WO2021057834A1 - 一种酯化合物的晶型及其制备方法 - Google Patents

一种酯化合物的晶型及其制备方法 Download PDF

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WO2021057834A1
WO2021057834A1 PCT/CN2020/117325 CN2020117325W WO2021057834A1 WO 2021057834 A1 WO2021057834 A1 WO 2021057834A1 CN 2020117325 W CN2020117325 W CN 2020117325W WO 2021057834 A1 WO2021057834 A1 WO 2021057834A1
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crystal form
solvent
baloxavir marboxil
ray powder
powder diffraction
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PCT/CN2020/117325
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English (en)
French (fr)
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叶辉青
周自洪
陈勇
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080057717.3A priority Critical patent/CN114258395A/zh
Publication of WO2021057834A1 publication Critical patent/WO2021057834A1/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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine and chemical engineering, and relates to a crystal form of an ester compound and a preparation method thereof.
  • Baloxavir marboxil is a Cap-dependent endonuclease inhibitor that can inhibit the proliferation of influenza viruses. Its structure is shown in the following formula:
  • Baloxavir marboxil is an ester, which has polymorphism, and different crystal forms have different properties such as stability, solubility, charge, appearance and shape. These different properties contribute to the preparation and production of crystal forms, and crystal forms are used for the preparation of medicines.
  • the difficulty of the preparation, the pros and cons of the obtained preparation, the absorption and bioavailability of the drug all have a certain influence. Therefore, it is necessary to study the crystal form of the drug, find a stable crystal form suitable for the preparation of pharmaceutical preparations, such as developing a better chargeability, better appearance and shape, more conducive to flow, production and/or more favorable Formulation production, formulation stability, drug absorption and bioavailability, etc. crystal form.
  • the inventors conducted related research on the crystal form of Baloxavir marboxil.
  • the present invention provides a crystal form of Baloxavir marboxil and a preparation method thereof.
  • the crystal form has good stability, solubility, and powder fluidity, which is beneficial to the preparation of pharmaceutical preparations.
  • the crystalline form of the present invention has peaks in the X-ray powder diffraction pattern at 2 ⁇ of approximately 8.9°, 17.8°, 20.3°, 22.3°, 24.4° and 31.5°.
  • the crystal form of the present invention melts at 235°C ⁇ 2°C.
  • the differential scanning calorimetry curve of the crystal form of the present invention shows that it does not absorb heat before melting.
  • the preparation method includes: dissolving Baloxavir marboxil in a good solvent, stirring, mixing the resulting mixed solution with an anti-solvent, controlling the temperature, and depositing a solid to obtain the crystal form.
  • the good solvent can be tetrahydrofuran, 1,4-dioxane, or a combination thereof;
  • the anti-solvent can be methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, cyclohexane , N-hexane, isopropyl ether, methyl tert-butyl ether, or a combination thereof.
  • the present invention also provides a composition, which comprises the crystal form provided by the present invention and a pharmaceutically acceptable carrier or adjuvant.
  • the composition can be used to prepare pharmaceutical preparations for inhibiting the proliferation of viruses such as influenza viruses.
  • the crystal form C is at least 90% of Baloxavir marboxil, or the crystal form C does not exceed 10% of Baloxavir marboxil, or the crystal form C is not less than 10% of Baloxavir marboxil.
  • the pharmaceutically acceptable carrier may include fillers, disintegrants, and/or lubricants and the like.
  • substantially as shown in the figure means that a certain "crystal form” that is substantially pure has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least in the X-ray powder diffraction pattern. 90%, or at least 95%, or at least 99% of the peaks appear in the X-ray powder diffraction pattern given.
  • the content of a certain crystal form in the sample gradually decreases, some diffraction peaks attributable to the crystal form in the X-ray powder diffraction pattern may be reduced due to the detection sensitivity of the instrument.
  • relative intensity refers to the ratio of the intensity of other peaks to the intensity of the first strong peak when the intensity of the first strong peak in a set of diffraction peaks belonging to a certain crystal form is defined as 100%.
  • the term "diffraction peak" refers to a feature that is not attributed to background noise by those skilled in the art.
  • the 2 ⁇ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).
  • the X-ray powder diffraction peak of the crystal form, the 2 ⁇ or diffraction peak measurement of the X-ray powder diffraction pattern has experimental errors, between one machine and another machine and between one sample and another sample
  • the measurement of 2 ⁇ or diffraction peak of X-ray powder diffraction pattern may be slightly different, and the experimental error or difference value may be +/-0.2 unit or +/-0.1 unit or +/-0.05 unit Therefore, the value of the 2 ⁇ or diffraction peaks cannot be regarded as absolute.
  • the differential scanning calorimetry curve (DSC) of the crystal form has experimental errors.
  • the position and peak of the endothermic peak may be slightly different between one machine and another machine and between one sample and another sample. Difference, experimental error or the value of the difference may be less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute of.
  • thermogravimetric analysis curve (TGA) of the crystal form has experimental errors.
  • the endothermic curve or weight loss rate may be slightly different between one machine and another machine and between one sample and another sample.
  • the value of the error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or its weight loss rate cannot be regarded as absolute.
  • Root temperature refers to a temperature of about 20°C-35°C or about 23°C-28°C or about 25°C.
  • good solvent can be a single solvent or a mixed solvent, which means that the solubility of the sample in the single solvent or mixed solvent is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/ L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L.
  • the solubility of the sample in the good solvent is greater than that of the anti-solvent; in some embodiments, the difference between the solubility of the good solvent and the anti-solvent to the sample is about 10%, 20%, 30%, 40%, 50%. %, 60%, 70%, 80% or 90%; in some embodiments, the solubility of the good solvent to the sample is greater than that of the anti-solvent, greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%.
  • anti-solvent can be a single solvent or a mixed solvent.
  • the solubility of the sample in the anti-solvent is less than 100g/L, or less than 80g/L, or less than 70g/L, or less than 60g/L, or less than 50g/L, or less than 40g/L, or less than 30g/L, or less than 20g/L, or less than 15g/L, or less than 10g/L, or less than 5g/L, or less than 4g /L, or less than 3g/L, or less than 2g/L, or less than 1g/L, or less than 0.5g/L.
  • crystal form C a new crystal form of Baloxavir marboxil as shown in the following formula, which is called crystal form C.
  • the crystal form C of Baloxavir marboxil has the following characteristics: its X-ray powder diffraction pattern has peaks at 2 ⁇ of approximately 8.9°, 17.8°, 20.3°, 22.3°, 24.4° and 31.5° (degrees).
  • the crystal form C of Baloxavir marboxil has the following characteristics: its X-ray powder diffraction pattern is approximately 4.5°, 8.9°, 13.3°, 17.8°, 20.3°, 22.3°, 24.4° in 2 ⁇ , There are peaks at 28.0° and 31.5°.
  • the crystal form C of Baloxavir marboxil has the following characteristics: its X-ray powder diffraction pattern is approximately 4.5°, 8.9°, 10.6°, 11.7°, 13.3°, 17.8°, 20.3° in 2 ⁇ , There are peaks at 22.3°, 24.4°, 28.0°, 30.7°, 31.5° and 36.1°.
  • the crystal form C of Baloxavir marboxil has the following characteristics: its X-ray powder diffraction pattern is approximately 4.5°, 8.9°, 10.6°, 11.7°, 13.3°, 17.8°, 20.3° in 2 ⁇ , There are peaks at 22.3°, 24.4°, 26.5°, 26.9°, 28.0°, 30.7°, 31.5°, 34.1°, 36.1° and 39.0°.
  • the crystal form C of Baloxavir marboxil has the following characteristics: its X-ray powder diffraction pattern is approximately 4.5°, 8.9°, 10.6°, 11.7°, 13.3°, 14.8, 17.8°, 19.1 in 2 ⁇ . There are peaks at, 20.3°, 22.3°, 24.4°, 26.5°, 26.9°, 28.0°, 30.7°, 31.5°, 34.1°, 36.1°, 37.1° and 39.0°.
  • the relative intensity of the peak at 2 ⁇ of about 8.9° or 22.3° is greater than 50%, or greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%. In some embodiments, in the X-ray powder diffraction pattern of the crystal form C of Baloxavir marboxil, the relative intensity of the peak at 2 ⁇ of approximately 8.9° or 22.3° is greater than 95%.
  • the X-ray powder diffraction pattern of the crystal form C of Baloxavir marboxil is shown in FIG. 1.
  • the crystal form C also has the following characteristics: its differential scanning calorimetry curve (DSC) shows that there is no endothermic peak before it melts.
  • the differential scanning calorimetry (DSC) of the crystalline form C shows that it begins to endothermic melting at about 228°C, with a peak at 235°C ⁇ 2°C, and then decomposes.
  • the differential scanning calorimetry curve (DSC) of the crystalline form C is shown in FIG. 2.
  • thermogravimetric analysis curve (TGA) of the crystalline form C shows that it has a weight loss of about 2.6% at 50°C to 150°C, and the crystalline form C remains after drying. It is presumed that the adsorbed solvent causes the weight loss. .
  • the thermogravimetric analysis curve (TGA) of the crystal form C shows that its weight loss at 50°C-150°C is less than 1%.
  • the thermogravimetric analysis curve (TGA) of the crystal form C is shown in FIG. 3.
  • the crystalline form C is a powder with good appearance and fluidity, and has good performance in terms of stability, solubility, dissolution, fluidity, etc., is conducive to storage, transfer, and operation in the production process, and is suitable for preparing into it Pharmaceutical composition or pharmaceutical preparation.
  • the crystal form A (obtained in Example 6) is a needle-shaped crystal with relatively large long diameter and poor crystal fluidity;
  • the crystal form C provided by the present invention is a massive rod-shaped crystal with relatively small long diameter and crystal fluidity. Good, it is conducive to the production and preparation of crystal forms and the preparation of pharmaceutical preparations.
  • the crystal form C is stable and has good solubility, and can be used to prepare pharmaceutical preparations for inhibiting viruses such as influenza virus, or for preparing pharmaceutical preparations for treating diseases such as influenza.
  • the present invention provides a method for preparing the crystal form C.
  • a method for preparing crystalline form C of Baloxavir marboxil includes: dissolving Baloxavir marboxil in a good solvent, stirring, mixing the resulting mixed solution with an anti-solvent, controlling the temperature, and depositing solids to obtain crystalline form C.
  • the good solvent may be tetrahydrofuran, 1,4-dioxane, or a combination thereof.
  • the anti-solvent can be methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, cyclohexane, n-hexane, isopropyl ether, methyl tert-butyl ether, or a combination thereof.
  • a method for preparing the crystal form C of Baloxavir marboxil comprising: dissolving Baloxavir marboxil in a good solvent, stirring, mixing the resulting mixed solution with an anti-solvent, controlling the temperature, and separating out solids to obtain crystal form C;
  • the good solvent Is tetrahydrofuran, 1,4-dioxane, or a combination thereof
  • the anti-solvent is methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, cyclohexane, n-hexane, isopropanol Ether, methyl tert-butyl ether, or a combination thereof.
  • the amount of good solvent can be 1mL-50mL. In some embodiments, per gram of Baloxavir marboxil, the amount of the good solvent is 10mL-50mL. In some embodiments, per gram of Baloxavir marboxil, the amount of good solvent is 30mL-50mL. In some embodiments, per gram of Baloxavir marboxil, the amount of good solvent is 20 mL-40 mL.
  • the amount of anti-solvent can be 1mL-200mL. In some embodiments, per gram of Baloxavir marboxil, the amount of anti-solvent may range from 20 mL to 200 mL. In some embodiments, per gram of Baloxavir marboxil, the amount of anti-solvent may be 50 mL-200 mL. In some embodiments, per gram of Baloxavir marboxil, the amount of anti-solvent may range from 50 mL to 100 mL. In some embodiments, per gram of Baloxavir marboxil, the amount of anti-solvent can be 100 mL-200 mL.
  • the mixed solution and the anti-solvent are mixed at room temperature.
  • the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled to be -10°C to 30°C, or 0°C to 5°C, and a solid is precipitated to obtain crystal form C. In some embodiments, the temperature of the system formed after the mixed solution and the anti-solvent is mixed is controlled to be 15° C. to 30° C., a solid is precipitated, and crystal form C is obtained. In some embodiments, the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled to be 20° C. to 30° C., and solids are precipitated to obtain crystal form C.
  • the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled to be -10°C to 10°C, and a solid is precipitated to obtain crystal form C. In some embodiments, the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled to be 0°C to 5°C, and solids are precipitated to obtain crystal form C. In some embodiments, the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled to be -5°C-5°C, and a solid is precipitated to obtain crystal form C. In some embodiments, the temperature of the system formed after the mixed solution and the anti-solvent are mixed is controlled at 25°C, 5°C or 0°C, and a solid is precipitated to obtain crystal form C.
  • a method for preparing the crystal form C of Baloxavir marboxil includes: dissolving Baloxavir marboxil in a good solvent tetrahydrofuran, stirring, and mixing the resulting mixed solution with the anti-solvent at room temperature, and controlling the temperature at -5°C. At 5° C., a solid precipitates to obtain crystal form C; wherein the anti-solvent is methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, or a combination thereof.
  • a method for preparing the crystal form C of Baloxavir marboxil includes: dissolving Baloxavir marboxil in a good solvent of 1,4-dioxane, stirring, and mixing the resulting mixed solution with the anti-solvent at room temperature , The temperature is controlled at 15°C-30°C, and a solid is precipitated to obtain crystal form C; wherein the anti-solvent is methanol, ethanol, isobutanol, n-butanol, isopropanol, n-propanol, cyclohexane, and n-hexane , Isopropyl ether, methyl tert-butyl ether, or a combination thereof.
  • a method for preparing crystalline form C of Baloxavir marboxil includes: dissolving Baloxavir marboxil in tetrahydrofuran, stirring, mixing the resulting mixed solution with an anti-solvent, and controlling the temperature at -10°C to 10°C to precipitate a solid. Obtained crystal form C; wherein, per gram of Baloxavir marboxil, the amount of tetrahydrofuran is 1mL-50mL, the amount of anti-solvent is 1mL-200mL; the anti-solvent is methanol, ethanol, isobutanol, n-butanol, isopropanol, n Propanol, or a combination thereof.
  • a method for preparing the crystal form C of Baloxavir marboxil includes: dissolving Baloxavir marboxil in 1,4-dioxane, stirring, mixing the resulting mixed solution with an anti-solvent, and controlling the temperature at 15°C- At 30°C, a solid was precipitated to obtain crystal form C; wherein, for each gram of Baloxavir marboxil, the amount of 1,4-dioxane was 1mL-50mL, the amount of anti-solvent was 1mL-200mL, and the anti-solvent was methanol.
  • the crystal form C of the present invention has stable properties, good fluidity, and better solubility, can be used for preparing pharmaceutical preparations, and its preparation method is simple, easy for industrial production, and favorable for industrial application.
  • the present invention also provides a composition.
  • a composition comprising the aforementioned crystalline form C of Baloxavir marboxil and a pharmaceutically acceptable carrier.
  • the composition includes the crystalline form C of Baloxavir marboxil and a pharmaceutically acceptable carrier, and the crystalline form C is at least 90% of Baloxavir marboxil based on the mass ratio.
  • the crystal form C in the composition is at least 95% of Baloxavir marboxil.
  • calculated by mass ratio the crystal form C in the composition is at least 97% of Baloxavir marboxil.
  • calculated according to the mass ratio, the crystal form C in the composition is at least 98% or 99% of Baloxavir marboxil.
  • the composition includes the crystal form C of Baloxavir marboxil and a pharmaceutically acceptable carrier, and the crystal form C does not exceed 10% of Baloxavir marboxil by mass ratio. In some embodiments, in the composition, the crystal form C does not exceed 5% of Baloxavir marboxil calculated by mass ratio. In some embodiments, in the composition, the crystal form C does not exceed 1% of Baloxavir marboxil calculated by mass ratio. In some embodiments, in the composition, the crystal form C does not exceed 0.5% of Baloxavir marboxil in terms of mass ratio.
  • the composition includes the crystal form C of Baloxavir marboxil and a pharmaceutically acceptable carrier, and the crystal form C is not less than 10% of Baloxavir marboxil by mass ratio. In some embodiments, in the composition, the crystal form C is not less than 5% of Baloxavir marboxil based on the mass ratio. In some embodiments, in the composition, the crystal form C is not less than 3% of Baloxavir marboxil calculated by mass ratio. In some embodiments, in the composition, the crystal form C is not less than 1% of Baloxavir marboxil based on the mass ratio. In some embodiments, in the composition, the crystal form C is not less than 0.5% of Baloxavir marboxil based on the mass ratio.
  • the crystal form C provided by the present invention can be used to prepare the composition, for example, it can be used in the preparation of dosage forms such as tablets, capsules, granules, suspensions, dispersions or injections.
  • composition may be in the form of tablets, capsules, granules or suspensions.
  • the pharmaceutically acceptable carrier may include fillers, diluents, disintegrants, binders, lubricants, or suspending agents and the like.
  • the composition can be used for inhibiting the proliferation of viruses such as influenza virus, or for anti-virus or treatment of diseases infected by influenza virus.
  • FIG. 1 shows the X-ray powder diffraction pattern (XRPD) of the crystal form C obtained in Example 1.
  • FIG. 1 shows the differential scanning thermal curve (DSC) of the crystal form C obtained in Example 1.
  • FIG. 3 shows the thermogravimetric analysis chart (TGA) of the crystal form C obtained in Example 1.
  • Example 4 shows the X-ray powder diffraction pattern (XRPD) of the crystal form A obtained in Example 6.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • mg means milligrams
  • mL means milliliters
  • h means hours
  • RH means relative humidity
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 6.6mm. Using ⁇ - ⁇ continuous scanning mode, to obtain an effective 2 ⁇ range of 3° ⁇ 60°.
  • the DSC measurement is performed with a sealed disk device in TA Instruments TM model Q2000. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between 30°C and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
  • TGA data on TA Instruments Q500 Use certified nickel to calibrate the temperature of the instrument. Usually 8-12 mg of sample is loaded on a pre-weighed platinum crucible and heated from 30°C to 300°C at 10°C/min. Maintain a 60 mL/min nitrogen purge above the sample.
  • the abscissa represents temperature (Temperature, °C), and the ordinate represents the percentage of weight loss (Weight (%)).
  • High temperature test Take appropriate amounts of crystal samples, lay them flat in a weighing bottle, place them in a constant temperature and humidity box at 60°C ⁇ 5°C, RH 75 ⁇ 5%, and then take the above samples for approximately 0, 5, and 15 days. 100mg, using powder X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) to test its crystal form.
  • XRPD powder X-ray powder diffraction
  • DSC differential scanning calorimetry
  • High-humidity test Take appropriate amounts of crystalline samples, place them in a weighing bottle, place them in a constant temperature and humidity box at 25°C, RH 92.5 ⁇ 5%, and then take about 100 mg of the above samples on 0, 5, and 15 days.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Illumination test Take appropriate amounts of crystal samples and spread them in a weighing bottle. Place them in a constant temperature and humidity box (25°C, RH 60%) with visible light 4500Lux ⁇ 500Lux(VIS) and ultraviolet light 1.7W*h/m2(UV). Place it under ⁇ 5%), and then take about 100 mg of the above sample on 0, 5, and 15 days, and test its crystal form by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
  • XRPD powder X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Reference substance accurately weigh 20 mg of reference substance into a 1000 mL volumetric flask, add water to a constant volume, and obtain the control solution.
  • HPLC High Performance Liquid Chromatography
  • the density of water was calculated according to 1.00 g/mL, and the solubility of the two crystal samples in water at 37.0°C was tested.
  • the solubility test results are shown in Table 2.

Abstract

一种酯化合物的晶型及其制备方法，属于医药化工技术领域。所述晶型具有较好的稳定性和溶解性，粉末流动性较好，可以应用于药物制剂的制备。

Description

一种酯化合物的晶型及其制备方法 技术领域
本发明属于医药化工技术领域，涉及一种酯化合物的晶型及其制备方法。
背景技术
Baloxavir marboxil，CAS：1985606-14-1，是一种Cap依赖型核酸内切酶抑制剂，可以抑制流感病毒的增殖，其结构如下式所示：
Figure PCTCN2020117325-appb-000001
现有技术中，TW201808963等申请公开了Baloxavir marboxil的3种晶型，但未公开其稳定性等性质，且其公开的3种晶型难以制备。
Baloxavir marboxil是一种酯，其存在多晶型现象，而不同晶型存在稳定性、溶解性、电荷性，外观形状等不同性质，这些不同性质对晶型的制备生产，晶型用于制备药物制剂的难易，所得制剂的优劣，药物的吸收、生物利用度等都有一定的影响。因此，需要研究药物的晶型，寻找稳定的，适合用于制备药物制剂的晶型，如开发具有更好的电荷性，外观形状更好，更有利于流动、生产获得和/或更有利于制剂生产，制剂稳定、药物吸收和生物利用度等的晶型。为解决这一问题，发明人对Baloxavir marboxil的晶型进行了相关研究。
发明内容
发明概述
本发明提供了Baloxavir marboxil的一种晶型及其制备方法，所述晶型具备较好的稳定性，溶解性，粉末流动性，有利于制备药物制剂。
本发明所述晶型，其X-射线粉末衍射图中在2θ大约为8.9°，17.8°，20.3°，22.3°，24.4°和31.5°的位 置有峰。
本发明所述晶型，其在235℃±2℃熔融。本发明所述晶型，其差示扫描量热曲线显示其熔融前不吸热。
所述制备方法，包括：Baloxavir marboxil于良溶剂中溶解，搅拌，将所得混合溶液与反溶剂混合，控温，析出固体，得到所述晶型。所述良溶剂可为四氢呋喃，1,4-二氧六环，或其组合；所述反溶剂可为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
本发明还提供了一种组合物，所述组合物包括本发明提供的晶型和药学上可接受的载体或辅料。所述组合物可用于制备药物制剂，用于抑制病毒如流感病毒的增殖。
本发明所述组合物，其中，按照质量比计算，晶型C为Baloxavir marboxil的至少90％，或者晶型C不超过Baloxavir marboxil的10％，或者晶型C不低于Baloxavir marboxil的10％。
所述药学上可接受的载体可包括填充剂，崩解剂，和/或润滑剂等。
术语定义
本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术等等)，以本申请为准。
应进一步认识到，本发明的某些特征，为清楚可见，在多个独立的实施方案中进行了描述，但也可以在单个实施例中以组合形式提供。反之，本发明的各种特征，为简洁起见，在单个实施方案中进行了描述，但也可以单独或以任意合适的子组合提供。
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“基本上如图所示”是指基本上纯净的某种“晶型”其X-射线粉末衍射图中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰出现在所给出的X-射线粉末衍射图中。当样品中某种晶型的含量逐渐降低时，其X-射线粉末衍射图中的一些归属于该晶型的衍射峰可能会由于仪器的检测灵敏度的因素而变少。
术语“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的强度与第一强峰的强度的比值。
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。
所述晶型的差示扫描量热曲线(DSC)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
所述晶型的热重分析曲线(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热曲线或失重率可能会略有差别，实验误差或差别的数值可能小于等于0.004％或0.003％或0.002％或0.001％，因此所述热重分析曲线或其失重率不能视为绝对的。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值；基于公开的数字，每一个数字的数值有可能会出现+/-1％，+/-2％，或+/-5％等差异。当大约用来形容X-射线粉末衍射峰的2θ(又称2theta或衍射峰)值时，大约表示所述2θ值可能有+/-0.2个单位或+/-0.1个单位或+/-0.05个单位差异。
“室温”是指温度在大约20℃-35℃或大约23℃-28℃或大约25℃。
术语“良溶剂”可以是单一溶剂或混合溶剂，指样品在该单一溶剂或混合溶剂中的溶解度大于1g/L,或大于2g/L,或大于3g/L,或大于4g/L,或大于5g/L,或大于6g/L,或大于7g/L,或大于8g/L,或大于9g/L,或大于10g/L,或大于15g/L,或大于20g/L,或大于30g/L,或大于40g/L,或大于50g/L,或大于60g/L,或大于70g/L,或大于80g/L,或大于100g/L。在一些实施例中，样品在良溶剂中的溶解度比反溶剂大；在一些实施例中，良溶剂和反溶剂对样品的溶解度之差大约为10％,20％,30％,40％,50％,60％,70％,80％或90％；在一些实施例中，良溶剂对样品的溶解度比反溶剂大，大于10％,20％,30％,40％,50％,60％,70％,80％或90％。
术语“反溶剂”可以是单一溶剂或混合溶剂，样品在反溶剂中的溶解度低于100g/L，或低于80g/L，或低于70g/L，或低于60g/L，或低于50g/L，或低于40g/L，或低于30g/L，或低于20g/L，或低于15g/L，或低于10g/L，或低于5g/L，或低于4g/L，或低于3g/L，或低于2g/L，或低于1g/L，或低于0.5g/L。
发明详述
第一方面，发明人通过研究开发了下式所示的Baloxavir marboxil的新晶型，称为晶型C
Figure PCTCN2020117325-appb-000002
Baloxavir marboxil的晶型C，其具有如下特性：其X-射线粉末衍射图中在2θ大约为8.9°，17.8°，20.3°，22.3°，24.4°和31.5°(度)的位置有峰。
一些实施方式中，Baloxavir marboxil的晶型C，其具有如下特性：其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，13.3°，17.8°，20.3°，22.3°，24.4°，28.0°，和31.5°的位置有峰。
一些实施方式中，Baloxavir marboxil的晶型C，其具有如下特性：其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，10.6°，11.7°，13.3°，17.8°，20.3°，22.3°，24.4°，28.0°，30.7°，31.5°和36.1°的位置有峰。
一些实施方式中，Baloxavir marboxil的晶型C，其具有如下特性：其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，10.6°，11.7°，13.3°，17.8°，20.3°，22.3°，24.4°，26.5°，26.9°，28.0°，30.7°，31.5°，34.1°，36.1°和39.0°的位置有峰。
一些实施方式中，Baloxavir marboxil的晶型C，其具有如下特性：其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，10.6°，11.7°，13.3°，14.8，17.8°，19.1，20.3°，22.3°，24.4°，26.5°，26.9°，28.0°，30.7°，31.5°，34.1°，36.1°，37.1°和39.0°的位置有峰。
一些实施例中，Baloxavir marboxil的晶型C的X-射线粉末衍射图中，在2θ大约为8.9°或22.3°的峰的相对强度大于50％，或大于70％，或大于80％，或大于90％，或大于99％。一些实施例中，Baloxavir marboxil的晶型C的X-射线粉末衍射图中，在2θ大约为8.9°或22.3°的峰的相对强度大于95％。
一些实施例中，Baloxavir marboxil的晶型C的X-射线粉末衍射图如图1所示。
所述的晶型C，还具有如下特性：其差示扫描量热曲线(DSC)显示在其熔融前无吸热峰。在一具体实施方式中，所述的晶型C的差示扫描量热曲线(DSC)显示其在约228℃开始吸热熔融，峰值在235℃±2℃，随后分解。在一些实施方式中，所述的晶型C的差示扫描量热曲线(DSC)如图2所示。
一些实施例中，所述的晶型C的热重分析曲线(TGA)显示其在50℃-150℃具有约2.6％的失重，而干燥后仍然为晶型C，推测为吸附的溶剂导致失重。一些实施例中，所述的晶型C的热重分析曲线(TGA)显示其在50℃-150℃的失重低于1％。在一具体实施方式中，所述的晶型C的热重分析曲线(TGA)如图3所示。
所述的晶型C为具有良好外观和流动性的粉末，在稳定性、溶解性溶出度、流动性等方面具有良好的性能，有利于储存、转移、生产工艺中操作，适于制备成其药用组合物或药物制剂。
根据偏光显微镜观测结果，发现晶型A(实施例6所得)为针状晶体，长径比较大，晶体流动性差；本发明提供的晶型C为块棒状晶体，长径比较小，晶体流动性好，有利于晶型的生产制备和用于制备药物制剂。
所述晶型C稳定，溶解性好，可以用于制备抑制抑制流感病毒等病毒的药物制剂，或用于制备治疗流感等疾病的药物制剂。
第二方面，本发明提供了所述的晶型C的制备方法。
一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于良溶剂中溶解，搅拌，将所得混合溶液与反溶剂混合，控温，析出固体，得到晶型C。
所述良溶剂可为四氢呋喃，1,4-二氧六环，或其组合。所述反溶剂可为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于良溶剂中溶解，搅拌，将所得混合溶液与反溶剂混合，控温，析出固体，得到晶型C；其中，所述良溶剂为四氢呋喃，1,4-二氧六环，或其组合；所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。每一克Baloxavir marboxil，良溶剂的用量可为1mL-50mL。在一些实施方式中，每一克Baloxavir marboxil，良溶剂的用量为10mL-50mL。在一些实施方式中，每一克Baloxavir marboxil，良溶剂的用量为30mL-50mL。在一些实施方式中，每一克Baloxavir marboxil，良溶剂的用量为20mL-40mL。
每一克Baloxavir marboxil，反溶剂的用量可为1mL-200mL。在一些实施方式中，每一克Baloxavir marboxil，反溶剂的用量可为20mL-200mL。在一些实施方式中，每一克Baloxavir marboxil，反溶剂的用量可为50mL-200mL。在一些实施方式中，每一克Baloxavir marboxil，反溶剂的用量可为50mL-100mL。在一些实施方式中，每一克Baloxavir marboxil，反溶剂的用量可为100mL-200mL。
在一些实施方式中，混合溶液与反溶剂在室温条件下混合。
在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为-10℃-30℃，或者0℃-5℃，析出固体，得到晶型C。在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为15℃-30℃，析出固体，得到晶型C。在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为20℃-30℃，析出固体，得到晶型C。在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为-10℃-10℃，析出固体，得到晶型C。在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为0℃-5℃，析出固体，得到晶型C。在一些实施方式中，混合溶液与反溶剂混合后形成的体系控温为-5℃-5℃，析出固体，得到晶型C。在一些实施方 式中，混合溶液与反溶剂混合后形成的体系控温为25℃，5℃或0℃，析出固体，得到晶型C。
在一些实施方式中，一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于良溶剂四氢呋喃中溶解溶清，搅拌，将所得混合溶液与反溶剂于室温混合，控温-5℃-5℃，析出固体，得到晶型C；其中，反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，或其组合。
在一些实施方式中，一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于良溶剂1,4-二氧六环中溶解溶清，搅拌，将所得混合溶液与反溶剂于室温混合，控温15℃-30℃，析出固体，得到晶型C；其中，所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
在一些实施方式中，一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于四氢呋喃中溶解，搅拌，将所得混合溶液与反溶剂混合，控温-10℃-10℃，析出固体，得到晶型C；其中，每一克Baloxavir marboxil，四氢呋喃的用量为1mL-50mL，反溶剂的用量为1mL-200mL；反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，或其组合。
在一些实施方式中，一种制备Baloxavir marboxil的晶型C的方法，包括：Baloxavir marboxil于1,4-二氧六环中溶解，搅拌，将所得混合溶液与反溶剂混合，控温15℃-30℃，析出固体，得到晶型C；其中，每一克Baloxavir marboxil，1,4-二氧六环的用量为1mL-50mL，反溶剂的用量为1mL-200mL，所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
本发明所述的晶型C，性质稳定，流动性较好，而且溶解性更好，可以用于制备药物制剂，且其制备方法简单，易于工业化生产，有利于工业化应用。
另一方面，本发明还提供一种组合物。一种组合物，包括前述的Baloxavir marboxil的晶型C和药学上可接受的载体。
在一些实施方式中，所述组合物，包括Baloxavir marboxil的晶型C和药学上可接受的载体，按照质量比计算，晶型C为Baloxavir marboxil的至少90％。在一些实施方式中，按照质量比计算，所述组合物中，晶型C为Baloxavir marboxil的至少95％。在一些实施方式中，按照质量比计算，所述组合物中，晶型C为Baloxavir marboxil的至少97％。在一些实施方式中，按照质量比计算，所述组合物中，晶型C为Baloxavir marboxil的至少98％或99％。
在一些实施方式中，所述组合物，包括Baloxavir marboxil的晶型C和药学上可接受的载体，按照质量比计算，晶型C不超过Baloxavir marboxil的10％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不超过Baloxavir marboxil的5％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不超过Baloxavir marboxil的1％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不超过 Baloxavir marboxil的0.5％。
在一些实施方式中，所述组合物，包括Baloxavir marboxil的晶型C和药学上可接受的载体，按照质量比计算，晶型C不低于Baloxavir marboxil的10％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不低于Baloxavir marboxil的5％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不低于Baloxavir marboxil的3％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不低于Baloxavir marboxil的1％。在一些实施方式中，所述组合物中，按照质量比计算，晶型C不低于Baloxavir marboxil的0.5％。
本发明提供的晶型C，可以用于制备所述组合物，如可以用于制备片剂，胶囊剂，颗粒剂，混悬剂，分散体或注射剂等剂型的组合物中。
前述的组合物，可以为片剂，胶囊剂，颗粒剂或混悬剂等剂型。
所述药学上可接受的载体可包括填充剂，稀释剂，崩解剂，粘合剂，润滑剂，或助悬剂等。
所述组合物，可以用于抑制病毒如流感病毒的增殖，或用于抗病毒或治疗流感病毒感染的疾病等。
附图说明
图1示实施例1所得的晶型C的X-射线粉末衍射图(XRPD)。
图2示实施例1所得的晶型C的差示扫描热曲线(DSC)。
图3示实施例1所得的晶型C的热重分析图(TGA)。
图4示实施例6所得晶型A的X-射线粉末衍射图(XRPD)。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。
本发明中，mg表示毫克，mL表示毫升，h表示小时，RH表示相对湿度。
仪器参数
除非参数中另行规定，以下所有分析都在室温下进行。
粉末X-射线衍射(XRPD)研究
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2020117325-appb-000003
1.540598；Kα2
Figure PCTCN2020117325-appb-000004
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的 有效尺寸，为6.6mm.采用θ-θ连续扫描模式，得到3°～60°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0168°的扫描步长在3～60°2θ±0.2°范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。
差示扫描量热法(DSC)
DSC测量在TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在30℃到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。
热重分析法(TGA)
在TA Instruments Q500上采集TGA数据。使用认证的镍校准仪器的温度。通常将8-12mg样品加载到预称重的铂金坩埚上，并以10℃/min从30℃加热至300℃。在样品上方保持60mL/min的氮气清扫。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示失重的百分含量(Weight(％))。
实施例1
将20mg Baloxavir marboxil固体置于1mL四氢呋喃中搅拌溶清，在25℃下将该溶液滴入4mL异丁醇中，搅拌降温至0℃，析出白色固体，搅拌3小时，过滤，干燥，经过检测，确定为Baloxavir marboxil晶型C，参见图1-图3。
实施例2
将20mg Baloxavir marboxil固体置于1mL四氢呋喃中搅拌溶清，在25℃下将4mL异丁醇滴入该溶液中，搅拌降温至0℃，析出白色固体，搅拌3小时，过滤，干燥，经过检测，确定为Baloxavir marboxil晶型C，图谱与图1-图3一致。
实施例3
将20mg Baloxavir marboxil固体置于1mL二氧六环中搅拌溶清，在25℃下将该溶液滴入4mL异丁醇中，搅拌析出白色固体，搅拌3小时，过滤，干燥，经过检测，确定为Baloxavir marboxil晶型C。
实施例4
将20mg Baloxavir marboxil固体置于1mL二氧六环中搅拌溶清，在25℃下将4mL异丁醇滴入该溶液中，搅拌析出白色固体，经过检测，确定为Baloxavir marboxil晶型C。
实施例5
将20mg Baloxavir marboxil固体置于1mL二氧六环中搅拌溶清，在25℃下将4mL正己烷滴入该溶 液中，搅拌析出白色晶体，经过检测，确定该晶体为Baloxavir marboxil晶型C。
实施例6晶型A的制备
根据专利申请CN109504721A公开的方法，将2.0g Baloxavir marboxil粗品加入至5ml异丙醇和5ml水室温下打浆24h，过滤，得到的固体在50℃真空干燥至干，得到固体1.83g，检测XRPD，为晶型A，参见图4。
将50mg Baloxavir marboxil加入到0.5mL二甲基乙酰胺中，加热至50℃溶清，随后降温至室温滴加1mL水，析出固体，过滤，用水洗涤，所得固体在50℃真空干燥至干，得到白色固体44mg，检测XRPD，与图4基本一致，为晶型A。
实施例7稳定性测试
根据药物制剂稳定性试验指导原则，对晶型进行影响因素实验，包括高温试验、高湿试验和强光照射试验，考察影响其晶型的稳定性条件，参见表1所示。
高温试验：分别取晶型样品适量，平铺置称量瓶中，在60℃±5℃、RH 75±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
高湿试验：分别取晶型样品适量，平铺置称量瓶中，在25℃、RH 92.5±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
光照试验：分别取晶型样品适量，平铺至称量瓶中，在可见光4500Lux±500Lux(VIS)、紫外光1.7W*h/m2(UV)的恒温恒湿箱(25℃、RH 60％±5％)条件下放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
表1：晶型C的稳定性试验条件
Figure PCTCN2020117325-appb-000005
结果：晶型样品在高温、高湿和光照三个影响因素试验条件下的粉末X-射线衍射(XRPD)、差示扫描量热法(DSC)检测表明晶型C在各影响因素下未发生转晶，具有良好的稳定性。
实施例8溶解度测试
分别取适量晶型样品置于20mL顶空瓶中，加入1mL水，使其成为饱和水溶液，放置于恒温震荡摇床中，温度设置为37.0℃，振摇至平衡后，取过饱和溶液，过0.22微米水系滤膜，即得样品待测液；
对照品：精确称取20mg对照品至1000mL容量瓶中，加入水定容，即得对照液。
使用HPLC(高效液相色谱法)分别测试对照品和晶型样品待测液，计算出晶型A和晶型C的溶解度。
水的密度按照1.00g/mL计算，分别测试这两种晶型样品在37.0℃的水中的溶解度，溶解度测试实验结果见表2。
表2：晶型的溶解度测试实验结果
温度 晶型 溶解度(ug/mL)
37.0℃ 晶型A 25.67
37.0℃ 晶型C 37.53
结论：晶型的溶解度测试实验结果显示，晶型A的溶解度约为25.67ug/ml，而晶型C的溶解度达到37.53ug/ml，其比晶型A的溶解度提高约46％，晶型C具有良好的溶解性，有利于应用于药物制剂的制备。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (14)

  1. 一种Baloxavir marboxil的晶型C，其特征在于，其X-射线粉末衍射图中在2θ大约为8.9°，17.8°，20.3°，22.3°，24.4°和31.5°的位置有峰。
  2. 根据权利要求1所述的晶型C，其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，13.3°，17.8°，20.3°，22.3°，24.4°，28.0°和31.5°的位置有峰。
  3. 根据权利要求1所述的晶型C，其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，10.6°，11.7°，13.3°，17.8°，20.3°，22.3°，24.4°，28.0°，30.7°，31.5°和36.1°的位置有峰。
  4. 根据权利要求1所述的晶型C，其X-射线粉末衍射图中在2θ大约为4.5°，8.9°，10.6°，11.7°，13.3°，17.8°，19.1°，20.3°，22.3°，24.4°，26.5°，26.9°，28.0°，30.7°，31.5°，34.1°，36.1°和39.0°的位置有峰。
  5. 根据权利要求1-4任一所述的晶型C，其X-射线粉末衍射图基本上如附图1所示。
  6. 根据权利要求1-5任一所述的晶型C，其在235℃±2℃熔融。
  7. 根据权利要求1-6任一所述的晶型C，其差示扫描量热曲线显示其熔融前不吸热。
  8. 根据权利要求1-6任一所述的晶型C，其为块棒状晶体。
  9. 一种组合物，其包含权利要求1-8任一所述的晶型C和药学上可接受的载体。
  10. 根据权利要求9所述的组合物，其中，按照质量比计算，晶型C为Baloxavir marboxil的至少90％，或者晶型C不超过Baloxavir marboxil的10％，或者晶型C不低于Baloxavir marboxil的0.5％。
  11. 一种制备权利要求1-8任一所述的晶型C的方法，包括：Baloxavir marboxil于良溶剂中溶解，搅拌，将所得混合溶液与反溶剂混合，控温，析出固体，得到晶型C；其中，所述良溶剂为四氢呋喃，1,4-二氧六环，或其组合；所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
  12. 权利要求11所述的方法，其中，每一克Baloxavir marboxil，良溶剂的用量为1mL-50mL，反溶剂的用量为1mL-200mL。
  13. 权利要求11所述的方法，其中，混合溶液与反溶剂混合后形成的体系控温为-10℃-30℃。
  14. 权利要求11所述的方法，包括：Baloxavir marboxil于四氢呋喃中溶解，搅拌，将所得混合溶液与反溶剂混合，控温-10℃-10℃，析出固体，得到晶型C；其中，每一克Baloxavir marboxil，四氢呋喃的用量为1mL-50mL，反溶剂的用量为1mL-200mL,所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，或其组合；或者包括：Baloxavir marboxil于1,4-二氧六环中溶解，搅拌，将所得混合溶液与反溶剂混合，控温15℃-30℃，析出固体，得到晶型C；其中，每一克Baloxavir marboxil，1,4-二氧六环的用量为1mL-50mL，反溶剂的用量为1mL-200mL，所述反溶剂为甲醇，乙醇，异丁醇，正丁醇，异丙醇，正丙醇，环己烷，正己烷，异丙醚，甲基叔丁基醚，或其组合。
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