WO2015106674A1 - 一种安塞曲匹的晶型及其制备方法、其药物组合物和用途 - Google Patents

一种安塞曲匹的晶型及其制备方法、其药物组合物和用途 Download PDF

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WO2015106674A1
WO2015106674A1 PCT/CN2015/070597 CN2015070597W WO2015106674A1 WO 2015106674 A1 WO2015106674 A1 WO 2015106674A1 CN 2015070597 W CN2015070597 W CN 2015070597W WO 2015106674 A1 WO2015106674 A1 WO 2015106674A1
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crystal form
crystal
days
anseltrex
preparation
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PCT/CN2015/070597
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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 CN201580000216.0A priority Critical patent/CN104955816B/zh
Publication of WO2015106674A1 publication Critical patent/WO2015106674A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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 relates to the field of medicinal chemical crystallization technology.
  • it relates to a novel crystalline form of the cholesteryl ester transporter inhibitor, acesulfame, and a process for the preparation of the novel crystalline form, a pharmaceutical composition thereof and use thereof.
  • Anserepi is a cholesterol ester transporter inhibitor developed by Merck.
  • the drug has the function of raising blood high-density cholesterol and lowering blood low-density cholesterol, and can improve blood lipid levels in patients with dyslipidemia without affecting blood samples, plasma electrolytes and aldosterone levels, and can be used for preventing and treating atherosclerosis.
  • atherosclerosis Such as sclerosis, hyperlipidemia, coronary heart disease, stroke and peripheral vascular disease.
  • Anserepi is (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3- ⁇ [2-(4-fluoro-2-methoxy-5) -isopropylphenyl)-5-(trifluoromethyl)phenyl]methyl ⁇ -4-methyl-1,3-oxazolidin-2-one.
  • the English name is Anacetrapib, alias MK-0859, and the molecular formula is C 30 H 25 F 10 NO 3 .
  • the chemical structure is as follows:
  • Patent document WO2006014413A1 discloses Anserepi compounds and their nuclear magnetic data. Specifically, Example 73 produces acesulfame in the form of clear glass, but the literature does not disclose crystal form information.
  • Patent document WO2007005572A1 discloses an amorphous substance of acesulfame, a crystalline unsolvate and a crystalline heptane solvate, and discloses their XRPD pattern, solid carbon-13 NMR spectrum, solid fluorine-19 NMR spectrum. Characterization data such as DSC curve.
  • the crystalline heptane solvate is desolvated to give the crystalline unsolvate.
  • the crystalline unsolvate is an anhydrate, which melts at about 69 ° C and leaves the crystal form unchanged at room temperature, but it is slowly converted to an amorphous substance after being left for a long time, and is converted into an amorphous form at a faster temperature. Things. This shows that the anhydrate is unstable.
  • Patent document WO2013064188A1 discloses an anhydrate crystal form B of Ansempi and a preparation method thereof, wherein the X ⁇ D pattern has a 2 ⁇ characteristic peak at 5.1 ⁇ 0.2°, 7.7 ⁇ 0.2°, 19.4 ⁇ 0.2°, 20.7 ⁇ 0.2°, and 21.2 ⁇ 0.2 °, DSC shows an endothermic peak at 75 ° C ⁇ 95 ° C, preferably 85 ° C ⁇ 90 ° C, a melting point of about 87 ° C.
  • the preparation method comprises the steps of: adding an anti-solvent to a solution of a soluble solvent of the anesthetide amorphous substance, and crystallization to obtain an Anserepi form B.
  • WO2013064188A1 mentions that the anhydrate form B is more stable than the anhydrate of WO2007005572A1.
  • WO2013064188A1 also mentions that the clarified glass-like acesulfame prepared in WO2006014413A1 is an amorphous substance.
  • Form B is relatively stable in crystalline form.
  • the stability of the crystal form B is still poor, for example, under accelerated conditions (40 ° C, 75% RH) for 15 days, it will be converted into an amorphous substance under high temperature, high humidity and strong light conditions. Unstable, high purity changes are not conducive to the preservation of the sample. In the pharmaceutical process, this change will cause changes in the properties and bioavailability of the formulation, thereby affecting the efficacy; and Form B is a fine particle crystal, easy to agglomerate, Poor fluidity is not conducive to subsequent processing of the formulation.
  • the object of the present invention is to develop a new crystalline form of acesulfame which is stable, easy to store, suitable for solid formulation applications, and to a process for its preparation, a pharmaceutical composition thereof and use thereof.
  • the present invention provides Ancele crystal form 1 having the following structural formula:
  • the X-ray powder diffraction pattern of the Anseltrex Form 1 has characteristic peaks at the following diffraction angle 2 ⁇ : 5.9 ⁇ 0.2°, 6.9 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.4 ⁇ 0.2 °, 18.3 ⁇ 0.2 ° and 20.6 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystal of Anstrex has a characteristic peak at the following diffraction angle 2 ⁇ : 5.9 ⁇ 0.2°, 6.9 ⁇ 0.2°, 7.6 ⁇ 0.2°, 13.6 ⁇ 0.2°, 15.3 ⁇ 0.2°, 16.3 ⁇ 0.2°, 17.4 ⁇ 0.2°, 18.3 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.1 ⁇ 0.2°, 22.3 ⁇ 0.2°, 25.7 ⁇ 0.2°, and 27.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal of Anstrex has a characteristic peak and its relative intensity at the following diffraction angle 2 ⁇ :
  • a typical example of the crystal form of Anseltrex has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern of the Anseltrex Form 1 shows that it is an anhydrate.
  • the crystal form of the Anseltrex is placed in a room environment of 20% to 80% relative humidity for one month, and the crystal form is unchanged; under accelerated conditions (40 ° C, relative humidity: 75%), it is left for 15 days.
  • the type did not change; under high temperature, high humidity, strong light conditions (65 ° C, 80% relative humidity, 7000 ⁇ 500 lx illuminance) for 15 days, the purity change was small.
  • the present invention provides a method for preparing the crystal form of the Ansetripe.
  • the preparation method of the crystal form of the Ansetripe comprises the steps of: forming a suspension of the ampoule amorphous substance in water, and further adding a C 6 - C 7 alkane, wherein the C 6 - C 7 alkane and water The volume ratio of 1:50 to 1:20 was stirred and crystallized to obtain the crystal form of the Ansetripe.
  • the C 6 -C 7 alkane includes n-hexane, cyclohexane, n-heptane, methylcyclohexane; preferably, the C 6 -C 7 alkane is selected from n-heptane, n-hexane, methylcyclohexane Alkane or a mixture thereof; more preferably n-heptane.
  • the volume ratio of the C 6 -C 7 alkane to water is from 1:40 to 1:35.
  • the temperature of the crystallization is from 1 ° C to 10 ° C; more preferably from 1 ° C to 3 ° C.
  • the crystallization time is from 2 days to 30 days; more preferably from 7 days to 15 days.
  • the mass-to-volume ratio of the Anseltrexose amorphous substance to water is 10 mg: 1 mL to 100 mg: 1 mL; more preferably 25 mg: 1 mL to 50 mg: 1 mL.
  • the starting material Ansetripe amorphous substance can be prepared according to the method disclosed in Example 73 of the patent document WO2006014413A1, which is incorporated herein by reference.
  • the stirring may be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring or the like.
  • the stirring rate is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the precipitated crystals are separated and dried by a conventional method in the art.
  • the separation is carried out by a conventional method in the art such as filtration, centrifugation, etc.; the specific operation of the filtration is: placing the sample to be separated on the filter paper and vacuum-filtering; the specific operation of the centrifugation is: placing the sample to be separated In a centrifuge tube, after high speed rotation until the solids all sink to the bottom of the centrifuge tube, the centrifugation rate is, for example, 6000 rpm.
  • the drying is carried out by a conventional method in the art such as natural drying, blast drying or reduced pressure drying; the drying device is a fume hood, a blast oven or a vacuum oven; the drying can be carried out under reduced pressure or no reduced pressure, preferably pressure. It is less than 0.09 MPa; the drying temperature is about 20 to 30 ° C; and the drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.
  • the Ansetripe Form 1 of the present invention has the following beneficial properties:
  • the crystal form of the dexamethasone crystal form 1 of the present invention is more stable and has better storage stability than the prior art acesulfame form B, and is better able to resist drug manufacture and/or In the process of storage, etc., the uneven content and the decrease of purity caused by factors such as time, temperature and humidity are more conducive to accurate quantification and post-transportation and storage in the preparation of unit preparations, and lower by active substances.
  • the risk of decreased efficacy due to unstable amount and increased impurity content is more suitable for solid preparation applications;
  • the crystal form of Ansempi 1 of the present invention is a bulk crystal with better fluidity and better subsequent processing (eg The characteristics of filtration, drying, weighing, sieving, etc. in the manufacturing process of the drug are beneficial to improve the uniformity of the preparation; the preparation process of the ampoule crystal form 1 of the invention is short, and is beneficial to the parameter control in the production process. reduce manufacturing cost.
  • room temperature means a temperature of 10 to 30 °C.
  • the crystal form of Anseltrex of the present invention is pure, unitary, and substantially free of any other crystal form or amorphous form.
  • substantially free when used to refer to a new crystalline form means that the other crystalline form or amorphous substance contained in the new crystalline form is less than 20% by weight, more preferably less than 10% by weight. In particular, it means less than 5% by weight, especially less than 1% by weight.
  • crystal in the present invention, “crystal”, “crystal form” or “amorphous” means that it is confirmed by the X-ray diffraction pattern characterization shown.
  • the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Anseltrex Form 1 or Ansetripe Form 1 obtained by the preparation method of the present invention, and at least A pharmaceutically acceptable excipient.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms, amorphous forms or salts of acesulfame, including but not limited to the solid forms disclosed in WO2006014413A1, WO2007005572A1 and WO2013064188A1.
  • the pharmaceutical composition comprises one or more additional pharmaceutically active ingredients, such as, but not limited to, other compounds that improve lipid distribution, such as HMG-CoA reductase inhibitors, which are typically statins , including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, ivavastatin, pitavastatin, etc.; cholesterol absorption inhibitors, such as stanol, --sitosterol, sterol glycosides and azetidinones such as ezetimibe; or selected from compounds capable of treating other diseases such as diabetes, hypertension, obesity, atherosclerosis, inflammation or metabolic syndrome One or more.
  • HMG-CoA reductase inhibitors which are typically statins , including lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, ivavastatin,
  • the above pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, Powders, pills, powders and capsules; liquid oral dosage forms including solutions, syrups, suspensions, dispersions and emulsions; injectable preparations including solutions, dispersions and lyophilizates.
  • the formulation may be adapted for rapid release, delayed 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, rectal administration, topical administration, parenteral administration (including subcutaneous, intramuscular, and intravenous), ocular administration, pulmonary administration, nasal administration, and the like.
  • the pharmaceutically acceptable excipients of the present invention include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, Powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose , hydroxypropyl methylcellulose, polyethylene glycol, etc.; disintegrating agents, such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal dioxide Silicon or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, caprylyl hexanoyl polyoxygly
  • diluents such as starch, pregelatinized starch, lactos
  • the pharmaceutically acceptable excipients of the invention include, but are not limited to, water, ethanol, glycerol, liquid polyethylene glycols, oils and the like.
  • Other pharmaceutically acceptable excipients that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, and the like.
  • the size of the tablet or capsule of the present invention is, for example, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg, based on acesulfame.
  • the pharmaceutical composition is prepared by methods well known to those skilled in the art.
  • the crystal form of Ansetripe of the present invention is mixed with one or more pharmaceutically acceptable excipients, optionally with other pharmaceutically acceptable crystal forms of Ansetripe,
  • the amorphous or salt phase is mixed, optionally with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a conventional process such as mixing, granulation, or the like.
  • the solution used in the capsule can be prepared by dissolving the crystal form of the acesulfame in an oil solvent and/or a mixture of an oil solvent and a surfactant.
  • the present invention provides Anseltrex Form 1 of the present invention or Ansetripe Form 1 obtained by the preparation method of the present invention for preparing and preventing or treating atherosclerosis, coronary heart disease, stroke, peripheral blood vessels Disease, dyslipidemia, high ⁇ -lipoproteinemia, high alpha-lipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disease, angina pectoris, local Ischemia, heart Use in muscle ischemia, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, diabetic vascular complications, obesity, endotoxemia, or metabolic syndrome.
  • the present invention provides a method for treating and/or preventing atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, dyslipidemia, high ⁇ -lipoproteinemia, high ⁇ -lipoproteinemia, and high Cholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disease, angina pectoris, ischemia, myocardial ischemia, myocardial infarction, reperfusion injury, restenosis after angioplasty, hypertension, A method of diabetic vascular complications, obesity, endotoxemia or metabolic syndrome, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of Ansetripe Form 1 of the present invention or prepared by the present invention Method of obtaining Anseltrex Form 1 or a pharmaceutical composition thereof.
  • the patient refers to a mammal including a human.
