WO2017067506A1 - 帕博西尼的新晶型 - Google Patents

帕博西尼的新晶型 Download PDF

Info

Publication number
WO2017067506A1
WO2017067506A1 PCT/CN2016/102876 CN2016102876W WO2017067506A1 WO 2017067506 A1 WO2017067506 A1 WO 2017067506A1 CN 2016102876 W CN2016102876 W CN 2016102876W WO 2017067506 A1 WO2017067506 A1 WO 2017067506A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal form
ray powder
diffraction pattern
powder diffraction
peak
Prior art date
Application number
PCT/CN2016/102876
Other languages
English (en)
French (fr)
Inventor
陈敏华
张炎锋
杨朝惠
杨存波
张晓宇
Original Assignee
苏州晶云药物科技有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 苏州晶云药物科技有限公司 filed Critical 苏州晶云药物科技有限公司
Publication of WO2017067506A1 publication Critical patent/WO2017067506A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the invention relates to the field of chemical medicine, in particular to a crystal form of paboxini and a preparation method thereof.
  • Palbociclib (a compound of formula I) is a cell cycle-dependent kinase (CDK4/6) inhibitor developed by Pfizer, and received the FDA's "breakthrough therapy” in April 2013. qualifications. Phase III clinical trials have shown that paboxini can reverse the drug resistance of endocrine therapy in breast cancer patients. On February 5, 2015, Pabusini made a trade name. Listed in the United States for the treatment of ER+/HER2-post-menopausal advanced breast cancer.
  • WO2014128588 reports Form A and Form B of Paboxini free base, and discloses that the Pabsini free base is in many solvents including but not limited to isopropanol, isobutanol, ethanol, toluene, tetrahydrofuran, etc.
  • the crystals obtained by the intermediate recrystallization are all crystalline form A, and WO2014128588 does not report how the crystalline form B is obtained, but it is disclosed that the crystalline form A is more stable than the crystalline form B.
  • One of the objects of the present invention is to provide a variety of new crystal forms of Pabsini, designated as Form IX, Form X, and Form XII, respectively.
  • Another object of the present invention is to provide a method and use for the preparation of the above novel crystal form.
  • the present invention provides a crystalline form IX of Paboxini with an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C at a value of 16.8 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 24.3 Characteristic peak at ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Formos IX of Paboxini is also one or more of the 2theta values of 23.1 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 4.8 ° ⁇ 0.2 ° Has a diffraction peak. Further and/or preferably, the X-ray powder diffraction pattern of Forms IX of Paboxini is also one or more of 2theta values of 20.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 20.2° ⁇ 0.2°. Has a diffraction peak.
  • the X-ray powder diffraction pattern of Formosa IX of Paboxini has characteristic peaks at 16.8 ° ⁇ 0.2 °, 8.4 ° ⁇ 0.2 °, 24.3 ° ⁇ 0.2 ° There are diffraction peaks at 23.1 ° ⁇ 0.2 °, 11.8 ° ⁇ 0.2 °, 4.8 ° ⁇ 0.2 °, 20.7 ° ⁇ 0.2 °, 13.7 ° ⁇ 0.2 °, and 20.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Formos IX of Paboxini has a 2theta value of 23.1° ⁇ 0.2° and/or 20.2° ⁇ 0.2° in addition to the characteristic peaks described. Diffraction peaks.
  • the peak intensity of the characteristic peak is 30% or more, more preferably 50% or more.
  • the peak intensity of the characteristic peak at a 2theta value of 16.8 ° ⁇ 0.2 ° is the largest.
  • the X-ray powder diffraction pattern of Form IX is as shown in FIG.
  • the crystalline form IX provided by the present invention begins to exhibit an endothermic peak near heating to about 62 ° C, and an endothermic peak begins to appear near heating to 263 ° C.
  • the differential scanning calorimetry diagram is substantially as shown in FIG. 2 . Show.
  • the crystalline form IX provided by the present invention has a weight loss gradient of about 4.3% when heated to 100 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
  • the present invention also provides a crystal form X of Paboxini with an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C in 2theta values of 21.5 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 17.5 ° ⁇ 0.2 ° There are characteristic peaks.
  • the X-ray powder diffraction pattern of Formos X of Paboxini has a diffraction peak at one or more of the 2theta values of 7.8 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, and 12.0 ° ⁇ 0.2 °. Further and/or preferably, the X-ray powder diffraction pattern also has diffraction peaks at one or more of the 2theta values of 10.0° ⁇ 0.2°, 4.9° ⁇ 0.2°, and 8.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form X of Paboxini is at 2theta values of 21.5° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.5 ° ⁇ 0.2°. It has characteristic peaks with diffraction peaks at 2theta values of 7.8° ⁇ 0.2°, 20.5° ⁇ 0.2°, 12.0° ⁇ 0.2°, 10.0° ⁇ 0.2°, 4.9° ⁇ 0.2°, and 8.5° ⁇ 0.2°.
  • the intensity of the characteristic peak at a 2theta value of 21.5° ⁇ 0.2° is greater than or equal to 10%.
  • the intensity of the characteristic peak at a 2theta value of 17.5 ° ⁇ 0.2 ° is 20% or more.
  • the X-ray powder diffraction pattern of the crystal form X of Paboxini at 25 ° C (CuK ⁇ ) Radiation) has a characteristic peak at 2theta values of 21.4° to 21.7°, 16.9° to 17.2°, and 17.4° to 17.7°, and has a value of 7.8° to 8.0°, 20.5° to 20.7°, and 12.0° to 12.2° at 2theta.
  • One or more of 10.0° to 10.2°, 4.9° to 5.1°, and 8.5° to 8.7° have diffraction peaks. More preferably, the diffraction peak is obtained at a 2theta value of 7.8 to 8.0, 20.5 to 20.7, 12.0 to 12.2, 10.0 to 10.2, 4.9 to 5.1, and 8.5 to 8.7.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the crystal form X of Paboxini at 25 ° C has a 2theta value of 10.4 ° ⁇ 0.2 ° in addition to the aforementioned characteristic peaks. Diffraction peaks.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of the crystal form X of Paboxini at 25 ° C is in addition to the aforementioned characteristic peak, and the value of 2theta is also 19.9 ° ⁇ 0.2 ° and / or 23.0 ° ⁇ 0.2 ° has a diffraction peak.
  • the peak intensity of the diffraction peak at a 2theta value of 19.9 ° ⁇ 0.2 ° is 20% or more, more preferably 25% or more, and most preferably 30% or more.
  • the peak intensity of the diffraction peak at a 2theta value of 23.0 ⁇ 0.2° is 35% or more, more preferably 45% or more, and most preferably 55% or more.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C has a diffraction peak at a 2theta value of 6.9 ⁇ 0.2° and a diffraction peak intensity of 10% or more; and/or
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C also has a diffraction peak at 24.4 ⁇ 0.2 ° and a diffraction peak intensity of 20% or more.
  • the peak intensity of the diffraction peak at a 2theta value of 6.9 ⁇ 0.2° is 25% or more, more preferably 30% or more; and the peak intensity of the diffraction peak at a 2theta value of 24.4 ⁇ 0.2° is 30% or more. More preferably, it is 40% or more, and most preferably 50% or more.
  • the Form X is as X-1 of Example 2, and its X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C is substantially as shown in FIG. Further, a total of 29 diffraction peaks were shown in the X-ray diffraction pattern of the crystal form X, and the positions and peak intensities of these diffraction peaks are shown in Table 2.
  • the crystal form X begins to show an endothermic peak near heating to 259 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 5 .
  • the crystal form X when subjected to thermogravimetric analysis, had a weight loss gradient of about 0.7% when heated to 120 ° C, and the thermogravimetric analysis chart is shown in FIG. 6 .
  • the crystal form X is as X-2 in Example 3, and its X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C is substantially as shown in FIG.
  • the crystal form X when performing differential scanning calorimetry, begins to show an endothermic peak near heating to 51 ° C, and an endothermic peak begins to appear near heating to 266 ° C, and the differential scanning calorimetry chart is basically As shown in Figure 8.
  • the crystal form X when subjected to thermogravimetric analysis, had a weight loss gradient of about 0.8% when heated to 250 ° C, and the thermogravimetric analysis chart is shown in FIG.
  • the crystal form X such as X-3 in Example 4 has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C substantially as shown in FIG.
