CN113845520A - Palbociclib orotate and preparation method thereof - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention provides a palbociclib orotate, wherein the molar ratio of palbociclib to orotic acid in the salt form is 1:1, and the structure is shown in a formula (1):
Description
Technical Field
The invention relates to a palbociclib orotate and a preparation method thereof, belonging to the technical field of medicines and chemistry.
Background
Palbociclib (Palbociclib), chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2- [5- (1-piperazinyl) pyridin-2-ylamino ] -8H-pyrido [2,3-d ] pyrimidin-7-one, is a selective, once daily inhibitor of Cyclin Dependent Kinase (CDK)4/6 developed by feverfew, which was approved for marketing in the united states for the treatment of Estrogen Receptor (ER) -positive, human epidermal growth factor receptor 2(HER2) -negative advanced breast cancer in postmenopausal women in combination with letrozole on 2/3 days 2015.
WO2014128588a1 discloses two crystalline forms of the free base of palbociclib, form a and form B of the free base. WO2016090257a1 discloses that palbociclib comprises isethionate salt forms α, β, γ, δ, epsilon; a sulfate salt form a; phosphate form a; acetate form A, B; l-lactate form A; maleate form A, B; fumarate salt form A, B; citrate crystalline form A, B; succinate crystalline form A, B, C; crystalline form A, B of L-tartrate; glutarate salt form A, B; adipate crystalline form A, B; glycolate form a; ethanesulfonate crystalline form A, B, C; hippurate crystalline form A, B; ethanesulfonate crystal form A, B, and other salt forms.
WO2005005426A1 protects a crystal form A, B, D of palbociclib mono-isethionate, and a preparation method and application thereof, and discloses a related spectrogram of palbociclib mono-mesylate (crystal form A, B, C, D), dimesylate, mono-hydrochloric acid and di-hydrochloric acid.
CN105008357A discloses that the use of the free base form of palbociclib presents challenges for drug development. The free base provided by the conventional salt splitting procedure (e.g. in example 4 of WO2005005426a 1) is very prone to generate static electricity and forms small primary particles which agglomerate into large, hard agglomerates which are difficult to disperse by sieving and are not suitable for further development.
CN107666914A solid dosage form of palbociclib, disclosing that palbociclib is a dibasic (dibasic) compound and has two basic groups with pKa of about 7.3 (secondary piperazine nitrogen) and 4.1 (pyridine nitrogen). The solubility of palbociclib free base is pH dependent. Palbociclib is water soluble at low pH (2.1-4.5), but solubility drops sharply when pH rises above 4.5. Palbociclib had poor water solubility (9 μ g/mL) at pH 7.9. Concomitant administration of agents that increase gastric pH will alter the solubility and absorption of the palbociclib free base formulation.
When administered orally, the absorption and bioavailability of therapeutic agents can be affected by a number of factors, including whether the subject is in a fed or fasted state, certain drugs used, such as Proton Pump Inhibitors (PPIs) or H2 receptor antagonists, and certain medical conditions. Compounds with pH-dependent solubility (particularly basic compounds) may exhibit undesirable pharmacokinetic properties such as poor absorption and/or reduced bioavailability, which may lead to significant inter-and intra-patient variability.
Disclosure of Invention
The invention provides a palbociclib orotate and a preparation method thereof.
According to the crystal form A of the palbociclib orotate, orotic acid is vitamin B13, the palbociclib orotate has a liver protection effect, and a referable solution is provided for toxic and side effects caused by palbociclib in the treatment process. And the stability of the orotate is good, and compared with the free alkali crystal form A, the solubility of the orotate is improved by nearly 10 times.
The invention provides a novel palbociclib salt, namely palbociclib orotate, wherein the molar ratio of palbociclib to orotic acid in the salt form is 1:1, and the structure is shown in a formula (1):
the crystal form A of the palbociclib orotate has characteristic peaks at about 7.56 degrees, 13.02 degrees and 23.14 +/-0.2 degrees in an X-ray powder diffraction pattern detected by Cu-Kalpha radiation.
The crystalline form A of the palbociclib orotate has characteristic peaks at about 7.56, 7.86, 11.90, 13.02, 13.64, 14.12, 18.40 and 23.14 +/-0.2 degrees in an X-ray powder diffraction pattern detected by Cu-Kalpha radiation.
