved Pharmaceutical Properties, a process for preparing the same, and a pharmaceutical composition containing the same | |
| JP2022540466A (en) | amorphous umbularisib monotosylate | |
| CN110036003B (en) | Novel crystal form of AP26113 and preparation method thereof | |
| WO2019105359A1 (en) | Crystal form of acalabrutinib, preparation method therefor and application thereof | |
| TW202102510A (en) | Crystalline forms of acid addition salts of furopyrimidine compound and pharmaceutical composition | |
| CN106065016B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |