WO2019019959A1 - 瑞博西尼的单琥珀酸盐晶型及其制备方法和用途 - Google Patents

瑞博西尼的单琥珀酸盐晶型及其制备方法和用途 Download PDF

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WO2019019959A1
WO2019019959A1 PCT/CN2018/096586 CN2018096586W WO2019019959A1 WO 2019019959 A1 WO2019019959 A1 WO 2019019959A1 CN 2018096586 W CN2018096586 W CN 2018096586W WO 2019019959 A1 WO2019019959 A1 WO 2019019959A1
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crystal
crystal form
ray powder
powder diffraction
iii
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PCT/CN2018/096586
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English (en)
French (fr)
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陈敏华
张炎锋
刘远
刘凯
张晓宇
钱佳乐
陈宇浩
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苏州晶云药物科技股份有限公司
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Priority to CN201880040521.6A priority Critical patent/CN111094290B/zh
Publication of WO2019019959A1 publication Critical patent/WO2019019959A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • 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

Definitions

  • the invention relates to the technical field of pharmaceutical crystals, in particular to a crystalline form of a monosuccinate of Rebsini and a preparation method and use thereof.
  • Cyclin-dependent kinase 4/6 (CDK4/6) is a class of silk/threonine kinase that binds to Cyclin D and regulates cell turnover from G1 to S phase. .
  • CDK4/6 Cyclin D-CDK4/6-INK4-Rb pathway
  • CDK4/6 has thus become one of the targets for anti-tumor.
  • Rebocicli also known as Ribociclib, LEE011
  • Ribociclib LEE011
  • Rebizzini is a drug developed by Novartis for the treatment of advanced or metastatic breast cancer with HR+/HER2-.
  • Rebsini 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-yl-amino)-7H-pyrrolo[2,3-d]pyrimidine-6- Carboxylic acid dimethylamide (hereinafter referred to as compound (I)) having a structure as shown in formula (I):
  • the patent CN103201275A discloses a hydrate form of the compound (I) monosuccinate and a non-hydrate form (hereinafter referred to as “hydrate form” and “non-hydrate form”), and the compound CN105085533A discloses a compound (I).
  • Monosuccinate Form I hereinafter referred to as "Form I”).
  • the non-hydrate form is lower, less than 0.5 mg/mL, and the solubility of the non-hydrate form is better. Therefore, we choose the non-hydrate form as the comparative crystal form, but the non-hydrate is at 80 ⁇ 3 °C.
  • the reaction is crystallized in isopropanol under conditions, and the high temperature increases the risk of esterification of succinic acid and isopropanol, and also increases the risk of degradation.
  • the non-hydrate form is easily crystallized, and at 90% RH, up to 7.35% of the non-hydrate form will be converted into a hydrate form, and the transformation of the drug form will bring about efficacy and safety to the drug.
  • non-hydrate form is poor in powder properties, which may reduce the production efficiency of tableting and filling in the formulation, and at the same time bring greater difficulty in controlling the quality of the drug.
  • Form I overcomes the problem of high temperature and prone to side reaction and easy degradation during the preparation of non-hydrate form, it still has some unsatisfactory properties, such as low chemical stability, poor physical stability under high humidity conditions, and powder. The nature of the study is not ideal.
  • the inventors of the present application have unexpectedly discovered the monosuccinate crystal form X, crystal form III, crystal form of the compound (I) provided by the present invention in an attempt to prepare different crystal forms.
  • V which has advantages in at least one of solubility, melting point, stability, dissolution, wettability, adhesion, fluidity, bioavailability, and processability, purification, formulation production, etc., particularly wettability Low, good stability, good fluidity, excellent compressibility, small adhesion, solubility meets medicinal requirements, and provides a new and better choice for the preparation of drugs containing compound (I) monosuccinate. Development is very important.
  • the main object of the present invention is to provide a novel crystalline form of the monosuccinate of the compound (I), a process for its preparation and use.
  • the present invention provides a crystal form X of a monosuccinate of the compound (I) (hereinafter referred to as "Form X").
  • the X-ray powder diffraction of the Form X has a diffraction angle 2 ⁇ of 20.0° ⁇ 0.2°, 12.9° ⁇ 0.2°, 8.8° ⁇ 0.2°, and 7.8° ⁇ 0.2°. Characteristic peaks.
  • the X-ray powder diffraction of the Form X has a characteristic peak at one, or two, or three of the diffraction angle 2 ⁇ of 15.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, and 23.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form X has a characteristic peak at a diffraction angle 2 ⁇ value of 15.6° ⁇ 0.2°, 10.9° ⁇ 0.2°, and 23.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form X has a characteristic peak at one, or two, or three of the diffraction angle 2 ⁇ of 18.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form X has a characteristic peak at a diffraction angle 2 ⁇ of 18.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, and 19.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form X is 1 in the diffraction angle 2 ⁇ of 21.1° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.2° ⁇ 0.2°, 24.9° ⁇ 0.2°, 22.0° ⁇ 0.2°. Characteristic peaks at, or at 2, or 3, or 4, or 5; preferably, the X-ray powder diffraction of the Form X is at a diffraction angle 2 ⁇ of 21.1° ⁇ 0.2°, 12.3° ⁇ 0.2° , 17.2 ° ⁇ 0.2 °, 24.9 ° ⁇ 0.2 °, 22.0 ° ⁇ 0.2 ° with characteristic peaks.
  • the X-ray powder diffraction of the Form X is at a diffraction angle 2 ⁇ of 20.0° ⁇ 0.2°, 12.9° ⁇ 0.2°, 8.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 15.6° ⁇ 0.2°, 10.9. ° ⁇ 0.2°, 23.0° ⁇ 0.2°, 18.7° ⁇ 0.2°, 13.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, 21.1° ⁇ 0.2°, 12.3° ⁇ 0.2°, 17.2° ⁇ 0.2°, 24.9° ⁇ Any of 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 of 0.2 °, 22.0 ° ⁇ 0.2 °, Or there are characteristic peaks at 13, or 14 or at 15.
  • the present invention also provides a method for preparing the crystalline form X, the preparation method comprising:
  • the compound (I) and succinic acid are added to a single solvent of an alcohol or a mixed solvent of acetonitrile and an alcohol, and the seed crystal is suspended and stirred to form a crystal.
  • the solid is centrifuged and dried in a vacuum to obtain a crystal form X.
  • the seed crystal is Form X or Form I
  • the Form I is a monosuccinate of Compound (I) having an X-ray powder diffraction at a diffraction angle 2 ⁇ of 11.9° ⁇ 0.2°, 19.4°. ⁇ 0.2°, 20.6° ⁇ 0.2°, 22.7° ⁇ 0.2°, 24.4° ⁇ 0.2°, 26.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 15.7° ⁇ 0.2°, and 16.7° ⁇ 0.2° have characteristic peaks.
  • the molar ratio of the compound (I) to succinic acid is 1:1 to 1:2; more preferably, the molar ratio of the compound (I) to succinic acid is 1:1.8;
  • the mixed solvent is a mixed solvent of acetonitrile and methanol; more preferably, the volume ratio of acetonitrile to methanol in the mixed solvent is 1:1 to 15:1;
  • the stirring reaction temperature is 40-60 ° C;
  • the stirring reaction time is from 12 to 120 hours; more preferably, the stirring reaction time is from 12 to 24 hours.
  • the crystal form X of the present invention has lower moisture absorbing property than the prior art, and can overcome the drawbacks caused by high wettability.
  • the test results show that the wettability of Form X at 0-80% and 0-90% relative humidity is lower than that of non-hydrate form, and the non-hydrate form has a wettability of 0-80% and 0-90% relative humidity.
  • the weight gain under conditions is 2 times and 4 times that of Form X, respectively. Further, in the crystal form X of the present invention, the crystal form is not changed after the wettability test, and the physical stability is good.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. At the same time, the wettability will affect the preparation, storage and post-treatment of the drug.
  • the low wettability crystal form is not critical to storage conditions, reducing material storage and quality control costs, and is of great value.
  • the crystal form X provided by the present invention has better mechanical stability than the prior art, and reduces the risk of crystal transformation during the grinding or tableting process during preparation of the preparation.
  • the crystal form X of the invention has high polishing stability, and the crystallinity does not change significantly after grinding, while the crystallinity of the prior art non-hydrate form is significantly reduced after grinding, and a burr peak appears at the baseline and a bulge appears, which indicates that The amorphous form of the hydrate form is significantly increased after grinding.
  • Form X The better grinding stability of Form X can reduce the risk of crystallinity change and crystal transformation of the drug substance during the processing of the preparation.
  • process of crystal form X for direct processing of the preparation is highly feasible, which greatly simplifies the preparation process and reduces the cost of research and development and production.
  • the crystal form X provided by the present invention has better stability than the prior art.
  • the crystal form X of the present invention is placed under the condition of 60 ° C / 75% relative humidity, and the chemical purity does not change for at least 2 weeks, and is placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, at least 2
  • the chemical purity of the month did not change, and it was placed under the condition of 97.3% relative humidity, and the crystal form did not change for at least 24 hours.
  • the prior art crystal form (non-hydrate form and crystal form I) is placed at 60 ° C / 75% relative humidity for 2 weeks, and placed under 40 ° C / 75% relative humidity for 2 months, the chemical purity is more obvious.
  • the reduction, which was placed under the condition of 97.3% relative humidity for 24 h was converted into a hydrate form, whereby it can be seen that the crystal form X of the present invention has good stability.
  • the crystal form has good physical and chemical stability.
  • the crystal form has good physical stability, ensuring that the bulk drug is not easily converted into other crystal forms during storage and formulation processes, thereby ensuring consistent and controllable sample quality.
  • the crystal form has good chemical stability, and the purity is basically unchanged during the storage process, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the stable crystal form is more controllable during the crystallization process, and impurities and mixed crystals are less likely to occur, which is advantageous for industrial production.
  • the crystal form X provided by the present invention has better thermodynamic stability than the prior art.
  • the crystalline form X of the present invention and the non-hydrated form are suspended and stirred under different temperature conditions in an organic solvent to obtain the crystalline form X of the present invention, indicating that the crystalline form X of the present invention has higher thermodynamic stability.
  • the stability of the drug is crucial, especially maintaining good stability during the commercial period, reducing the drug dissolution rate and bioavailability due to changes in crystal form, ensuring drug efficacy and safety, and preventing drugs.
  • the occurrence of adverse reactions is of great significance.
  • the thermodynamically stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystals; it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent and controllable sample quality and ensuring the preparation of the product.
  • the dissolution profile does not change with the time of storage.
  • the crystalline form X of the present invention has good solubility in simulated biological medium and pure water, and the solubility is more than 13.3 mg/mL, which is in compliance with medicinal requirements.
  • Solubility is the rate limiting factor of drug bioavailability. Therefore, the solubility of Form X meets the requirements of medicinal requirements, and it can meet the high bioavailability of Rebizzini drugs, thus ensuring the drug-forming properties and efficacy of drugs.
  • Form X of the present invention has good chemical stability. Take an appropriate amount of Form X, mix well with the auxiliary materials, roll into a thin sheet and pulverize into granules, mix well with the external auxiliary materials, press the appropriate mold to form, and place it for 1 month under long-term and accelerated conditions, the impurities do not increase significantly, indicating The formulation of Form X of the present invention has good chemical stability.
  • the basic requirements of pharmaceutical preparations are safe, effective and stable.
  • the pharmaceutical preparation has good chemical stability, can ensure the drug efficacy, reduce the risk of producing toxic side effects and irritating reactions, and ensure people's medication safety.
  • the crystalline form X of the present invention also has the following beneficial effects:
  • the crystal form X of the present invention can have better fluidity than the prior art crystal form.
  • the experimental results show that the crystal form X has good fluidity, while the crystal form I has poor fluidity and the non-hydrate form has poor fluidity.
  • the crystal form has better fluidity, which can effectively increase the production speed of tableting and filling, and improve production efficiency. In addition, it can improve the feasibility of direct compression and direct filling of powder, greatly simplifying the production process and reducing production cost.
  • the better flowability of Form X ensures the mixing uniformity and content uniformity of the preparation, reduces the weight difference of the dosage form, and improves the product quality.
  • the crystal form X of the present invention can have superior compressibility compared to the prior art crystal form.
  • the tensile strength of the crystalline form X of the present invention is 1.36 MPa, which is much higher than that of the prior art crystal form, about 5 times the tensile strength of the non-hydrate form, and is a crystalline form. 2 times more than I.
  • the good compressibility of the crystal form X can effectively improve the problems of hardness/friability of the raw material processing process, reduce the requirements for the processing of the previous product, make the process more stable, improve the appearance of the product, and improve the product quality.
  • the direct processing of the Form X formulation is highly feasible, greatly simplifying the formulation process and reducing the cost of research and development and production.
  • the present invention provides the crystal form III of the monosuccinate of the compound (I) (hereinafter referred to as "Form III").
  • the X-ray powder diffraction of Form III has a characteristic peak at a diffraction angle 2 ⁇ of 18.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 10.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form III has characteristics at one, or two, or three points in the diffraction angle 2 ⁇ value of 22.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 9.4° ⁇ 0.2°. Peak; preferably, the X-ray powder diffraction of the Form III has a characteristic peak at a diffraction angle 2 ⁇ of 22.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 9.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form III has a characteristic peak at a diffraction angle 2 ⁇ value of 20.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form III has a diffraction angle 2 ⁇ of 18.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 10.7° ⁇ 0.2°, 22.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, There are characteristic peaks at any 3, or 4, or 5, or 6, or 7 of 9.4 ° ⁇ 0.2 °, 20.9 ° ⁇ 0.2 °.
  • the present invention also provides a method for preparing the crystal form III, which comprises the following two methods:
  • Method 1 using a single succinate crystal form II of the compound (I), heating to a certain temperature, crystallizing, cooling and separating;
  • the crystal transformation temperature is from 140 to 190 ° C, more preferably from 165 ° C.
  • the compound (I) and succinic acid are added to an alcohol solvent, and the mixture is suspended and stirred to crystallize, and the solid is centrifuged, and dried under vacuum to obtain a crystal form III.
  • the alcohol is methanol
  • the molar ratio of the compound (I) to succinic acid is 1:1 to 1:2; more preferably, the molar ratio of the compound (I) to succinic acid is 1:1.8;
  • the suspension stirring time is 12-72 h
  • the stirring reaction temperature is 15-40 ° C;
  • the vacuum drying temperature is 70-160 ° C;
  • the vacuum drying time is 10-60 minutes;
  • the crystalline form III of the present invention has better stability than the prior art crystalline form.
  • the crystal form of the present invention has no change in crystal form after DVS test, and the crystal form of the prior art non-hydrate form is converted into a hydrate form after being tested by DVS.
  • the crystal form As the most important active ingredient in the drug, it is important that the crystal form has good physical stability.
  • the crystal form has good physical stability, ensuring that the bulk drug is not easily converted into other crystal forms during storage and formulation processes, thereby ensuring consistent and controllable sample quality.
  • the crystalline form III of the present invention has good solubility in simulated biological medium and pure water, and the solubility is higher than 13 mg/mL, which is in compliance with medicinal requirements.
  • Solubility is the rate limiting factor of drug bioavailability. Therefore, the solubility of Form III meets the requirements of medicinal requirements, which can meet the higher bioavailability of Rebizzini drugs, thus ensuring the drug-forming properties and efficacy of the drug.
  • the crystal form III provided by the present invention has good stability.
  • the crystal form III of the invention is placed under the condition of 25 ° C / 60% relative humidity, the crystal form remains unchanged for at least 6 months, and is placed under the condition of 40 ° C / 75% relative humidity, and the crystal form remains unchanged for at least 3 months. It is indicated that the crystalline form III of the present invention has good stability.
  • the crystal form As the most important active ingredient in the drug, it is important that the crystal form has good physical stability.
  • the crystal form has good physical stability, ensuring that the bulk drug is not easily converted into other crystal forms during storage and formulation processes, thereby ensuring consistent and controllable sample quality.
  • the crystalline form III of the present invention also has the following beneficial effects:
  • the crystal form III of the present invention has better fluidity than the prior art crystal form.
  • the experimental results show that the crystal form III has good fluidity, while the crystal form I has poor fluidity and the non-hydrate form has poor fluidity.
  • the crystal form has better fluidity, which can effectively increase the production speed of tableting and filling, and improve production efficiency. In addition, it can improve the feasibility of direct compression and direct filling of powder, greatly simplifying the production process and reducing production cost.
  • the better flowability of Form III ensures the uniformity of mixing and content uniformity of the formulation, reduces the weight difference of the dosage form, and improves product quality.
  • the crystal form III of the present invention has superior compressibility compared to the prior art crystal form.
  • the tensile strength of the crystalline form III of the present invention is 1.41 MPa, which is much higher than the prior art crystalline form, about 5 times the tensile strength of the non-hydrate form, and is a crystalline form. 2 times more than I.
  • Form III can effectively improve the hardness/friability of the raw material processing process, reduce the requirements for the processing of the previous product, make the process more stable, improve the appearance of the product, and improve the product quality.
  • the direct processing of the Form III preparation is highly feasible, greatly simplifying the formulation process and reducing the cost of research and development and production.
  • the crystal form III of the present invention has less adhesion than the prior art crystal form.
  • the average adhesion amount of Form III is 0.030 mg, while the average adsorption amount of the prior art non-hydrate form is 0.075, and the average adsorption amount of Form I is 0.085 mg, which is the present invention. More than twice the amount of Form III adsorbed.
  • the low adhesion of Form III can effectively improve or avoid the phenomenon of sticky wheel and sticking caused by dry granulation and tablet tableting, which is beneficial to improve the appearance and weight difference of the product.
  • the low adhesion of Form III can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. The uniformity of the amount of raw materials.
  • the present invention provides a crystal form V of a monosuccinate of the compound (I) (hereinafter referred to as "Form V").
  • the X-ray powder diffraction of the Form V has a characteristic peak at diffraction angles 2 ⁇ of 9.4° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 12.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V has a characteristic peak at one, or two, or three of the diffraction angles 2 ⁇ of 22.0° ⁇ 0.2°, 18.9° ⁇ 0.2°, and 20.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V has a characteristic peak at a diffraction angle 2 ⁇ of 22.0° ⁇ 0.2°, 18.9° ⁇ 0.2°, 20.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V has a characteristic peak at one or two of the diffraction angle 2 ⁇ of 23.0° ⁇ 0.2° and 17.6° ⁇ 0.2°; preferably, the crystal form V
  • the X-ray powder diffraction has a characteristic peak at a diffraction angle 2 ⁇ of 23.0° ⁇ 0.2° and 17.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form V is 9.4 ° ⁇ 0.2 °, 18.3 ° ⁇ 0.2 °, 12.8 ° ⁇ 0.2 °, 22.0 ° ⁇ 0.2 °, 18.9 ° ⁇ 0.2 °, 20.5 at the diffraction angle 2 ⁇ .
  • the present invention also provides a method for preparing the crystal form V, the preparation method comprising:
  • the certain temperature is 90-120 ° C, more preferably 100 ° C;
  • the certain period of time is from 15 minutes to 90 minutes, more preferably 30 minutes.
  • the crystalline form V provided by the present invention has the following beneficial effects:
  • the crystal form V provided by the present invention has good mechanical stability and reduces the risk of crystal transformation during grinding or tableting of the preparation.
  • the crystal form V of the present invention has high polishing stability, and the crystal form does not change after grinding.
  • Form V The better grinding stability of Form V can reduce the risk of crystallinity change and crystal transformation of the drug substance during the processing of the preparation.
  • the process of crystal form V for direct processing of the preparation is highly feasible, which greatly simplifies the preparation process and reduces the cost of research and development and production.
  • the crystalline form V of the present invention has good solubility in simulated biological medium and pure water, and has a solubility of about 10 mg/mL, which meets medicinal requirements.
  • Solubility is the rate limiting factor of drug bioavailability. Therefore, the solubility of crystal form V meets the requirements of medicinal requirements, which can meet the high bioavailability of Rebizzini drugs, thus ensuring the drug-forming properties and efficacy of drugs.
  • the crystal form V provided by the present invention has good physical stability.
  • the crystal form V of the present invention is placed under the condition of 25 ° C / 60% relative humidity, and the crystal form remains unchanged for at least 7 months, indicating that the crystal form V of the present invention has good stability.
  • the crystal form As the most important active ingredient in the drug, it is important that the crystal form has good physical stability.
  • the crystal form has good physical stability, ensuring that the bulk drug is not easily converted into other crystal forms during storage and formulation processes, thereby ensuring consistent and controllable sample quality.
  • the crystal form V of the present invention also has the following beneficial effects:
  • the crystal form V of the present invention can have better fluidity than the prior art crystal form.
  • the experimental results show that the crystal form V has good fluidity, while the crystal form I has poor fluidity and the non-hydrate form has poor fluidity.
  • the crystal form has better fluidity, which can effectively increase the production speed of tableting and filling, and improve production efficiency. In addition, it can improve the feasibility of direct compression and direct filling of powder, greatly simplifying the production process and reducing production cost.
  • the better flowability of the crystal form V ensures the uniformity of the preparation and the uniformity of the content, reduces the weight difference of the dosage form, and improves the product quality.
  • the crystal form V of the present invention can have less adhesion than the prior art crystal form.
  • the average adhesion of Form V was 0.040 mg, while the average adsorption amount of the prior art non-hydrate form was 0.075, and the average adsorption amount of Form I was 0.085 mg, which was approximately
  • the crystal form V is twice as large.
  • the low adhesion of the crystal form V can effectively improve or avoid the phenomenon of sticking wheel and sticking caused by dry granulation and tablet tableting, and is beneficial to improving the appearance and weight difference of the product.
  • the low adhesion of Form V can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. The uniformity of the amount of raw materials.
  • the present invention provides a crystal form II of a monosuccinate of the compound (I) (hereinafter referred to as "form II").
  • the X-ray powder diffraction of the Form II is 4.6 ° ⁇ 0.2 °, 19.9 ° ⁇ 0.2 °, 7.4 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 15.6 ° ⁇ 0.2 °, 6.3 ° ⁇ 0.2 ° at the diffraction angle 2 ⁇ . Characteristic peaks at 10.2 ° ⁇ 0.2 °, 12.2 ° ⁇ 0.2 °, and 13.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II is shown in FIG.
  • the present invention also provides a method for preparing the crystal form II, the preparation method comprising:
  • the free base of the compound (I) is reacted with succinic acid in a mixed system of an alcohol and an alkane, stirred and crystallized at a certain temperature, separated, and dried;
  • the molar ratio of succinic acid to compound (I) free base is from 1.0 to 1.5, preferably 1.0;
  • the alcohol is a C 1 -C 5 alcohol or a mixture thereof, the alkane is a C 5 -C 8 alkane or a mixture thereof;
  • the alcohol is selected from one of methanol and ethanol, or a mixture thereof, the alkane is one selected from n-hexane, n-heptane or a mixture thereof; more preferably, the alcohol is ethanol, an alkane Is n-heptane;
  • the crystallization temperature is -20 to 50 ° C, more preferably 4 ° C;
  • the crystallization time is from 4 to 72 hours, more preferably 20 hours.
  • the present invention provides a tetrahydrofuran solvate crystal form S2 of a compound (I) monosuccinate (hereinafter referred to as "crystal form S2").
  • the X-ray powder diffraction of the crystal form S2 is 19.6° ⁇ 0.2°, 8.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, 12.3° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.4° ⁇ 0.2° at the diffraction angle 2 ⁇ . Characteristic peaks at 14.1 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 20.0 ° ⁇ 0.2 °, and 25.9 ° ⁇ 0.2 °.
  • the present invention also provides a method for preparing the crystalline form S2, the preparation method comprising:
  • the molar ratio of succinic acid to the free base of the compound (I) is from 1.0 to 2.0, preferably 1.5;
  • the crystallization temperature is 10 to 40 ° C, more preferably 25 ° C;
  • the reaction crystallization time is from 4 to 72 hours, more preferably 20 hours.
  • the crystalline form S2 can be used as an intermediate for the preparation of Form V.
  • the present invention provides a methanol solvate crystal form S4 of a compound (I) monosuccinate (hereinafter referred to as "crystal form S4").
  • the X-ray powder diffraction of the crystal form S4 is 18.8° ⁇ 0.2°, 9.3° ⁇ 0.2°, 21.2° ⁇ 0.2°, 20.1° ⁇ 0.2°, 23.1° ⁇ 0.2°, 23.8° ⁇ 0.2° at the diffraction angle 2 ⁇ . Characteristic peaks at 7.5 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, and 15.0 ° ⁇ 0.2 °.
  • the present invention also provides a method for preparing the crystalline form S4, the preparation method comprising:
  • the reaction temperature is 10-40 ° C;
  • the stirring reaction time is 12 to 120 hours, more preferably 12 to 24 hours;
  • the vacuum drying temperature is 25 °C.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • the "drying” can be carried out at room temperature or higher.
  • the drying temperature is from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. Drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • 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. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not absolute.
  • 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.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • Form X of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Form X of the present invention, Form III, Form V or any mixture thereof
  • a pharmaceutically acceptable carrier, diluent or excipient e.g., a pharmaceutically acceptable styrene, aminoethyl sulfonate, aminoethyl sulfonyl, a pharmaceutically acceptable carrier, diluent or excipient.
  • Form X Form III, Form V or any mixture thereof of the present invention for the preparation of a cyclin-dependent kinase 4/6 inhibitor drug.
  • the present invention provides the use of Form X, Form III, Form V or any combination thereof in the preparation of a medicament for treating breast cancer.
  • Example 1 is an XRPD pattern of Form X prepared in Example 1.
  • Example 2 is an XRPD pattern of Form X prepared in Example 2.
  • Example 3 is a DSC chart of Form X prepared in Example 2.
  • Example 4 is a TGA diagram of Form X prepared in Example 2.
  • Figure 5 is a 1 H NMR chart of Form X prepared in Example 2.
  • Figure 6 is a DVS diagram of Form X
  • Figure 7 is an XRPD overlay of Form X before and after DVS test (the above figure shows the XRPD pattern of Form X before DVS test, and the figure below shows the XRPD pattern of Form X after DVS test)
  • Figure 8 is an XRPD overlay of the crystal X before and after polishing (the upper graph shows the XRPD pattern of the crystal form X before polishing, and the lower graph shows the XRPD pattern of the crystal form X after the polishing)
  • Figure 9 is an XRPD overlay of the non-hydrate form before and after grinding (the figure above shows the XRPD pattern of the non-hydrate form before grinding, and the figure below shows the XRPD pattern of the non-hydrate form after grinding)
  • Figure 10 is an XRPD overlay of Form X before and after 24 h at 97.3% relative humidity (top panel is an XRPD pattern of Form X before placement, and Figure 4 is an XRPD pattern of Form X after placement)
  • Figure 11 is an XRPD overlay of the non-hydrate form before and after 24 h of 97.3% relative humidity (XRPD pattern before top-down release in non-hydrate form, XRPD of Form X after non-hydrate form) Figure, XRPD pattern of hydrate form)
  • Figure 12 is an XRPD overlay of Form I before and after 24 hours of 97.3% relative humidity (from top to bottom, XRPD pattern before Form I is placed, XRPD pattern of Form X after Form I is placed, Hydration Object form of XRPD)
  • Figure 13 is a DSC chart of Form III prepared in Example 12.
  • Figure 15 is an XRPD pattern of Form III prepared in Example 14.
  • Figure 16 is an XRPD overlay of Form III before and after DVS test (the above figure shows the XRPD pattern of Form III before DVS test, and the figure below shows the XRPD pattern of Form III after DVS test)
  • Figure 17 is an XRPD overlay before and after the placement of Form III (from the top to the bottom, the XRPD pattern before the placement of Form III, and the XRPD pattern after leaving for six months at 25 ° C / 60% relative humidity, 40 ° C / 75% XRPD pattern after three months of relative humidity)
  • Figure 18 is an XRPD pattern of Form V prepared in Example 21.
  • Figure 19 is a TGA diagram of Form V prepared in Example 21.
  • Figure 20 is a DSC chart of Form V prepared in Example 21.
  • Example 21 is a 1H NMR chart of Form V prepared in Example 21.
  • Figure 22 is an XRPD overlay of the crystal form V before and after polishing (the above figure shows the XRPD pattern before the crystal form V is polished, and the figure below shows the XRPD pattern after the form V is ground)
  • Figure 23 is an XRPD overlay of the Form V placed at 25 °C / 60% relative humidity for seven months (the upper image shows the XRPD pattern before the Form V is placed, and the figure below shows the XRPD pattern after the Form V is placed)
  • Figure 24 is an XRPD pattern of Form II prepared in Example 27.
  • Figure 25 is an XRPD pattern of the crystalline form S2 prepared in Example 28.
  • Figure 26 is an XRPD pattern of the crystalline form S4 prepared in Example 29.
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • Nuclear magnetic resonance spectroscopy data (1H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated water to prepare a solution of 2-10 mg/mL.
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • the compound (I) and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) and/or a salt thereof as a raw material is in the form of a solid powder.
  • the obtained crystalline solid is the crystalline form X of the present invention, and the X-ray powder diffraction data thereof is shown in Fig. 1 and Table 1.
  • the obtained crystalline solid is the crystalline form X of the present invention, and its X-ray powder diffraction data is shown in Fig. 2 and Table 2.
  • the compound (I) monosuccinate crystal form X prepared by the above method has a 1 H NMR spectrum as shown in Fig. 5, and the identification data is as follows:
  • the DSC of this crystal form is shown in Fig. 3, in which there is an endothermic peak, and the endothermic peak which starts to appear near 206 ° C is a melting endothermic peak.
  • the TGA of this crystalline form as shown in Figure 4, had a weight loss gradient of about 0.1% when heated to 150 °C.
  • Form X of the present invention was taken for dynamic moisture adsorption (DVS) testing. The results are shown in Table 3.
  • the DVS pattern of Form X is shown in Figure 6.
  • the XRPD stack of Form X before and after the DVS test is shown in Figure 7.
  • the hygroscopicity data for the non-hydrate form is derived from CN103201275A [page 16/17, Table 1, Cycle 1]
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Form X, non-hydrated form were placed in a mortar and manually ground for 5 minutes to test the solid XRPD pattern.
  • Form X, non-hydrate form before and after XRPD stacking is shown in Figure 8, Figure 9 (the above figure is the XRPD pattern before crystal polishing, the figure below is the polished XRPD pattern), the grinding results are shown in Table 4.
  • the results show that after the crystal form X is ground, the crystallinity does not change significantly, and the stable physical properties can be maintained.
  • the non-hydrate form has a weak diffraction peak after grinding, and a bulge appears, indicating that a large amount of amorphous shape appears after grinding.
  • the mechanical polishing stability of Form X of the present invention is significantly better than that of the non-hydrated form.
  • Form X was placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity, 60 ° C / 75% relative humidity to determine its chemical stability
  • Form I placed at 40 ° C / 75% relative humidity
  • the chemical stability was investigated under the condition of 60 ° C / 75% relative humidity.
  • the chemical stability of the non-hydrate form was observed under the condition of 60 ° C / 75% relative humidity.
  • the results of crystal form purity change are shown in Table 5 below.
  • the chemical purity of the crystal form did not change under the condition of /75% relative humidity for at least 2 weeks.
  • Form I was placed at 60 ° C / 75% relative humidity for 2 weeks, at 40 ° C / 75% relative humidity for 2 months, and the non-hydrate form was placed at 60 ° C / 75% relative humidity for 2 weeks.
  • the chemical purity of the crystal form was significantly reduced (about 0.1% reduction), indicating that the crystal form X of the present invention has good chemical stability.
  • Form X of the present invention 10 mg of each of the non-hydrate forms was added to a 1.5 mL glass bottle, and 1 mL of a solvent was added thereto, and stirred at different temperatures to prepare a suspension, which was magnetically stirred at a rate of 500 rpm for 24 hours, and centrifuged. Take the solid test XRPD and the results are shown in Table 6.
  • Form X, non-hydrate form and Form I were placed in an environment of 97.3% relative humidity for 24 h, respectively.
  • the XRPD pattern of the solid was measured.
  • the XRPD pattern of Form X, non-hydrate form and Form I before and after placement was as shown in the figure. 10, 11, 12, the test results are shown in Table 7.
  • the experimental results show that the form X is prepared into a preparation, and the chemical purity is maintained above 99% under accelerated and long-term conditions for one month, and the chemical form X of the preparation is chemically stable.
  • Form III prepared by the present invention was investigated by the compressibility coefficient according to the "United States Pharmacopoeia", and the bulk density and tap density of Form X and the prior art Form I and non-hydrate forms were determined, respectively. Calculate the compressibility factor according to the formula below.
  • Compressibility coefficient (%) (tap density - bulk density) / tap density ⁇ 100%
  • Crystal form Bulk density (g/ml) Tap density (g/ml) Compressibility coefficient (%) Form X 0.166 0.190 13% Crystal form I 0.085 0.120 29% Non-hydrate form 0.248 0.372 33%
  • Example 11 Compressibility of Form X
  • the tablet is pressed by a manual tableting machine, and when pressed, a circular flush (which ensures the isotropy of the tablet) which can be pressed into a cylindrical tablet is selected.
  • a circular flush which ensures the isotropy of the tablet
  • the recommended parameters in the table below can be used for testing.
  • the DSC of this crystal form is shown in Fig. 13, which has an endothermic peak, and an endothermic peak starts to appear near 182 ° C, and the endothermic peak is a melting endotherm.
  • the TGA of this crystalline form had a weight loss gradient of about 2.7% when heated to 150 °C.
  • the obtained crystalline solid was the crystalline form III of the present invention, and its X-ray powder diffraction data is shown in Fig. 15 and Table 13.
  • the wettability of the crystal form III of the present invention was measured by a dynamic moisture adsorption (DVS) instrument, and the XRPD comparison chart before and after DVS is shown in Fig. 16.
  • DVD dynamic moisture adsorption
  • Form III prepared by the present invention was investigated by the compressibility coefficient according to the "United States Pharmacopoeia", and the bulk density and tap density of Form III and the prior art Form I and non-hydrate forms were determined, respectively. Calculate the compressibility factor according to the formula below.
  • Compressibility coefficient (%) (tap density - bulk density) / tap density ⁇ 100%
  • Crystal form Bulk density (g/ml) Tap density (g/ml) Compressibility coefficient (%) Crystal form III 0.191 0.217 12% Crystal form I 0.085 0.120 29% Non-hydrate form 0.248 0.372 33%
  • the tablet is pressed by a manual tableting machine, and when pressed, a circular flush (which ensures the isotropy of the tablet) which can be pressed into a cylindrical tablet is selected.
  • a circular flush which ensures the isotropy of the tablet
  • test the diameter with a tablet hardness tester.
  • the test can be carried out by using a ⁇ 6 mm circular flush, a sample amount of 80 mg, and a pressure of 10 kN.
  • the average adsorption amount of the crystalline form III of the present invention is only 0.03 mg compared with the crystalline form I and the non-hydrate form, which is far lower than the adsorption amount of the crystalline form I and the non-hydrate form, and has obvious adhesion advantage. .
  • Form III was placed under conditions of 40 ° C / 75% relative humidity, and the change in crystal form at 3 months was accelerated by XRPD measurement.
  • Form III was allowed to stand at 25 ° C / 60% relative humidity for 6 months, and the change in crystal form was determined by XRPD.
  • the obtained crystalline solid was the crystalline form V of the present invention, and its X-ray powder diffraction data is shown in Fig. 18 and Table 19, and the 1 H NMR chart is shown in Fig. 21.
  • the compound (I) succinate crystal form V prepared by the above method has the following 1 H NMR identification data as follows:
  • the TGA of this crystal form as shown in Figure 19, had a weight loss gradient of about 1.0% when heated to 140 °C.
  • the DSC of this crystal form is shown in Fig. 20, which has an endothermic peak, and the endothermic peak which starts to appear near 180 °C is a melting endothermic peak.
  • Form III prepared by the present invention was investigated by the compressibility coefficient according to the "United States Pharmacopoeia", and the bulk density and tap density of Form V and the prior art Form I and non-hydrate forms were determined, respectively. Calculate the compressibility factor according to the formula below.
  • Compressibility coefficient (%) (tap density - bulk density) / tap density ⁇ 100%
  • the average adsorption amount of the crystalline form V of the present invention is only 0.04 mg compared with the crystalline form I and the non-hydrate form, which is far lower than the adsorption amount of the crystalline form I and the non-hydrate form, and has obvious adhesion advantage. .
  • Form V was placed in a mortar and manually ground for 5 minutes to test the solid XRPD pattern.
  • the XRPD stack before and after the crystal form V grinding is shown in Fig. 22 (the above figure shows the XRPD pattern before the crystal form V is polished, and the figure below shows the XRPD pattern after the crystal form V is ground).
  • the experimental results show that the crystal form solubility of the present invention is higher than 10 mg/mL, and has high solubility, which meets the requirements of medicinal requirements.
  • the crystal form V was stored under the condition of 25 ° C / 60% relative humidity for 7 months to examine its physical stability, and the change of the crystal form was determined by XRPD. The measurement results are shown in Table 23.
  • the obtained crystalline solid is the crystalline form S2 of the present invention, and the X-ray powder diffraction data thereof is shown in FIG. 25 and Table 25.
  • the obtained crystalline solid was the crystalline form S4 of the present invention, and the X-ray powder diffraction data thereof is shown in Fig. 26 and Table 26.

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Abstract

如式（I）所示的化合物瑞博西尼的单琥珀酸盐的晶型X、III和V，以及其制备方法。含有所述晶型的药物组合物。所述晶型在制备周期蛋白依赖性激酶4/6抑制剂和治疗乳腺癌的药物制剂中的用途。

Description

瑞博西尼的单琥珀酸盐晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域，具体而言，涉及瑞博西尼的单琥珀酸盐的晶型及其制备方法和用途。
背景技术
周期蛋白依赖性激酶4/6(Cyclin-dependent kinase4/6,CDK4/6)是一类丝/苏氨酸激酶，与细胞周期素D(Cyclin D)结合，调节细胞由G1期向S期转换。在很多肿瘤中，都存在“Cyclin D-CDK4/6-INK4-Rb通路”异常，这条通路的改变，加速了G1期进程，使得肿瘤细胞增殖加快而获得生存优势。因此，对其的干预成为一种治疗策略，CDK4/6因此成为抗肿瘤的靶点之一。
瑞博西尼(又名Ribociclib,LEE011)是一种周期蛋白依赖性激酶4/6的抑制剂，于2017年03月13日获得美国FDA的批准，以单琥珀酸盐的形式上市。瑞博西尼是由诺华开发的药物，用于治疗HR+/HER2-的晚期或转移性乳腺癌。
瑞博西尼的化学名称为7-环戊基-2-(5-哌嗪-1-基-吡啶-2-基-氨基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸二甲酰胺(以下称为化合物(I))，其结构如式(I)所示：
Figure PCTCN2018096586-appb-000001
化合物(I)
目前，专利CN103201275A公开了化合物(I)单琥珀酸盐的一个水合物形式和一个非水合物形式(以下简称为“水合物形式”和“非水合物形式”)，专利CN105085533A公开了化合物(I)单琥珀酸盐晶型I(以下简称为“晶型I”)。
发明人经研究发现，水合物形式溶解度较低，低于0.5mg/mL，非水合物形式溶解度较好，因此，我们选择非水合物形式为对比晶型，但非水合物在80±3℃条件下在异丙醇中反应结晶得到，高温增加了琥珀酸和异丙醇发生酯化反应的风险，也增加了降解的风险。此外，非水合物形式易转晶，在90％RH下，高达7.35％的非水合物形式会转化成水合物形式，药物晶型的转变会给药物带来疗效、安全性等问题。另外，非水合物形式粉体学性质差，这些不利性质可能降低制剂中压片和填充的生产效率，同时对药品质量的控制带来较 大的困难。晶型I虽然克服了非水合物形式制备过程中高温易发生副反应、易降解的问题，但其仍然存在一些不理想的性质，如化学稳定性低，高湿度条件下物理稳定性差，粉体学性质不理想等。
为克服现有技术的缺点，本申请的发明人在尝试不同晶型制备方法中，意外发现了本发明提供的化合物(I)的单琥珀酸盐晶型晶型X、晶型III、晶型V，其在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势，特别是引湿性低，稳定性好，流动性好，可压性优，黏附性小，溶解度符合药用要求，为含化合物(I)单琥珀酸盐的药物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。
发明内容
针对现有技术的不足，本发明的主要目的是提供化合物(I)的单琥珀酸盐的新晶型及其制备方法和用途。
根据本发明的目的，本发明提供化合物(I)的单琥珀酸盐的晶型X(以下称作“晶型X”)。
一方面，使用Cu-Kα辐射，所述晶型X的X射线粉末衍射在衍射角2θ值为20.0°±0.2°,12.9°±0.2°,8.8°±0.2°,7.8°±0.2°处有特征峰。
进一步地，所述晶型X的X射线粉末衍射在衍射角2θ为15.6°±0.2°,10.9°±0.2°,23.0°±0.2°中的1处、或2处、或3处具有特征峰；优选地，所述晶型X的X射线粉末衍射在衍射角2θ值为15.6°±0.2°,10.9°±0.2°,23.0°±0.2°处有特征峰。
进一步地，所述晶型X的X射线粉末衍射在衍射角2θ为18.7°±0.2°,13.7°±0.2°,19.5°±0.2°中的1处、或2处、或3处具有特征峰；优选地，所述晶型X的X射线粉末衍射在衍射角2θ为18.7°±0.2°,13.7°±0.2°,19.5°±0.2°处有特征峰。
进一步地，所述晶型X的X射线粉末衍射在衍射角2θ为21.1°±0.2°,12.3°±0.2°,17.2°±0.2°,24.9°±0.2°,22.0°±0.2°中的1处、或2处、或3处、或4处、或5处具有特征峰；优选地，所述晶型X的X射线粉末衍射在衍射角2θ为21.1°±0.2°,12.3°±0.2°,17.2°±0.2°,24.9°±0.2°,22.0°±0.2°处具有特征峰。
另一方面，所述晶型X的X射线粉末衍射在衍射角2θ为20.0°±0.2°,12.9°±0.2°,8.8°±0.2°,7.8°±0.2°,15.6°±0.2°,10.9°±0.2°,23.0°±0.2°,18.7°±0.2°,13.7°±0.2°,19.5°±0.2°，21.1°±0.2°,12.3°±0.2°,17.2°±0.2°,24.9°±0.2°，22.0°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处、或14处、或15处有特征峰。
非限制性地，晶型X的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型X的制备方法，所述制备方法包括：
将化合物(I)和琥珀酸加入醇类单一溶剂中或乙腈和醇类的混合溶剂中，加入晶种悬浮搅拌反应析晶，离心分离固体，真空干燥，得到晶型X。
其中：
优选地，所述晶种为晶型X或晶型I，所述晶型I为化合物(I)的单琥珀酸盐，其X射线粉末衍射在衍射角2θ为11.9°±0.2°,19.4°±0.2°,20.6°±0.2°,22.7°±0.2°,24.4°±0.2°,26.3°±0.2°,7.8°±0.2°,15.7°±0.2°,16.7°±0.2°处具有特征峰。
优选地，所述化合物(I)和琥珀酸的摩尔比为1:1-1:2；更优选地，所述化合物(I)和琥珀酸的摩尔比为1:1.8；
优选地，所述混合溶剂为乙腈和甲醇的混合溶剂；更优选地，所述混合溶剂中乙腈和甲醇的体积比为1:1-15:1；
优选地，所述搅拌反应温度为40-60℃；
优选地，所述搅拌反应时间为12-120小时；更优选地，所述搅拌反应时间为12-24小时。
本发明提供的晶型X具有以下有益效果：
(1)本发明晶型X相比现有技术具有更低的引湿性，能够克服高引湿性带来的弊端。测试结果表明，晶型X在0-80％和0-90％相对湿度下的引湿性均低于非水合物形式，非水合物形式的引湿性在0-80％和0-90％相对湿度条件下增重分别是晶型X的2倍和4倍。并且，本发明晶型X经引湿性实验后晶型未发生改变，物理稳定性好。
引湿性会影响药物的稳定性、加工时的流动性和均匀性等，最终影响药物制剂的质量。同时，引湿性会影响药物的制备、储存与后处理工艺。低引湿性晶型对储存条件要求不苛刻，降低了物料储存以及质量控制成本，具有很强的价值。
(2)本发明提供的晶型X相比现有技术具有更好的机械稳定性，降低制剂制备时研磨或压片过程发生转晶的风险。本发明的晶型X具有高的研磨稳定性，经研磨后结晶度没有明显变化，而现有技术非水合物形式经研磨后结晶度明显降低，基线出现毛刺峰并有鼓包出现，这表明非水合物形式经研磨后无定形含量显著升高。
晶型X较好的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。另外，晶型X用于制剂直接加工的工艺可行性高，大大简化了制剂工艺过程，降低了研发和生产的成本。
(3)本发明提供的晶型X相比现有技术具有更好的稳定性。本发明的晶型 X在60℃/75％相对湿度条件下放置，至少2周化学纯度未发生变化，在25℃/60％相对湿度、40℃/75％相对湿度条件下放置，至少2个月化学纯度未发生变化，在97.3％相对湿度条件下放置，至少24h晶型未发生变化。而现有技术晶型(非水合物形式和晶型I)在60℃/75％相对湿度条件下放置2周，40℃/75％相对湿度条件下放置2个月，化学纯度均有较为明显的降低，在97.3％相对湿度条件下放置24h，均会转变为水合物形式，由此可见，本发明的晶型X具有良好的稳定性。
作为药物中最关键的活性成分，晶型具有良好的物理和化学稳定性至关重要。晶型具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。晶型具有良好的化学稳定性，储存过程中纯度基本不变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。此外，稳定的晶型在结晶工艺过程中更加可控，不容易出现杂质和混晶，利于工业化生产。
(4)本发明提供的晶型X相比现有技术具有更好的热力学稳定性。本发明的晶型X与非水合物形式在有机溶剂中不同温度条件下混悬搅拌，均得到本发明晶型X，说明本发明晶型X具有更高的热力学稳定性。
药物的稳定性是至关重要的，尤其在市售有效期内保持较好的稳定性，减少药物由于晶型变化而导致药物溶出速率及生物利用度改变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。热力学稳定的晶型在结晶工艺过程中更加可控，不容易出现混晶；在制剂工艺及储存过程中，不容易转变成其它晶型，从而保证样品的质量一致可控，并确保制剂产品的溶出曲线不会随着存储的时间变化而发生改变。
(5)本发明晶型X在模拟生物介质和纯水中具有良好的溶解度，溶解度均大于13.3mg/mL，符合药用要求。
溶解度是药物生物利用度的限速因素，因此，晶型X溶解度符合药用要求，能够满足瑞博西尼药物实现其较高的生物利用度，从而保证药物的成药性及药效。
(6)本发明晶型X的制剂具有良好的化学稳定性。取适量晶型X，与辅料混合均匀，棍压制成薄片并粉碎成颗粒，与外加辅料混合均匀，选用合适的模具压制成形，在长期与加速条件下放置1个月，杂质没有明显增长，表明本发明晶型X的制剂具有良好的化学稳定性。
药物制剂的基本要求是安全、有效、稳定。药物制剂具有良好的化学稳定性，可以保证药品的药效，降低产生毒副反应和刺激反应的风险，确保人们用药安全。
优选地，本发明的晶型X还具有如下有益效果：
(1)本发明晶型X相比于现有技术晶型可具有更好的流动性。在一个具体的 流动性评价实验中，实验结果表明晶型X流动性好，而晶型I为流动性差，非水合物形式为流动性很差。
晶型具备更好的流动性可以有效提升压片和充填的生产速度，提升生产效率；此外，可以提高直接压片和粉末直接充填的可行性，大大简化生产工艺，降低生产成本。晶型X更好的流动性能保证制剂的混合均匀度及含量均匀度、降低剂型的重量差异，提升产品质量。
(2)本发明晶型X相比于现有技术晶型可具有更优的可压性。在一个具体的可压性评价实验中，本发明晶型X的抗张强度为1.36MPa，远远高于现有技术晶型，约为非水合物形式抗张强度的5倍，为晶型I的2倍以上。
晶型X可压性好可以有效改善原料药加工过程中的硬度/脆碎度不合格等问题，降低对前续产品工艺处理的要求，使工艺更为稳健，改善产品外观，提升产品质量。另外，晶型X制剂直接加工的工艺可行性高，大大简化了制剂工艺过程，降低了研发和生产的成本。
根据本发明的目的，本发明提供化合物(I)的单琥珀酸盐的晶型III(以下称作“晶型III”)。
一方面，使用Cu-Kα辐射，所述晶型III的X射线粉末衍射在衍射角2θ值为18.0°±0.2°,13.0°±0.2°,10.7°±0.2°处有特征峰。
进一步地，所述晶型III的X射线粉末衍射在衍射角2θ值为22.0°±0.2°,20.0°±0.2°,9.4°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型III的X射线粉末衍射在衍射角2θ为22.0°±0.2°,20.0°±0.2°,9.4°±0.2°处有特征峰。
进一步地，所述晶型III的X射线粉末衍射在衍射角2θ值为20.9°±0.2°处有特征峰。
另一方面，所述晶型III的X射线粉末衍射在衍射角2θ值为18.0°±0.2°,13.0°±0.2°,10.7°±0.2°，22.0°±0.2°,20.0°±0.2°,9.4°±0.2°,20.9°±0.2°中的任意3处、或4处、或5处、或6处、或7处有特征峰。
非限制性地，晶型III的X射线粉末衍射谱图如图15所示。
根据本发明的目的，本发明还提供所述晶型III的制备方法，所述制备方法包括如下两种方法:
方法一：使用化合物(I)的单琥珀酸盐晶型II加热至一定温度下转晶，冷却后分离而获得；
其中：
所述转晶温度为140-190℃，更优选为165℃。
方法二：
将化合物(I)和琥珀酸加入醇类溶剂中，悬浮搅拌反应析晶，离心分离固体，真空干燥，得到晶型III。
其中：
优选地，醇类为甲醇；
优选地，所述化合物(I)和琥珀酸的摩尔比为1:1-1:2；更优选地，所述化合物(I)和琥珀酸的摩尔比为1:1.8；
优选地，悬浮搅拌时间为12-72h；
优选地，所述搅拌反应温度为15-40℃；
优选地，所述真空干燥温度为70-160℃；
优选地，所述真空干燥时间为10-60分钟；
本发明提供的晶型III具有以下有益效果：
(1)本发明晶型III相比于现有技术晶型具有更好的稳定性。特别是本发明晶型III经DVS测试后晶型未发生改变，而现有技术非水合物形式经DVS测试后晶型即发生转变，转变成为了水合物形式。
作为药物中最关键的活性成分，晶型具有良好的物理稳定性至关重要。晶型具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。
(2)本发明晶型III在模拟生物介质和纯水中具有良好的溶解度，溶解度高于13mg/mL，符合药用要求。
溶解度是药物生物利用度的限速因素，因此，晶型III溶解度符合药用要求，能够满足瑞博西尼药物实现其较高的生物利用度，从而保证药物的成药性及药效。
(3)本发明提供的晶型III具有好的稳定性。本发明的晶型III在25℃/60％相对湿度条件下放置，至少6个月晶型保持不变，在40℃/75％相对湿度条件下放置，至少3个月晶型保持不变，说明本发明的晶型III具有良好的稳定性。
作为药物中最关键的活性成分，晶型具有良好的物理稳定性至关重要。晶型具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。
优选的，本发明的晶型III还具有如下有益效果：
(1)本发明晶型III相比于现有技术晶型具有更好的流动性。在一个具体的流动性评价实验中，实验结果表明晶型III流动性好，而晶型I为流动性差，非水合物形式为流动性很差。
晶型具备更好的流动性可以有效提升压片和充填的生产速度，提升生产效率；此外，可以提高直接压片和粉末直接充填的可行性，大大简化生产工艺，降低生产成本。晶型III更好的流动性能保证制剂的混合均匀度及含量均匀度、降低剂型 的重量差异，提升产品质量。
(2)本发明晶型III相比于现有技术晶型具有更优的可压性。在一个具体的可压性评价实验中，本发明晶型III的抗张强度为1.41MPa，远远高于现有技术晶型，约为非水合物形式抗张强度的5倍，为晶型I的2倍以上。
晶型III可压性好可以有效改善原料药加工过程中的硬度/脆碎度不合格等问题，降低对前续产品工艺处理的要求，使工艺更为稳健，改善产品外观，提升产品质量。另外，晶型III制剂直接加工的工艺可行性高，大大简化了制剂工艺过程，降低了研发和生产的成本。
(3)本发明晶型III相比于现有技术晶型具有更小的黏附性。在一个具体的黏附性评价实验中，晶型III的平均黏附量为0.030mg，而现有技术非水合物形式的平均吸附量为0.075，晶型I的平均吸附量为0.085mg，是本发明晶型III吸附量的两倍以上。
晶型III的黏附性低可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型III的黏附性低还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品含原料药量的均匀度。
根据本发明的目的，本发明提供化合物(I)的单琥珀酸盐的晶型V(以下称作“晶型V”)。
一方面，使用Cu-Kα辐射，所述晶型V的X射线粉末衍射在衍射角2θ为9.4°±0.2°、18.3°±0.2°、12.8°±0.2°处具有特征峰。
进一步地，所述晶型V的X射线粉末衍射在衍射角2θ为22.0°±0.2°、18.9°±0.2°、20.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型V的X射线粉末衍射在衍射角2θ为22.0°±0.2°、18.9°±0.2°、20.5°±0.2°处具有特征峰。
进一步地，所述晶型V的X射线粉末衍射在衍射角2θ为23.0°±0.2°、17.6°±0.2°中的1处、或2处有特征峰；优选地，所述晶型V的X射线粉末衍射在衍射角2θ为23.0°±0.2°、17.6°±0.2°处具有特征峰。
另一方面，所述晶型V的X射线粉末衍射在衍射角2θ为9.4°±0.2°、18.3°±0.2°、12.8°±0.2°、22.0°±0.2°、18.9°±0.2°、20.5°±0.2°、23.0°±0.2°、17.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处有特征峰。
非限制性地，晶型V的X射线粉末衍射谱图如图18所示。
根据本发明的目的，本发明还提供所述晶型V的制备方法，所述制备方法包括:
使用化合物(I)的单琥珀酸盐四氢呋喃溶剂合物晶型S2在一定温度下放置一段时间，获得晶型V；
其中：
优选地，所述一定温度为90-120℃，更优选为100℃；
优选地，所述一定时间为15分钟-90分钟，更优选为30分钟。
优选的，本发明提供的晶型V具有以下有益效果：
(1)本发明提供的晶型V具有好的机械稳定性，降低制剂制备时研磨或压片过程发生转晶的风险。本发明的晶型V具有高的研磨稳定性，经研磨后晶型未发生变化。
晶型V较好的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。另外，晶型V用于制剂直接加工的工艺可行性高，大大简化了制剂工艺过程，降低了研发和生产的成本。
(2)本发明晶型V在模拟生物介质和纯水中具有良好的溶解度，溶解度约为10mg/mL，符合药用要求。
溶解度是药物生物利用度的限速因素，因此，晶型V溶解度符合药用要求，能够满足瑞博西尼药物实现其较高的生物利用度，从而保证药物的成药性及药效。
(3)本发明提供的晶型V具有好的物理稳定性。本发明的晶型V在25℃/60％相对湿度条件下放置，至少7个月晶型保持不变，说明本发明的晶型V具有良好的稳定性。
作为药物中最关键的活性成分，晶型具有良好的物理稳定性至关重要。晶型具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。
优选的，本发明的晶型V还具有如下有益效果：
(1)本发明晶型V相比于现有技术晶型可具有更好的流动性。在一个具体的流动性评价试验中，实验结果表明晶型V流动性好，而晶型I为流动性差，非水合物形式为流动性很差。
晶型具备更好的流动性可以有效提升压片和充填的生产速度，提升生产效率；此外，可以提高直接压片和粉末直接充填的可行性，大大简化生产工艺，降低生产成本。晶型V更好的流动性能保证制剂的混合均匀度及含量均匀度、降低剂型的重量差异，提升产品质量。
(2)本发明晶型V相比于现有技术晶型可具有更小的黏附性。在一个具体的黏附性评价实验中，晶型V的平均黏附量为0.040mg，而现有技术非水合物形式的平均吸附量为0.075，晶型I的平均吸附量为0.085mg，约为本发明晶型V的两倍之多。
晶型V的黏附性低可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型V的黏附性低还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品含原料药量的均匀度。
根据本发明的目的，本发明提供化合物(I)的单琥珀酸盐的晶型II(以下称作“晶型II”)。
所述晶型II的X射线粉末衍射在衍射角2θ为4.6°±0.2°、19.9°±0.2°、7.4°±0.2°、17.1°±0.2°、15.6°±0.2°、6.3°±0.2°、10.2°±0.2°、12.2°±0.2°、13.9°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型II的X射线粉末衍射谱图如图23所示。
根据本发明的目的，本发明还提供所述晶型II的制备方法，所述制备方法包括:
使用化合物(I)的游离碱在醇类和烷烃类混合体系中与琥珀酸反应，于一定温度下搅拌反应析晶，分离，再经过干燥而获得；
其中：
琥珀酸与化合物(I)游离碱的摩尔比为1.0-1.5，优选为1.0；
所述醇为C 1～C 5醇类或者它们的混合物，烷烃为C 5～C 8烷烃类或者它们的混合物；
优选地，所述醇选自甲醇、乙醇中的一种或它们的混合物，烷烃为选自正己烷、正庚烷中的一种或它们的混合物；更优选地，所述醇为乙醇，烷烃为正庚烷；
优选地，所述析晶温度为-20～50℃，更优选为4℃；
优选地，所述析晶时间为4-72小时，更优选为20小时。
根据本发明的目的，本发明提供化合物(I)单琥珀酸盐的四氢呋喃溶剂合物晶型S2(以下称作“晶型S2”)。
所述晶型S2的X射线粉末衍射在衍射角2θ为19.6°±0.2°、8.0°±0.2°、10.6°±0.2°、12.3°±0.2°、20.7°±0.2°、21.4°±0.2°、14.1°±0.2°、18.0°±0.2°、20.0°±0.2°、25.9°±0.2°处有特征峰。
非限制性地，晶型S2的X射线粉末衍射谱图如图24所示。
根据本发明的目的，本发明还提供所述晶型S2的制备方法，所述制备方法包括:
使用化合物(I)的游离碱在四氢呋喃中与琥珀酸反应，于一定温度下搅拌反应析晶，分离，干燥而获得晶型S2；
其中：
琥珀酸与化合物(I)的游离碱的摩尔比为1.0-2.0，优选为1.5；
优选地，所述析晶温度为10～40℃，更优选为25℃；
优选地，所述反应析晶时间为4-72小时，更优选为20小时。
进一步地，所述晶型S2可用作制备晶型V的中间体。
根据本发明的目的，本发明提供化合物(I)单琥珀酸盐的甲醇溶剂合物晶型S4(以下称作“晶型S4”)。
所述晶型S4的X射线粉末衍射在衍射角2θ为18.8°±0.2°、9.3°±0.2°、21.2°±0.2°、20.1°±0.2°、23.1°±0.2°、23.8°±0.2°、7.5°±0.2°、16.3°±0.2°、15.0°±0.2°处有特征峰。
非限制性地，晶型S4的X射线粉末衍射谱图如图25所示。
根据本发明的目的，本发明还提供所述晶型S4的制备方法，所述制备方法包括:
将一定比例的LEE-011游离碱和琥珀酸加入甲醇溶剂中，悬浮搅拌析晶，离心分离固体，真空干燥，得到晶型S4。
其中：
优选地，所述反应温度为10-40℃；
优选地，所述搅拌反应时间为12～120小时，更优选为12～24小时；
优选地，所述真空干燥温度为25℃。
所述“室温”不是精确的温度值，是指10-30℃温度范围。
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约60℃，或者到40℃，或者到50℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
本发明中，“晶体”或“多晶型”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。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向 有关，本文所示的峰强度为说明性而非用于绝对比较。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，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。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。
在一些实施方案中，本发明的晶型X是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
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。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明的晶型X，晶型III，晶型V或它们的任意混合及药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提的晶型X，晶型III，晶型V或它们的任意混合在制备周期蛋白依赖性激酶4/6抑制剂药物中的用途。
更进一步地，本发明提供的晶型X，晶型III，晶型V或它们的任意混合在制备治疗乳腺癌药物中的用途。
附图说明
图1为实施例1制备的晶型X的XRPD图
图2为实施例2制备的晶型X的XRPD图
图3为实施例2制备的晶型X的DSC图
图4为实施例2制备的晶型X的TGA图
图5为实施例2制备的晶型X的 1H NMR图
图6为晶型X的DVS图
图7为晶型X在DVS测试前后的XRPD叠图(上图为DVS测试前的晶型X的XRPD图，下图为DVS测试后晶型X的XRPD图)
图8为晶型X研磨前后的XRPD叠图(上图为研磨前的晶型X的XRPD图， 下图为研磨后的晶型X的XRPD图)
图9为非水合物形式研磨前后的XRPD叠图(上图为研磨前的非水合物形式的XRPD图，下图为研磨后的非水合物形式的XRPD图)
图10为晶型X置于97.3％相对湿度条件下24h前后的XRPD叠图(上图为放置前的晶型X的XRPD图，下图为放置后的晶型X的XRPD图)
图11为非水合物形式置于97.3％相对湿度条件下24h前后的XRPD叠图(由上而下分别为非水合物形式放置前的XRPD图，非水合物形式放置后的晶型X的XRPD图，水合物形式的XRPD图)
图12为晶型I置于97.3％相对湿度条件下24h前后的XRPD叠图(由上而下分别为晶型I放置前的XRPD图，晶型I放置后的晶型X的XRPD图，水合物形式的XRPD图)
图13为实施例12制备的晶型III的DSC图
图14为实施例12制备的晶型III的TGA图
图15为实施例14制备的晶型III的XRPD图
图16为晶型III在DVS测试前后的XRPD叠图(上图为DVS测试前的晶型III的XRPD图，下图为DVS测试后晶型III的XRPD图)
图17为晶型III放置前后的XRPD叠图(由上而下分别为晶型III放置前的XRPD图，25℃/60％相对湿度下放置六个月后的XRPD图，40℃/75％相对湿度下放置三个月后的XRPD图)
图18为实施例21制备的晶型V的XRPD图
图19为实施例21制备的晶型V的TGA图
图20为实施例21制备的晶型V的DSC图
图21为实施例21制备的晶型V的1H NMR图
图22为晶型V研磨前后的XRPD叠图(上图为晶型V研磨前的XRPD图，下图为晶型V研磨后的XRPD图)
图23为晶型V放置于25℃/60％相对湿度下七个月前后的XRPD叠图(上图为晶型V放置前的XRPD图，下图为晶型V放置后的XRPD图)
图24为实施例27制备的晶型II的XRPD图
图25为实施例28制备的晶型S2的XRPD图
图26为实施例29制备的晶型S4的XRPD图
具体实施方式
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。
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
1H NMR：核磁共振氢谱
DVS：动态水分吸附
本发明所述的X射线粉末衍射图在Bruker D2 PHASER 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 PCTCN2018096586-appb-000002
1.54060；Kα2
Figure PCTCN2018096586-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10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TA Q500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
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据(1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代水溶解，配成2-10mg/mL的溶液。
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极 管阵列检测器(DAD)。本发明所述的测试溶解度的HPLC方法参数如下：
1、色谱柱：Waters CORTECS C18 150×4.6mm,2.7μm
2、流动相：A：25mmol/L KH 2PO 4水溶液+0.1％TEA 水溶液,pH＝3.5
B：乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 20
15 35
25 80
30 80
30.1 20
35 20
3、流速：1ml/min
4、进样量：5μl
5、检测波长：紫外210nm&306nm,对照500nm
6、柱温：40℃
7、稀释剂：50％乙腈
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物(I)和/或其盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述化合物(I)和/或其盐为固体粉末形式。
以下实施例中所使用的化合物(I)和/或其盐可根据现有技术制备得到，例如根据CN102186856B文献所记载的方法制备获得。
实施例1：晶型X的晶种的制备
将100.8mg化合物(I)与32.5mg琥珀酸加入5.5mL乙腈和甲醇(V:V＝10:1)的混合溶剂中，50℃下悬浮搅拌析晶24小时，然后向其中加入晶种(CN105085533B的晶型I)，50℃下悬浮搅拌析晶72小时，离心分离固体，室温真空干燥，得白色的固体结晶。
经检测，所得结晶固体为本发明所述之晶型X，其X射线粉末衍射数据如图1，表1所示。
表1
衍射角2θ d值 强度％
7.79 11.35 10.16
8.78 10.07 100.00
10.91 8.11 63.27
11.23 7.88 12.36
12.32 7.19 11.53
12.93 6.85 47.91
13.49 6.57 10.86
13.66 6.48 32.72
14.99 5.91 7.31
15.64 5.67 12.60
17.17 5.16 12.80
17.66 5.02 3.79
18.36 4.83 13.19
18.54 4.78 15.07
18.82 4.72 26.67
19.47 4.56 12.72
19.97 4.45 60.38
21.08 4.21 15.20
21.39 4.15 12.39
21.97 4.05 25.85
22.56 3.94 3.17
22.96 3.87 20.88
23.25 3.83 7.53
23.78 3.74 5.17
24.86 3.58 17.66
26.14 3.41 11.89
26.82 3.32 5.34
27.28 3.27 5.35
27.47 3.25 8.48
28.43 3.14 3.40
28.90 3.09 5.26
29.56 3.02 5.18
30.29 2.95 2.88
31.56 2.83 8.01
33.08 2.71 2.84
37.51 2.40 4.20
实施例2：晶型X的制备
将401.4mg化合物(I)与129.3mg琥珀酸加入19.8mL乙腈和甲醇(V:V＝10:1)的混合溶剂中，50℃下悬浮搅拌析晶24小时，取9mL悬浊液于另一玻璃瓶中，向其中加入晶型X的晶种，50℃下悬浮搅拌析晶68小时，离心分离固体，室温下真空干燥，得白色的结晶固体。
经检测，所得结晶固体为本发明所述之晶型X，其X射线粉末衍射数据如图2，表2所示。
上述方法制备得到的化合物(I)单琥珀酸盐晶型X，其 1H NMR谱图如图5所示，鉴定数据如下：
1H NMR(400MHz,D 2O)δ8.63(s,1H),7.83(d,J＝1.2Hz,1H),7.65–7.53(m,2H),6.62(s,1H),4.58(p,J＝8.9Hz,1H),3.39(dd,J＝14.4,6.0Hz,8H),3.09(d,J＝15.4Hz,6H),2.44(s,4H),2.27–2.08(m,2H),2.09–1.77(m,4H),1.72–1.54(m,2H).
表2
衍射角2θ d值 强度％
7.79 11.34 7.50
8.78 10.07 37.68
10.91 8.11 38.28
11.22 7.89 16.05
12.31 7.19 19.54
12.93 6.85 60.32
13.48 6.57 12.31
13.66 6.48 36.24
14.98 5.92 9.14
15.64 5.67 22.24
15.85 5.59 7.91
16.68 5.31 3.76
17.17 5.17 16.68
18.18 4.88 9.71
18.35 4.83 13.57
18.74 4.74 37.47
19.46 4.56 16.60
19.97 4.45 100.00
21.07 4.22 28.56
21.39 4.15 20.90
21.63 4.11 9.82
21.98 4.04 20.07
22.56 3.94 6.30
22.96 3.87 44.44
23.23 3.83 7.12
23.78 3.74 6.97
24.87 3.58 17.45
25.83 3.45 2.95
26.15 3.41 8.94
26.83 3.32 8.74
27.28 3.27 8.18
27.58 3.23 5.93
28.42 3.14 9.96
28.89 3.09 5.71
29.49 3.03 13.38
30.26 2.95 5.98
30.64 2.92 2.55
31.56 2.83 8.13
32.33 2.77 2.32
33.07 2.71 5.56
37.50 2.40 4.82
该晶型的DSC如图3所示，其中有一个吸热峰，在206℃附近开始出现的吸热峰为熔融吸热峰。
该晶型的TGA如图4所示，将其加热至150℃时，具有约0.1％的重量损失梯度。
实施例3晶型X的引湿性
取约10mg本发明的晶型X进行动态水分吸附(DVS)测试。结果如表3 所示，晶型X的DVS图见附图6，晶型X在DVS测试前后的XRPD叠图见附图7。
表3
Figure PCTCN2018096586-appb-000004
注：非水合物形式的引湿性数据来源于CN103201275A[第16/17页，表1，循环1]
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，与现有技术非水合物形式相比，晶型X的引湿性更低，在80％相对湿度条件下仅增重0.24％，在90％相对湿度条件下仅增重0.53％，远远小于非水合物形式的引湿性。此外，晶型X在DVS后晶型未发生转变，说明晶型X在不同湿度条件下均稳定。
实施例4晶型X的机械稳定性
将晶型X，非水合物形式分别置于研钵中，手动研磨5分钟，测试固体XRPD图。晶型X，非水合物形式研磨前后的XRPD叠图见附图8，附图9(上图为晶型研磨前的XRPD图，下图为研磨后的XRPD图)，研磨结果见表4。
表4
起始晶型 晶型 结晶度
晶型X 晶型X 结晶度无明显变化
非水合物形式 非水合物形式 结晶度明显降低
结果表明，晶型X经研磨后，结晶度无明显变化，可保持稳定的物理性质，而非水合物形式经研磨后衍射峰变弱，出现鼓包，表明经研磨后出现了大量的无定形，由此可见，本发明的晶型X的机械研磨稳定性明显优于非水合物形式。
实施例5晶型X的长期与加速化学稳定性
将晶型X放置在25℃/60％相对湿度，40℃/75％相对湿度，60℃/75％相对湿度条件下考察其化学稳定性，晶型I放置在40℃/75％相对湿度，60℃/75％相对湿度条件下考察其化学稳定性，非水合物形式放置在60℃/75％相对湿度条件下考察其化学稳定性，晶型纯度变化结果见下表5。
表5
Figure PCTCN2018096586-appb-000005
结果表明，本发明晶型X在25℃/60％相对湿度条件下和40℃/75％相对湿度条件下至少放置2个月，晶型化学纯度不发生变化，在更为苛刻的条件60℃/75％相对湿度条件下至少放置2周，晶型化学纯度不发生变化。而晶型I在60℃/75％相对湿度条件下放置2周，在40℃/75％相对湿度条件下放置2个月，非水合物形式在60℃/75％相对湿度条件下放置2周，晶型化学纯度均有明显降低(降低约0.1％)，表明本发明晶型X具有很好的化学稳定性。
实施例6晶型X的热力学稳定性
取本发明的晶型X，非水合物形式各10mg加入到1.5mL玻璃瓶，加入1mL溶剂，在不同温度下搅拌，制成悬浊液，以500转每分钟的速率磁力搅拌24小时，离心，取固体测试XRPD，结果如表6所示。
表6
起始晶型 温度 溶剂 最终晶型
晶型X，非水合物形式 5℃ 异丙醇 晶型X
晶型X，非水合物形式 25℃ 异丙醇 晶型X
晶型X，非水合物形式 50℃ 异丙醇 晶型X
结果表明，晶型X，非水合物形式在不同温度下搅拌24小时，均转化为晶型X。可见，晶型X比非水合物形式具有更高的热力学稳定性。
实施例7晶型X的高湿度物理稳定性
将晶型X、非水合物形式、晶型I分别置于97.3％相对湿度的环境下24h，取固体测XRPD图，晶型X、非水合物形式、晶型I放置前后的XRPD图如图10，11，12所示，检测结果见表7。
表7
起始晶型 晶型变化
晶型X 晶型X
非水合物形式 水合物形式
晶型I 水合物形式
结果表明，在高湿度条件下，晶型X的晶型没有发生变化，而非水合物形式和晶型I均转变为水合物形式，说明晶型X在高湿度条件下更稳定，不容易受高湿度影响而发生转晶。
实施例8晶型X的动态溶解度
精密称取本发明的晶型X原料5mg，分别置于小瓶中，分别用pH为1.8的SGF，pH为5.0的FeSSIF，pH为6.5的FaSSIF以及水进行混合。在旋转器上以25转/分钟的速率旋转，并分别于1小时、4小时和24小时取样，在使用0.45μm聚四氟乙烯(PTFE)过滤器离心分离后，收集滤液进行HPLC分析。其结果如表8所示。
表8
Figure PCTCN2018096586-appb-000006
实验结果表明，本发明晶型溶解度大于13.3mg/mL，具有较高的溶解度，符合药用要求。
实施例9晶型X的制剂稳定性
取适量晶型X，与辅料混合均匀，棍压制成薄片并粉碎成颗粒，与外加辅料混合均匀，选用合适的模具压制成形，在25℃/60％相对湿度，40℃/75％相对湿度条件下考察其储存稳定性。
实验结果表明，晶型X制备成制剂，在加速和长期条件下放置1个月，化学纯度均保持高于99％，制剂中的晶型X化学稳定性良好。
实施例10:晶型X的流动性
按照《美国药典》通过可压性系数对本发明制备得到的晶型III的流动性进行研究，分别测定晶型X以及现有技术晶型I和非水合物形式的堆密度和振实密度，然后根据下面的公式计算可压性系数。
可压性系数(％)＝(振实密度-堆密度)/振实密度×100％
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型X、晶型I及非水合物形式的测定结果见表9。
表9
晶型 堆密度(g/ml) 振实密度(g/ml) 可压性系数(％)
晶型X 0.166 0.190 13％
晶型I 0.085 0.120 29％
非水合物形式 0.248 0.372 33％
结果表明，本发明晶型X的可压性系数为13％，属于流动性好，而晶型I和非水合物形式的压力稳定性系数为29％和33％，属于流动性差和很差，说明本发明晶型X与现有技术晶型相比具有更好的流动性。
实施例11：晶型X的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲(保证片剂的各向同性)。分别取一定量的非水合物形式、晶型I以及晶型X，采用一定的压力压制成圆形片剂，放置于干燥器中24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，N)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。筛选阶段样品量较少时，可采用下表中的推荐参数进行测试。
抗张强度测试推荐参数
模具 样品量 压力
Φ6mm圆形平冲 80mg 10kN
晶型X、晶型I和非水合物形式的实验测定结果如表10所示。
表10
晶型 厚度(mm) 直径(mm) 硬度(N) 抗张强度(MPa)
晶型X 2.31 6.73 34.3 1.36
晶型I 2.34 6.47 12.8 0.54
非水合物形式 2.56 6.70 7.2 0.27
结果表明，晶型X的抗张强度为1.36MPa，而晶型I和非水合物形式的抗张强度分别为0.54MPa和0.27MPa，本发明晶型X的可压性相较于晶型I和非水合物形式具有有明显的优势。
实施例12:晶型III的制备
将9.7mg本发明晶型II加热至165℃并恒温，冷却至室温得淡黄色琥珀酸盐固体结晶。
经检测，所得结晶固体为本发明晶型III，其X射线粉末衍射数据如表11所示。
表11
衍射角2θ d值 强度％
4.45 19.87 7.22
9.44 9.37 15.40
10.82 8.17 40.67
12.31 7.19 6.28
13.00 6.81 49.55
13.95 6.35 24.19
16.06 5.52 14.87
18.00 4.93 100.00
19.06 4.66 11.63
19.75 4.49 27.46
20.09 4.42 30.03
20.89 4.25 20.17
22.02 4.04 55.53
23.63 3.77 20.64
24.34 3.66 10.15
26.06 3.42 7.08
26.58 3.35 10.23
28.25 3.16 4.55
该晶型的DSC如图13所示，其有一个吸热峰，在182℃附近开始出现吸热峰，该吸热峰为熔化吸热。
该晶型的TGA如图14所示，将其加热至150℃时，具有约2.7％的重量损失梯度。
实施例13:晶型III的制备
将2.1mg本发明晶型II加热至160℃并恒温，冷却至室温得淡黄色琥珀酸盐固体结晶。
经检测，所得结晶固体为本发明晶型III，其X射线粉末衍射数据如表12所示。
表12
衍射角2θ d值 强度％
4.43 19.97 3.96
8.99 9.84 8.53
9.36 9.45 14.23
10.73 8.24 48.31
12.26 7.22 8.04
12.89 6.87 48.43
13.70 6.47 11.53
15.94 5.56 15.87
16.39 5.41 11.57
17.99 4.93 100.00
18.98 4.68 14.40
19.67 4.51 25.85
20.00 4.44 32.13
20.80 4.27 23.27
21.44 4.15 29.76
21.97 4.05 62.69
22.92 3.88 15.41
23.51 3.78 21.52
24.28 3.67 12.42
26.04 3.42 12.09
27.33 3.26 6.09
28.44 3.14 8.20
30.35 2.94 3.80
31.15 2.87 4.04
33.87 2.65 1.89
实施例14:晶型III的制备方法
将1.0012g化合物(I)与324.7mg琥珀酸加入50mL甲醇溶剂中，室温(25℃)下悬浮搅拌析晶42小时，90℃真空干燥30分钟，得白色的固体结晶。
经检测，所得结晶固体为本发明晶型III，其X射线粉末衍射数据如图15，表13所示。
表13
衍射角2θ d值 强度％
4.53 19.52 16.13
9.10 9.72 24.71
9.39 9.42 19.95
10.41 8.50 19.94
10.74 8.24 51.67
12.91 6.86 14.16
13.66 6.48 27.88
15.94 5.56 14.69
17.44 5.09 24.54
18.00 4.93 100.00
18.92 4.69 27.40
19.83 4.48 38.85
20.91 4.25 27.99
21.96 4.05 47.05
22.97 3.87 27.30
23.68 3.76 15.85
25.62 3.48 6.89
27.69 3.22 4.34
实施例15:晶型III的物理稳定性
称取本发明晶型III约10mg采用动态水分吸附(DVS)仪测试其引湿性，DVS前后XRPD对比图见图16。
实验结果表明，晶型III经DVS测试后晶型未发生转变，说明本发明晶型III在不同湿度条件下物理性质稳定。
实施例16:晶型III的流动性
按照《美国药典》通过可压性系数对本发明制备得到的晶型III的流动性进行研究，分别测定晶型III以及现有技术晶型I和非水合物形式的堆密度和振实密度，然后根据下面的公式计算可压性系数。
可压性系数(％)＝(振实密度-堆密度)/振实密度×100％
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型III、晶型I及非水合物形式的测定结果见表14。
表14
晶型 堆密度(g/ml) 振实密度(g/ml) 可压性系数(％)
晶型III 0.191 0.217 12％
晶型I 0.085 0.120 29％
非水合物形式 0.248 0.372 33％
结果表明，本发明晶型III的可压性系数为12％，属于流动性好，而晶型I 和非水合物形式的压力稳定性系数为29％和33％，属于流动性差和很差，说明本发明晶型III与现有技术晶型相比具有更好的流动性。
实施例17：晶型III的可压性
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲(保证片剂的各向同性)。分别取一定量的非水合物形式、晶型I以及晶型III，采用一定的压力压制成圆形片剂，放置于干燥器中24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，N)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。筛选阶段样品量较少时，可采用Φ6mm圆形平冲，80mg样品量，10kN压力进行测试。
抗张强度测试推荐参数
模具 样品量 压力
Φ6mm圆形平冲 80mg 10kN
晶型III、晶型I和非水合物形式的实验测定结果如表15所示。
表15
晶型 厚度(mm) 直径(mm) 硬度(N) 抗张强度(MPa)
晶型III 2.31 6.73 34.3 1.41
晶型I 2.34 6.47 12.8 0.54
非水合物形式 2.56 6.70 7.2 0.27
结果表明，晶型III的抗张强度为1.41MPa，而晶型I和非水合物形式的抗张强度分别为0.54MPa和0.27MPa，本发明晶型III的可压性相较于晶型I和非水合物形式具有有明显的优势。
实施例18：晶型III的黏附性
将适量的晶型III和晶型I以及非水合物形式加入到合适的模具中，采用一定的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续进行数次压制后，记录冲头累计的最终吸附量、压制过程中的最高吸附量和平均吸附量。实验数据见表16。
表16
晶型 累计最终吸附量(mg) 最高吸附量(mg) 平均吸附量(mg)
晶型III 0.06 0.09 0.030
晶型I 0.17 0.20 0.085
非水合物形式 0.15 0.08 0.075
结果表明，本发明晶型III和晶型I及非水合物形式相比，平均吸附量仅为0.03mg，远远低于晶型I和非水合物形式的吸附量，有明显的黏附性优势。
实施例19：晶型III的溶解度
精密称取本发明的晶型III原料5mg，分别置于小瓶中，分别用pH为1.8的SGF，pH为5.0的FeSSIF，pH为6.5的FaSSIF以及水进行混合。在旋转器上以25转/分钟的速率旋转，并分别于1小时、4小时和24小时取样，在使用0.45μm聚四氟乙烯(PTFE)过滤器离心分离后，收集滤液进行HPLC分析。其结果如表17所示。
表17
Figure PCTCN2018096586-appb-000007
实验结果表明，本发明晶型溶解度大于13.3mg/mL，具有较高的溶解度，符合药用要求。
实施例20：晶型III的长期与加速物理稳定性
将晶型III放置在40℃/75％相对湿度条件下，采用XRPD测定加速3个月时晶型的变化。
将晶型III在25℃/60％相对湿度条件下放置6个月，采用XRPD测定晶型的变化。
测定结果见表18。
表18
Figure PCTCN2018096586-appb-000008
结果表明，本发明晶型III在25℃/60％相对湿度条件下放置至少6个月晶型不发生转变，在40℃/75％相对湿度条件下放置至少3个月晶型不发生变化，表明本发明晶型III具有很好的物理稳定性。
实施例21：晶型V的制备
将化合物(I)单琥珀酸盐四氢呋喃溶剂合物(晶型S2)在110℃的烘箱内放置70分钟，得白色的琥珀酸盐固体结晶。
经检测，所得结晶固体为本发明所述之晶型V，其X射线粉末衍射数据如图18，表19所示， 1H NMR图如图21所示。
上述方法制备得到的化合物(I)琥珀酸盐晶型V，其 1H NMR鉴定数据如下：
1H NMR(400MHz,D 2O)δ8.59(s,1H),7.79(s,1H),7.55(d,J＝3.8Hz,2H),6.59(s,1H),4.56(d,J＝17.7Hz,1H),3.37(d,J＝12.2Hz,8H),3.08(d,J＝17.9Hz,6H),2.45(s,4H),2.15(s,2H),1.98(s,2H),1.86(s,2H),1.63(s,2H).
表19
衍射角2θ d值 强度％
9.41 9.40 29.88
9.84 8.99 5.58
10.86 8.14 18.93
11.44 7.74 11.66
12.82 6.90 46.76
13.84 6.40 14.18
15.12 5.86 11.73
15.73 5.64 16.55
16.55 5.36 10.27
17.65 5.03 31.85
18.29 4.85 95.78
18.94 4.69 49.58
19.94 4.45 19.77
20.47 4.34 28.88
21.99 4.04 100.00
23.01 3.87 27.17
23.90 3.72 12.46
25.81 3.45 14.99
该晶型的TGA如图19所示，将其加热至140℃时，具有约1.0％的重量损失梯度。
该晶型的DSC如图20所示，其有一个吸热峰，在180℃附近开始出现的吸热峰为熔融吸热峰。
实施例22:晶型V的流动性
按照《美国药典》通过可压性系数对本发明制备得到的晶型III的流动性进行研究，分别测定晶型V以及现有技术晶型I和非水合物形式的堆密度和振实密度，然后根据下面的公式计算可压性系数。
可压性系数(％)＝(振实密度-堆密度)/振实密度×100％
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型V、晶型I及非水合物形式的测定结果见表20。
表20
晶型 堆密度(g/ml) 振实密度(g/ml) 可压性系数(％)
晶型V 0.194 0.220 12％
晶型I 0.085 0.120 29％
非水合物形式 0.248 0.372 33％
结果表明，本发明晶型V的压力稳定性系数为12％，属于流动性好，而晶型I和非水合物形式的压力稳定性系数为29％和33％，属于流动性差和很差。
实施例23：晶型V的黏附性
将适量的晶型V和晶型I以及非水合物形式加入到合适的模具中，采用一定的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续进行数次压制后，记录冲头累计的最终吸附量、压制过程中的最高吸附量和平均吸附量。实验数据见表21。
表21
晶型 累计最终吸附量(mg) 最高吸附量(mg) 平均吸附量(mg)
晶型V 0.08 3.21 0.040
晶型I 0.17 0.20 0.085
非水合物形式 0.15 0.08 0.075
结果表明，本发明晶型V和晶型I及非水合物形式相比，平均吸附量仅为0.04mg，远远低于晶型I和非水合物形式的吸附量，有明显的黏附性优势。
实施例24晶型V的机械稳定性
将晶型V置于研钵中，手动研磨5分钟，测试固体XRPD图。晶型V研磨前后的XRPD叠图见附图22(上图为晶型V研磨前的XRPD图，下图为晶型V研磨后的XRPD图)。
结果表明，晶型V经研磨后晶型未发生转变，说明晶型V具有好的机械稳定性。
实施例25：晶型V的溶解度
精密称取本发明的晶型V原料5mg，分别置于小瓶中，分别用pH为1.8的SGF，pH为5.0的FeSSIF，pH为6.5的FaSSIF以及水进行混合。在旋转器上以25转/分钟的速率旋转，并分别于1小时、4小时和24小时取样，在使用0.45μm聚四氟乙烯(PTFE)过滤器离心分离后，收集滤液进行HPLC分析。其结果如表22所示。
表22
Figure PCTCN2018096586-appb-000009
实验结果表明，本发明晶型溶解度高于10mg/mL，具有较高的溶解度，符合药用要求。
实施例26：晶型V的长期与加速物理稳定性
将晶型V在25℃/60％相对湿度条件下储存7个月考察其物理稳定性，采用XRPD测定晶型的变化，测定结果见表23。
表23
Figure PCTCN2018096586-appb-000010
结果表明，本发明晶型V在25℃/60％相对湿度条件下放置至少7个月晶型不发生转变，表明本发明晶型V具有很好的物理稳定性。
实施例27：晶型II的制备
将141.2mg化合物(I)游离碱和44.7mg琥珀酸加入至4.0mL乙醇和正庚 烷(4:1,v/v)中，4℃悬浮搅拌过夜析晶，真空抽滤，室温下真空干燥，得淡黄色琥珀酸盐固体结晶。
经检测，所得结晶固体为晶型II，其X射线粉末衍射数据如图24，表24所示。
表24
衍射角2θ d值 强度％
4.57 19.35 100.00
6.26 14.11 18.30
7.40 11.95 48.21
10.21 8.66 14.17
11.21 7.89 10.17
11.62 7.61 9.99
12.21 7.25 18.04
13.22 6.70 8.69
13.52 6.55 13.75
13.94 6.35 17.91
14.92 5.94 12.64
15.43 5.74 42.10
15.64 5.67 41.84
17.06 5.20 43.15
17.32 5.12 23.19
18.57 4.78 9.68
19.66 4.52 23.89
19.89 4.46 77.79
20.16 4.41 36.09
20.66 4.30 14.67
21.36 4.16 19.34
22.48 3.96 14.68
23.48 3.79 7.82
24.46 3.64 19.47
26.73 3.34 4.70
28.40 3.14 3.99
29.13 3.07 4.37
30.54 2.93 2.26
31.47 2.84 2.05
实施例28：晶型S2的制备
将702.86mg化合物(I)游离碱和223.40mg琥珀酸加入14.0mL四氢呋喃溶剂中，室温下悬浮搅拌析晶20小时，离心，室温下真空干燥，得白色的琥珀酸盐固体结晶。
经检测，所得结晶固体为本发明所述之晶型S2，其X射线粉末衍射数据如图25，表25所示
表25
衍射角2θ d值 强度％
7.97 11.09 45.71
8.31 10.64 11.38
9.37 9.44 6.90
10.64 8.31 40.97
10.98 8.06 10.51
12.32 7.18 37.23
13.80 6.42 5.10
14.10 6.28 22.21
15.34 5.77 6.55
16.20 5.47 12.09
16.47 5.38 11.65
17.48 5.07 8.57
17.97 4.94 18.43
18.30 4.85 9.67
18.86 4.71 8.73
19.58 4.53 100.00
20.00 4.44 26.74
20.68 4.30 33.52
21.38 4.16 36.53
23.05 3.86 9.69
24.12 3.69 5.39
24.57 3.62 10.27
24.80 3.59 12.78
25.15 3.54 14.62
25.54 3.49 5.80
25.91 3.44 27.05
26.97 3.31 5.47
27.51 3.24 6.60
28.21 3.16 8.19
实施例29：晶型S4的制备
将30.06mg化合物(I)与10.13mg琥珀酸加入1mL甲醇溶剂中，室温悬浮搅拌析晶24小时，离心分离固体，室温(25℃)真空干燥，得白色的固体结晶。
经检测，所得结晶固体为本发明所述之晶型S4，其X射线粉末衍射数据如图26，表26所示。
表26
衍射角2θ d值 强度％
4.42 19.98 1.27
7.46 11.84 16.23
8.14 10.86 14.02
9.33 9.48 45.44
12.70 6.97 5.39
13.87 6.39 10.02
14.12 6.27 19.51
14.45 6.13 7.03
14.96 5.92 15.22
16.32 5.43 21.79
16.68 5.32 6.87
17.43 5.09 2.75
18.47 4.80 13.34
18.78 4.72 100.00
19.33 4.59 6.65
20.09 4.42 37.60
20.55 4.32 11.47
21.18 4.20 57.57
21.43 4.15 24.22
22.11 4.02 8.88
23.09 3.85 32.94
23.79 3.74 31.72
24.63 3.61 10.03
24.94 3.57 6.98
25.62 3.48 11.41
26.02 3.42 5.75
26.96 3.31 9.78
29.04 3.07 2.92
30.21 2.96 4.25
31.64 2.83 2.94
33.06 2.71 4.76
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 (29)

  1. 一种化合物(I)的单琥珀酸盐晶型X：
    Figure PCTCN2018096586-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为20.0°±0.2°,12.9°±0.2°,8.8°±0.2°,7.8°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型X，其特征在于：其X射线粉末衍射图在2theta值为15.6°±0.2°,10.9°±0.2°,23.0°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型X，其特征在于：其X射线粉末衍射图在2theta值为18.7°±0.2°,13.7°±0.2°,19.5°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1所述的晶型X的制备方法，其特征在于：将化合物(I)和琥珀酸加入醇类单一溶剂中或乙腈和醇类的混合溶剂中，加入晶种悬浮搅拌反应析晶，离心分离固体，真空干燥得到晶型X。
  5. 根据权利要求4所述的晶型X的制备方法，其特征在于：所述晶种为权利要求1所述的晶型X或晶型I，所述晶型I为化合物(I)的单琥珀酸盐晶型，其X射线粉末衍射图在2theta值为11.9°±0.2°,19.4°±0.2°,20.6°±0.2°,22.7°±0.2°,24.4°±0.2°,26.3°±0.2°,7.8°±0.2°,15.7°±0.2°,16.7°±0.2°处具有特征峰。
  6. 根据权利要求4所述的晶型X的制备方法，其特征在于：所述化合物(I)的游离碱和琥珀酸的摩尔比为1:1-1:2。
  7. 根据权利要求4所述的晶型X的制备方法，其特征在于：所述混合溶剂为乙腈和甲醇的混合溶剂。
  8. 根据权利要求7所述的晶型X的制备方法，其特征在于：所述乙腈和甲醇的体积比为1:1-15:1。
  9. 根据权利要求4所述的晶型X的制备方法，其特征在于：所述搅拌反应温度为40-60℃。
  10. 根据权利要求4所述的晶型X的制备方法，其特征在于：所述搅拌反应时间为12-120小时。
  11. 根据权利要求10所述的晶型X的制备方法，其特征在于：所述搅拌反应时间为12-24小时。
  12. 一种化合物(I)的单琥珀酸盐晶型III，其特征在于，其X射线粉末衍射图在2theta值为18.0°±0.2°,13.0°±0.2°,10.7°±0.2°处具有特征峰。
  13. 根据权利要求12所述的晶型III，其特征在于：其X射线粉末衍射图还在2theta值为22.0°±0.2°,20.0°±0.2°,9.4°±0.2°中的一处或两处或三处具有特征峰。
  14. 一种如权利要求12所述的晶型III的制备方法，其特征在于所述晶型III可通过如下两种方法 制备得到：
    方法一：使用化合物(I)的单琥珀酸盐晶型II加热至140-190℃转晶，冷却后分离而获得，所述晶型II的X射线粉末衍射图在2theta值为4.6°±0.2°、19.9°±0.2°、7.4°±0.2°、17.1°±0.2°、15.6°±0.2°、6.3°±0.2°、10.2°±0.2°、12.2°±0.2°、13.9°±0.2°处具有特征峰。
    方法二：将化合物(I)和琥珀酸加入醇类溶剂中，悬浮搅拌反应析晶，离心分离固体，真空干燥，得到晶型III。
  15. 根据权利要求14所述的晶型III的制备方法，其特征在于：所述化合物(I)的游离碱和琥珀酸的摩尔比为1:1-1:2。
  16. 根据权利要求14所述的晶型III的制备方法，其特征在于：所述悬浮搅拌时间为12-72h。
  17. 根据权利要求14所述的晶型III的制备方法，其特征在于：所述搅拌反应温度为15-40℃。
  18. 根据权利要求14所述的晶型III的制备方法，其特征在于：所述真空干燥温度为70-160℃。
  19. 根据权利要求14所述的晶型III的制备方法，其特征在于：所述真空干燥时间为10-60分钟。
  20. 一种化合物(I)的单琥珀酸盐晶型V，其特征在于，其X射线粉末衍射图在2theta值为9.4°±0.2°、18.3°±0.2°、12.8°±0.2°处具有特征峰。
  21. 根据权利要求20所述的晶型V，其特征在于：其X射线粉末衍射图还在2theta值为22.0°±0.2°、18.9°±0.2°、20.5°±0.2°中的一处或两处或三处具有特征峰。
  22. 根据权利要求20所述的晶型V，其特征在于：其X射线粉末衍射图还在2theta值为23.0°±0.2°、17.6°±0.2°中的一处或两处具有特征峰。
  23. 一种如权利要求20所述的晶型V的制备方法，其特征在于：使用化合物(I)的单琥珀酸盐四氢呋喃溶剂合物晶型S2在90-120℃条件下放置后获得，所述晶型S2的X射线粉末衍射在衍射角2θ为19.6°±0.2°、8.0°±0.2°、10.6°±0.2°、12.3°±0.2°、20.7°±0.2°、21.4°±0.2°、14.1°±0.2°、18.0°±0.2°、20.0°±0.2°、25.9°±0.2°处有特征峰。
  24. 根据权利要求23所述的晶型V的制备方法，其特征在于：所述放置温度为100℃。
  25. 根据权利要求23所述的晶型V的制备方法，其特征在于：所述放置时间为15分钟-90分钟。
  26. 根据权利要求25所述的晶型V的制备方法，其特征在于：所述放置时间为30分钟。
  27. 一种药物组合物，所述药物组合物包含效量治疗量的权利要求1中所述的晶型X，权利要求12中所述的晶型III，权利要求20中所述的晶型V或其三种晶型的任意混合以及药学上可接受的载体、稀释剂或赋形剂。
  28. 权利要求1中所述的晶型X，权利要求12所述的晶型III，权利要求20所述的晶型V或三种晶型的任意混合在制备周期蛋白依赖性激酶4/6抑制剂药物中的用途。
  29. 权利要求1中所述的晶型X，权利要求12所述的晶型III，权利要求20所述的晶型V或三种晶型的任意混合在制备治疗乳腺癌药物中的用途。
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