Further, crystalline palbociclib orotate form a has a characteristic peak at about 7.56, 7.86, 9.98, 11.42, 11.90, 13.02, 13.64, 14.12, 14.72, 15.66, 16.66,16.70, 16.96, 17.22, 18.12, 18.40, 18.88, 19.20, 20.60, 22.24, 22.64, 23.14, 23.84, 24.90, 25.40, 25.92, 26.26, 27.44, 28.04, 28.90, 29.72, 30.38, 31.52, 34.06, 34.60, 35.48, 36.30, 36.70, 37.64, 38.10 (+ 0.2) degrees in an X-ray powder diffraction pattern measured using Cu-ka radiation.
Further, the crystalline form A of the palbociclib orotate has an X-ray powder diffraction pattern shown in the attached figure 1 in the specification.
The DSC pattern of the crystalline form A of the palbociclib orotate has an endothermic peak at 300.86 +/-5 ℃;
further, the crystalline form A of the palbociclib orotate has a DSC spectrum shown in the attached figure 2 in the specification.
In some embodiments of the invention, the thermogravimetric analysis (TGA) of form a above shows no significant weight loss at 100 ℃ and 1.87% weight loss of the sample at 200 ℃.
Further, the crystalline form A of the palbociclib orotate has a TGA spectrum shown in the attached figure 3 of the specification.
In some embodiments of the invention, the crystalline palbociclib orotate form a, as shown by a polarizing microscope (PLM), has a granular shape with an average particle size of less than 10 μm.
Further, a polarization microscope (PLM) picture of the crystalline form a of palbociclib orotate is shown in fig. 4.
In some embodiments of the invention, the Particle Size Distribution (PSD) result of the crystalline form a of the palbociclib orotate shows that the particle size of the crystalline form a is normally distributed, and D90 is less than 10 μm; further, D [3,2] is 1.28 μm, D [4,3] is 2.99 μm, Dv (10) is 0.608 μm, Dv (50) is 1.89 μm, and Dv [90] is 5.42 μm.
Further, the crystalline form a of the palbociclib orotate has a PSD spectrum shown in fig. 5.
The invention provides a preparation method of palbociclib orotate (such as crystal form A), which comprises the following steps:
the invention provides a method for preparing palbociclib orotate, which comprises the steps of dissolving palbociclib in a solvent, adding orotate for reaction, stirring for 1-72 hours at the temperature of 20-70 ℃ after the reaction is finished, filtering and drying to obtain the palbociclib orotate.
In the method of the present invention, the temperature is preferably 20 to 50 ℃, and more preferably 20 to 30 ℃.
The method of the present invention, wherein the stirring is performed for at least 12 hours, or at least 16 hours, or at least 24 hours, or 48 hours; further preferably, the stirring time is 12 to 48 hours.
The molar feeding ratio of the palbociclib to the orotate is selected from 1 (1-1.2), more preferably 1 (1-1.05), and further preferably 1 (1-1.02);
the amount of the palbociclib (g) and the amount of the solvent with a proper volume (mL) are selected from 1 (1-30) g/mL, preferably 1 (5-20) g/mL, and more preferably 1 (6-15) g/mL.
In the method of the present invention, the solvent is selected from water or an organic solvent, the organic solvent is selected from one or any combination of an alcohol solvent, an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent and a chloroalkane, and is not limited to these solvents; preferably, the organic solvent is selected from: one or any combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran THF, acetone and dichloromethane, and preferably one or any combination of methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate; more preferably methanol, ethanol or isopropanol.
In the method, the drying is preferably vacuum drying, the drying temperature is 40-50 ℃, and the drying time is 1-24 hours.
The method for the crystal form A of the palbociclib orotate can also be used for selectively adding seed crystals into the solution.
The invention relates to a method for preparing a crystal form A of palbociclib orotate, wherein a seed crystal is obtained by the following method:
preferably, a typical example of the seed crystal according to the present invention includes:
in some preferred schemes of the invention, the invention provides a preparation method of a crystalline form A of palbociclib orotate, wherein the crystalline form A of palbociclib orotate can be obtained by putting 47.7mg (0.1mmol) of palbociclib and 15.6mg (0.1mmol) of orotic acid into a 4mL centrifuge tube, adding 0.5mL of solvent, and stirring at room temperature for 1-3 days.
The invention has the beneficial effects that:
compared with the crystal form A of the free alkali of the palbociclib, the crystal form A of the palbociclib orotate obtained by the invention has higher solubility, and has great significance for improving the drug effect and reducing the drug loading capacity.
The crystal form A of the obtained palbociclib orotate is stored under an open accelerated stability experiment under the conditions of 25 ℃/60% RH and 40 ℃/75% RH, the shape, the color and the crystal form of a sample are not changed, the chemical purity is not obviously changed, and the physicochemical property is stable.