  • the daily dose of Ansetripe Form 1 of the present invention is from 0.01 to 100 mg/kg body weight, preferably as a single daily dose or divided into two to six administrations per day or in a controlled release dosage form.
  • Figure 1 is an XRPD pattern of an exemplified amorphous form prepared according to WO2006014413A1.
  • Figure 2 is an XRPD pattern of the crystal form B of Anseltrex prepared according to WO2013064188A1.
  • Figure 3 is a PLM map of crystal form B of Anseltrex prepared according to WO2013064188A1.
  • Figure 4 is a TGA diagram of crystal form B of Anseltrex prepared according to WO2013064188A1.
  • Figure 5 is an XRPD pattern of the crystal form of Anseltrex form 1 of the present invention.
  • Figure 6 is a PLM map of the crystal form of Anseltrex form 1 of the present invention.
  • Figure 7 is a TGA map of the crystal form of Anseltrex form 1 of the present invention.
  • Figure 8 is an XRPD pattern of Anstrex Form B prepared according to WO2013064188A1 at 0 °C and 75% RH for 0 days and 15 days (bottom to top corresponds to 0 days and 15 days).
  • Figure 9 is an XRPD pattern of the Ansetripe Form 1 of the present invention placed at 40 ° C, 75% RH for 0 days and 15 days (corresponding to 0 days and 15 days from bottom to top in the figure).
  • the instrument used for X-ray powder diffraction was a Bruker D8 Advance Diffractometer equipped with a ⁇ -2 ⁇ goniometer, a Mo monochromator, and a Lynxeye detector.
  • the acquisition software is Diffrac Plus XRD Commander.
  • the instrument is calibrated with the standard (usually corundum) supplied with the instrument before use. Test strip The pieces are: 2 ⁇ scanning angle range 3 ⁇ 40°, step size 0.02°, speed 0.2 seconds/step.
  • Detection process Ka X-ray with a copper target wavelength of 1.54 nm was used. Under the operating conditions of 40 kV and 40 mA, the sample was tested at room temperature, and the sample to be tested was placed on an organic glass slide. Samples were not ground prior to testing unless otherwise stated.
  • 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 the slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover slip, and then place the sample on the stage of the XP-500E polarized light microscope, select the appropriate magnification Multiply observe the morphology of the sample and take a picture.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually, 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C by a stepwise high-resolution detection method at a heating rate of 10 ° C / min under a dry N 2 protection of 40 ml / min. The TA software records the change in weight of the sample during the temperature increase.
  • High performance liquid phase analysis (HPLC) data was taken from Waters 2695/2487 and instrument control software and analysis software was Empower. Using C18 column, 250mm ⁇ 4.6mm, 5 ⁇ m, column temperature 25 ° C, wavelength 220nm, flow rate 1.0ml / min, injection volume 10 ⁇ l, running time 20min.
  • the mobile phase A was water
  • the mobile phase B was acetonitrile
  • the HPLC gradient conditions are shown in Table 1.
  • the single punching machine has a tableting pressure of 5 MPa and a tablet diameter of 10 mm.
  • the amposite ampoule amorphous material was synthesized according to the synthesis method of Example 73 of the patent document WO2006014413A1. Specifically: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl -1,3-oxazolidin-2-one (50 mg; 0.084 mmol), (4-fluoro-5-isopropyl-2-methoxyphenyl)boronic acid (22 mg; 0.105 mmol), palladium acetate ( 6 mg; 0.0103 mmol) and potassium carbonate (29 mg; 0.257 mmol) were heated to reflux in a 5:1 mixture of acetone/water (6 mL) for one hour.
  • the 1 H-NMR data is consistent with the literature reports.
  • the XRPD pattern is shown in Figure 1 and is shown as an amorphous material.
  • the XRPD pattern is shown in Figure 2 and is shown to be consistent with the crystal form B of Anserepi disclosed in WO2013064188A1.
  • the PLM spectrum is shown in Figure 3 and is shown as fine grain crystals, which are easy to agglomerate.
  • the TGA map is shown in Figure 4 and is shown as an anhydrate.
  • the PLM map is shown in Figure 6 and is shown as a bulk crystal.
  • the TGA map is shown in Figure 7 and is shown as an anhydrate.
  • Example 1 The "n-heptane” in Example 1 was replaced with “n-hexane”, and the other experimental procedures were the same as in Example 1, to obtain 46.0 mg of Ansemib crystal form 1.
