WO2015158202A1 - 一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途 - Google Patents

一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途 Download PDF

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WO2015158202A1
WO2015158202A1 PCT/CN2015/075178 CN2015075178W WO2015158202A1 WO 2015158202 A1 WO2015158202 A1 WO 2015158202A1 CN 2015075178 W CN2015075178 W CN 2015075178W WO 2015158202 A1 WO2015158202 A1 WO 2015158202A1
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infection
pyridin
fluorophenyl
methyltetrazol
dihydrogen phosphate
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PCT/CN2015/075178
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English (en)
French (fr)
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朱涛
盛晓霞
盛晓红
贾强
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杭州普晒医药科技有限公司
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Priority to CN201580000670.6A priority Critical patent/CN105229001B/zh
Priority to US15/119,490 priority patent/US10189870B2/en
Publication of WO2015158202A1 publication Critical patent/WO2015158202A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to the field of medicinal chemical crystallization technology.
  • the present invention relates to a crystalline form of an oxazolidinone antibiotic TR-701FA, a process for its preparation, a pharmaceutical composition and use.
  • TR-701FA is a novel oxazolidinone derivative developed by Trius Pharmaceuticals. It has entered Phase III clinical trials and has shown excellent antibacterial activity and low toxicity against a broad spectrum of bacteria.
  • the chemical name of TR-701FA is (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)-5-hydroxymethyl Oxazolidine-2-one dihydrogen phosphate, the chemical structural formula of which is shown below;
  • TR-701FA is a prodrug and is the active ingredient Tedizolid Phosphate.
  • Tedizolid is also known as TR-700 or torezolid, and its chemical name is (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)-3-fluorophenyl)- 5-hydroxymethyloxazolidin-2-one, whose chemical structural formula is as follows:
  • TR-701FA can be converted into the active metabolite Tedizolid by the esterase and phosphatase in the blood in the body to exert an antibacterial effect.
  • TR-701FA has more excellent solubility than Tedizolid and is stable in water or acidic solution, and thus has been developed for injection or oral preparation.
  • Patent document WO2005/058886A1 discloses Tedizolid, TR-701FA and a preparation method thereof.
  • the patent document WO 2010/091131 A1 discloses a crystalline TR-701FA (referred to as "crystal form I" in the present invention for convenience) and a preparation method thereof, and a nuclear magnetic resonance spectrum, an X-ray powder diffraction pattern, Form I was characterized by Fourier-Raman spectroscopy, infrared spectroscopy, differential scanning calorimetry and dynamic moisture adsorption.
  • TR-701FA Form I has the disadvantages of low crystallinity, low solubility in water and moisture absorption. In order to meet the stringent requirements of drug development for the crystalline form of active pharmaceutical ingredients, it is of great practical significance to develop a new crystalline form of TR-701FA with more advantageous properties.
  • the novel crystal form of the invention should have one or more improved properties, such as: good stability; good solubility; fast dissolution rate; high crystallinity; not hygroscopic; easy to purify and handle High chemical purity; low residual solvent; low toxicity; good particle morphology; suitable formulation processability such as good fluidity, favorable powder viscosity, tightness and compactability; improved formulation appearance; improved bioavailability Degree, preparation efficacy; prolong the shelf life of the preparation; suitable for the application of new dosage forms, especially for higher crystallinity and better solubility.
  • the present invention provides Form II of TR-701FA having the structural formula shown below (for convenience, it is referred to as "Form II" in the present invention):
  • the X-ray powder diffraction pattern of the Form II expressed in terms of 2 ⁇ angle has the following characteristic peaks: 10.5 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.3 ⁇ 0.2°, 21.0 ⁇ 0.2 ° and 26.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form II in terms of 2 ⁇ angle has the following characteristic peaks: 10.5 ⁇ 0.2°, 12.1 ⁇ 0.2°, 13.9 ⁇ 0.2°, 15.7 ⁇ 0.2°. 16.5 ⁇ 0.2°, 17.3 ⁇ 0.2°, 20.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, 23.9 ⁇ 0.2°, 24.5 ⁇ 0.2°, 26.3 ⁇ 0.2° and 27.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II in terms of 2 theta angle has the following characteristic peaks and their relative intensities:
  • a typical example of the Form II has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the polarized light microscopy (PLM) pattern of Form II is shown as a plate crystal.
  • thermogravimetric analysis (TGA) pattern of Form II showed a weight loss of about 0.41% before 150 ° C, an anhydrate, and a decomposition temperature of about 226 ° C.
  • the differential thermal analysis (DSC) pattern of Form II showed a melting temperature of about 233 °C.
  • the isothermal adsorption curve of Form II shows a weight change of about 0.49% in the range of 20% to 80% relative humidity.
  • the present invention provides a process for the preparation of Form II of the TR-701FA comprising the steps of dissolving TR-701FA in a solvent selected from the group consisting of amines, amides or mixtures thereof, and the resulting solution Volatilization to dryness gave the crystalline form II of the TR-701FA.
  • the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, pyridine or mixtures thereof, more preferably N,N-dimethylformamide.
  • the volatilization temperature is from 25 ° C to 80 ° C, more preferably from 60 ° C to 80 ° C.
  • the specific operation of "volatilization” is: the reaction flask containing the solution is opened at a corresponding temperature for volatilization and crystallization.
  • the starting material TR-701FA may be a known compound or crystal form of TR-701FA, for example, but not limited to, the TR-701FA compound obtained by the preparation method of the example 58 of the patent document WO2005058886A1.
  • Form II of the present invention has better solubility in water than known Form I.
  • the crystalline form II of the present invention has a high degree of crystallinity.
  • the crystal form II of the present invention is stored at a temperature of 25 ° C and a relative humidity of 60% for 6 months, and the purity and crystal form remain unchanged; after being stored at 80 ° C - 6000 l x of high temperature light for 10 days, the purity thereof is maintained. Both the decrease and the increase in the maximum single impurity content are significantly lower than the data for the known Form I. Therefore, the crystalline form II of the present invention has high chemical stability and crystal form stability.
  • Form II of the present invention is more suitable for pharmaceutical formulation applications than known Form I. It can have better particle flowability and better subsequent processing characteristics, simplify the post-treatment process of the drug substance (such as filtration operation), improve the uniformity of the active ingredient caused by fluidity in the production of the preparation, and is beneficial to the production of the preparation. Accurate metering, improved efficiency and stable quality; the formulation has higher dissolution and bioavailability, better antibacterial effect; good stability of active ingredients, better able to resist temperature and humidity during drug manufacturing and / or storage Problems such as uneven content, decreased purity, and reduced processability of the formulation caused by factors such as light, reduce the risk and safety risks of the resulting reduction, and are also conducive to later transportation and storage.
  • amorphous substance in the present invention for convenience
  • preparation method thereof an amorphous substance of TR-701FA
  • a typical example of the amorphous material has an X-ray powder diffraction (XRPD) pattern as shown in Figure 9, showing no characteristic peaks.
  • XRPD X-ray powder diffraction
  • the differential thermal analysis (DSC) pattern of the amorphous material showed a broad exothermic peak at 140-190 ° C and a melting temperature of about 226 ° C.
  • the method for producing the amorphous substance comprises the steps of dissolving TR-701FA in a mixed solvent of water and trifluoroethanol, and concentrating the resulting solution to dryness under reduced pressure to obtain the amorphous substance.
  • the volume ratio of water to trifluoroethanol in the mixed solvent of water and trifluoroethanol is from 1:2 to 1:5, preferably 1:4.
  • the concentration temperature is from 40 ° C to 60 ° C, preferably 50 ° C.
  • the specific operation of the "concentration under reduced pressure” is: placing the container containing the solution in a rotary evaporator at a temperature of from room temperature to the boiling temperature of the solvent, less than atmospheric pressure (preferably, the pressure is less than 0.08 MPa), to 10
  • the rotation speed of ⁇ 180 rpm (preferably 50 to 100 rpm) is used to remove the solvent.
  • the starting material TR-701FA may be a known compound or crystal form of TR-701FA, for example, including but not limited to the TR-701FA compound obtained by the preparation method of the example 58 of the patent document WO2005/058886A1.
  • room temperature means 10-30 °C.
  • crystalline means confirmed by the X-ray powder diffraction pattern characterization shown.
  • Field It is well known to the skilled person that the experimental error therein depends on the instrument conditions, sample preparation and sample purity. The map will usually change with the instrument conditions: the relative intensity of the peak may vary with the experimental conditions, so the order of peak intensities cannot be the sole or decisive factor; the experimental error of the peak angle should also be taken into account, usually ⁇ 0.2 The error of °; the influence of experimental factors such as the height of the sample will cause the overall angle of the peak to shift, usually allowing a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • the "single crystal form” refers to a single crystal form detected by X-ray powder diffraction.
  • Form II of the present invention is pure, unitary, and substantially free of any other crystalline or amorphous form.
  • substantially free when used to refer to a new crystalline form means that the other crystalline form or other amorphous form contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight, especially Refers to less than 5% by weight, especially less than 1% by weight.
  • the "anhydrous" means that the sample contains not more than 1.5% by weight, or not more than 1.0% by weight, of water as measured by TGA.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the TR-701FA Form II of the present invention or prepared by the preparation method of the present invention.
  • TR-701FA Form II and at least one pharmaceutically acceptable carrier or adjuvant.
  • the pharmaceutical composition may also comprise a pharmaceutically acceptable salt of TR-701FA, other crystalline forms or amorphous forms.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
  • the pharmaceutical composition may be solid, semi-solid or liquid, and may be prepared into a suitable dosage form such as a solid dosage form including tablets, granules, powders, pills, powders and capsules; liquid dosage forms including solutions, syrups, Suspensions, dispersing agents and emulsions; injectable preparations, including solutions, dispersions, solid forms suitable for dissolving or suspending in liquids prior to injection, such as lyophilizates.
  • the formulation may be adapted for rapid release, sustained release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • Routes of administration include oral administration, feeding through the stomach, feeding through the duodenum, intravenous, intra-arterial, intramuscular, subcutaneous, intraosseous, intradermal, intravaginal, intrarectal, intraperitoneal, transdermal, intranasal Eye drops, ear drops, etc.
  • a pharmaceutically acceptable carrier or adjuvant in the pharmaceutical composition includes but is not limited to: a diluent such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, none Water calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sucrose, etc.; binders, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, Polyethylene glycol, copolyvidone, etc.; disintegrating agents, such as starch, sodium carboxymethyl starch, sodium starch glycolate, pre-glue Starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; A flow agent such as colloidal silica or the
  • compositions include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.
  • carriers or adjuvants include sugars such as lactose, sucrose, mannitol or sorbitol, cellulose products such as corn starch, wheat starch, gelatin, methylcellulose, hydroxypropyl methylcellulose, Sodium hydroxymethylcellulose and polyvinylpyrrolidone may also be added with a lubricant such as magnesium stearate, a disintegrating agent such as cross-linked polyvinylpyrrolidone, and further coated with a tablet core, for example, a sugar-coated layer; an oral capsule
  • useful carriers or adjuvants include lactose, high and low molecular weight polyethylene glycols and dry corn starch; in the case of gelatin capsules, powder carriers such as lactose, starch, cellulose
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the TR-701FA Form II of the present invention is mixed with one or more pharmaceutically acceptable carriers or adjuvants, optionally with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • Liquid preparations can be prepared by processes such as dissolution, dispersion, and the like.
  • the present invention provides the use of the TR-701FA Form II of the present invention or the TR-701FA Form II obtained by the preparation method of the present invention for the preparation of a medicament for treating and/or preventing a microbial infectious disease.
  • the present invention provides a method for treating and/or preventing a microbial infectious disease, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the TR-701FA Form II of the present invention or obtained by the preparation method of the present invention.
  • TR-701FA Form II or a pharmaceutical composition thereof The patient refers to a mammal such as a human. It will be apparent to those skilled in the art that the dosage administered and the particular mode of administration will vary depending on factors such as the age, weight, diet, degree of infection, and the condition of the drug being used at the same time.
  • the therapeutically effective amount means effective prevention and alleviation. Or an amount that ameliorates the symptoms of the disease or prolongs the survival of the subject.
  • the daily oral dose of the active ingredient is approximately 0.1 mg to 2000 mg, preferably about 1 mg to 500 mg, of the active ingredient is administered intravenously, subcutaneously or intramuscularly at a dose of from about 0.01 mg to 100 mg, preferably from about 0.1 mg to 60 mg.
  • the aforementioned microbial infections include, but are not limited to, skin infections, pneumonia, infection after viral infection, abdominal infection, urinary tract infection, bacteremia, septicemia, endocarditis, atrioventricular septal infection, vascular infection, meningitis , surgical prevention, peritoneal infection, bone infection, joint infection, methicillin-resistant Staphylococcus aureus infection, vancomycin-resistant enterococci infection, linezolid-resistant organism infection, and tuberculosis.
  • Figure 1 is an XRPD pattern of Form II of the present invention.
  • Figure 2 is a PLM map of Form II of the present invention.
  • Figure 3 is a DSC chart of Form II of the present invention.
  • Figure 4 is a TGA map of Form II of the present invention.
  • Figure 5 is an isotherm adsorption curve of Form II of the present invention.
  • Figure 6 is an XRPD pattern of a known Form I prepared in accordance with WO2005/058886A1.
  • Figure 7 is a PLM spectrum of a known Form I prepared in accordance with WO2005/058886A1.
  • Figure 8 is an isotherm adsorption curve of a known Form I prepared in accordance with WO2005/058886A1.
  • Figure 9 is an XRPD pattern of an amorphous material of the present invention.
  • Figure 10 is a DSC chart of an amorphous form of the present invention.
  • X-ray powder diffraction (XRPD): The instrument used was a Bruker D8 Advance diffractometer with a KaX-ray with a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer at 40 kV and 40 mA, a Mo color Instrument, Lynxeye detector. The instrument is calibrated with silicon carbide before use. The acquisition software is Diffrac Plus XRD Commander. The sample is tested at room temperature and the sample to be tested is placed on a non-reflecting plate. The detailed detection conditions are as follows, the angle range is 3 - 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Polarized light microscopy (PLM) spectra were taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on a glass slide and add a small amount of mineral oil to better Disperse the powder sample, cover the coverslip, then place the sample on the stage, select the appropriate magnification to observe the shape of the sample and take a picture.
  • PLM Polarized light microscopy
  • DSC Differential Thermal Analysis
  • Thermogravimetric Analysis (TGA): The data was taken from the TA Instruments Q500TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 5 to 15 mg is usually placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C under the protection of 40 mL/min dry N 2 at a heating rate of 10 ° C/min by means of segmented high-resolution detection.
  • Isothermal adsorption curve (DVS): The data was taken from the TA Instruments Q5000TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. A sample of 1 to 10 mg is usually placed in a platinum crucible, and the TA software records the change in weight of the sample during a change in relative humidity from 0% to 80% to 0%. Depending on the specifics of the sample, different adsorption and desorption steps are also applied to the sample.
  • HPLC High Performance Liquid Chromatography
  • TR-701FA is obtained by the preparation method of the example 58 of the patent document WO2005/058886A1, and the specific operation is as follows:
  • the TR-701FA obtained in Preparation Example 1 is the TR-701FA crystal described in the patent document WO2010/091131A1, that is, the TR-701FA crystal form I.
  • the XRPD pattern is shown in Fig. 6; the PLM spectrum is shown in Fig. 7, which shows that it is crystalline, and the particles are small and the crystallinity is low; the isothermal adsorption curve is shown in Fig. 8, which shows a relative humidity of 20% to 80%.
  • the weight change in the range is approximately 1.56%.
  • the XRPD pattern of the product is shown in Figure 1 and is shown as TR-701FA Form II.
  • the PLM spectrum of the product is shown in Figure 2 and is shown as a plate crystal.
  • the DSC spectrum of the product is shown in Figure 3 and shows a melting temperature of about 233 °C.
  • the TGA profile of the product is shown in Figure 4. It shows that the weight loss is about 0.41% before 150 ° C, which is an anhydrate, and the decomposition temperature is about 226 ° C.
  • the isothermal adsorption curve of the product is shown in Figure 5, which shows that the 20% RH to 80% RH weight change is 0.49%.