Placing samples of the palbociclib orotate crystal form A and the palbociclib free base crystal form A in pure water at 37 ℃ to prepare saturated solutions, and determining the concentration of the samples in the solutions by High Performance Liquid Chromatography (HPLC) after 1 hour, 4 hours and 8 hours respectively and 24 hours later.
The results of the experiment are shown in table 1:
table 1 comparison study of solubility of crystalline form a of paulib orotate with crystalline form a of the free base
The comparison results of the crystal form A of the palbociclib orotate after completely dissolving and placing for 1 hour, 4 hours, 8 hours and 24 hours show that the palbociclib orotate has higher solubility in pure water than the palbociclib free alkali crystal form A, powder detection XRPD is obtained after the test is finished, and both the palbociclib orotate and the powder detection XRPD have no crystal form change and are palbociclib orotate crystal forms A; and (4) detecting the pH, wherein the result shows that the pH of the solution is 6.52 after the free base test is finished, and the pH of the solution is 6.34 after the test of the palbociclib orotate crystal form A is finished.
Drawings
Figure 1 is an X-ray powder diffraction (XPRD) pattern of crystalline form a of paulib orotate.
Figure 2 is a Differential Scanning Calorimetry (DSC) profile of crystalline form a of pabulib orotate.
Figure 3 is a thermogravimetric analysis (TGA) profile of crystalline form a of pabulib orotate.
Figure 4 is a polarization microscope (PLM) picture of pabulicoxib orotate form a.
Figure 5 is a Particle Size Distribution (PSD) profile of crystalline form a of paulib orotate.
Detailed Description
Example 1 preparation of Palbociclib orotate form A
Weighing 953.6mg (2mmol) of palbociclib and 312.3mg (2mmol) of orotic acid, mixing, putting into a 40mL glass vial, adding 10mL MeOH, magnetically stirring at 500rmp for 2 days at room temperature, performing suction filtration on the obtained material by using filter paper, and performing vacuum drying at 40 ℃ for 24 hours to obtain 1.169g of palbociclib orotate crystal form A, wherein the yield is 92%, and the XRPD pattern of the product is shown in figure 1.
Example 2 XPRD Spectrum Collection of crystalline form A of Palbociclib orotate
XPRD spectrogram is collected on a DX-21700BH diffractometer, and the method parameters of X-ray powder diffraction are as follows:
x-ray reflectance parameters: cu, K alpha
Tube voltage: 40 KV (kV)
Tube current: 40 milliampere (mA)
Slit: 2# scattering slit: 1 °, 3# anti-scatter slit: 1 °, 4# receiving slit: 0.3 mm.
Scanning mode: stepping operation
Step angle: 0.02 °, sampling time: 1 s;
scanning range: from 3.0 to 40.0 degrees
Diffraction results are shown in figure 1 and table 2, and the X-ray powder diffraction pattern of the crystalline form A of the palbociclib orotate has corresponding characteristic diffraction peaks at corresponding positions of a 2 theta value.
Table 2X-ray powder diffraction absorption peak 2 θ values for crystalline form a of paxilb orotate.
Example 3 DSC Spectrum acquisition of Palbociclib orotate form A
DSC spectra were obtained from a TA Instruments Discovery DSC 250 instrument, and the method parameters of differential scanning calorimetry are as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Diffraction results are shown in figure 2, differential scanning calorimetry of crystalline form A of Palbociclib orotate
3-5mg of the sample was weighed into an aluminum crucible, sealed with an unsealed lid, and loaded onto a DSC instrument for collection. The sample was heated from room temperature to 350 ℃ under nitrogen at a scan rate of 10 ℃/min. As shown in FIG. 2, the DSC spectrum showed an endothermic peak at 300.86. + -. 5 ℃.
Example 4 TGA Spectroscopy Collection of Palbociclib orotate form A
TGA spectra were collected on a TA Instruments Discovery TGA 55 instrument, and the thermogravimetric analysis parameters were as follows:
scanning rate: 10 ℃/min
Protective gas: nitrogen gas
Weigh 5-10mg of sample into a platinum pan and load the sample onto the TGA instrument for collection. The sample was heated from room temperature to 500 ℃ at a scan rate of 10 ℃/min under a nitrogen blanket. The data are shown in FIG. 3, where no significant weight loss was detected at 100 ℃ and 1.87% of the sample weight was lost at 200 ℃.