  • Example 1 The "n-heptane” in Example 1 was replaced with "methylcyclohexane", and the other experimental procedures were the same as in Example 1, to obtain 46.2 mg of Ansemib crystal form 1.
  • Anseltrexi amorphous substance prepared in Preparation Example 1 was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, and 0.05 mL of n-heptane was added thereto, and the mixture was stirred at 5 ° C for 15 days, filtered, and vacuumed at room temperature. After drying overnight, 172.8 mg of acesulfame crystal form 1 was obtained with a molar yield of 86.4%.
  • Anseltrexi amorphous substance prepared in Preparation Example 1 was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, and 0.04 mL of n-heptane was added thereto, and the mixture was stirred at 3 ° C for 20 days, filtered, and vacuumed at room temperature. After drying overnight, 45.6 mg of acesulfame crystal form 1 was obtained with a molar yield of 91.2%.
  • Anseltrexi amorphous substance prepared in Preparation Example 1 was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, and 0.05 mL of n-heptane was added thereto, and the mixture was stirred at 10 ° C for 15 days, filtered, and vacuumed at room temperature. After drying overnight, 43.6 mg of acesulfame crystal form 1 was obtained with a molar yield of 87.2%.
  • Anseltrexi amorphous substance prepared in Preparation Example 1 was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, and 0.05 mL of n-heptane was added thereto, and the mixture was stirred at 2 ° C for 10 days, filtered, and vacuumed at room temperature. After drying overnight, 64.5 mg of acesulfame crystal form 1 was obtained with a molar yield of 92.1%.
  • Anseltrexe amorphous form prepared in Preparation Example 1 80 mg was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, and 0.05 mL of n-heptane was added thereto, and stirred at 3 ° C for 30 days, filtered, and vacuumed at room temperature. After drying overnight, 72.3 mg of acesulfame crystal form 1 was obtained with a molar yield of 90.4%.
  • Anseltrexi amorphous substance prepared in Preparation Example 1 was placed in a 5 mL reaction flask, 2 mL of water was added to form a suspension, 0.1 mL of n-heptane was further added, and the mixture was stirred at 3 ° C for 2 days, filtered, and vacuumed at room temperature. After drying overnight, 39.8 mg of acesulfame crystal form 1 was obtained with a molar yield of 79.6%.
  • the samples prepared in Examples 2 to 14 had the same or similar XRPD patterns, PLM patterns, and TGA patterns (not shown) as the samples of Example 1, indicating that the samples of Examples 2 to 14 and the samples of Example 1 were the same crystal form.
  • the capsule formulation is shown in Table 2.
  • Method for preparing capsules Mixing acesulfame form 1 prepared with the present invention with hydroxypropylcellulose, croscarmellose sodium and lactose on a scale of 1000 tablets according to the formulation of Table 2 at room temperature. The mixture was mixed into a mixed powder, and sodium lauryl sulfate was dissolved in water to form a 0.5% aqueous solution, and added to the above mixture to prepare wet granules. The granules were dried and filled into capsules to prepare corresponding capsules.
  • Method for preparing tablets prepared according to the formula of Table 3 at room temperature, on the scale of 1000 tablets Ancelex crystal form 1 and microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silica mixed with a mixer to form a mixed powder, sodium lauryl sulfate dissolved in water to form 0.5%
  • the aqueous solution is added to the above mixture to prepare wet granules, and the wet granules are dried, and the magnesium stearate is added and mixed, and then tableted in a single punch tablet machine to obtain a corresponding tablet.
  • the XRPD pattern detection results show that the prior art Anserepi form B is converted into an amorphous form after being placed for 15 days and is in a glass state, and the result is shown in FIG. 8; the crystal form of the Ansetripe crystal form 1 of the present invention does not occur. Change, the result is shown in Figure 9. It is demonstrated that the crystal form of Anseltrex form 1 of the present invention has better crystal form stability.
  • the HPLC purity test results of Table 4 show that under the conditions of high temperature, high humidity and strong light, the prior art Anserepi amorphous form and the prior art Anserepi form B are pure after being placed for 15 days. 99.0% and 99.2% were reduced to 95.4% and 96.6%, respectively, and the purity decreased by 3.6% and 2.6%, respectively.
  • the purity of the Ansetripe crystal form 1 of the present invention decreased from 99.1% to 98.6% after 15 days of storage, and the purity decreased by 0.5. %. It is indicated that the crystal of Ansetripe of the present invention has better stability.

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Abstract

本发明涉及安塞曲匹晶型1，与现有技术相比，本发明的安塞曲匹晶型1具有更好的晶型稳定性、易于储存、适于固体制剂应用。本发明还涉及所述晶型1的制备方法、其药物组合物及其在制备用于治疗和/或预防动脉粥样硬化、高脂血症等疾病的药物中的用途。

Description

一种安塞曲匹的晶型及其制备方法、其药物组合物和用途 技术领域
本发明涉及药物化学结晶技术领域。具体而言，涉及胆固醇酯转运蛋白抑制剂安塞曲匹的新晶型，以及所述新晶型的制备方法、其药物组合物和用途。
背景技术
安塞曲匹是由默沙东公司开发的胆固醇酯转运蛋白抑制剂。该药具有升高血液高密度胆固醇、降低血液低密度胆固醇的作用，可改善异常脂血症患者的血脂水平，而不会对血样、血浆电解质、醛固酮水平造成影响，可用于预防和治疗动脉粥样硬化、高脂血症、冠心病、中风和外周血管疾病等。
安塞曲匹的化学名称为(4S,5R)-5-[3,5-双(三氟甲基)苯基]-3-{[2-(4-氟-2-甲氧基-5-异丙基苯基)-5-(三氟甲基)苯基]甲基}-4-甲基-1,3-噁唑烷-2-酮。英文名称为Anacetrapib，别名为MK-0859，分子式为C30H25F10NO3，其化学结构式如下所示：
Figure PCTCN2015070597-appb-000001
专利文献WO2006014413A1公开了安塞曲匹化合物及其核磁数据，具体地，实施例73制备了呈澄清玻璃状的安塞曲匹，但该文献没有公开其晶型信息。
专利文献WO2007005572A1公开了安塞曲匹的一种无定型物、一种结晶非溶剂化物和一种结晶庚烷溶剂化物，并公开了它们的XRPD图、固态碳-13NMR光谱、固态氟-19NMR光谱、DSC曲线等表征数据。所述结晶庚烷溶剂化物脱溶剂后得到所述结晶非溶剂化物。该文献称，结晶非溶剂化物是无水物，在约69℃熔化，室温下放置晶型不变，但放置很长时间会缓慢转化为无定型物，并且升温下更快地转化为无定型物。由此显示该无水物不稳定。
专利文献WO2013064188A1公开了安塞曲匹的无水物晶型B及其制备方法，其XRPD图的2θ特征峰位于5.1±0.2°、7.7±0.2°、19.4±0.2°、20.7±0.2°和 21.2±0.2°，DSC显示吸热峰位于75℃～95℃，优选85℃～90℃，熔点约87℃。其制备方法是：在安塞曲匹无定型物的可溶溶剂的溶液中，加入抗溶剂，析晶，得到安塞曲匹晶型B。WO2013064188A1提及所述无水物晶型B较WO2007005572A1的无水物稳定。WO2013064188A1还提及WO2006014413A1中制备的澄清玻璃状的安塞曲匹为无定型物。因此，在先文献公开的安塞曲匹无水物晶型中，晶型B相对而言为稳定的晶型。
本发明人研究发现，晶型B的稳定性仍较差，例如在加速实验条件下(40℃、75％RH)放置15天会转变为无定型物，在高温、高湿、强光条件下不稳定、纯度变化较大，不利于样品的保存，在制药过程中，这种变化会引起制剂性质和生物利用度的变化，从而影响药效；且晶型B为细小颗粒晶体，易团聚，流动性差，不利于制剂的后续加工。
因此，本领域仍需要开发安塞曲匹的新晶型，该晶型应具备更好的稳定性、易于保存和适合固体制剂应用。
发明内容
针对现有技术的不足，本发明目的是开发稳定性好、易于保存、适合固体制剂应用的安塞曲匹的新晶型，并涉及其制备方法、其药物组合物和用途。
本发明提供具有如下结构式的安塞曲匹晶型1：
Figure PCTCN2015070597-appb-000002
使用Cu-Kα辐射，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.9±0.2°、6.9±0.2°、16.3±0.2°、17.4±0.2°、18.3±0.2°和20.6±0.2°。
优选地，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.9±0.2°、6.9±0.2°、7.6±0.2°、13.6±0.2°、15.3±0.2°、16.3±0.2°、17.4±0.2°、18.3±0.2°、20.6±0.2°、21.1±0.2°、22.3±0.2°、25.7±0.2°和27.7±0.2°。