  • TR-701FA 100 mg was taken, dissolved in 8 mL of N,N-dimethylformamide at 60 ° C, kept at a constant temperature for 10 min, and then evaporated to dryness at 60 ° C to obtain 95 mg of TR-701FA Form II, yield 95.0%.
  • TR-701FA 150 mg was taken, dissolved in 8 mL of pyridine at 25 ° C, filtered, and the filtrate was evaporated to dryness at 25 ° C to obtain 142 mg of TR-701FA Form II in a yield of 94.7%.
  • the samples prepared in Examples 2 and 3 had the same or similar XRPD patterns, PLM patterns, DSC patterns, and TGA patterns (not shown) as the samples of Example 1.
  • the samples of Examples 2 and 3 are identical to the samples of Example 1 in the same crystalline form.
  • TR-701FA 100 mg was taken, dissolved in 100 mL of a mixed solvent of water and trifluoroethanol in a volume ratio of 1:4 at 25 ° C, filtered, and the filtrate was concentrated at 40 ° C under reduced pressure and evaporated to dryness to give 52 mg of TR-701FA.
  • the final product had a yield of 52%.
  • the amorphous material has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • XRPD X-ray powder diffraction
  • the differential thermal analysis (DSC) pattern of the amorphous material is shown in Figure 10: it has a broad exothermic peak at 140-190 ° C and a melting temperature of about 226 ° C.
  • An immediate release tablet containing the crystalline form II of TR-701FA of the present invention as a pharmaceutically active ingredient was prepared in a form containing 200 mg of TR-701FA.
  • Table 1 shows the formulation of the amounts of the ingredients in the production of the instant release tablet. Table 1 includes all ingredients used in the manufacture of the drug, whether or not the ingredient is included in the final product, wherein the purified water is removed during the manufacturing process.
  • TR-701FA Form II, mannitol, microcrystalline cellulose and crospovidone were sieved and mixed.
  • step 5 Continuously apply the film of the core of step 4 with an aqueous solution of the Opadry II yellow coating material until the increase 3.4% of the target weight.
  • a capsule containing the crystalline form II of TR-701FA of the present invention as a pharmaceutically active ingredient was prepared in a form of 182 mg of TR-701FA.
  • Table 2 shows the formulation of the amounts of the ingredients in the capsule production. Table 2 includes all ingredients used in the manufacture of the drug, whether or not the ingredient is included in the final product, wherein the purified water is removed during the manufacturing process.
  • TR-701FA Form II, microcrystalline cellulose and crospovidone were sieved and mixed.
  • the magnesium stearate is sieved and mixed with the dry granules in the step 3, and the mixture is filled on the capsule filling machine for capsule filling.
  • the TR-701FA Form I prepared in Preparation Example 1 and the TR-701FA Form II of the present invention were subjected to a stability test under high temperature illumination for 10 days.
  • the high temperature condition is 80 ° C, and the illumination condition is 6000 lx illuminance.
  • the HPLC purity and the maximum single impurity content of the compound before and after the standing were examined, and the results are shown in Table 3.
  • the purity of TR-701FA crystal form I is lowered under the condition of high temperature light for 10 days.
  • the decrease was 2.1%
  • the maximum single impurity content was increased by 1.2%
  • the purity of the TR-701FA crystal form II of the present invention was substantially unchanged, and the maximum single impurity content was only increased by 0.1%. Therefore, the stability of the TR-701FA Form II of the present invention under high temperature illumination is significantly better than the known TR-701FA Form I.

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Abstract

本发明涉及一种噁唑烷酮类抗生素的新晶型，所述新晶型在溶解度、吸湿性、结晶度和稳定性方面具有优势。本发明还涉及所述新晶型的制备方法、其药物组合物及其用于制备治疗和/或预防微生物感染疾病的药物中的用途。

Description

一种噁唑烷酮类抗生素的晶型及制备方法、组合物和用途 技术领域
本发明涉及药物化学结晶技术领域。具体而言，本发明涉及一种噁唑烷酮类抗生素TR-701FA的晶型及其制备方法、药物组合物和用途。
背景技术
TR-701FA是Trius制药公司开发的一种新型噁唑烷酮类衍生物，已进入III期临床试验，显示对广谱菌优异的抗菌活性和低毒性。TR-701FA的化学名称为(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯，其化学结构式如下所示；
Figure PCTCN2015075178-appb-000001
TR-701FA是一种前体药物，是活性成分Tedizolid的二氢磷酸酯(Tedizolid Phosphate)。Tedizolid又名TR-700或torezolid，化学名称为(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮，其化学结构式如下所示：
Figure PCTCN2015075178-appb-000002
TR-701FA在体内通过血液中的酯酶和磷酸酯酶可转化成活性代谢物Tedizolid，发挥抗菌作用。TR-701FA比Tedizolid具有更优异的溶解性，在水或酸性溶液中稳定，由此被开发用于注射或口服的制剂。
专利文献WO2005/058886A1公开了Tedizolid、TR-701FA及其制备方法。
专利文献WO2010/091131A1公开了结晶态的TR-701FA(为了方便，在本发明中称其为“晶型I”)及其制备方法，并通过核磁共振氢谱图、X-射线粉末衍射图、傅立叶-拉曼光谱图、红外光谱图、差示扫描量热分析图和动态湿气吸附图对晶型I进行了表征。
本发明人研究发现，按照WO2010/091131A1实施例1描述方法制备得到 的TR-701FA晶型I具有结晶度低、在水中溶解度低和易吸湿的缺点。为了满足药物开发对药物活性成分晶型的严苛要求，开发具有更多优势性能的TR-701FA新晶型具有十分重要的现实意义。
发明内容
针对现有技术的不足，本发明的目的是提供TR-701FA的新晶型，并提供其制备方法、药物组合物和用途。与已知晶型相比，本发明新晶型应具有一种或多种改进的特性，例如：稳定性好；溶解性好；溶出速度快；结晶度高；不易吸湿性；易于纯化和处理；化学纯度高；低残留溶剂；低毒性；颗粒形貌佳；适宜的制剂可加工性例如流动性好、有利的粉体粘度、紧密度和可压实性；改进制剂表观；改善生物利用度、制剂药效；延长制剂保存期；适合制剂新剂型应用等方面，特别是应具备更高的结晶度和更优良的溶解性能。
根据本发明的目的，本发明提供结构式如下所示的TR-701FA的晶型II(为了方便，在本发明中称其为“晶型II”)：
Figure PCTCN2015075178-appb-000003
使用Cu-Kα辐射，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.5±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、21.0±0.2°和26.3±0.2°。
在本发明优选的一个实施方案中，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.5±0.2°、12.1±0.2°、13.9±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、20.1±0.2°、21.0±0.2°、23.9±0.2°、24.5±0.2°、26.3±0.2°和27.6±0.2°。
在本发明更优选的一个实施方案中，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2015075178-appb-000004
Figure PCTCN2015075178-appb-000005
非限制性地，所述晶型II的一个典型实例具有如图1所示的X-射线粉末衍射(XRPD)图谱。
所述晶型II的偏正光显微镜(PLM)图谱显示为片状晶体。
所述晶型II的热重分析(TGA)图谱显示：在150℃之前失重约0.41％，为无水物，分解温度约为226℃。
所述晶型II的差热分析(DSC)图谱显示：熔融温度约为233℃。
所述晶型II的等温吸附曲线显示：在20％～80％相对湿度范围内的重量变化约为0.49％。
根据本发明的目的，本发明提供所述TR-701FA的晶型II的制备方法，包括以下步骤：将TR-701FA溶解于溶剂中，所述溶剂选自胺、酰胺或其混合物，将所得溶液挥发至干，得到所述TR-701FA的晶型II。
优选地，所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶或其混合物，更优选为N,N-二甲基甲酰胺。
优选地，所述挥发温度为25℃～80℃，更优选为60℃～80℃。“挥发”的具体操作是：将装有溶液的反应瓶在相应温度下敞口进行挥发结晶。
上述晶型II的制备方法中：起始原料TR-701FA可以是TR-701FA的已知的化合物或晶型，例如包括但不限于参照专利文献WO2005058886A1实施例58制备方法得到的TR-701FA化合物，或参照专利文献WO2010091131A1实施例1描述方法制备得到的TR-701FA晶型I；起始原料TR-701FA也可以是本发明开发的TR-701FA无定型物。
本发明的晶型II具有以下有益性质及应用效果：
1)本发明晶型II和已知晶型I在室温下的水中溶解度分别为168μg/mL和118μg/mL，因此，本发明晶型II比已知晶型I具有更好的水中溶解度。
2)由等温吸附曲线可知，本发明晶型II比已知晶型I具有更低的吸湿性。
3)由XRPD和PLM图可知，本发明晶型II具有较高的结晶度。
4)本发明晶型II在温度25℃、相对湿度60％的条件下保存6个月，纯度和晶型都保持不变；在80℃-6000lx的高温光照条件下保存10天后，其纯度 的下降和最大单杂含量的增长都明显低于已知晶型I的数据。因此本发明晶型II具有较高的化学稳定性和晶型稳定性。
本发明晶型II的上述优势性质表明：与已知晶型I相比，本发明晶型II更适合药物制剂应用。可具有更好的颗粒流动性和更优良的后续加工特性，简化原料药后处理过程(如过滤操作等)，提高制剂生产中由流动性引起的有效成分的均匀度，有利于制剂生产中的准确计量、提高效率和稳定质量；制剂具有更高的溶出度和生物利用度，抗菌效果更好；活性成分的稳定性好，能够更好地对抗药物制造和/或存储过程中由温度、湿度、光照等因素引起的含量不均匀、纯度下降、制剂可加工性降低等问题，减少由此带来的疗效下降风险和安全风险，也有利于后期的运输和储存。
本发明人在研究中还开发了TR-701FA的无定型物(为了方便，在本发明中称其为“无定型物”)及其制备方法。
非限制性地，所述无定型物的一个典型实例具有如图9所示的X-射线粉末衍射(XRPD)图谱，显示无特征峰。
所述无定型物的差热分析(DSC)图谱显示：在140-190℃有一宽大放热峰，熔融温度约为226℃。
所述无定型物的制备方法，包括以下步骤：将TR-701FA溶解于水和三氟乙醇的混合溶剂中，将所得溶液减压浓缩至干，得到所述无定型物。
优选地，所述水和三氟乙醇的混合溶剂中水和三氟乙醇的体积比为1:2～1:5，优选为1:4。
优选地，所述浓缩的温度为40℃～60℃，优选为50℃。
所述“减压浓缩”的具体操作为：将装有溶液的容器置于旋蒸仪中，在室温至溶剂沸点的水浴温度下，小于大气压的压力下(优选压力小于0.08MPa)，以10～180转/分的旋转速度(优选50～100转/分)，将溶剂除尽。
无定型物的制备方法中：起始原料TR-701FA可以是TR-701FA的已知的化合物或晶型，例如包括但不限于参照专利文献WO2005/058886A1实施例58制备方法得到的TR-701FA化合物，或参照专利文献WO2010/091131A1实施例1描述方法制备得到的TR-701FA晶型I；起始原料TR-701FA也可以是本发明开发的TR-701FA晶型II。
本发明中，“室温”是指10-30℃。
本发明中，“晶型”是指被所示X-射线粉末衍射图表征所证实的。本领域 技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。图谱通常会随着仪器条件而有所改变：峰的相对强度可能随实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素；峰角度的实验误差也应被考虑进去，通常允许±0.2°的误差；样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。所述“单一晶型”是指经X-射线粉末衍射检测为单一的晶型。
本发明的晶型II是纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本没有”当用来指新晶型时，指这个新晶型中含有的其他晶型或非晶态少于20％(重量)，更指少于10％(重量)，尤其指少于5％(重量)，特别是指少于1％(重量)。
本发明中，所述“无水物”指样品经TGA测量含有不多于1.5％(重量)，或不多于1.0％(重量)的水。
根据本发明目的，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的TR-701FA晶型II或者由本发明制备方法制备得到的TR-701FA晶型II，以及至少一种药学上可接受的载体或助剂。此外，所述药物组合物还可以包含TR-701FA的可药用盐、其它晶型或无定型物。任选地，所述药物组合物还可以包含一种或多种其他的药物活性成分。
所述药物组合物可为固态、半固态或液态，可制备成合适的剂型例如固体剂型，包括片剂、颗粒剂、散剂、丸剂、粉末和胶囊剂；液体剂型，包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，包括溶液剂、分散剂、适于注射前在液体中溶解或悬浮的固体形式例如冻干剂。配方可适于活性成分的快速释放、持续释放或调节释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。给药途径包括口服、通过胃喂食管、通过十二指肠喂食管、静脉内、动脉内、肌肉内、皮下、骨内、皮肤内、阴道内、直肠内、腹膜内、透皮、鼻内、眼滴、耳滴等。
所述药物组合物中药学上可接受的载体或助剂，在固态制剂的情况下包括但不限于：稀释剂，例如淀粉、改性淀粉、乳糖、粉状纤维素、微晶纤维素、无水磷酸氢钙、磷酸三钙、甘露醇、山梨醇、蔗糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇、共聚维酮等；崩解剂，例如淀粉、羧甲基淀粉钠、羟基乙酸淀粉钠、预胶 化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。其他药学上可接受的载体或助剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。口服片剂中，通常使用的载体或助剂包括糖比如乳糖、蔗糖、甘露醇或山梨醇，纤维素制品比如玉米淀粉、小麦淀粉、明胶、甲基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠和聚乙烯吡咯烷酮，还可以加入润滑剂比如硬脂酸镁、崩解剂比如交联聚乙烯吡咯烷酮，进一步地可对片剂核心进行包衣，例如形成糖衣层；口服胶囊剂中，有用的载体或助剂包括乳糖、高和低分子量聚乙二醇和干玉米淀粉；明胶胶囊剂的情况下，粉末载体例如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸与类似物；软胶囊的情况下，活性化合物可以溶解或悬浮于合适的液体中，比如脂肪油、液体石蜡或液体聚乙二醇；当以混悬液口服给药时，所述活性成分与乳化剂和悬浮剂混合；如果需要，可以加入某些甜味剂和/或调味剂和/或着色剂。每一种载体或助剂必须是可接受的，能与配方中的其他成分兼容并且对于病患无害。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，本发明的TR-701FA晶型II与一种或多种药学上可接受的载体或助剂相混合，任选地，与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。液体制剂可以通过溶解、分散等工艺来制备。
进一步地，本发明提供一种本发明TR-701FA晶型II或者由本发明制备方法得到的TR-701FA晶型II在制备用于治疗和/或预防微生物感染疾病的药物中的用途。
进一步地，本发明提供一种治疗和/或预防微生物感染疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的TR-701FA晶型II或由本发明制备方法得到的TR-701FA晶型II或其药物组合物。所述患者是指哺乳动物例如人。对于本领域技术人员显而易见的是，施用的剂量和特定的给药方式将根据患者的年龄、体重、饮食、感染程度、同时使用的药物情况等因素而变化，治疗有效量是指有效预防、缓解或改善疾病症状，或延长治疗对象存活的化合物的量。对于成人患者，活性成分的每日口服剂量大约0.1mg到 2000mg，优选地大约1mg到500mg，活性成分使用静脉、皮下或肌肉给药的剂量大约0.01mg到100mg，优选地大约0.1mg到60mg。
前述的微生物感染，包括但不限于皮肤感染，肺炎，病毒感染后感染，腹部感染，泌尿道感染，菌血症，败血病，心内膜炎，房室间隔感染，血管穿刺感染，脑膜炎，外科手术预防，腹膜感染，骨感染，关节感染，具有甲氧西林抗性的金黄色葡萄球菌感染，具有万古霉素抗性的肠球菌感染，具有利奈唑胺抗性的有机体感染以及肺结核。
附图说明
图1为本发明晶型II的XRPD图谱。
图2为本发明晶型II的PLM图谱。
图3为本发明晶型II的DSC图谱。
图4为本发明晶型II的TGA图谱。
图5为本发明晶型II的等温吸附曲线。
图6为参照WO2005/058886A1制备得到的已知晶型I的XRPD图谱。
图7为参照WO2005/058886A1制备得到的已知晶型I的PLM图谱。
图8为参照WO2005/058886A1制备得到的已知晶型I的等温吸附曲线。
图9为本发明无定型物的XRPD图谱。
图10为本发明无定型物的DSC图谱。
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：所使用的仪器为Bruker D8 Advance diffractometer，采用铜靶波长为1.54nm的KaX-射线，在40kV和40mA的操作条件下、θ-2θ测角仪、Mo单色仪、Lynxeye探测器。仪器在使用前用金刚砂校准。采集软件是Diffrac Plus XRD Commander。样品在室温条件下测试，把需要检测的样品放在无反射板上。详细检测条件如下，角度范围：3–40°2θ，步长：0.02°2θ，速度：0.2秒/步。
偏振光显微镜(PLM)图谱采自于XP-500E偏振光显微镜(上海长方光学仪器有限公司)。取少量粉末样品置于载玻片上，滴加少量矿物油以更好地 分散粉末样品，盖上盖玻片，然后将样品放置在载物台上，选择合适的放大倍数观测样品的形貌并拍照。
差热分析(DSC)：数据采自于TA Instruments Q200MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10毫克的样品放置于铝盘内，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至300℃。
热重分析(TGA)：数据采自于TA Instruments Q500TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至300℃。
等温吸附曲线(DVS)：数据采自于TA Instruments Q5000TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10mg的样品放置于白金坩埚内，TA软件记录样品在相对湿度从0％到80％到0％变化过程中的重量变化。根据样品的具体情况，也会对样品采用不同的吸附和脱吸附步骤。
高效液相色谱(HPLC)：分析数据采自于Agilent 1260，化学工作站是B.04。相应参数如下：色谱柱Eclipst XDB-C18，5μm，4.6×250mm，H-005#，柱温25℃，流速0.3ml/min，流动相为13％乙腈和87％水(0.0025M碳酸氢铵)，波长254nm，进样量10μL和运行时间20分钟。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1 TR-701FA的制备
参照专利文献WO2005/058886A1实施例58的制备方法得到TR-701FA，具体操作如下：
1)将1g(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮溶于10mL混合溶剂(四氢呋喃：二氯甲烷＝1:1)中。在室温下将0.6g四唑和2.3g双四丁基二异丙基磷酰胺加入溶液中并在室温下搅拌15小时。反应混合物冷冻至-78℃，加入0.7g间氯过苯甲酸并搅拌2小时。反应混合物搅拌2小时后，反应混合物升温至室温。将乙酸乙酯加入反应混合物中。用硫酸氢钠、碳酸氢钠和盐水洗涤分离所得的有机层、脱水、过滤并真空浓缩，随后通过色谱柱提纯，由此得到0.68g(R)-(3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-2-氧代-5-噁唑烷基)甲基磷酸双(四丁基酯)，收率68％。
2)将0.6g上述制得的化合物溶于30mL二氯甲烷中。室温下将15mL三氟乙酸加入溶液中并搅拌1小时。将反应混合物真空浓缩，制得残留物。残留物用乙醇和乙醚结晶，得到320mg单-(R)-(3-(4-(2-(2-甲基四唑-5-基)吡啶-3-氟苯基)-2-氧代-5-噁唑烷基)甲基)磷酸酯，即TR-701FA，产率为53％。
进一步检测表明，制备例1所得的TR-701FA即为专利文献WO2010/091131A1所述TR-701FA结晶，即TR-701FA晶型I。其XRPD图谱如图6所示；PLM图谱如图7所示，显示其为晶态，且颗粒较小，结晶度低；等温吸附曲线如图8所示，显示在20％～80％相对湿度范围内重量变化约为1.56％。
实施例1
取200mgTR-701FA，在80℃下用10mLN,N-二甲基甲酰胺溶清，恒温保持10min，之后置于80℃下挥发至干，得到196mg白色固体产物，产率98.0％。
产物的XRPD图谱如图1所示，显示为TR-701FA晶型II。
产物的PLM图谱如图2所示，显示为片状晶体。
产物的DSC图谱如图3所示，显示熔融温度约为233℃。
产物的TGA图谱如图4所示。显示在150℃之前失重约0.41％，为无水物，分解温度约为226℃。
产物的等温吸附曲线如图5所示，显示：20％RH～80％RH重量变化为0.49％。
实施例2
取100mgTR-701FA，在60℃下用8mL N,N-二甲基甲酰胺溶清，恒温保持10min，之后置于60℃下挥发至干，得到95mgTR-701FA晶型II，产率95.0％。
实施例3
取150mgTR-701FA，在25℃下用8mL吡啶溶清，过滤，滤液置于25℃下挥发至干，得到142mgTR-701FA晶型II，产率为94.7％。
实施例2、3制备的样品具有与实施例1样品相同或相似的XRPD图谱、PLM图谱、DSC图谱和TGA图谱(未示出)。说明实施例2、3样品与实施例1样品是相同的晶型。
实施例4
取100mgTR-701FA，在25℃下用100mL体积比为1:4的水和三氟乙醇的混合溶剂溶清，过滤，滤液置于40℃下减压浓缩旋蒸至干，得到52mgTR-701FA无定型物，产率为52％。
无定型物具有如图9所示的X-射线粉末衍射(XRPD)图谱。
无定型物的差热分析(DSC)图谱如图10所示显示：在140-190℃有一宽大放热峰，熔融温度约为226℃。
实施例5
分别取制备例1制备的晶型I和实施例1制备的晶型II各20.0mg，分别加入100mL水在25℃搅拌10小时，分别过滤取清液，直接测定HPLC含量，结果为：晶型I的溶解度为118μg/mL，晶型II的溶解度为168μg/mL。
实施例6
制备含本发明TR-701FA晶型II作为药物活性成分的速释片剂，规格为含200mgTR-701FA。表1示出了该速释片剂生产中各成分的用量配方。表1包括药品生产过程中使用的所有成分，无论该成分是否包含在最终产品中，其中纯化水在生产过程中除去。
表1  速释片剂处方
Figure PCTCN2015075178-appb-000006
制备步骤：
1：将TR-701FA晶型II、甘露醇、微晶纤维素和交联聚维酮过筛混合。
2：将聚维酮溶解于纯化水中得粘合剂溶液。
3：将步骤2的粘合剂溶液加入到步骤1的混合物中，进行湿法制粒并干燥。
4：将硬脂酸镁过筛后与步骤3中干颗粒混合，混合物于旋转压片机上压成片芯。
5：用欧巴代II黄涂膜材料的水溶液对步骤4的片芯持续涂膜，直到增加 3.4％目标重量为止。
实施例7
制备含本发明TR-701FA晶型II作为药物活性成分的胶囊，规格为含182mgTR-701FA。表2示出了该胶囊生产中各成分的用量配方。表2包括药品生产过程中使用的所有成分，无论该成分是否包含在最终产品中，其中纯化水在生产过程中除去。
表2  胶囊剂处方
Figure PCTCN2015075178-appb-000007
制备步骤：
1：将TR-701FA晶型II、微晶纤维素和交联聚维酮过筛混合。
2：将聚维酮溶解于纯化水中得粘合剂溶液。
3：将步骤2的粘合剂溶液加入到步骤1的混合物中，进行湿法制粒并干燥。
4：将硬脂酸镁过筛后与步骤3中干颗粒混合，混合物于胶囊填充机上进行胶囊填充。
对比例1
取制备例1制备的TR-701FA晶型I和本发明的TR-701FA晶型II，进行高温光照条件下放置10天的稳定性实验。高温条件为80℃，光照条件为6000lx照度。检测化合物在放置前后的HPLC纯度和最大单杂含量，结果见表3。
表3  稳定性实验的结果
Figure PCTCN2015075178-appb-000008
由表3数据可知：在高温光照10天的条件下，TR-701FA晶型I的纯度降 低了2.1％，最大单杂含量增加了1.2％，而本发明的TR-701FA晶型II的纯度基本无变化，最大单杂含量仅增加了0.1％。因此，本发明的TR-701FA晶型II在高温光照下的稳定性明显优于已知的TR-701FA晶型I。
本说明书中所引用的所有专利文献及非专利文献，均通过引用以其全文的方式并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (10)

  1. 结构式如下所示的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯的晶型II:
    Figure PCTCN2015075178-appb-100001
    使用Cu-Kα辐射，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.5±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、21.0±0.2°和26.3±0.2°。
  2. 根据权利要求1所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II，其特征在于，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.5±0.2°、12.1±0.2°、13.9±0.2°、15.7±0.2°、16.5±0.2°、17.3±0.2°、20.1±0.2°、21.0±0.2°、23.9±0.2°、24.5±0.2°、26.3±0.2°和27.6±0.2°。
  3. 根据权利要求2所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II，其特征在于，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2015075178-appb-100002
  4. 权利要求1-3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II的制备方法，包括以下步骤：将(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯溶解于溶剂中，所述溶剂选自胺、酰胺或其混合物，将所得溶液挥发至干， 得到所述晶型II。
  5. 根据权利要求4所述的制备方法，其特征在于，所述溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、吡啶或其混合物，优选为N,N-二甲基甲酰胺。
  6. 根据权利要求4所述的制备方法，其特征在于，所述挥发温度为25℃～80℃，优选为60℃～80℃。
  7. 一种药物组合物，其包含治疗和/或预防有效量的选自权利要求1-3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II或根据权利要求4～6中任一项所述制备方法得到的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II，以及至少一种药学上可接受的载体或助剂。
  8. 根据权利要求7所述的药物组合物，其特征在于，所述药物组合物为注射剂、片剂或胶囊剂，优选为片剂。
  9. 权利要求1～3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II或根据权利要求4～6中任一项所述制备方法得到的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II在治疗和/或预防微生物感染疾病的药物中的用途；其中所述微生物感染选自于由下述所组成的组中的感染：皮肤感染，肺炎，病毒感染后感染，腹部感染，泌尿道感染，菌血症，败血病，心内膜炎，房室间隔感染，血管穿刺感染，脑膜炎，外科手术预防，腹膜感染，骨感染，关节感染，具有甲氧西林抗性的金黄色葡萄球菌感染，具有万古霉素抗性的肠球菌感染，具有利奈唑胺抗性的有机体感染以及肺结核。
  10. 一种治疗和/或预防微生物感染疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的选自权利要1～3中任一项所述的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II、根据权利要求4～6中任一项所述制备方法得到的(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮二氢磷酸酯晶型II或权利要求7或8所述的药物组合物；其中所述微生物感染选自于由下述所组成的组中的感染：皮肤感染，肺炎，病毒感染后感染，腹部感染，泌尿道感染，菌血症，败血病，心内膜炎，房室间隔感染，血管穿刺感染，脑膜炎，外科手术预防，腹膜感染，骨感染，关节感染，具有甲氧西林抗性的金黄色葡萄球菌感染，具有万古霉素抗性的肠球菌感染，具有利奈唑胺抗性的有机体感染以及肺结核。
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