Example 5 stability Studies of Palbociclib orotate form A in various organic solvents
The paulib orotate form a was subjected to a high temperature suspension experiment (50 ℃). And (4) inspecting whether the crystal form A of the palbociclib orotate has crystal transformation phenomenon in different types of common solvents and is stable. Specifically, the organic solvent and water in the following table 3 are adopted, the palbociclib orotate crystal form A is suspended in the organic solvent or water, the suspension temperature is 50 ℃, the suspension amount is about 25mg, the solvent is 1mL, and the suspension time is 72 hours. The experimental conditions and results are shown in Table 3 below. The solid suspended by water and organic solvent has 2 theta characteristic peak of crystal form A through XRPD detection, and the peak is shown in figure 1.
TABLE 3 high temperature 50 ℃ suspension experiment and results
The result shows that the palbociclib orotate crystal form A is subjected to a high-temperature suspension experiment at 50 ℃, and the result shows that the palbociclib orotate crystal form A does not have a crystal transformation phenomenon in common solvents such as ethanol, acetone, ethyl acetate, acetonitrile, water or dichloromethane, so that the palbociclib orotate crystal form A can be proved to be the most thermodynamically stable crystal form.
Example 6 Palbociclib orotate form A equilibrium solubility contrast with Palbociclib form A
Weighing about 150mg of the palbociclib orotate crystal form A and the palbociclib free base crystal form A, dissolving the palbociclib orotate crystal form A and the palbociclib free base crystal form A in 10mL of pure water at 37 ℃, stirring at the rotating speed of 500 r/min to prepare saturated solutions, and measuring the concentration of a sample in the solutions by High Performance Liquid Chromatography (HPLC) after 1 hour, 4 hours and 24 hours respectively. The results of the experiment are shown in table 1. Compared with the crystal form A of the free base of the palbociclib, the solubility of the palbociclib orotate crystal form A is improved by 6-9 times.
Example 7 stability assessment of Palbociclib orotate form A
About 150mg of the crystalline form a of the palbociclib orotate was weighed, placed in an open environment at 25 ℃/60% RH and 40 ℃/75% RH for accelerated humidity stability testing, and the points were taken at 1/2/4 weeks, respectively, tested for XRPD and HPLC, and observed for changes in physicochemical properties, with the results shown in table 3.
Table 3 stability assessment of the crystalline form a of paulib orotate
The results show that the palbociclib orotate crystal form A does not have a crystal transformation phenomenon and the product purity does not obviously change under the accelerated stability test evaluation of the palbociclib orotate crystal form A at 40 ℃/75% RH/open and 25 ℃/60% RH/open, and the palbociclib orotate crystal form A is proved to have excellent physical and chemical stability.
In conclusion, the obtained crystalline form A of the palbociclib orotate is the most thermodynamically stable crystalline form, has unique powder XRD and DSC fingerprint spectrums, is stable in physical and chemical properties, and has equilibrium solubility which is 10 times higher than that of the palbociclib free base crystalline form A, so that the palbociclib orotate crystalline form A has excellent characteristics of being developed into a pharmaceutical preparation.
Claims (10)
1. The structure of the palbociclib orotate is shown as the formula 1:
2. the paxilb orotate of claim 1, wherein said paxilb orotate is form a, having characteristic peaks in 2 Θ at 7.56, 13.02 and 23.14 ± 0.2 degrees in an X-ray powder diffraction pattern measured using Cu-ka radiation; further preferably, there are characteristic peaks at 7.56, 7.86, 11.90, 13.02, 13.64, 14.12, 18.40 and 23.14 ± 0.2 degrees.
3. The paulib orotate of claim 2, further characterized in that said crystalline form a of paulib orotate has characteristic 2 Θ peaks at 7.56, 7.86, 9.98, 11.42, 11.90, 13.02, 13.64, 14.12, 14.72, 15.66, 16.66,16.70, 16.96, 17.22, 18.12, 18.40, 18.88, 19.20, 20.60, 22.24, 22.64, 23.14, 23.84, 24.90, 25.40, 25.92, 26.26, 27.44, 28.04, 28.90, 29.72, 30.38, 31.52, 34.06, 34.60, 35.48, 36.30, 36.70, 37.64 and 38.10 ± 0.2 degrees in an X-ray powder diffraction pattern measured using Cu-ka radiation; further preferably, the palbociclib orotate crystal form A has an X-ray powder diffraction pattern shown in the attached figure 1 in the specification.
