WO2021233434A1 - 比克替拉韦钠的新晶型及其制备方法 - Google Patents

比克替拉韦钠的新晶型及其制备方法 Download PDF

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WO2021233434A1
WO2021233434A1 PCT/CN2021/095237 CN2021095237W WO2021233434A1 WO 2021233434 A1 WO2021233434 A1 WO 2021233434A1 CN 2021095237 W CN2021095237 W CN 2021095237W WO 2021233434 A1 WO2021233434 A1 WO 2021233434A1
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crystal form
sodium
another preferred
organic solvent
crystal
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PCT/CN2021/095237
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English (en)
French (fr)
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安晓霞
赵楠
王锰
彭思情
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上海迪赛诺生物医药有限公司
上海迪赛诺化学制药有限公司
江西迪赛诺制药有限公司
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Publication of WO2021233434A1 publication Critical patent/WO2021233434A1/zh

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    • 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
    • C07D498/18—Bridged systems
    • 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
    • A61K31/537—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 spiro-condensed or forming part of bridged 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a new crystal form of bictegravir sodium and a preparation method thereof.
  • Patent WO2015196116A1 discloses the crystal form of Biktegravir sodium, and its X-ray powder diffraction (XRPD) pattern is at 5.5°, 16.1°, 17.9°, 19.5°, 22.1°, 22.5°, 23.3°, 26.6° and 28.5 There is a peak at 2 ⁇ of ° ⁇ 0.2°, and this crystal form is named Form I.
  • Patent WO2019154634A1 reports another crystal form of Biktegravir sodium, Form II, and its X-ray powder diffraction pattern is at 6.5°, 7.5°, 13.0°, 14.6°, 16.8°, 18.1° , 18.8°, 19.4°, 20.9°, 23.5°, 24.2°, 24.7° and 26.5 ⁇ 0.1°.
  • the crystal form II needs to be obtained in the 2,2,2-trifluoroethanol system in the solvate form, and then after 15 hours of vacuum drying at 50°C before it can be transformed into the form.
  • Solvate a combination of solvents, makes it difficult to dry.
  • Patent WO2019207602A1 discloses five crystal forms of bicotegravir M1 to M5 and a preparation method thereof, and discloses the amorphous form of bicotegravir sodium and a preparation method thereof.
  • the crystal forms of Biquetegravir M1 ⁇ M5 are all free crystal forms of Biquetegravir, which have poor solubility and cannot be used directly as pharmaceutical crystal forms.
  • the preparation of amorphous Biquetegravir sodium needs to be prepared in water In the solvent system, it is obtained by freeze-drying or spray-drying, which has higher requirements on equipment and at the same time increases production costs.
  • the liquidity of amorphous Biktigravir sodium powder is poor, which is not conducive to the production of preparations.
  • the purpose of the present invention is to provide a new crystal form of Biktegravir sodium that can be used as a final medicinal form, has good fluidity, is easy to large-scale industrial production, and has low requirements for production equipment.
  • the X-ray powder diffraction pattern of the crystal form L1 has characteristic peaks at 2 ⁇ of 5.3 ⁇ 0.2°, 6.8 ⁇ 0.2°, 16.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 25.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L1 also has characteristic peaks at 2 ⁇ of 10.2 ⁇ 0.2°, 17.1 ⁇ 0.2°, 22.5 ⁇ 0.2°, and/or 23.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L1 has characteristic peaks at least 5 (preferably all) 2 ⁇ selected from the following group: 5.3 ⁇ 0.2°, 6.8 ⁇ 0.2°, 10.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.2 ⁇ 0.2° and 25.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L1 is basically as shown in FIG. 1.
  • the differential scanning calorimetry spectrum of the L1 crystal form has two endothermic peaks in the range of 350-380°C.
  • the first endothermic peak of the differential scanning calorimetry spectrum of the crystal form L1 is at 366 ⁇ 5°C and the second endothermic peak is at 375 ⁇ 5°C.
  • the differential scanning calorimetry spectrum of the crystal form L1 is basically as shown in FIG. 2.
  • the TGA diagram of the crystal form L1 is basically as shown in FIG. 3.
  • the crystal habit of the crystal form L1 is a spherical crystal habit.
  • the X-ray powder diffraction pattern of the crystal form L2 has characteristic peaks at 2 ⁇ of 4.8 ⁇ 0.2°, 6.7 ⁇ 0.2°, 12.5 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 25.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L2 is still 5.3 ⁇ 0.2°, 11.4 ⁇ 0.2°, 13.7 ⁇ 0.2°, 14.4 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.1 ⁇ 0.2° , 20.9 ⁇ 0.2° and/or 28.8 ⁇ 0.2° 2 ⁇ have characteristic peaks.
  • the X-ray powder diffraction patterns of the crystal form L2 are at least 5 (preferably, at least 7, more preferably at least 10, and most preferably, all) selected from the following group There are characteristic peaks at 2 ⁇ : 4.8 ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.7 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.5 ⁇ 0.2°, 13.7 ⁇ 0.2°, 14.4 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.1 ⁇ 0.2° , 20.9 ⁇ 0.2°, 22.8 ⁇ 0.2°, 25.6 ⁇ 0.2° and 28.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form L2 is basically as shown in FIG. 4.
  • the differential scanning calorimetry spectrum of the crystal form L2 has an endothermic peak at 388 ⁇ 5°C.
  • the differential scanning calorimetry spectrum of the crystal form L2 is basically as shown in FIG. 5.
  • the TGA diagram of the crystal form L2 is basically as shown in FIG. 6.
  • the crystal habit of the crystal form L2 is a spherical crystal habit.
  • a crystal form for preparing crystal form L1 is provided, and the crystal form is crystal form L2 as described in the second aspect.
  • a method for preparing the crystal form L1 as described in the first aspect is provided, and the method is method 1, method 2, or method 3.
  • the method 1 includes the step of drying the crystal form L2 at a drying temperature to obtain the crystal form L1.
  • the method 2 includes the steps:
  • step (2.2) Add a sodium-containing compound to the solution of step (1.1), crystallize, and collect the precipitated solid;
  • step (2.3) Dry the solid obtained in step (1.2) at a drying temperature to obtain crystal form L1.
  • the sodium-containing compound is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, or a combination thereof.
  • the first organic solvent is selected from the following group: ethylene glycol dimethyl ether, methyl isobutyl ketone, or a combination thereof.
  • the concentration of the sodium-containing compound aqueous solution is 0.5-50% by weight; preferably, 5-30% by weight; more preferably, 10-20% by weight.
  • the volume ratio of the solution in step (2.1) to the aqueous sodium-containing compound solution is (1-20):1; preferably, (2-15):1; more preferably, (5-10) ):1.
  • the mass-volume (g:ml) ratio of Biktegravir to the first organic solvent is 1:(5-20); preferably, 1:(10 ⁇ 1).
  • the concentration of bictegravir in the solution of step (2.1) is 0.1 ⁇ 0.05 g/ml.
  • step (2.1) includes the step of dissolving Biktigravir in a first organic solvent to obtain a solution for Biktigravir in the first organic solvent.
  • the crystallization is carried out at 0 ⁇ 70°C; preferably, it is carried out at 5 ⁇ 50°C; more preferably, it is carried out at 10 ⁇ 40°C; most preferably, it is carried out at 15 Performed at ⁇ 30°C.
  • the crystallization is performed at room temperature.
  • the precipitated solid is collected by filtration in step (2.2).
  • the method 3 includes the steps:
  • step (3.2) Stir the mixture in step (3.1) at a stirring temperature, and collect the solids in the mixture;
  • step (3.3) Dry the solid obtained in step (3.2) at a drying temperature to obtain crystal form L1.
  • the second organic solvent is selected from the following group: ethylene glycol dimethyl ether, methyl isobutyl ketone, or a combination thereof.
  • the stirring temperature is -10 to 10°C; preferably, it is -5 to 5°C.
  • step (3.1) the mass-volume (g:ml) ratio of Biktigravir sodium to the second organic solvent is 1:(5-20); preferably, 1:(10) ⁇ 1).
  • the bictitgravir sodium is a crystal form and/or amorphous form of critecavir sodium.
  • the bictegravir sodium is the crystal form I of WO2015196116A1.
  • step (3.1) includes the step of suspending bicotegravir sodium in a second organic solvent to obtain a mixture of bicotegravir in the second organic solvent.
  • the stirring time of the stirring in step (3.2) is 10-50 hours; preferably, 15-40 hours; more preferably, 20-30 hours.
  • step (3.2) the mixed solids are collected by filtration.
  • the drying temperature is 20-40°C.
  • the drying time of the drying is ⁇ 10 hours; preferably, 3 to 7 hours; more preferably, 3 to 6 hours.
  • Method 1 in Method 1, Method 2, and/or Method 3, the drying is performed under vacuum.
  • the vacuum drying refers to drying at 0 to -0.1 MPa.
  • a method for preparing the crystal form L2 as described in the second aspect is provided, and the method is method A or method B.
  • the method A includes the steps:
  • step (A2) Add a sodium-containing compound to the solution of step (A1), crystallize, and collect the precipitated solid to obtain crystal form L2;
  • the sodium-containing compound is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium methoxide, sodium ethoxide, or a combination thereof.
  • the first organic solvent is selected from the following group: ethylene glycol dimethyl ether, methyl isobutyl ketone, or a combination thereof.
  • the sodium-containing compound is added in the form of an aqueous solution of sodium-containing substance.
  • the concentration of the sodium-containing compound in the aqueous solution is 0.5-50% by weight; preferably, 5-30% by weight; more preferably, 10-20% by weight.
  • the volume ratio of the solution of step (A1) to the aqueous solution of sodium-containing compound is (1-20):1; preferably, (2-15):1; more preferably, (5 ⁇ 10):1.
  • the mass-volume (g:ml) ratio of Biktegravir to the first organic solvent is 1:(5-20); preferably, 1:(10 ⁇ 1).
  • the concentration of bicotegravir in the solution of step (A1) is 0.1 ⁇ 0.05 g/ml.
  • step (A1) includes the step of dissolving bicotegravir in a first organic solvent to obtain a solution of bicotegravir in the first organic solvent.
  • step (A2) includes the step of adding dropwise an aqueous sodium hydroxide solution to the solution of step (A1), stirring and crystallization, so as to obtain crystal form L2.
  • the crystallization is carried out at 0-70°C; preferably, it is carried out at 5-50°C; more preferably, it is carried out at 10-40°C; most preferably ⁇ , ⁇ 15 ⁇ 30°C ⁇
  • the crystallization is performed at room temperature.
  • the precipitated solid is collected by filtration in step (A2).
  • step (A1) is the same as step (2.1).
  • step (A2) is the same as step (2.2).
  • the method B includes the steps:
  • step (B2) The step (B1) mixture is stirred at a stirring temperature, and the solids in the mixture are collected to obtain crystal form L2.
  • the second organic solvent is selected from the following group: ethylene glycol dimethyl ether, methyl isobutyl ketone, or a combination thereof.
  • the stirring temperature is -10 to 10°C; preferably, it is -5 to 5°C.
  • step (B1) the mass-volume (g:ml) ratio of bictegravir sodium to the second organic solvent is 1:(5-20); preferably, 1:(10 ⁇ 1).
  • the bicotegravir sodium is the crystalline and/or amorphous form of bicotegravir sodium.
  • the bictegravir sodium is crystalline form I of WO2015196116A1.
  • step (B1) includes the step of suspending bicotegravir sodium in a second organic solvent to obtain a mixture for bicotegravir in the second organic solvent.
  • the stirring time of the stirring in step (B2) is 10-50 hours; preferably, 15-40 hours; more preferably, 20-30 hours.
  • step (B2) the mixed solids are collected by filtration.
  • step (B1) is the same as step (3.1).
  • step (B2) is the same as step (3.2).
  • composition comprising
  • Figure 1 shows the X-ray powder diffraction pattern (XRPD) of crystal form L1
  • FIG. 2 shows the differential scanning calorimetry (DSC) spectra of crystal form L1
  • FIG. 3 shows the thermogravimetric analysis data (TGA) of crystal form L1
  • Figure 4 shows the X-ray powder diffraction pattern (XRPD) of crystal form L2
  • FIG. 5 shows the differential scanning calorimetry (DSC) spectra of crystal form L2
  • FIG. 6 shows the thermogravimetric analysis data (TGA) of crystal form L2
  • Figure 7 shows the X-ray powder diffraction pattern (XRPD) of Form I
  • Figure 8 shows the crystal habit of crystal form L1
  • the inventors unexpectedly obtained a new crystal form of bicotegravir sodium in a medicinal form in a special solvent system.
  • the new crystal form itself has excellent fluidity, stability and high purity.
  • the preparation of the new crystal form is simple, and it is very suitable for industrial production. Based on this, the inventor completed the present invention.
  • crystal form L1 and “crystal form L1” can be used interchangeably to refer to the crystal form of bicotegravir sodium as described in the first aspect.
  • crystal form L2 and “crystal form L2” can be used interchangeably to refer to the crystal form of bicotegravir sodium as described in the second aspect.
  • Different crystal forms of drugs may have significant differences in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, color, filterability, density, fluidity, etc.
  • the research on drug polymorphs is helpful to find drug forms with better physical and chemical properties or better processing forms, thereby broadening the formulation forms of drugs and developing valuable formulation forms, which are convenient for all kinds of people to use.
  • Biktigravir sodium is a new HIV integrase inhibitor and a blockbuster product for the treatment of HIV. Therefore, the development of its polymorphs and the discovery of stable and medicinal crystal forms are of great significance for the development of its formulations.