进一步地，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2015070597-appb-000003
非限制性地，所述安塞曲匹晶型1的一个典型实例具有如图5所示的X-射线粉末衍射(XRPD)图谱。
所述安塞曲匹晶型1的热重分析(TGA)图谱显示其为无水物。
所述安塞曲匹晶型1，在室温、20％～80％相对湿度环境中放置一个月，晶型无变化；在加速实验条件下(40℃、相对湿度75％)放置15天，晶型未发生变化；在高温、高湿、强光的条件下(65℃、80％相对湿度、7000±500lx照度)放置15天，纯度变化较小。
进一步地，本发明提供所述安塞曲匹晶型1的制备方法。
所述安塞曲匹晶型1的制备方法，包括如下步骤：形成安塞曲匹无定型物在水中的悬浮液，再加入C6～C7烷烃，其中C6～C7烷烃与水的体积比为1∶50～1∶20，搅拌析晶，得到所述安塞曲匹晶型1。
所述C6～C7烷烃包括正己烷、环己烷、正庚烷、甲基环己烷；优选地，所述C6～C7烷烃选自正庚烷、正己烷、甲基环己烷或其混合物；更优选为正庚烷。
优选地，所述C6～C7烷烃与水的体积比为1∶40～1∶35。
优选地，所述析晶的温度为1℃～10℃；更优选为1℃～3℃。
优选地，所述析晶的时间为2天～30天；更优选为7天～15天。
优选地，所述安塞曲匹无定型物与水的质量体积比为10mg:1mL～100mg:1mL；更优选为25mg:1mL～50mg:1mL。
本发明上述制备方法中，起始原料安塞曲匹无定型物可根据专利文献WO2006014413A1实施例73公开的方法制备，该文献通过引用全文的方式并入到本申请中。
本发明上述制备方法中，所述搅拌可以采用本领域的常规方法进行，例如磁力搅拌、机械搅拌等。搅拌速率为50～1800转/分，优选300～900转/分。
本发明上述制备方法中，采用本领域的常规方法将析出的晶体进行分离和干燥。所述分离，采用本领域的常规方法例如过滤、离心等；过滤的具体操作为：将欲分离的样品置于滤纸上，减压抽滤；离心的具体操作为：将欲分离的样品置于离心管中，之后高速旋转直至固体全部沉至离心管底部，离心速率例如为6000转/分。所述干燥，采用本领域的常规方法例如自然干燥、鼓风干燥或减压干燥；干燥设备为通风橱、鼓风烘箱或真空烘箱；干燥可以在减压或不减压下进行，优选为压力小于0.09Mpa；干燥温度约20～30℃；干燥时间为10～72小时，优选为10～48小时，更优选为10～24小时。
与现有技术的安塞曲匹无水物晶型B相比，本发明的安塞曲匹晶型1具有以下有益性质：
1)由XRPD图谱和PLM图谱可知，现有技术的安塞曲匹无水物晶型B为易团聚的细小颗粒状晶体，而本发明的安塞曲匹晶型1为块状晶体，不易团聚，流动性好，制剂可加工性好；
2)由加速实验(40℃、75％相对湿度条件下放置15天)可知，现有技术的安塞曲匹无水物晶型B转变为无定型物，本发明的安塞曲匹晶型1的晶型未发生变化，因此，发明的安塞曲匹晶型1具有更好的晶型稳定性，有利于样品的保存和制剂的稳定性；
3)由高温、高湿、强光条件下的放置试验可知，现有技术的安塞曲匹晶型B和无定型物的纯度变化较大，纯度分别下降2.6％和3.6％，而本发明安塞曲匹晶型1的纯度变化较小，下降0.5％，因此，本发明安塞曲匹晶型1具有更好的稳定性，有利于样品的保存和制剂的稳定性；
上述有益性质表明：与现有技术的安塞曲匹晶型B相比，本发明安塞曲匹晶型1的晶型更稳定，储存稳定性好，能够更好地对抗药物制造和/或存储等过程中由时间、温度、湿度等因素所引起的含量不均匀以及纯度降低等问题，更有利于单位制剂制备中的准确定量和后期的运输和储存，并降低由活性物质含 量不稳定及杂质含量增加所带来的疗效下降的风险，更适合固体制剂应用；本发明安塞曲匹晶型1为块状晶体，具有更好的流动性和更优良的后续加工(如药物制造过程中的过滤、干燥、称量、过筛等操作)特性，有利于提高制剂的均一性；本发明安塞曲匹晶型1的制备流程短，有利于生产过程中的参数控制，降低生产成本。
本发明中，“室温”是指10～30℃的温度。