  • the present invention also provides a crystalline form XI having an X-ray powder diffraction pattern (CuK ⁇ radiation) having characteristic peaks at 2theta values of 21.7 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, and 12.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form XI has a diffraction peak at one or more of the 2theta values of 17.7 ° ⁇ 0.2 °, 10.1 ° ⁇ 0.2 °, and 10.4 ° ⁇ 0.2 °. Further, the X-ray powder diffraction pattern of Form XI has a diffraction peak at one or more of the 2theta values of 7.9 ° ⁇ 0.2 °, 5.1 ° ⁇ 0.2 °, and 17.1 ° ⁇ 0.2 °. Preferably, Form XI has a diffraction peak at the aforementioned six 2theta values.
  • the X-ray powder diffraction pattern (CuK ⁇ radiation) of Form XI at 25 ° C is the same as X-2 in Example 3.
  • the invention also provides a crystal form XII of Paboxini with an X-ray powder diffraction pattern (CuK ⁇ radiation) having characteristic peaks at 2theta values of 21.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 20.5° ⁇ 0.2°. .
  • the X-ray powder diffraction pattern of the crystal form XII of Pabsini has a diffraction peak at one or more of the 2theta values of 18.7° ⁇ 0.2°, 10.2° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form XII of Pabusini has a diffraction peak at one or more of the 2theta values of 17.1 ° ⁇ 0.2 °, 19.6 ° ⁇ 0.2 °, and 11.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal form XII of Paboxini has a characteristic peak at 2theta values of 21.4° ⁇ 0.2°, 22.4° ⁇ 0.2°, 20.5 ° ⁇ 0.2°, at a 2theta value
  • the X-ray powder diffraction pattern of the crystal form XII of Pabotini is substantially as shown in FIG.
  • the crystalline form XII provided by the present invention begins to exhibit an endothermic peak near the temperature of 275 ° C when subjected to differential scanning calorimetry, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • the crystalline form XII provided by the present invention has a weight loss gradient of about 0.4% when heated to 250 ° C when subjected to thermogravimetric analysis, and the thermogravimetric analysis chart is shown in FIG.
  • the present invention also provides a process for the preparation of the above crystal form.
  • the present invention provides a process for the preparation of the above Form IX, which comprises: dissolving the free form of Pabsini in a mixed system of a halogenated hydrocarbon, an alcohol and water at 0 to -40 ° C The temperature was slowly volatilized to a solid precipitation at a temperature of (minus 40 ° C), and the obtained solid was further dried at a temperature of from 0 to -40 °C. Among them, volatilization and drying are preferably carried out at 0 to -20 ° C, more preferably at -10 to -20 ° C, respectively.
  • the halogenated hydrocarbon is preferably dichloromethane or a mixture of dichloromethane and other halogenated hydrocarbons; the alcohol solvent is preferably methanol or a mixture of methanol and other alcohols.
  • the volume fraction of water is preferably from 1% to 20%, more preferably from 2% to 10%, according to a specific aspect, the volume of water The score is 3% to 5%.
  • the volume ratio of the halogenated hydrocarbon to the alcohol may be from 0.1 to 10:1, preferably from 1 to 10:1, more preferably from 2 to 5:1. In a specific embodiment, the volume ratio of the halogenated hydrocarbon to the alcohol is 3:1.
  • the present invention also provides a method for preparing Form X, which comprises: obtaining a Form X of the Pobosine Form IX under heating, the heating condition being 80 ° C to 240 ° C.
  • the heating condition is 80 to 120 °C.
  • the present invention also provides a method for preparing Form X/Form XI, which comprises dissolving the free form of Pabsini in a mixed system of a halogenated hydrocarbon and an alcohol at 25 to -40 ° C (minus 40 ° C)
  • the temperature is slowly volatilized, and the solid obtained by volatilization is heated to 50-150 ° C to obtain.
  • the heating condition is about 120 °C.
  • the volatilization is preferably carried out at 0 to -20 ° C (minus 20 ° C), more preferably at -10 to 20 ° C.
  • the halogenated hydrocarbon is preferably dichloromethane or a mixture of dichloromethane and other halogenated hydrocarbons;
  • the alcohol solvent is preferably methanol or a mixture of methanol and other alcohols.
  • the volume ratio of the halogenated hydrocarbon to the alcohol may be from 0.1 to 10:1, preferably from 1 to 10:1, more preferably from 2 to 5:1. In a specific embodiment, the volume ratio of the halogenated hydrocarbon to the alcohol is 3:1.
  • the invention also provides a preparation method of Form XII, which comprises dissolving the free form of Pabsini in a mixed system of a halogenated hydrocarbon and an alcohol, and slowly at a temperature of 25 to -40 ° C (minus 40 ° C) Volatilization is carried out by heating the solid obtained by volatilization to 260-275 ° C, wherein volatilization is preferably carried out at 10 to -20 ° C, more preferably at -10 to -20 ° C.
  • the halogenated hydrocarbon is preferably dichloromethane or a mixture of dichloromethane and other halogenated hydrocarbons;
  • the alcohol solvent is preferably methanol or a mixture of methanol and other alcohols.
  • the volume ratio of the halogenated hydrocarbon to the alcohol may be from 0.1 to 10:1, preferably from 1 to 10:1, more preferably from 2 to 5:1. In a specific embodiment, the volume ratio of the halogenated hydrocarbon to the alcohol is 3:1.
  • the heating temperature is about 263 to 270 °C.
  • Form XII of the present invention can be obtained by heating Form IX or Form X or Form XI to 260-275 °C.
  • a third object of the present invention is to provide a pharmaceutical composition comprising an effective amount of Form IX, Form X or Form XII or any combination thereof and a pharmaceutically acceptable adjuvant.
  • the pharmaceutical composition is particularly suitable for the treatment of cancer.
  • a fourth object of the present invention is to provide a use of a combination of one or more of the above crystalline forms for the preparation of a medicament for the treatment of an anticancer drug.
  • the Pabsini or Pabsini free form or the Pabsini free base as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil of the compound of the formula (I). form.
  • the Pabsini as a raw material is in the form of a solid powder. Specifically, for example, Pabsini crystal form A disclosed in WO2014128588.
  • the present invention has the following advantages compared with the prior art:
  • the present invention provides various new crystal forms of Pabsini, which have higher solubility and more suitable medicinal particle size distribution and morphology than the existing crystal forms, and include Pabsini.
  • the preparation of pharmaceutical preparations provides new and better choices and is of great importance for drug development.
  • Example 1 is an XRPD pattern of the Paboxini Form IX prepared in Example 1;
  • Example 2 is a DSC chart of the Pabsini crystal form IX prepared in Example 1;
  • Example 3 is a TGA diagram of the Paboxini Form IX prepared in Example 1;
  • Example 4 is an XRPD pattern of the Pabsini crystal form X prepared in Example 2;
  • Figure 5 is a DSC chart of the Paboxini Form X prepared in Example 2.
  • Example 6 is a TGA diagram of the Paboxini Form X prepared in Example 2.
  • Example 7 is an XRPD pattern of the Pabsini crystal form X prepared in Example 3.
  • Figure 8 is a DSC chart of the Paboxini Form X prepared in Example 3.
  • Figure 9 is a TGA diagram of the Paboxini Form X prepared in Example 3.
  • Figure 10 is an XRPD pattern of the Paboxini Form X prepared in Example 4.
  • Figure 11 is an XRPD pattern of the Paboxini Form XII prepared in Example 5.
  • Figure 12 is a DSC chart of the Paboxini Form XII prepared in Example 5.
  • Figure 13 is a TGA diagram of the Paboxini Form XII prepared in Example 5.
  • Figure 14 is a polarizing microscope (PLM) diagram of Form IX prepared in Example 1;
  • Figure 15 is a particle size distribution diagram of Form X prepared in Example 2.
  • Figure 16 is a comparison of XRPD of Form X prepared in Example 2 before and after being placed at 25 ° C / 60% relative humidity for 1 month (the upper graph shows the XRPD pattern of the pre-placement X), and the lower graph shows the crystal after placement. X-ray image of type X);
  • Figure 17 is an XRPD of Form X prepared in Example 2, placed at 40 ° C / 75% relative humidity for 1 month before and after. Comparison chart (the upper image shows the XRPD pattern of the former crystal form X, and the lower image shows the XRPD pattern of the crystal form X after the placement);
  • Figure 19 is a DVS diagram of Form X prepared in Example 2.
  • PLM 21 is a polarizing microscope (PLM) diagram of the Pabsini crystal form XII prepared in Example 5.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those 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, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or exhibiting a disease or condition of the disease, disorder or disorder; and (3) Ameliorating the disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a condition or symptom of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a lesion that may be predisposed to a disease, disorder or disorder, but has not yet suffered or shows the disease or Preventing the disease, condition or disorder in the symptomatic individual
  • inhibiting the disease for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • pharmaceutically acceptable excipient means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulated Substance or blending aid.
  • materials useful as pharmaceutical excipients are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose And cellulose acetate; powdered xanthine; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Glycols, such as propylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic moisture adsorption
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of differential scanning calorimetry (DSC) according to the present invention are as follows: scan rate: 10 ° C / min;
  • thermogravimetric analysis (TGA) map of the present invention was collected on a TAQ5000.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows: scan rate: 10 ° C / min; protective gas: nitrogen.
  • the particle size distribution results of the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates a particle diameter corresponding to 90% of the particle size distribution (volume distribution).
  • Pabsini solid powder 500.0 mg was added to a glass vial, then 14.4 mL of dichloromethane, 4.8 mL of methanol and 0.8 mL of water were added, dissolved at room temperature and allowed to stand at -20 ° C, and 1.5 ml of solution was taken. Filtration, the filtrate was slowly evaporated to dryness at -20 ° C, and the resulting solid was tested for XRPD, DSC and TGA.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 1.
  • the XRPD pattern is shown in Fig. 1
  • the DSC chart is shown in Fig. 2
  • the TGA chart is shown in Fig. 3.
  • the diffraction peaks at 2theta values of 16.78°, 8.39° and 24.32° are characteristic peaks, and the 2theta values are 23.14° and 11.84°.
  • the diffraction peak at 4.84° is an important peak
  • the diffraction peak at 2theta values of 20.69°, 13.70°, and 20.22° is the second most important peak.
  • Pabsini solid powder 500.0 mg was added to a glass vial, then 14.4 mL of dichloromethane, 4.8 mL of methanol and 0.8 mL of water were added, dissolved at room temperature and allowed to stand at -20 ° C, and 1.5 mL was taken. The solution was filtered, the filtrate was slowly evaporated at -20 ° C, and the dried solid was heated to 120 ° C. The obtained solids were tested for XRPD, DSC and TGA.
  • the solid obtained in this example was designated as X-1.
  • the X-ray powder diffraction data is shown in Table 2. Its XRPD diagram is shown in Figure 4, its DSC diagram is shown in Figure 5, and its TGA diagram is shown in Figure 6. Considering various factors such as d value, low angle, intensity, characteristic line and peak shape integrity, the diffraction peaks at 2theta values of 21.54°, 17.02°, and 17.54° are characteristic peaks, and the 2theta value is The diffraction peaks at 7.81°, 20.49°, and 12.00° are important peaks, and the diffraction peaks at 2theta values of 10.02°, 4.98°, and 8.54° are the most important peaks.
  • the solid obtained in this example is denoted as X-2, the XRPD pattern thereof is shown in Fig. 7, the DSC chart is shown in Fig. 8, and the TGA chart is shown in Fig. 9.
  • the X-ray powder diffraction data contained the peaks shown in Table 3.
  • the XRPD pattern of the solid obtained in this embodiment is shown in Fig. 11, the DSC chart is shown in Fig. 12, and the TGA chart is shown in Fig. 13.
  • the X-ray powder diffraction data contained the peaks shown in Table 5.
  • the grain morphology of the crystal form IX was observed by a polarizing microscope. The results are shown in Fig. 14. As can be seen from the figure, the morphology of the crystal form IX is short rod-shaped, and the short rod shape is favorable for the filtration operation in the process.
  • the crystallite size A has a D10 of between 5 and 10 microns, a D50 of between 10 and 45 microns, and a D90 of between 30 and 125 microns.
  • the D90 of the crystalline form IX obtained by the invention is 90% of the particles smaller than 24.11 micrometers
  • the D50 is 50% of the particles is less than 10.28 micrometers
  • the D10 that is, the 10% particles are less than 4.53 micrometers
  • the crystal size of the crystal form can be seen from the existing ones.
  • the crystal form A is slightly reduced and narrow in distribution. It is a very suitable particle size, which not only ensures the dissolution rate of the drug, but also facilitates drug absorption and improves bioavailability; it is not easy to agglomerate and maintain good fluidity.
  • Example 2 The X-1 and Form A samples prepared in Example 2 were made into a saturated solution with pure water, and the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The content of the sample. The experimental results are shown in Table 7.
  • the crystal form X of the present invention has a higher solubility than the existing crystal form A after 4 hours and 24 hours after standing in pure water for 1 hour.
  • the crystallite size A has a D10 of between 5 and 10 microns, a D50 of between 10 and 45 microns, a D90 of between 30 and 125 microns and a specific surface area of less than 2 m 2 /g.
  • the D90 of X-1 of Example 2 obtained by the present invention that is, 90% of the particles is less than 21.35 micrometers
  • D50, that is, 50% of the particles is less than 7.44 micrometers
  • D10 that is, 10% of the particles is less than 2.65 micrometers, a single point of X-1.
  • the specific surface area is 5.2666 m 2 /g
  • the multi-layer adsorption BET specific surface area is 5.4090 m 2 /g. It can be seen that the crystal form has a small particle size and a narrow particle size distribution, which can increase the surface area of the drug and is advantageous for increasing the dissolution rate of the drug. It is conducive to drug absorption and improves bioavailability and efficacy.
  • the X-1 prepared in Example 2 was placed at 25 ° C / 60% RH, 40 ° C / 75% RH and 60 ° C / 75% RH, respectively. After 1 month, the solid test XRPD was taken out. The results are shown in Figures 16-18. It can be seen that the crystal form X has not changed before and after the standing, indicating that the crystal form X has good stability.
  • the X-2 and Form A samples prepared in Example 3 were made into a saturated solution with pH 5.0 FeSSIF (intestines in the fed state), and subjected to high performance liquid chromatography after 1 hour, 4 hours, and 24 hours ( The content of the sample in the saturated solution was determined by HPLC method. The experimental results are shown in Table 9.
  • the particles of X-2 are finer and more uniform than the existing crystal form A.
  • the small particles are beneficial to improve the solubility of the drug, increase the bioavailability of the drug, facilitate drug absorption, and improve the organism. Utilization. Uniform dispersion of particle size facilitates the development of the formulation process.
  • the crystal form XII and the crystal form A sample prepared in Example 5 were made into a saturated solution by SGF (simulated artificial gastric juice), and determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours and 24 hours. The amount of sample in a saturated solution.
  • SGF simulated artificial gastric juice
  • HPLC high performance liquid chromatography
  • the crystal form XII of the present invention has higher solubility than the existing crystal form A after 4 hours and 24 hours.
  • the morphology of the crystal form XII is short rod-shaped, and the short rod shape is advantageous for the filtration operation in the process.
  • the crystal form XII has a smaller particle size and a narrow particle size distribution than the existing crystal form A, which can increase the surface area of the drug, is advantageous for increasing the dissolution rate of the drug, and is advantageous for drug absorption. Improve bioavailability.

Abstract

本发明涉及帕博西尼的新晶型IX、晶型X以及晶型XII及它们的制备方法和用途，其中晶型IX的X射线粉末衍射图在2theta值为16.8°±0.2°、8.4°±0.2°、24.3°±0.2°处具有特征峰；晶型X的X射线粉末衍射图在2theta值为21.5°±0.2°、17.0°±0.2°、17.5°±0.2°处具有特征峰；晶型XII的X射线粉末衍射图在2theta值为21.4°±0.2°、22.4°±0.2°、20.5°±0.2°处具有特征峰。本发明晶型与现有晶型相比具有更高的溶解度和更适于药用的粒径分布和形态，为含帕博西尼的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。

Description

帕博西尼的新晶型 技术领域
本发明涉及化学医药领域，特别是涉及帕博西尼的晶型及其制备方法。
背景技术
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型的存在或多晶型形式的数量均不可预见。另外，在什么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式，包括所有的多晶型形式，对于提供具有改善的性能例如储存稳定性、良好溶解度特性以及工艺可操作性等的药物是非常必要的。
帕博西尼(Palbociclib，式I所示化合物)是由辉瑞(Pfizer)公司开发的一种细胞周期依赖性激酶(CDK4/6)抑制剂，2013年4月获得美国FDA的″突破性疗法″资格。III期临床试验研究结果显示，帕博西尼可以逆转乳腺癌患者内分泌治疗的耐药性。2015年2月5日，帕博西尼以商品名
Figure PCTCN2016102876-appb-000001
在美国上市，用于治疗ER+/HER2-绝经后晚期乳腺癌。
Figure PCTCN2016102876-appb-000002
目前，关于帕博西尼游离碱或其盐的制备方法的专利有WO2003/062236，US6,936,612，US7,208,489，US7,456,168，WO2005/005426，US7,345,171，US7,863,278，CN201410691233.0，CN 201410693091.1，WO2014128588等。其中WO2014128588报道了帕博西尼游离碱的晶型A和晶型B，并公开了将帕博西尼游离碱在很多溶剂包括但不限于异丙醇，异丁醇，乙醇，甲苯，四氢呋喃等中重结晶得到的均是晶型A，WO2014128588没有报道晶型B是如何获得的，但是公开了晶型A比晶型B更稳定。
发明内容
本发明的目的之一是提供多种帕博西尼的新晶型，分别命名为晶型IX、晶型X以及晶型XII。
本发明的目的之二是提供上述新晶型的制备方法和用途。
为实现上述目的，本发明提供一种帕博西尼的晶型IX，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为16.8°±0.2°、8.4°±0.2°、24.3°±0.2°处具有特征峰。
根据本发明的一个方面，帕博西尼的晶型IX的X射线粉末衍射图还在2theta值为23.1°±0.2°、11.8°±0.2°、4.8°±0.2°中的一处或多处具有衍射峰。进一步和/或优选地，帕博西尼的晶型IX的X射线粉末衍射图还在2theta值为20.7°±0.2°、13.7°±0.2°、20.2°±0.2°中的一处或多处具有衍射峰。
在根据本发明的一个具体且优选的实施方案中，帕博西尼的晶型IX的X射线粉末衍射图在16.8°±0.2°、8.4°±0.2°、24.3°±0.2°处具有特征峰，在23.1°±0.2°、11.8°±0.2°、4.8°±0.2°、20.7°±0.2°、13.7°±0.2°、20.2°±0.2°处均具有衍射峰。
根据本发明又一个方面，帕博西尼的晶型IX的X射线粉末衍射图除了具有所述的特征峰外，还在2theta值为23.1°±0.2°和/或20.2°±0.2°处具有衍射峰。
作为本发明的一种优选方案：所述特征峰的峰强度大于等于30％，更优选大于等于50％。
作为本发明的又一优选方案：2theta值为16.8°±0.2°处的特征峰的峰强度最大。
根据本发明的一个具体且优选方面，晶型IX的X射线粉末衍射图如图1所示。
优选地，本发明提供的晶型IX，在加热至62℃附近开始出现一个吸热峰，在加热至263℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图2所示。
优选地，本发明提供的晶型IX，加热至100℃时，具有约4.3％的重量损失梯度，其热重分析图如图3所示。
本发明还提供一种帕博西尼的晶型X，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为21.5°±0.2°、17.0°±0.2°、17.5°±0.2°处具有特征峰。
进一步地，帕博西尼的晶型X的X射线粉末衍射图还在2theta值为7.8°±0.2°、20.5°±0.2°、12.0°±0.2°中的一处或多处具有衍射峰。进一步地和/或优选地，X射线粉末衍射图还在2theta值为10.0°±0.2°、4.9°±0.2°、8.5°±0.2°中的一处或多处具有衍射峰。
在根据本发明的一个具体且优选的实施方案中，帕博西尼的晶型X的X射线粉末衍射图在2theta值为21.5°±0.2°、17.0°±0.2°、17.5°±0.2°处具有特征峰，在2theta值为7.8°±0.2°、20.5°±0.2°、12.0°±0.2°、10.0°±0.2°、4.9°±0.2°、8.5°±0.2°处具有衍射峰。
根据本发明的一个优选方面，2theta值为21.5°±0.2°处的特征峰的强度大于等于10％。
根据本发明的又一优选方面，2theta值为17.5°±0.2°处的特征峰的强度大于等于20％。
根据本发明的又一优选方面，帕博西尼的晶型X在25℃下的X射线粉末衍射图(CuKα 辐射)在2theta值为21.4°～21.7°、16.9°～17.2°、17.4°～17.7°处具有特征峰，在2theta值为7.8°～8.0°、20.5°～20.7°、12.0°～12.2°、10.0°～10.2°、4.9°～5.1°、8.5°～8.7°中的一处或多处具有衍射峰。更优选地，在2theta值为7.8°～8.0°、20.5°～20.7°、12.0°～12.2°、10.0°～10.2°、4.9°～5.1°、8.5°～8.7°处均具有衍射峰。
根据本发明的一个具体且优选方面，帕博西尼的晶型X在25℃下的X射线粉末衍射图(CuKα辐射)除了前述特征峰外，还在2theta值为10.4°±0.2°处具有衍射峰。
根据本发明的又一具体且优选方面，帕博西尼的晶型X在25℃下的X射线粉末衍射图(CuKα辐射)除了前述特征峰外，还在2theta值为19.9°±0.2°和/或23.0°±0.2°处具有衍射峰。
优选地，2theta值为19.9°±0.2°处的衍射峰的峰强度大于等于20％，更优选大于等于25％，最优选大于等于30％。
优选地，2theta值为23.0±0.2°处的衍射峰的峰强度大于等于35％，更优选大于等于45％，最优选大于等于55％。
根据本发明的还一具体且优选方面，其25℃下的X射线粉末衍射图(CuKα辐射)还在2theta值为6.9±0.2°处具有衍射峰且衍射峰强度大于等于10％；和/或，其25℃下的X射线粉末衍射图(CuKα辐射)还在24.4±0.2°处具有衍射峰且衍射峰强度大于等于20％。优选地，在2theta值为6.9±0.2°处的衍射峰的峰强度大于等于25％，更优选大于等于30％；在2theta值为24.4±0.2°处的衍射峰的峰强度大于等于30％，更优选大于等于40％，最优选大于等于50％。
在本发明的一个具体实施方式中，所述晶型X如实施例2的X-1，其在25℃下的X射线粉末衍射图(CuKα辐射)基本如图4所示。进一步地，该晶型X的X射线衍射图中显示了共29个衍射峰，这些衍射峰的位置以及峰强度如表2所示。该晶型X，在加热至259℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图5所示。该晶型X，当进行热重分析时，加热至120℃时，具有约0.7％的重量损失梯度，其热重分析图如图6所示。
在本发明的又一具体实施方式中，所述晶型X如实施例3中的X-2，其在25℃下的X射线粉末衍射图(CuKα辐射)基本如图7所示。该晶型X，当进行差示扫描量热分析时，在加热至51℃附近开始出现一个吸热峰，在加热至266℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图8所示。该晶型X，当进行热重分析时，加热至250℃时，具有约0.8％的重量损失梯度，其热重分析图如图9所示。
在本发明的还一具体实施方式中，所述晶型X如实施例4中的X-3，在25℃下的X射线粉末衍射图(CuKα辐射)基本如图10所示。
本发明还提供一种晶型XI，其X射线粉末衍射图(CuKα辐射)在2theta值为21.7°±0.2°、20.6°±0.2°、12.1°±0.2°处具有特征峰。
进一步地，晶型XI的X射线粉末衍射图还在2theta值为17.7°±0.2°、10.1°±0.2°、10.4°±0.2°中的一处或多处具有衍射峰。更进一步地，晶型XI的X射线粉末衍射图还在2theta值为7.9°±0.2°、5.1°±0.2°、17.1°±0.2°中的一处或多处具有衍射峰。优选地，晶型XI在前述6个2theta值处均具有衍射峰。
根据一个具体方面，晶型XI在25℃下的X射线粉末衍射图(CuKα辐射)与实施例3中的X-2相同。
本发明还提供一种帕博西尼的晶型XII，其X射线粉末衍射图(CuKα辐射)在2theta值为21.4°±0.2°、22.4°±0.2°、20.5°±0.2°处具有特征峰。
进一步地，帕博西尼的晶型XII的X射线粉末衍射图还在2theta值为18.7°±0.2°、10.2°±0.2°、17.9°±0.2°中的一处或多处具有衍射峰。
进一步地，帕博西尼的晶型XII的X射线粉末衍射图还在2theta值为17.1°±0.2°、19.6°±0.2°、11.8°±0.2°中的一处或多处具有衍射峰。
根据一个具体且优选方面，帕博西尼的晶型XII的X射线粉末衍射图在2theta值为21.4°±0.2°、22.4°±0.2°、20.5°±0.2°处具有特征峰，在2theta值为18.7°±0.2°、10.2°±0.2°、17.9°±0.2°、17.1°±0.2°、19.6°±0.2°、11.8°±0.2°处具有衍射峰。
根据一个具体方面，帕博西尼的晶型XII的X射线粉末衍射图基本如图11所示。
优选地，本发明提供的晶型XII，当进行差示扫描量热分析时，在加热至275℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图12所示。
优选地，本发明提供的晶型XII，当进行热重分析时，加热至250℃时，具有约0.4％的重量损失梯度，其热重分析图如图13所示。
进一步地，本发明还提供上述晶型的制备方法。
根据本发明的一个方面，本发明提供上述的晶型IX的制备方法，其包括：将帕博西尼游离形式溶解于卤代烃、醇类与水的混合体系中，在0至-40℃(零下40℃)的温度下缓慢挥发至固体析出，将所得固体在0至-40℃的温度下继续干燥得到。其中，挥发和干燥分别优选在0至-20℃下进行，更优选在-10～-20℃下进行。所述卤代烃优选二氯甲烷或二氯甲烷与其他卤代烃的混合物；所述的醇类溶剂优选甲醇或甲醇与其他醇的混合物。所述的混合体系中，水的体积分数优选为1％～20％，更优选2％～10％，根据一个具体方面，水的体积 分数为3％～5％。所述的卤代烃、醇类的体积比可以为0.1～10∶1，优选为1～10∶1，更优选2～5∶1。在一个具体实施方式中：所述的卤代烃、醇类的体积比为3∶1。
本发明还提供一种晶型X的制备方法，其包括：将帕博西尼晶型IX在加热条件下得到晶型X，所述加热条件为80℃～240℃。
优选地，所述加热条件为80～120℃。
本发明还提供一种晶型X/晶型XI的制备方法，其包括将帕博西尼游离形式溶解于卤代烃与醇类的混合体系中，在25至-40℃(零下40℃)的温度下缓慢挥发，将挥发所得固体加热至50-150℃得到。优选地，所述加热条件为120℃左右。其中，挥发优选在0至-20℃(零下20℃)下进行，更优选在-10～20℃下进行。所述卤代烃优选二氯甲烷或二氯甲烷与其他卤代烃的混合物；所述的醇类溶剂优选甲醇或甲醇与其他醇的混合物。所述的卤代烃、醇类的体积比可以为0.1～10∶1，优选为1～10∶1，更优选2～5∶1。在一个具体实施方式中：所述的卤代烃、醇类的体积比为3∶1。
本发明还提供一种晶型XII的制备方法，其包括将帕博西尼游离形式溶解于卤代烃与醇类的混合体系中，在25至-40℃(零下40℃)的温度下缓慢挥发，将挥发所得固体加热至260-275℃得到，其中，挥发优选在10至-20℃下进行，更优选在-10～-20℃下进行。所述卤代烃优选二氯甲烷或二氯甲烷与其他卤代烃的混合物；所述的醇类溶剂优选甲醇或甲醇与其他醇的混合物。所述的卤代烃、醇类的体积比可以为0.1～10∶1，优选为1～10∶1，更优选2～5∶1。在一个具体实施方式中：所述的卤代烃、醇类的体积比为3∶1。
优选地，所述加热温度为263～270℃左右。
或者，本发明的晶型XII可由晶型IX或晶型X或晶型XI加热至260-275℃得到。
本发明的目的之三是提供一种药用组合物，该药用组合物包含有效量的晶型IX、晶型X或晶型XII或它们的任意组合及药学上可接受的辅料。该药用组合物特别地适于治疗癌症。
本发明目的之四是提供上述晶型中的一种或多种的组合用于制备治疗抗癌药物制剂的用途。
根据本发明，作为原料的所述帕博西尼或帕博西尼游离形式或帕博西尼游离碱是指式(I)化合物的固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述帕博西尼为固体粉末形式。具体例如WO2014128588公开的帕博西尼晶型A。
Figure PCTCN2016102876-appb-000003
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供了帕博西尼的多种新晶型，这些晶型与现有的晶型相比具有更高的溶解度和更适于药用的粒径分布和形态，为含帕博西尼的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
附图说明
图1为实施例1所制备的帕博西尼晶型IX的XRPD图；
图2为实施例1所制备的帕博西尼晶型IX的DSC图；
图3为实施例1所制备的帕博西尼晶型IX的TGA图；
图4为实施例2所制备的帕博西尼晶型X的XRPD图；
图5为实施例2所制备的帕博西尼晶型X的DSC图；
图6为实施例2所制备的帕博西尼晶型X的TGA图；
图7为实施例3所制备的帕博西尼晶型X的XRPD图；
图8为实施例3所制备的帕博西尼晶型X的DSC图；
图9为实施例3所制备的帕博西尼晶型X的TGA图；
图10为实施例4所制备的帕博西尼晶型X的XRPD图；
图11为实施例5所制备的帕博西尼晶型XII的XRPD图；
图12为实施例5所制备的帕博西尼晶型XII的DSC图；
图13为实施例5所制备的帕博西尼晶型XII的TGA图；
图14为实施例1制备的晶型IX的偏光显微镜(PLM)图；
图15为实施例2所制备的晶型X的粒径分布图；
图16为实施例2所制备的晶型X在25℃/60％相对湿度条件下放置1个月前后的XRPD对比图(上图为放置前晶型X的XRPD图，下图为放置后晶型X的XRPD图)；
图17为实施例2所制备的晶型X在40℃/75％相对湿度条件下放置1个月前后的XRPD 对比图(上图为放置前晶型X的XRPD图，下图为放置后晶型X的XRPD图)；
图18为实施例2所制备的晶型X在60℃/75％相对湿度条件下放置1个月前后的XRPD对比图(上图为放置前晶型X的XRPD图，下图为放置后晶型X的XRPD图)；
图19为实施例2所制备的晶型X的DVS图；
图20为实施例3所制备的帕博西尼晶型X的偏光显微镜(PLM)图；
图21为实施例5所制备的帕博西尼晶型XII的偏光显微镜(PLM)图。
具体实施方式
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本发明中所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
术语“药用辅料”指任何类型的无毒、惰性固体、半固体或液体填充剂、稀释剂、囊封 物质或调配助剂。可用作药用辅料的物质的一些实施例为糖，诸如乳糖、葡萄糖及蔗糖；淀粉，诸如玉米淀粉及马铃薯淀粉；纤维素及其衍生物，诸如羧甲基纤维素钠、乙基纤维素及乙酸纤维素；粉状黄蓍；麦芽；明胶；滑石；赋形剂，诸如可可脂及栓剂蜡；油，诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油；二醇，诸如丙二醇；酯，诸如油酸乙酯及月桂酸乙酯；琼脂；缓冲剂，诸如氢氧化镁及氢氧化铝；褐藻酸；无热原质水；等张生理食盐水；林格氏溶液(Ringer′s solution)；乙醇及磷酸盐缓冲溶液，以及其他无毒相同润滑剂，诸如月桂基硫酸钠及硬脂酸镁，以及着色剂、释放剂、涂覆剂、甜味剂、调味剂及芳香剂，防腐剂及抗氧化剂亦可根据配方设计师的判断存在于组合物中。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射；DSC：差示扫描量热分析
TGA：热重分析；DVS：动态水分吸附。
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
Kα1
Figure PCTCN2016102876-appb-000004
1.540598；Kα2
Figure PCTCN2016102876-appb-000005
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)；电流：40毫安培(mA)；扫描范围：自3.0至40.0度。
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：扫描速率：10℃/min；
保护气体：氮气。
本发明所述的热重分析(TGA)图在TAQ5000上采集。本发明所述的热重分析(TGA)的方法参数如下：扫描速率：10℃/min；保护气体：氮气。
本发明所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。 Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。激光粒度分析仪的方法参数如下：
Figure PCTCN2016102876-appb-000006
*：流速60％为65毫升/秒的60％。
本发明中所用到的缩写的解释如下：
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径。
实施例1
帕博西尼晶型IX的制备：
将500.0mg的帕博西尼固体粉末加入玻璃小瓶中，然后加入14.4mL的二氯甲烷，4.8mL的甲醇和0.8mL水，于室温下溶解并置于-20℃静置，取1.5ml溶液过滤，将滤液置于-20℃缓慢挥发至干，所得固体测试XRPD，DSC和TGA。
本实施例所得固体的X射线粉末衍射数据如表1所示，其XRPD图如图1，其DSC图如图2，其TGA图如图3。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为16.78°、8.39°、24.32°处的衍射峰为特征峰，2theta值为23.14°、11.84°、4.84°处的衍射峰为重要的峰，2theta值为20.69°、13.70°、20.22°处的衍射峰为次重要的峰。
表1
2theta d间隔 强度％
4.84 18.27 41.37
5.76 15.35 2.61
6.81 12.99 4.76
8.39 10.54 96.65
9.69 9.13 12.77
11.84 7.48 45.22
13.70 6.46 13.10
14.52 6.10 11.19
16.15 5.49 10.82
16.78 5.28 100.00
17.55 5.05 14.76
18.42 4.82 11.37
19.21 4.62 12.15
19.34 4.59 12.67
19.98 4.44 21.79
20.22 4.39 21.20
20.69 4.29 22.71
21.36 4.16 9.47
22.26 3.99 10.27
23.14 3.84 48.68
23.86 3.73 13.04
24.32 3.66 55.43
25.38 3.51 5.45
26.85 3.32 6.21
28.07 3.18 8.21
29.20 3.06 7.74
30.22 2.96 1.49
31.75 2.82 1.69
34.00 2.64 1.82
34.87 2.57 1.09
37.85 2.38 1.62
实施例2
帕博西尼晶型X的制备：
将500.0mg的帕博西尼固体粉末加入一玻璃小瓶中，然后加入14.4mL的二氯甲烷，4.8mL的甲醇和0.8mL水，于室温下溶解并置于-20℃静置，取1.5mL溶液过滤，将滤液置于-20℃缓慢挥干，挥干固体加热至120℃，所得固体测试XRPD，DSC和TGA。
本实施例所得固体记为X-1。其X射线粉末衍射数据如表2所示。其XRPD图如图4，其DSC图如图5，其TGA图如图6。综合考虑d值、低角度、强度、特征线及峰形完整等多方面因素确定，2theta值为21.54°、17.02°、17.54°处的衍射峰为特征峰，2theta值为 7.81°、20.49°、12.00°处的衍射峰为重要的峰，2theta值为10.02°、4.98°、8.54°处的衍射峰为次重要的峰。
表2
2theta d间隔 强度％
4.98 17.73 38.96
6.80 13.00 24.92
7.81 11.31 83.53
8.54 10.36 30.58
10.02 8.83 65.15
10.29 8.59 21.26
12.00 7.37 65.24
12.13 7.30 45.21
13.81 6.41 7.48
14.62 6.06 7.45
15.84 5.60 24.00
17.02 5.21 87.90
17.54 5.06 83.80
18.80 4.72 11.52
19.78 4.49 12.93
20.49 4.33 73.29
21.54 4.13 100.00
22.37 3.97 20.03
22.85 3.89 25.02
24.27 3.67 25.55
26.52 3.36 5.07
27.55 3.24 9.90
28.16 3.17 8.87
29.30 3.05 7.13
29.74 3.00 6.63
31.69 2.82 3.67
34.52 2.60 2.14
35.85 2.51 1.79
36.13 2.49 1.40
实施例3
帕博西尼晶型X的制备方法：
将199.7mg的帕博西尼游离形式加入5.0mL玻璃瓶中，然后加入3.8mL的二氯甲烷和1.2mL的甲醇，室温下溶解过滤，将滤液放置于-20℃缓慢挥发，离心分离固体于室温环境下自然干燥，加热至120℃所得固体测试XRPD，DSC和TGA。
本实施例所得固体，记为X-2，其XRPD图如图7，DSC图如图8，TGA图如图9。X射线粉末衍射数据包含表3所示的峰值。
表3
2theta d间隔 强度％
5.05 17.50 19.24
6.84 12.93 2.77
7.89 11.21 22.41
8.59 10.30 7.37
10.11 8.75 45.23
10.40 8.51 39.43
12.10 7.32 55.14
13.98 6.33 6.62
15.95 5.56 8.94
17.13 5.18 18.95
17.66 5.02 52.51
18.95 4.68 13.89
20.62 4.31 69.03
21.65 4.10 100.00
22.49 3.95 16.83
24.40 3.65 11.38
26.61 3.35 6.30
27.66 3.23 7.00
28.20 3.16 5.47
29.82 3.00 4.85
31.73 2.82 4.89
实施例4
帕博西尼晶型X的制备方法：
称500mg帕博西尼游离碱固体粉末加到20ml小瓶中，加14.4毫升二氯甲烷，4.8毫升甲醇，0.8毫升水将样品溶清，然后放置在-20C冰箱30分钟，然后将清液分装成10个小瓶， 放置在-20℃下缓慢挥发至固体析出。将其中4个小瓶的样品收集至一5毫升小瓶中，加入2毫升(1440微升二氯甲烷，480微升甲醇，80微升水)放置在-20℃搅拌过夜，离心样品，并放置于80℃烘干，得到固体粉末，记为X-3，对该固体进行XRPD测试，结果如图10和表4所示。
表4
2theta d间隔 强度％
5.07 17.42 91.18
6.21 14.23 4.50
6.90 12.81 33.43
7.88 11.23 4.81
8.65 10.22 72.17
10.17 8.70 30.15
11.47 7.72 4.96
12.22 7.24 61.03
13.89 6.37 15.26
14.73 6.01 8.43
15.34 5.78 0.61
15.89 5.58 1.35
17.11 5.18 100.00
17.50 5.07 21.56
18.11 4.90 16.15
19.17 4.63 15.33
19.87 4.47 31.39
20.53 4.33 36.27
21.49 4.13 13.12
23.00 3.87 71.86
23.56 3.78 9.93
24.38 3.65 57.83
26.04 3.42 4.19
26.68 3.34 3.63
27.05 3.30 2.97
27.87 3.20 6.35
29.23 3.05 7.63
30.25 2.95 4.87
32.11 2.79 2.42
33.72 2.66 1.00
34.89 2.57 0.98
38.47 2.34 1.49
实施例5
帕博西尼晶型XII的制备方法：
将199.7mg的帕博西尼游离形式加入5.0mL玻璃瓶中，然后加入3.8mL的二氯甲烷和1.2mL的甲醇，室温下溶解过滤，将滤液放置于-20℃缓慢挥发，离心分离固体于室温环境下自然干燥，加热至263℃，所得固体测试XRPD，DSC和TGA。
本实施例得到固体的XRPD图如图11，DSC图如图12，TGA图如图13。X射线粉末衍射数据包含表5所示的峰值。
表5
2theta d间隔 强度％
5.33 16.57 0.01
7.83 11.29 3.27
8.84 10.01 2.57
10.16 8.71 13.06
11.45 7.73 6.25
11.84 7.48 7.02
13.52 6.55 2.32
15.90 5.57 3.98
17.10 5.19 10.20
17.86 4.97 12.80
18.53 4.79 14.97
18.72 4.74 17.53
19.65 4.52 9.91
20.52 4.33 18.41
21.03 4.22 9.40
21.45 4.14 100.00
21.54 4.12 89.33
22.23 4.00 20.62
22.42 3.96 29.31
23.72 3.75 2.35
25.28 3.52 1.64
26.64 3.35 0.19
27.53 3.24 0.53
28.34 3.15 1.82
31.57 2.83 6.09
35.51 2.53 1.50
实施例6
实施例1所制备的帕博西尼晶型IX的形貌和粒径分布测试：
采用偏光显微镜观察晶型IX的晶粒形貌，结果参见图14，从图上可以看出，晶型IX的形貌呈短棒状，短棒状有利于工艺过程中的过滤操作。
另，对晶型IX的粒度分布进行测试，结果参见表6。
表6
D10(um) D50(um) D90(um)
4.53 10.28 24.11
WO2014128588A1中提到其晶型A粒径的D10在5～10微米之间，D50在10～45微米之间，D90在30-125微米之间。根据PSD测试结果，本发明获得的晶型IX的D90即90％粒子小于24.11微米，D50即50％粒子小于10.28微米，D10即10％粒子小于4.53微米，可见该晶型粒径与现有的晶型A相比稍有减小且分布窄，是非常合适的粒径，既保证了药物的溶出速率，利于药物吸收，提高生物利用度；又不易团聚，保持好的流动性。
实施例7
帕博西尼晶型X的溶解性、粒度、稳定性以及引湿性研究：
1)晶型X与WO2014128588A1公开的晶型A溶解度对比研究：
将实施例2中制备得到的X-1与晶型A样品用纯水配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表7所示。
表7
Figure PCTCN2016102876-appb-000007
通过上述对比结果可以看出：在纯水中放置1个小时后，4个小时后和24个小时后本发明的晶型X与已有晶型A相比，溶解度更高。
2)对实施例2中制备得到的晶型X的粒度分布进行测试，结果参见表8和图15。
表8
D10(um) D50(um) D90(um)
2.65 7.44 21.35
WO2014128588A1中提到其晶型A粒径的D10在5～10微米之间，D50在10～45微米之间，D90在30-125微米之间，比表面积小于2m2/g。根据PSD测试结果，本发明获得的实施例2的X-1的D90即90％粒子小于21.35微米，D50即50％粒子小于7.44微米，D10即10％粒子小于2.65微米，X-1的单点比表面积为5.2666m2/g，多层吸附BET比表面积为5.4090m2/g，可见该晶型粒径较小，并且粒径分布窄，可增加药物的表面积，有利于提高药物的溶出速率，利于药物吸收，提高生物利用度和药效。
3)晶型X的稳定性研究
将实施例2中制备得到的X-1分别放置于25℃/60％RH，40℃/75％RH和60℃/75％RH，1个月之后取出固体测试XRPD，结果参见图16-18，可见放置前后晶型X未发生改变，表明晶型X具有良好的稳定性。
4)晶型X的引湿性研究
取约10mg按照实施例2方法制备的X-1进行动态水分吸附(DVS)测试。DVS图见图19。结果表明晶型X在80％相对湿度的增重为1.1％，在95％相对湿度下的增重为1.5％。根据中国药典2010年版附录XIX J药物引湿性试验指导原则：本发明的晶型X属于略有引湿性，表明晶型X不易受高湿度影响而潮解。
实施例8
晶型X的溶解性、形貌和粒度研究：
1)晶型X与WO2014128588A1公开的晶型A溶解度对比研究：
将实施例3所制备的X-2与晶型A样品用pH5.0FeSSIF(进食状态下人工肠液)制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表9所示。
表9
Figure PCTCN2016102876-appb-000008
通过上述对比结果可以看出：在FeSSIF中放置1个小时后，4个小时后和24个小时后本发明的新晶型X与已有专利的晶型A相比，溶解度更高。
2)采用偏光显微镜观察X-2的晶粒形貌，结果参见图20。此外，还对X-2的粒径分布进行测试，结果参见表10。
表10
D10(um) D50(um) D90(um)
0.64 12.60 58.96
综合上述结果可知，X-2的颗粒与已有的晶型A相比，比较细，且分散比较均匀，颗粒小有利于提高药物的溶解度，增加药物的生物利用度，利于药物吸收，提高生物利用度。颗粒大小分散均匀有利于制剂工艺的开发。
实施例9
帕博西尼晶型XII的溶解性、形貌和粒度研究：
1)晶型XII与WO2014128588A1公开的晶型A溶解度对比研究：
将实施例5制备得到的晶型XII与晶型A样品用SGF(模拟人工胃液)制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表11所示。
表11
Figure PCTCN2016102876-appb-000009
通过上述对比结果可以看出：在SGF中放置1个小时后，4个小时后和24个小时后本发明的晶型XII与已有的晶型A相比，溶解度更高。
2)晶型XII的形貌和粒径分布研究：
采用偏光显微镜观察晶型XII的晶粒形貌，结果参见图21。此外，还对晶型XII的粒径分布进行测试，结果参见表12。
表12
D10(um) D50(um) D90(um)
4.74 11.44 23.77
从图21可见，晶型XII的形貌呈短棒状，短棒状有利于工艺过程中的过滤操作。而且如表12所示，晶型XII与已有的晶型A相比，型粒径较小，并且粒径分布窄，可增加药物的表面积，有利于提高药物的溶出速率，利于药物吸收，提高生物利用度。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (30)