  • the purpose of the present invention is to provide stable physical and chemical properties, high purity, good reproducibility, simple production process and suitable for industrial production of new crystal forms of Biktigravir sodium: crystal form L1 and crystal form L2.
  • the present invention provides a crystal form L1 of bictegravir sodium.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the Biktegravir sodium crystal form L1 is 5.3 ⁇ 0.2°, 6.8 ⁇ 0.2°, 10.2 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.1 ⁇ 0.2°, 20.6
  • At least 5 (preferably, at least 7) of ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.2 ⁇ 0.2°, and 25.7 ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystal form L1 of Biktegravir sodium has at least 5 (preferably all) characteristic peaks as shown in the following table:
  • the X-ray powder diffraction pattern of the crystal form L1 of Biktegravir sodium has the characteristic peaks shown in the following table:
  • the X-ray powder diffraction pattern of the crystal form L1 is basically the same as that of FIG. 1.
  • the differential scanning calorimetry spectrum of the L1 crystal form has two endothermic peaks in the range of 350-380°C.
  • the first endothermic peak of the differential scanning calorimetry spectrum of the crystal form L1 is at 366 ⁇ 5°C (preferably, 366 ⁇ 2°C, more preferably 366 ⁇ 1°C), and the second The endothermic peak is at 375 ⁇ 5°C (preferably, 375 ⁇ 2°C).
  • the differential scanning calorimetry spectrum of the crystal form L1 is basically as shown in FIG. 2.
  • the TGA diagram of the crystal form L1 is basically as shown in FIG. 3.
  • the present invention also provides a method for preparing the crystal form L1, including the following steps:
  • organic solvents are selected from one or more of ethylene glycol dimethyl ether and methyl isobutyl ketone; the mass fraction of the sodium hydroxide aqueous solution is 0.5-50%, preferably 5%-30%, and more Preferably it is 10%-20%.
  • the present invention also provides a method for preparing the crystal form L1, which includes the following steps: vacuum drying the crystal form L2 at 20-40° C., and collecting the solid.
  • the invention also provides a crystal form L2 of bictegravir sodium.
  • the 2 ⁇ of the X-ray powder diffraction pattern of the crystal form L2 of Biktegravir sodium is at 4.8 ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.7 ⁇ 0.2°, 11.4 ⁇ 0.2°, 12.5 ⁇ 0.2°, At least 5 of 13.7 ⁇ 0.2°, 14.4 ⁇ 0.2°, 16.1 ⁇ 0.2°, 17.1 ⁇ 0.2°, 20.9 ⁇ 0.2°, 22.8 ⁇ 0.2°, 25.6 ⁇ 0.2° and 28.8 ⁇ 0.2° (preferably, at least 7 locations, more preferably at least 10 locations) have characteristic peaks.
  • the X-ray powder diffraction pattern of Biktegravir sodium crystal form L2 has at least 5, preferably, at least 7, more preferably at least 10, and most preferably, all) as shown in the following table Show characteristic peak:
  • the X-ray powder diffraction pattern of the crystal form L2 of Biktegravir sodium has the characteristic peaks shown in the following table:
  • the X-ray powder diffraction pattern of the crystal form L2 is basically consistent with FIG. 4.
  • the differential scanning calorimetry spectrum of the L2 crystal form has an endothermic peak at 388 ⁇ 5°C (preferably, 388 ⁇ 2°C).
  • the differential scanning calorimetry spectrum of the crystal form L2 is basically as shown in FIG. 5.
  • the TGA diagram of the crystal form L2 is basically as shown in FIG. 6.
  • the present invention also provides a method for preparing the crystal form L2, which includes the following steps: dissolving Biktigravir in an organic solvent, adding sodium hydroxide aqueous solution dropwise, stirring for crystallization, and filtering.
  • the organic solvent is selected from one or more of ethylene glycol dimethyl ether and methyl isobutyl ketone.
  • the crystal form of the present invention (such as crystal form L1 or crystal form L2) has excellent inhibitory ability against human immunodeficiency virus (HIV) integrase
  • the crystal form of bictegravir sodium of the present invention and the crystal form of the present invention contain
  • the pharmaceutical composition whose crystal form is the main active ingredient can be used to treat and/or prevent diseases caused by human immunodeficiency virus type 1, or the crystal form of the present invention can be used to prepare anti-HIV drugs. Therefore, the crystal form of the present invention or the crystal form (such as crystal form L1 or crystal form L2) of the present invention can be used to prepare anti-HIV drugs.
  • Biktegravir can be prepared by methods commonly used in the art.
  • the pharmaceutical composition of the present invention contains the crystal form of the present invention (crystal form L1) or the crystal form L1 of bicotegravir sodium prepared from the crystal form of the present invention (crystal form L2) in a safe and effective amount, and pharmacologically Acceptable excipients or carriers.
  • safe and effective amount refers to: the amount of the compound (or crystal form) is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the crystalline form/dose of the present invention, more preferably, 10-200 mg of the crystalline form/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the active ingredients of the present invention and between them without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting agents such as sodium lauryl sulfate
  • coloring agents such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc.
  • antioxidants
  • the method of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvent, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycerol, or
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of active ingredients in such compositions may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the polymorph of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the crystal form of the present invention (such as crystal form L1 and crystal form L2) is a crystal form of a medicinal form, and the crystal form is stable and easy for subsequent formulation development.
  • the crystal form L1 of the present invention is easy to prepare and easy to industrially produce.
  • the preparation of the crystalline form L1 of the present invention does not require freeze-drying or spraying, and has low equipment requirements, and is easy to form vacuum drying that only takes a short time (such as 3-6 hours), and can be obtained with high yield.
  • the crystal forms of the present invention have excellent stability.
  • the prior art crystalline form of Biktegravir sodium ie, the crystalline form I of WO2015196116A1
  • the crystal form of the present application has significantly better ratios.
  • the stability of the crystal form of keltegravir sodium in addition, the crystal form of the present application also has excellent storage stability, and the crystal form purity and crystal form of the present invention remain stable under long-term storage.
  • the crystal form L1 of the present invention has high purity (>99.9%), no solvent remains, and meets the quality standard of the bulk drug.
  • the crystal form of the present invention (such as crystal form L1 and crystal form L2) has spherical crystal habit, while crystal form I in the prior art has extremely small plate-like crystal habit, so the crystal form of the present application has more excellent crystal habit.
  • the fluidity which can make the prepared medicament have better compressibility. Specifically, the fluidity of the crystals affects the adaptability of tableting of the drug. The better the fluidity, the better the fluidity can avoid the powder stratification caused by machine vibration or uneven mixing during the tableting process, and the uniformity of material distribution and mixing can be improved. Reduce the difference between the tablets, improve the stability of the weight, content, and uniformity of each tablet.
  • the crystal form L2 of the present invention is very suitable for preparing the crystal form L1 of the present invention.
  • the crystal form L2 of the present invention only needs vacuum drying for 3-6 hours to obtain the crystal form L1 of the present invention.
  • test method is usually implemented in accordance with conventional conditions or the conditions recommended by the manufacturer, and the raw materials and reagents shown can be obtained commercially.
  • X-ray powder diffractometer Brucker D8 advanced X-ray powder diffractometer.
  • Step size 0.020°
  • Measurement time per step 0.1 second/step
  • DSC differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • Temperature range room temperature ⁇ 400°C,
  • thermogravimetric analysis (TGA) parameters are as follows:
  • Thermogravimetric analysis (TGA) instrument TGA55 type.
  • the XRPD pattern, DSC pattern and TGA pattern of the obtained solid 1 are shown in Figures 4, 5 and 6, respectively, and are crystal form L2; the XRPD pattern, DSC pattern and TGA pattern of the obtained solid 2 are shown in Figure 1, respectively. 2 and 3 show the crystal form L1.
  • the XRPD pattern, DSC pattern, and TGA pattern of solid 1 are basically the same as solid 1 of Example 1, which is crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of solid 1 are basically the same as solid 2 of Example 1.
  • solid 1 of Example 1 which is crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of solid 1 are basically the same as solid 2 of Example 1.
  • the XRPD pattern, DSC pattern and TGA pattern of solid 1 are basically the same as solid 1 of Example 1, and are crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of Solid 1 are basically the same as solid 2 of Example 1.
  • the crystal form L1 is basically the same as solid 1 of Example 1, and are crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of Solid 1 are basically the same as solid 2 of Example 1.
  • bicotegravir sodium crystal form I prepared according to the method of Comparative Example 1 in 50 ml of ethylene glycol dimethyl ether solvent, stir at -5 to 5°C for 20 to 30 hours, and filter. Obtain Biquetegravir Sodium Solid 1 and place the solid 1 in a vacuum drying oven at 20-25° C. for 5-6 hours to obtain Biquetegravir Sodium Solid 2 with a purity of 99.4% and a yield of 96.1%.
  • the XRPD pattern, DSC pattern and TGA pattern of solid 1 are basically the same as solid 1 of Example 1, and are crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of Solid 1 are basically the same as solid 2 of Example 1.
  • the crystal form L1 is basically the same as solid 1 of Example 1, and are crystal form L2; the XRPD pattern, DSC pattern, and TGA pattern of Solid 1 are basically the same as solid 2 of Example 1.

Abstract

一种比克替拉韦钠的新晶型及其制备方法。具体地，一种比克替拉韦钠的晶型L1和晶型L2以及它们的制备方法。比克替拉韦钠的晶型L1制备工艺简单，化学性质稳定，是一种具有优异工业化实施潜力的新晶型。

Description

比克替拉韦钠的新晶型及其制备方法 技术领域
本发明属于药物合成领域，具体涉及一种比克替拉韦钠的新晶型及其制备方法。
背景技术
比克替拉韦钠(Bictegravir Sodium)化学名称(2R，5S，13aR)-7，9-二氧代-10-((2，4，6-三氟苯甲基)氨基甲酰基)-2，3，4，5，7，9，13，13a-八氢-2，5-桥亚甲基吡啶并[1’，2’：4，5]吡嗪并[2，1-b][1，3]氧氮杂-8-酚钠，是由美国吉利德公司研发的一种人类免疫缺陷病毒(HIV)整合酶抑制剂，2018年2月7日，美国FDA批准含比克替拉韦钠，恩曲他滨和富马酸丙酚替诺福韦的复方上市用于治疗人类免疫缺陷病毒1型(HIV-1)，此复方在2019年即取得全球市场47.38亿美元的销售份额。
Figure PCTCN2021095237-appb-000001
吉利德公司最早在专利WO2014100323A1中公布了比克替拉韦的合成方法，但近年来，对其晶型的研究较少，仅有以下几篇专利。
专利WO2015196116A1中公布了比克替拉韦钠的晶体形式，其X射线粉末衍射(XRPD)图谱在5.5°、16.1°、17.9°、19.5°、22.1°、22.5°、23.3°、26.6°和28.5°±0.2°的2θ处具有峰，该晶型被命名为晶型I(Form I)。
专利WO2019154634A1中报道了比克替拉韦钠的另一种晶型即晶型II(Form II)，其X射线粉末衍射图谱在6.5°、7.5°、13.0°、14.6°、16.8°、18.1°、18.8°、19.4°、20.9°、23.5°、24.2°、24.7°和26.5±0.1°。一方面，晶型II需要先在2,2,2-三氟乙醇体系中获得溶剂化物形式，再经过15小时50℃的真空干燥才能转变形成，三氟乙醇与比克替拉韦钠形式的溶剂化物，溶剂结合形式，使其不容易干燥，需要通过延长干燥时间和提高干燥温度，才能获得，不利于生产规模晶型控制；另一方面，比克替拉韦钠在2,2,2-三氟乙醇体系中具有较好的溶解度，产品损失较大，收率只 有82.6％，不利于产品成本的控制。
专利WO2019207602A1中公开了比克替拉韦的M1～M5五种晶型及其制备方法，同时公开比克替拉韦钠的无定型及其制备方法。其中比克替拉韦M1～M5晶型均是游离比克替拉韦结晶形式，溶解度差，不能直接作为药用晶型使用，而无定型的比克替拉韦钠的制备需要在含水的溶剂体系中，通过冻干或喷雾干燥的形式得到，对设备的要求较高，同时增加了生产成本。而且，无定型的比克替拉韦钠粉体的流动性较差，不利于制剂的生产。
综上所述，本领域仍然迫切需要一种新的可作为最终药用形式、流动性好，且易于大规模工业化生产，对生产设备要求低的比克替拉韦钠的新晶型。
发明内容
本发明的目的就是提供一种新的可作为最终药用形式、流动性好，且易于大规模工业化生产，对生产设备要求低的比克替拉韦钠的新晶型。
在本发明的第一方面中，提供了一种如式I所示的比克替拉韦钠的晶型L1，其中，
Figure PCTCN2021095237-appb-000002
所述晶型L1的X-射线粉末衍射图谱在5.3±0.2°、6.8±0.2°、16.1±0.2°、20.6±0.2°和25.7±0.2°的2θ处具有特征峰。
在另一优选例中，所述晶型L1的X-射线粉末衍射图谱还在10.2±0.2°、17.1±0.2°、22.5±0.2°和/或23.2±0.2°的2θ处具有特征峰。
在另一优选例中，所述晶型L1的X-射线粉末衍射图谱在至少5个(较佳地所有)选自下组的2θ处具有特征峰：5.3±0.2°、6.8±0.2°、10.2±0.2°、16.1±0.2°、17.1±0.2°、20.6±0.2°、22.5±0.2°、23.2±0.2°和25.7±0.2°。
在另一优选例中，所述晶型L1的X-射线粉末衍射图谱基本如图1所示。
在另一优选例中，所述L1晶型的差示扫描量热法谱图在350～380℃范围内有两个吸热峰。
在另一优选例中，所述晶型L1的差式扫描量热图谱第一个吸热峰在366±5℃且第二个吸热峰在375±5℃。
在另一优选例中，所述的晶型L1的差示扫描量热法谱图基本如图2所示。
在另一优选例中，所述晶型L1的TGA图基本如图3所示。
在另一优选例中，所述晶型L1的晶习为球形晶习。
在本发明的第二方面中，提供了一种如式I所示的比克替拉韦钠的晶型L2，其特征在于，
Figure PCTCN2021095237-appb-000003
所述晶型L2的X-射线粉末衍射图谱在4.8±0.2°、6.7±0.2°、12.5±0.2°、22.8±0.2°和25.6±0.2°的2θ处具有特征峰。
在另一优选例中，所述晶型L2的X-射线粉末衍射图谱还在5.3±0.2°、11.4±0.2°、13.7±0.2°、14.4±0.2°、16.1±0.2°、17.1±0.2°、20.9±0.2°和/或28.8±0.2°的2θ处具有特征峰。
在另一优选例中，所述晶型L2的X-射线粉末衍射图谱在至少5个(较佳地，至少7个，更佳地至少10个，最佳地，所有)选自下组的2θ处具有特征峰：4.8±0.2°、5.3±0.2°、6.7±0.2°、11.4±0.2°、12.5±0.2°、13.7±0.2°、14.4±0.2°、16.1±0.2°、17.1±0.2°、20.9±0.2°、22.8±0.2°、25.6±0.2°和28.8±0.2°。
在另一优选例中，所述晶型L2的X-射线粉末衍射图谱基本如图4所示。
在另一优选例中，所述晶型L2的差示扫描量热法谱图在388±5℃有吸热峰。
在另一优选例中，所述晶型L2的差式扫描量热图谱基本如图5所示。
在另一优选例中，所述晶型L2的TGA图基本如图6所示。
在另一优选例中，所述晶型L2的晶习为球形晶习。
在本发明的第三方面中，提供了一种用于制备晶型L1的晶型，所述的晶型为如第二方面所述的晶型L2。
在本发明的第四方面中，提供了一种制备如第一方面所述晶型L1的方法，所述的方法为方法1、方法2或方法3。
在另一优选例中，所述方法1包括步骤：将晶型L2在干燥温度下干燥，从而得到晶型L1。
在另一优选例中，所述方法2包括步骤：
(2.1)提供比克替拉韦于第一有机溶剂中的溶液；和
(2.2)向步骤(1.1)的溶液中加入含钠化合物，析晶，收集析出固体；和
(2.3)将步骤(1.2)得到的固体在干燥温度下干燥，从而得到晶型L1。
在另一优选例中，所述含钠化合物选自下组：氢氧化钠、碳酸钠、甲醇钠、乙醇钠，或其组合。
在另一优选例中，所述第一有机溶剂选自下组：乙二醇二甲醚、甲基异丁基酮，或其组合。
在另一优选例中，所述含钠化合物水溶液中的浓度为0.5～50wt％；较佳地，5～30wt％；更佳地，10～20wt％。
在另一优选例中，步骤(2.1)的溶液与含钠化合物水溶液的体积比为(1～20)：1；较佳地，(2～15):1；更佳地，(5～10):1。
在另一优选例中，步骤(2.1)中，比克替拉韦与第一有机溶剂的质量体积(g：ml)比为1:(5～20)；较佳地，1:(10±1)。
在另一优选例中，步骤(2.1)的溶液中比克替拉韦的浓度为0.1±0.05g/ml。
在另一优选例中，步骤(2.1)包括步骤：将比克替拉韦溶清于第一有机溶剂中，从而得到供比克替拉韦于第一有机溶剂中的溶液。
在另一优选例中，所述的析晶在0～70℃下进行；较佳地，在5～50℃下进行；更佳地，在10～40℃下进行；最佳地，在15～30℃下进行。较佳地，所述的析晶在室温下进行。
在另一优选例中，步骤(2.2)中通过过滤收集析出固体。
在另一优选例中，所述方法3包括步骤：
(3.1)提供比克替拉韦钠于第二有机溶剂中的混合物；和
(3.2)将步骤(3.1)混合物在搅拌温度下搅拌，收集所述混合中固体；和
(3.3)将步骤(3.2)得到的固体在干燥温度下干燥，从而得到晶型L1。
在另一优选例中，所述第二有机溶剂选自下组：乙二醇二甲醚、甲基异丁基酮，或其组合。
在另一优选例中，所述搅拌温度为-10～10℃；较佳地，为-5～5℃。
在另一优选例中，步骤(3.1)中，比克替拉韦钠与第二有机溶剂的质量体积(g：ml)比为1:(5～20)；较佳地，1:(10±1)。
在另一优选例中，所述比克替拉韦钠为克替拉韦钠的晶型和/或无定型。
在另一优选例中，所述比克替拉韦钠为WO2015196116A1的晶型I。
在另一优选例中，步骤(3.1)包括步骤：将比克替拉韦钠悬浮于第二有机溶剂中，从而得到供比克替拉韦于第二有机溶剂中的混合物。
在另一优选例中，步骤(3.2)中所述搅拌的搅拌时间为10～50小时；较佳地，为15～40小时；更佳地，为20～30小时。
在另一优选例中，步骤(3.2)中通过过滤收集所述混合中固体。
在另一优选例中，方法1、方法2和/或方法3中，所述干燥温度为20～40℃。
在另一优选例中，方法1、方法2和/或方法3中，所述干燥的干燥时间为≤10小时；较佳地，3～7小时；更佳地，3～6小时。
在另一优选例中，方法1、方法2和/或方法3中，所述的干燥在真空下进行。
在另一优选例中，方法1、方法2和/或方法3中，所述的真空干燥是指在0～-0.1MPa下干燥。
在本发明的第五方面中，提供了一种制备如第二方面所述的晶型L2的方法，所述的方法为方法A或方法B。
在另一优选例中，所述方法A包括步骤：
(A1)提供比克替拉韦于第一有机溶剂中的溶液；和
(A2)向步骤(A1)的溶液中加入含钠化合物，析晶，收集析出固体，从而得到晶型L2；
在另一优选例中，所述含钠化合物选自下组：氢氧化钠、碳酸钠、甲醇钠、乙醇钠，或其组合。
在另一优选例中，所述第一有机溶剂选自下组：乙二醇二甲醚、甲基异丁基酮，或其组合。
在另一优选例中，所述含钠化合物以含钠物质水溶液的形式被加入。
在另一优选例中，方法A中，所述含钠化合物水溶液中的浓度为0.5～50wt％；较佳地，5～30wt％；更佳地，10～20wt％。
在另一优选例中，方法A中，步骤(A1)的溶液与含钠化合物水溶液的体积比为(1～20)：1；较佳地，(2～15):1；更佳地，(5～10):1。
在另一优选例中，步骤(A1)中，比克替拉韦与第一有机溶剂的质量体积(g：ml)比为1:(5～20)；较佳地，1:(10±1)。
在另一优选例中，方法A中，步骤(A1)的溶液中比克替拉韦的浓度为0.1±0.05g/ml。
在另一优选例中，方法A中，步骤(A1)包括步骤：将比克替拉韦溶清于第一有机溶剂中，从而得到供比克替拉韦于第一有机溶剂中的溶液。
在另一优选例中，方法A中，步骤(A2)包括步骤：向步骤(A1)的溶液中滴加氢氧化钠水溶液，搅拌析晶，从而得到晶型L2。
在另一优选例中，方法A中，所述的析晶在0～70℃下进行；较佳地，在5～50℃下进行；更佳地，在10～40℃下进行；最佳地，在15～30℃下进行。
在另一优选例中，方法A中，所述的析晶在室温下进行。
在另一优选例中，步骤(A2)中通过过滤收集析出固体。
在另一优选例中，步骤(A1)同步骤(2.1)。
在另一优选例中，步骤(A2)同步骤(2.2)。
在另一优选例中，所述方法B包括步骤：
(B1)提供比克替拉韦钠于第二有机溶剂中的混合物；和
(B2)将步骤(B1)混合物在搅拌温度下搅拌，收集所述混合中固体，从而得到晶型L2。
在另一优选例中，所述第二有机溶剂选自下组：乙二醇二甲醚、甲基异丁基酮，或其组合。
在另一优选例中，所述搅拌温度为-10～10℃；较佳地，为-5～5℃。
在另一优选例中，步骤(B1)中，比克替拉韦钠与第二有机溶剂的质量体积(g：ml)比为1:(5～20)；较佳地，1:(10±1)。
在另一优选例中，方法B中，所述比克替拉韦钠为比克替拉韦钠的晶型和/或无定型。
在另一优选例中，方法B中，所述比克替拉韦钠为WO2015196116A1的晶型I。
在另一优选例中，方法B中，步骤(B1)包括步骤：将比克替拉韦钠悬浮于第二有机溶剂中，从而得到供比克替拉韦于第二有机溶剂中的混合物。
在另一优选例中，方法B中，步骤(B2)中所述搅拌的搅拌时间为10～50小时；较佳地，为15～40小时；更佳地，为20～30小时。
在另一优选例中，步骤(B2)中通过过滤收集所述混合中固体。
在另一优选例中，步骤(B1)同步骤(3.1)。
在另一优选例中，步骤(B2)同步骤(3.2)。
在本发明的第六方面，提供了一种药物组合物，所述组合物包括
(i)如第一方面所述的晶型L1；以及(ii)药学上可接受的载体。
在本发明的第七方面，提供了如第一方面所述晶型L1在制备用于治疗抗HIV药物中的用途。
在本发明的第八方面，提供了如第二方面所述的晶型L2在制备用于治疗抗HIV药物中的用途。
在本发明的第九方面，提供了如第二方面所述的晶型L2在制备如第一方面所述的晶型L1中的用途。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了晶型L1的X-射线粉末衍射图谱(XRPD)，
图2显示了晶型L1差示扫描量热分析谱图(DSC)，
图3显示了晶型L1的热重分析数据(TGA)，
图4显示了晶型L2的X-射线粉末衍射图谱(XRPD)，
图5显示了晶型L2的差示扫描量热分析谱图(DSC)，
图6显示了晶型L2的热重分析数据(TGA)，
图7显示了晶型I的X-射线粉末衍射图谱(XRPD)，
图8显示了晶型L1的晶习，
图9显示了晶型I的晶习
具体实施方式
经过广泛而深入地研究。发明人意外地在特殊的溶剂体系中获得了一种药用形式的比克替拉韦钠的新晶型。该新晶型本身具有优异的流动性、稳定性、高纯 度。而且该新晶型的制备简单，十分适于工业化生产。基于此发明人完成了本发明。
术语
在本文中，“晶型L1”和“L1晶型”可以互换使用是指如第一方面所述的比克替拉韦钠的晶型。
在本文中，“晶型L2”和“L2晶型”可以互换使用是指如第二方面所述的比克替拉韦钠的晶型。
药物的晶型不同，在生物利用度，溶解度，溶解速率，化学物理稳定性，熔点，颜色，可滤性，密度，流动性等方面可能存在显著差异。对药物多晶型的研究，有利于寻找具有更好的理化特性或具有更好加工形式的药物形态，从而拓宽药物的制剂形式，开发有利用价值的制剂形式，方便各类人群使用。
比克替拉韦钠是一种新的HIV整合酶抑制剂，也是治疗HIV的重磅产品。因此，对其进行多晶型的开发，发现稳定，具有药用价值的晶型，对于其制剂的开发，具有重要意义。
因此，本发明的目的在于提供理化性质稳定，纯度高，重现性好，生产工艺简单且适合工业化生产的比克替拉韦钠的新晶型：晶型L1和晶型L2.
比克替拉韦钠的晶型L1及其制备方法
本发明提供了一种比克替拉韦钠的晶型L1。
优选的，所述比克替拉韦钠晶型L1的X-射线粉末衍射图谱的2θ在5.3±0.2°、6.8±0.2°、10.2±0.2°、16.1±0.2°、17.1±0.2°、20.6±0.2°、22.5±0.2°、23.2±0.2°和25.7±0.2°中的至少5处(较佳地，至少7处)有特征峰。
进一步优选的，所述比克替拉韦钠晶型L1的X-射线粉末衍射图具有至少5个(较佳地所有)下表所示特征峰：
Figure PCTCN2021095237-appb-000004
Figure PCTCN2021095237-appb-000005
更进一步优选的，所述比克替拉韦钠晶型L1的X-射线粉末衍射图具有下表所示特征峰：
2-θ d(晶面间距) I％(相对峰强)
5.329 16.5683 100
6.79 13.0072 24.2
10.217 8.6507 7.7
11.992 7.3742 2.9
12.611 7.0136 4.9
13.704 6.4566 7.6
16.058 5.515 16.1
17.152 5.1653 6.6
18.409 4.8154 3.4
19.054 4.6538 6
19.911 4.4554 5.9
20.592 4.3097 10.9
22.523 3.9443 11.1
23.241 3.824 7.9
25.675 3.4668 11.8
26.592 3.3493 3.8
28.399 3.1401 1.9
29.584 3.0171 4.7
32.098 2.7863 2.6
进一步优选的，所述晶型L1的X-射线粉末衍射图谱基本与图1一致。
进一步优选的，所述L1晶型的差示扫描量热法谱图在350～380℃范围内有两个吸热峰。
进一步优选的，所述晶型L1的差式扫描量热图谱第一个吸热峰在366±5℃(较佳地，366±2℃，更佳地366±1℃)处，第二个吸热峰在375±5℃(较佳地，375±2℃)。
进一步优选的，所述晶型L1的差式扫描量热图谱基本如图2所示。
进一步优选的，所述晶型L1的TGA图基本如图3所示。
本发明还提供了一种制备所述晶型L1的方法，包括以下步骤：
将比克替拉韦溶清于有机溶剂中，滴加氢氧化钠的水溶液，搅拌析晶；
将得到的湿品在20～40℃条件下真空干燥，收集固体
其中，所有有机溶剂选自乙二醇二甲醚、甲基异丁基酮中的一种或多种；所述氢氧化钠水溶液质量分数为0.5-50％，优选5％～30％，更优选10％～20％。
本发明还提供了一种制备所述晶型L1的方法，包括以下步骤：将晶型L2在20～40℃条件下真空干燥，收集固体。
比克替拉韦钠的晶型L2及其制备方法
本发明还提供了一种比克替拉韦钠的晶型L2。
优选的，所述比克替拉韦钠的晶型L2的X-射线粉末衍射图谱的2θ在4.8±0.2°、5.3±0.2°、6.7±0.2°、11.4±0.2°、12.5±0.2°、13.7±0.2°、14.4±0.2°、16.1±0.2°、17.1±0.2°、20.9±0.2°、22.8±0.2°、25.6±0.2°和28.8±0.2°中的至少5处(较佳地，至少7处，更佳地，至少10处)有特征峰。
进一步优选地，所述比克替拉韦钠晶型L2的X-射线粉末衍射图具有至少5个较佳地，至少7个，更佳地至少10个，最佳地，所有)下表所示特征峰：
2-θ I％(相对峰强)
4.823±0.1 100
5.292±0.1 35.6±5
6.677±0.1 12.7±5
11.425±0.1 4.5±5
12.537±0.1 15.1±5
13.682±0.1 8.6±5
14.482±0.1 4.6±5
16.133±0.1 24.6±5
17.089±0.1 6.9±5
20.946±0.1 4.6±5
22.813±0.1 14.2±5
25.539±0.1 12.3±5
28.812±0.1 7.5±5
更进一步优选的，所述比克替拉韦钠晶型L2的X-射线粉末衍射图具有下表所 示特征峰中：
2-θ d(晶面间距) I％(相对峰强)
4.823 18.3079 100
5.292 16.6854 35.6
6.677 13.2266 12.7
9.694 9.1162 2.1
10.202 8.6635 1.9
11.425 7.7389 4.5
12.537 7.0548 15.1
13.682 6.4668 8.6
14.482 6.1113 4.6
16.133 5.4894 24.6
17.089 5.1844 6.9
17.98 4.9293 5.9
19.266 4.6032 5.1
20.318 4.3672 3.7
20.946 4.2375 4.6
22.171 4.0062 2.8
22.813 3.8949 14.2
23.357 3.8054 5.7
23.975 3.7086 3.5
24.486 3.6324 4.9
25.539 3.485 12.3
26.396 3.3737 2.5
27.363 3.2566 2.6
28.812 3.0961 7.5
32.117 2.7846 2.7
进一步优选的，所述晶型L2的X-射线粉末衍射图谱基本与图4一致。
进一步优选的，所述L2晶型的差示扫描量热法谱图在388±5℃(较佳地，388±2℃)处有吸热峰。
进一步优选的，所述晶型L2的差式扫描量热图谱基本如图5所示。
进一步优选的，所述晶型L2的TGA图基本如图6所示。
本发明还提供了所述晶型L2的制备方法，包括以下步骤：将比克替拉韦溶清于有机溶剂中，滴加氢氧化钠水溶液，搅拌析晶，过滤。其中所述有机溶剂选择 乙二醇二甲醚、甲基异丁基酮中的一种或多种。
药物组合物和施用方法
由于本发明的晶型(如晶型L1或晶型L2)具有优异的对人类免疫缺陷病毒(HIV)整合酶的抑制能力，因此本发明的比克替拉韦钠的晶型以及含有本发明的晶型为主要活性成分的药物组合物可用于治疗和/或预防人类免疫缺陷病毒1型引起的疾病，或者本发明的晶型)可用于制备抗HIV药物。因此，本发明的晶型或由本发明的晶型(如晶型L1或晶型L2)可用于制备抗HIV药物。比克替拉韦可以通过本领域常用方法制得。本发明的药物组合物包含安全有效量范围内的本发明的晶型(晶型L1)或由本发明晶型(晶型L2)制得的比克替拉韦钠的晶型L1，及药学上可以接受的赋形剂或载体。
其中，“安全有效量”指的是：化合物(或晶型)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明的晶型/剂，更佳地，含有10-200mg本发明的晶型/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2021095237-appb-000006
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如， 琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明的主要优点包括：
(a)本发明的晶型(如晶型L1和晶型L2)是药用形式的晶型，且晶型稳定易于后续制剂开发。
(b)本发明的晶型L1易于制备，易于工业化生产。制备本发明的晶型L1无需冻干或喷雾对设备要求低，且易于形成仅需较短时间(如3-6h)的真空干燥，而且能以收率高获得。
(c)本发明的晶型(如晶型L1和晶型L2)具有优异的稳定性。特别地，现有技术的比克替拉韦钠晶型(即WO2015196116A1的晶型I)在溶剂打浆条件下将转化为本申请的晶型L2，因此可见本申请的晶型具有显著优于比克替拉韦钠晶型的稳定性。此外，本申请的晶型还具有优异的储存稳定性，长期储存下本发明的晶型纯度和晶型保持稳定。
(d)本发明的晶型L1的纯度高(＞99.9％)，无溶剂残留，满足原料药的质量标准。
(e)本发明的晶型(如晶型L1和晶型L2)为球形晶习，而现有技术中的晶型I为极小的片状晶习，因此本申请的晶型具有更优异的流动性，从而可以使得制得的药剂具有更好的可压片性。具体地，晶体的流动性影响药物压片的适应性，流动性越好，可避免压片过程中，因机器震动或搅拌不均匀带来的粉末分层，改善物料分布和混合的均匀度，减小各片剂之间的差异，提高各片剂重量，含量，均匀度方面的稳定性。
(f)本发明的晶型L2十分适于制备本发明的晶型L1。本发明的晶型L2仅需真空干燥3～6小时就能获得本发明的晶型L1。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另有说明，所述的试验方法通常按照常规条件或制造厂商建议的条件实施，所示的原料、试剂均可通过市售购买的方式获得。
测试方法
除非另外说明，实施例中所制得固体按照下述方法测试：
X-射线粉末衍射的参数如下(XRPD)：
X-射线粉末衍射仪器：Brucker D8 advance X-射线粉末衍射仪。
X-射线反射参数：铜靶
Figure PCTCN2021095237-appb-000007
在室温条件下扫描：
电压：40千伏特(kv)，
电流：40毫安培(mA)，
扫描模式：连续，
扫描范围：2.0～35.0度，
步长：0.020°，
每步测量时间:0.1秒/步；
差示扫描量热(DSC)分析方法参数如下：
差示扫描量热(DSC)仪器：TA Q2000型。
温度范围：室温～400℃，
扫描速度：10℃/分钟，
保护气体：氮气，50毫升/分钟；
热重分析(TGA)参数如下：
热重分析(TGA)仪器：TGA55型。
温度范围：室温～380℃
扫描速度：10℃/分钟
保护气体：氮气，60毫升/分钟
实施例1
称取2.0g比克替拉韦加入到20ml乙二醇二甲醚中室温溶清，然后再滴加10％氢氧化钠水溶液2ml，搅拌析晶，过滤得到比克替拉韦钠固体1，将固体1置于室温(20-25℃)条件下真空干燥箱中干燥5～6小时，得到比克替拉韦钠固体2，纯度99.95％，收率96％。
经测试，所得的固体1的XRPD图、DSC图及TGA图分别如图4、5和6所示，为晶型L2；所得的固体2的XRPD图、DSC图及TGA图分别如图1、2和3所示，为晶型L1。
实施例2
称取2g比克替拉韦加入到20ml乙二醇二甲醚中室温溶清，然后再滴加10％氢氧化钠水溶液4ml，搅拌析晶，过滤得到比克替拉韦钠固体1，将固体1置于室温 (20-25℃)条件下真空干燥箱中干燥1～2小时，然后再升温到35～40℃干燥2～3小时，得到比克替拉韦钠固体2，纯度99.94％，收率95.8％。
经测试，固体1的XRPD图、DSC图及TGA图基本与实施例1的固体1一致，为晶型L2；固体1的XRPD图、DSC图及TGA图基本与实施例1的固体2一致，为晶型L1。
实施例3
称取5g比克替拉韦加入到50ml甲基异丁基甲酮中加热溶清，冷却至室温(20-25℃)后，再滴加10％氢氧化钠水溶液10ml，搅拌析晶，过滤得到比克替拉韦钠固体1，将固体1置于30～35℃条件下真空干燥箱中干燥5～6小时，得到比克替拉韦钠固体2，纯度99.95％，收率96.3％。
经测试，固体1的XRPD图、DSC图及TGA图基本与实施例1的固体1一致，为晶型L2；固体1的XRPD图、DSC图及TGA图基本与实施例1的固体2一致，为晶型L1。
对比例1
参考专利WO2015196116A1实施例方法，制备比克替拉韦钠晶型I，其XRPD如图7所示。
实施例4
将按对比例1方法制备的比克替拉韦钠晶型I 5.0g(纯度99.3％)，悬浮在50ml乙二醇二甲醚溶剂中，-5～5℃搅拌20～30小时，过滤，得到比克替拉韦钠固体1，将固体1置于20～25℃真空干燥箱中干燥5～6小时，得到比克替拉韦钠固体2，纯度99.4％，收率96.1％。
经测试，固体1的XRPD图、DSC图及TGA图基本与实施例1的固体1一致，为晶型L2；固体1的XRPD图、DSC图及TGA图基本与实施例1的固体2一致，为晶型L1。
测试例1
(1)影响因素试验
Figure PCTCN2021095237-appb-000008
Figure PCTCN2021095237-appb-000009
(2)加速稳定性试验(40℃±2℃、75％RH±5％RH，)
Figure PCTCN2021095237-appb-000010
(3)长期稳定性试验
相对湿度约60±5％条件下市售包装(两层PE袋，一层铝箔袋)，分别于第0个月、第3个月、第6个月、第9个月、第12个月、第18个月和第24个月取样，检测样品晶型及化学纯度；
Figure PCTCN2021095237-appb-000011
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如式I所示的比克替拉韦钠的晶型L1，其特征在于，
    Figure PCTCN2021095237-appb-100001
    所述晶型L1的X-射线粉末衍射图谱在5.3±0.2°、6.8±0.2°、16.1±0.2°、20.6±0.2°和25.7±0.2°的2θ处具有特征峰。
  2. 如权利要求1所述晶型L1，其特征在于，所述晶型L1的X-射线粉末衍射图谱基本如图1所示。
  3. 如权利要求1所述的晶型L1，其特征在于，所述L1晶型的差示扫描量热法谱图在350～380℃范围内有两个吸热峰。
  4. 如权利要求3所述晶型L1，其特征在于，所述晶型L1的差式扫描量热图谱第一个吸热峰在366±5℃且第二个吸热峰在375±5℃。
  5. 一种如式I所示的比克替拉韦钠的晶型L2，其特征在于，
    Figure PCTCN2021095237-appb-100002
    所述晶型L2的X-射线粉末衍射图谱在4.8±0.2°、6.7±0.2°、12.5±0.2°、22.8±0.2°和25.6±0.2°的2θ处具有特征峰。
  6. 一种制备如权利要求1所述晶型L1的方法，其特征在于，所述的方法为方法1、方法2或方法3
    其中，
    所述方法1包括步骤：
    将晶型L2在干燥温度下干燥，从而得到晶型L1；
    所述方法2包括步骤：
    (2.1)提供比克替拉韦于第一有机溶剂中的溶液；和
    (2.2)向步骤(1.1)的溶液中加入含钠化合物，析晶，收集析出固体；和
    (2.3)将步骤(1.2)得到的固体在干燥温度下干燥，从而得到晶型L1；
    所述方法3包括步骤：
    (3.1)提供比克替拉韦钠于第二有机溶剂中的混合物；和
    (3.2)将步骤(3.1)混合物在搅拌温度下搅拌，收集所述混合中固体；和
    (3.3)将步骤(3.2)得到的固体在干燥温度下干燥，从而得到晶型L1。
  7. 如权利要求6所述的方法，其特征在于，所述第一有机溶剂和第二有机溶剂各自独立地选自下组：乙二醇二甲醚、甲基异丁基酮，或其组合。
  8. 一种制备如权利要求5所述的晶型L2的方法，其特征在于，所述的方法为方法A或方法B；
    其中，
    所述方法A包括步骤：
    (A1)提供比克替拉韦于第一有机溶剂中的溶液；和
    (A2)向步骤(A1)的溶液中加入含钠化合物，析晶，收集析出固体，从而得到晶型L2；
    所述方法B包括步骤：
    (B1)提供比克替拉韦钠于第二有机溶剂中的混合物；和
    (B2)将步骤(B1)混合物在搅拌温度下搅拌，收集所述混合中固体，从而得到晶型L2。
  9. 一种药物组合物，其特征在于，所述的药物组合物包括
    (i)如权利要求1所述的晶型L1，以及(ii)药学上可接受的载体。
  10. 如权利要求1所述晶型L1和如权利要求5所述晶型L2在制备用于治疗抗HIV药物中的用途。
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