4. The paxilib orotate according to any of claims 1 to 3, wherein said paxilib orotate is form A, having a DSC profile with an endothermic peak at 300.86 ± 5 ℃.
5. The paxilib orotate according to any one of claims 1 to 3, wherein the paxilib orotate is form A, the thermogravimetric analysis curve TGA of form A shows no significant weight loss at 100 ℃ and a sample weight loss of 1.87% at 200 ℃.
6. The paxilib orotate according to any of claims 1 to 3, wherein said paxilib orotate is form A, which is shown under a polarizing microscope (PLM), the crystals are in the form of particles with D90 less than 10 μm.
7. A process for the preparation of the pamicib orotate salt of claims 1 to 3, wherein said pamicib orotate salt is form a, comprising the steps of: dissolving the palbociclib in a solvent, adding orotate for reaction, stirring at the temperature of 20-70 ℃ for 1-72 hours after the reaction is finished, filtering, and drying to obtain the palbociclib.
8. The method according to claim 7, wherein the temperature is preferably 20 to 50 ℃, and more preferably 20 to 30 ℃; the stirring time is at least 12 hours, or at least 16 hours, or at least 24 hours, or 48 hours, and further preferably 12 to 48 hours.
9. The preparation method according to claim 7, wherein the molar inventory ratio of the palbociclib to the orotate is selected from 1 (1-1.2), more preferably 1 (1-1.05), and further preferably 1 (1-1.02); the dosage (g) of the palbociclib and the dosage (mL) of the solvent volume are selected from 1 (1-30) g/mL, preferably 1 (5-20) g/mL, and more preferably 1 (6-15) g/mL.
10. The preparation method according to claim 7, wherein the solvent is selected from water or an organic solvent, and the organic solvent is selected from one or any combination of an alcohol solvent, an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent and a chloroalkane; preferably, the organic solvent is selected from: one or any combination of methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, 1, 4-dioxane, tetrahydrofuran THF, acetone and dichloromethane, and preferably one or any combination of methanol, ethanol, isopropanol, ethyl acetate and isopropyl acetate; more preferably methanol, ethanol or isopropanol or any combination thereof; and drying, preferably vacuum drying, wherein the drying temperature is 40-50 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1835951A (en) * | 2003-07-11 | 2006-09-20 | 沃尼尔·朗伯有限责任公司 | Isethionate salt of a selective CDK4 inhibitor |
| CN103130660A (en) * | 2011-11-25 | 2013-06-05 | 厦门福满药业有限公司 | Acidic salt and crystal of dapoxetine and preparation method of crystal |
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| CN105418603A (en) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib |
| CN106336411A (en) * | 2016-04-27 | 2017-01-18 | 上海医药集团股份有限公司 | Preparation method and use of CDK4/6 inhibitor palbociclib highly-pure raw drug |
| WO2017197904A2 (en) * | 2016-05-08 | 2017-11-23 | 上海诚妙医药科技有限公司 | New crystal forms of palbociclib, and preparation method and use therefor |
| CN108210454A (en) * | 2016-12-14 | 2018-06-29 | 深圳市华力康生物医药有限公司 | A kind of Orally taken emulsion of Pabuk former times profit cloth and preparation method thereof |
-
2021
- 2021-10-26 CN CN202111247721.9A patent/CN113845520A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1835951A (en) * | 2003-07-11 | 2006-09-20 | 沃尼尔·朗伯有限责任公司 | Isethionate salt of a selective CDK4 inhibitor |
| CN103130660A (en) * | 2011-11-25 | 2013-06-05 | 厦门福满药业有限公司 | Acidic salt and crystal of dapoxetine and preparation method of crystal |
| CN105008357A (en) * | 2013-02-21 | 2015-10-28 | 辉瑞大药厂 | Solid forms of a selective CDK4/6 inhibitor |
| CN105418603A (en) * | 2015-11-17 | 2016-03-23 | 重庆莱美药业股份有限公司 | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib |
| CN106336411A (en) * | 2016-04-27 | 2017-01-18 | 上海医药集团股份有限公司 | Preparation method and use of CDK4/6 inhibitor palbociclib highly-pure raw drug |
| WO2017197904A2 (en) * | 2016-05-08 | 2017-11-23 | 上海诚妙医药科技有限公司 | New crystal forms of palbociclib, and preparation method and use therefor |
| CN108210454A (en) * | 2016-12-14 | 2018-06-29 | 深圳市华力康生物医药有限公司 | A kind of Orally taken emulsion of Pabuk former times profit cloth and preparation method thereof |
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