  1. 一种帕博西尼的晶型IX，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为16.8°±0.2°、8.4°±0.2°、24.3°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型IX，其特征在于，其X射线粉末衍射图还在2theta值为23.1°±0.2°、11.8°±0.2°、4.8°±0.2°中的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的晶型IX，其特征在于，其X射线粉末衍射图还在2theta值为20.7°±0.2°、13.7°±0.2°、20.2°±0.2°中的一处或多处具有衍射峰。
  4. 根据权利要求1所述的晶型IX，其特征在于，其X射线粉末衍射图还在2theta值为23.1°±0.2°和/或20.2°±0.2°处具有衍射峰。
  5. 根据权利要求1所述的晶型IX，其特征在于，所述特征峰的峰强度大于等于30％。
  6. 根据权利要求1或5所述的晶型IX，其特征在于，2theta值为16.8°±0.2°处的特征峰的峰强度最大。
  7. 根据权利要求1至6中任一项所述的帕博西尼的晶型IX的制备方法，其特征在于，所述方法包括：将帕博西尼游离形式溶解于卤代烃、醇类与水的混合体系中，在0至-40℃的温度下缓慢挥发至固体析出，将所得固体在0至-40℃的温度下继续干燥得到。
  8. 根据权利要求7所述的制备方法，其特征在于，所述卤代烃为二氯甲烷；所述的醇类溶剂为甲醇。
  9. 一种帕博西尼的晶型X，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为21.5°±0.2°、17.0°±0.2°、17.5°±0.2°处具有特征峰。
  10. 根据权利要求9所述的晶型X，其特征在于，其X射线粉末衍射图还在2theta值为7.8°±0.2°、20.5°±0.2°、12.0°±0.2°中的一处或多处具有衍射峰。
  11. 根据权利要求9或10所述的晶型X，其特征在于，其X射线粉末衍射图还在2theta值为10.0°±0.2°、4.9°±0.2°、8.5°±0.2°中的一处或多处具有衍射峰。
  12. 根据权利要求9所述的晶型X，其特征在于，2theta值为21.5°±0.2°处的衍射峰的强度大于等于10％，2theta值为17.5°±0.2°处的衍射峰的强度大于等于20％。
  13. 根据权利要求9所述的晶型X，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)在2theta值为21.4°～21.7°、16.9°～17.2°、17.4°～17.7°处具有特征峰，在7.8°～8.0°、20.5°～20.7°、12.0°～12.2°、10.0°～10.2°、4.9°～5.1°、8.5°～8.7°中的一处或多处具有衍射峰。
  14. 根据权利要求9或13所述的晶型X，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)还在2theta值为10.4°±0.2°处具有衍射峰。
  15. 根据权利要求14所述的晶型X，其特征在于，2theta值为10.4°±0.2°处的衍射峰的强度 大于等于30％。
  16. 根据权利要求9或13所述的晶型X，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)还在2theta值为19.9°±0.2°和/或23.0°±0.2°处具有衍射峰。
  17. 根据权利要求16所述的晶型X，其特征在于，2theta值为19.9°±0.2°和/或23.0°±0.2°处的衍射峰的强度大于等于30％。
  18. 根据权利要求9或13所述的晶型X，其特征在于，其25℃下的X射线粉末衍射图(CuKα辐射)还在2theta值为6.9±0.2°处具有衍射峰且衍射峰强度大于等于30％；和/或，其25℃下的X射线粉末衍射图(CuKα辐射)还在24.4±0.2°处具有衍射峰且衍射峰强度大于等于30％。
  19. 根据权利要求9所述的晶型X，其特征在于：所述晶型X在25℃下的X射线粉末衍射图(CuKα辐射)基本如图4、7或10所示。
  20. 一种如权利要求9至19中任一项所述的晶型X的制备方法，其特征在于，所述方法包括：将帕博西尼晶型IX在加热条件下得到晶型X，所述加热条件为80℃-240℃。
  21. 根据权利要求20所述的制备方法，其特征在于，所述加热条件为80～120℃。
  22. 一种如权利要求9至19中任一项所述的晶型X的制备方法，其特征在于，所述方法包括：将帕博西尼游离形式溶解于卤代烃与醇类的混合体系中，在25至-40℃的温度下缓慢挥发，将挥发所得固体加热至50-150℃得到。
  23. 根据权利要求22所述的制备方法，其特征在于，所述卤代烃为二氯甲烷，所述的醇类溶剂为甲醇。
  24. 一种帕博西尼的晶型XII，其特征在于，其X射线粉末衍射图(CuKα辐射)在2theta值为21.4°±0.2°、22.4°±0.2°、20.5°±0.2°处具有特征峰。
  25. 根据权利要求24所述的晶型XII，其特征在于，其X射线粉末衍射图还在2theta值为18.7°±0.2°、10.2°±0.2°、17.9°±0.2°中的一处或多处具有衍射峰。
  26. 根据权利要求24或25所述的晶型XII，其特征还在于，其X射线粉末衍射图还在2theta值为17.1°±0.2°、19.6°±0.2°、11.8°±0.2°中的一处或多处具有衍射峰。
  27. 一种如权利要求24至26中任一项所述的帕博西尼的晶型XII的制备方法，其特征在于，所述方法包括：将帕博西尼游离形式溶解于卤代烃与醇类的混合体系中，在25至-40℃的温度下缓慢挥发，将挥发所得固体加热至260-275℃得到。
  28. 根据权利要求27所述的制备方法，其特征在于，所述卤代烃为二氯甲烷，所述的醇类溶剂为甲醇。
  29. 一种药用组合物，所述药用组合物包含有效量的权利要求1至6中的任一项所述的晶型IX和/或权利要求9至19中的任一项所述的晶型X和/或权利要求24-26中任一项权利要求所述的晶型XII及药学上可接受的辅料。
  30. 如权利要求1至6中的任一项所述的晶型IX，权利要求9至19中的任一项所述的晶型X，权利要求24-26中任一项权利要求所述的晶型XII或它们的任意组合用于制备治疗抗癌药物制剂的用途。
PCT/CN2016/102876 2015-10-22 2016-10-21 帕博西尼的新晶型 WO2017067506A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510690287 2015-10-22
CN201510690287.X 2015-10-22
CN201511029959.9 2015-12-31
CN201511029959 2015-12-31

Publications (1)

Publication Number Publication Date
WO2017067506A1 true WO2017067506A1 (zh) 2017-04-27

Family

ID=58556699

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/102876 WO2017067506A1 (zh) 2015-10-22 2016-10-21 帕博西尼的新晶型

Country Status (1)

Country Link
WO (1) WO2017067506A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114149426A (zh) * 2021-12-13 2022-03-08 江苏海洋大学 帕博西尼药物共晶及其制备方法

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447743A (zh) * 2014-11-26 2015-03-25 苏州明锐医药科技有限公司 帕博西尼的制备方法
CN104478874A (zh) * 2014-12-08 2015-04-01 新发药业有限公司 一种帕博赛布的制备方法
CN104496983A (zh) * 2014-11-26 2015-04-08 苏州明锐医药科技有限公司 一种帕博西尼的制备方法
CN104610254A (zh) * 2015-01-26 2015-05-13 新发药业有限公司 一种帕博赛布的低成本制备方法
CN104892604A (zh) * 2015-06-19 2015-09-09 北京康立生医药技术开发有限公司 一种新型的cdk4抑制剂的合成方法
CN105418603A (zh) * 2015-11-17 2016-03-23 重庆莱美药业股份有限公司 一种高纯度帕布昔利布及其反应中间体的制备方法
CN105541832A (zh) * 2015-12-15 2016-05-04 南京艾德凯腾生物医药有限责任公司 一种羟乙基磺酸盐帕布昔利布的制备方法
CN105906622A (zh) * 2016-05-13 2016-08-31 青岛云天生物技术有限公司 一种用于治疗乳腺癌的帕博西尼的制备方法
CN105924439A (zh) * 2016-06-24 2016-09-07 石家庄海瑞药物科技有限公司 一种帕布昔利布的制备方法
CN105949189A (zh) * 2016-06-05 2016-09-21 童明琼 一种用于治疗乳腺癌的帕博西尼的制备方法

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447743A (zh) * 2014-11-26 2015-03-25 苏州明锐医药科技有限公司 帕博西尼的制备方法
CN104496983A (zh) * 2014-11-26 2015-04-08 苏州明锐医药科技有限公司 一种帕博西尼的制备方法
CN104478874A (zh) * 2014-12-08 2015-04-01 新发药业有限公司 一种帕博赛布的制备方法
CN104610254A (zh) * 2015-01-26 2015-05-13 新发药业有限公司 一种帕博赛布的低成本制备方法
CN104892604A (zh) * 2015-06-19 2015-09-09 北京康立生医药技术开发有限公司 一种新型的cdk4抑制剂的合成方法
CN105418603A (zh) * 2015-11-17 2016-03-23 重庆莱美药业股份有限公司 一种高纯度帕布昔利布及其反应中间体的制备方法
CN105541832A (zh) * 2015-12-15 2016-05-04 南京艾德凯腾生物医药有限责任公司 一种羟乙基磺酸盐帕布昔利布的制备方法
CN105906622A (zh) * 2016-05-13 2016-08-31 青岛云天生物技术有限公司 一种用于治疗乳腺癌的帕博西尼的制备方法
CN105949189A (zh) * 2016-06-05 2016-09-21 童明琼 一种用于治疗乳腺癌的帕博西尼的制备方法
CN105924439A (zh) * 2016-06-24 2016-09-07 石家庄海瑞药物科技有限公司 一种帕布昔利布的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEKAL, BRIAN P. ET AL.: "Palbociclib commercial manufacturing process development. Part III. deprotection followed by crystallization for API particle property control", «ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 20, no. 7, 9 June 2016 (2016-06-09), pages 1217 - 1226, XP055376350, ISSN: 1083-6160 *
TOOGOOD, PETER L. ET AL.: "Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6", JOURNAL OF MEDICINAL CHEMISTRY, vol. 48, no. 7, 2 March 2005 (2005-03-02), pages 2388 - 2406, XP002559229, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114149426A (zh) * 2021-12-13 2022-03-08 江苏海洋大学 帕博西尼药物共晶及其制备方法

Similar Documents

Publication Publication Date Title
EP3279201B1 (en) Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor
WO2019019959A1 (zh) 瑞博西尼的单琥珀酸盐晶型及其制备方法和用途
JP7235748B2 (ja) ４－アミノ－ｎ－（１－（（３－クロロ－２－フルオロフェニル）アミノ）－６－メチルイソキノリン－５－イル）チエノ［３，２－ｄ］ピリミジン－７－カルボキサミドの塩とその結晶形態
US20210171536A1 (en) Compound of eoc315 mod.i crystal form and preparation method thereof
JP2021527680A (ja) Ａｒｎ−５０９の結晶形、その製造方法及びその用途
WO2018157803A1 (zh) 维奈妥拉的晶型及其制备方法
WO2016155578A1 (zh) 达格列净的新晶型及其制备方法
WO2018103726A1 (zh) 一种溴结构域蛋白抑制剂药物的晶型及其制备方法和用途
WO2017063572A1 (zh) 细胞凋亡诱导剂的新晶型及其制备方法
WO2017067506A1 (zh) 帕博西尼的新晶型
WO2019205812A1 (zh) Acalabrutinib的新晶型及其制备方法和用途
WO2020057622A1 (zh) 卡博替尼苹果酸盐晶型及其制备方法和用途
WO2017020869A1 (zh) 2-[(2r)-2-甲基-2-吡咯烷基]-1h-苯并咪唑-7-甲酰胺的晶型b及其制备方法和应用
WO2022258060A1 (zh) 一种lanifibranor的晶型及其制备方法
WO2016078587A1 (zh) Lu AE58054的盐酸盐晶型A及其制备方法和用途
WO2019149262A1 (zh) Sb-939的晶型及其制备方法和用途
US10544129B2 (en) Crystalline forms of AP26113, and preparation method thereof
WO2022206937A1 (zh) 一种吡唑取代的烟酰胺类化合物的盐酸盐新晶型及其制备方法
WO2018157741A1 (zh) Sb-939的盐的晶型及其制备方法和用途
WO2017076358A1 (zh) 咪唑基联苯基化合物盐的新晶型及其制备方法
WO2022007752A1 (zh) 苯甲酰胺类化合物及其二盐酸盐的新晶型及其制备方法
WO2022105792A1 (zh) 一种喹唑啉酮衍生物的新晶型及其制备方法
WO2019148789A1 (zh) 布格替尼的晶型及其制备方法
WO2017032281A1 (zh) 帕比司他乳酸盐的新晶型
WO2016155631A1 (zh) 托吡司他的新晶型及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16856937

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16856937

Country of ref document: EP

Kind code of ref document: A1