本发明的安塞曲匹晶型1是纯的、单一的，基本没有混合任何其他晶型或无定型物。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无定型物少于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，“晶体”、“晶型”或“无定型物”指的是被所示的X射线衍射图谱表征所证实的。本领域技术人员能够理解，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明图谱特征峰相同或相似的晶型均属于本发明范畴内。所述“单一晶型”是指经X射线粉末衍射检测是单一晶型。
进一步地，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的安塞曲匹晶型1或者由本发明制备方法得到的安塞曲匹晶型1，以及至少一种药学上可接受的赋形剂。所述药物组合物还可以包含安塞曲匹其它可药用的晶型、无定型物或盐，包括但不限于WO2006014413A1、WO2007005572A1和WO2013064188A1公开的固体形式。任选地，所述药物组合物包含一种或多种其他的药物活性成分，例如包括但不限于能改善脂质分布的其他化合物，例如HMG-CoA还原酶抑制剂，其通常为他汀类药物，包括洛伐他汀、辛伐他汀、瑞舒伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、立伐他汀、伊伐他汀、匹伐他汀等；胆固醇吸收抑制剂，例如stanol脂、β-谷甾醇、甾醇糖苷和氮杂环丁酮类例如依泽替米贝；或选自能治疗其他疾病如糖尿病、高血压、肥胖症、动脉粥样硬化、炎症或代谢综合症的化合物中的一种或多种。
上述药物组合物可为固态或液态，例如固体口服剂型，包括片剂、颗粒剂、 散剂、丸剂、粉末和胶囊剂；液体口服剂型，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、分散剂和冻干剂。配方可适于活性成分的快速释放、延迟释放或调节释放。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。给药途径包括口服给药、直肠给药、局部给药、非肠道给药(包括皮下、肌肉内和静脉内)、经眼给药、经肺给药、经鼻给药等。
在固体口服制剂如片剂、胶囊(包括软胶囊)及粉末的情况下，本发明所述药学上可接受的赋形剂包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、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、聚乙二醇等；崩解剂，例如淀粉、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、辛酰己酰聚氧甘油酯等；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；抗氧化剂，例如丁基羟基茴香醚，二丁基羟基甲苯等；所述药物组合物为软胶囊时还可以包含液体赋形剂如脂肪油。在口服液体制剂如悬浮液、溶液的情况下，本发明所述药学上可接受的赋形剂包括但不限于水、乙醇、甘油、液体聚乙二醇、油类等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂等。
本发明的片剂或胶囊的规格例如为0.5毫克、1毫克、2毫克、5毫克、10毫克、25毫克、50毫克、100毫克、250毫克或500毫克，以安塞曲匹计。
所述药物组合物采用本领域技术人员公知的方法来制备。制备药物组合物时，本发明的安塞曲匹晶型1与一种或多种药学上可接受的赋形剂相混合，任选地，与安塞曲匹其它可药用的晶型、无定型物或盐相混合，任选地，与一种或多种其他的药物活性成分相混合。固体制剂可以通过混合、制粒等常规工艺来制备。为了提高制剂的生物利用度，可以通过将安塞曲匹晶型1溶解在油类溶剂和/或油类溶剂与表面活性剂的混和物中以制成胶囊中使用的溶液。
进一步地，本发明提供了本发明的安塞曲匹晶型1或由本发明制备方法得到的安塞曲匹晶型1在制备治疗和/或预防动脉粥样硬化、冠心病、中风、外周血管疾病、异常脂血症、高β-脂蛋白血症、高α-脂蛋白血症、高胆固醇血症、高甘油三酯血症、家族性高胆甾醇血症、心血管疾病、心绞痛、局部缺血、心 肌缺血、心肌梗死、再灌注损伤、血管成形术后再狭窄、高血压、糖尿病性血管并发症、肥胖症、内毒素血症或代谢综合症的药物中的用途。
进一步地，本发明提供了一种治疗和/或预防动脉粥样硬化、冠心病、中风、外周血管疾病、异常脂血症、高β-脂蛋白血症、高α-脂蛋白血症、高胆固醇血症、高甘油三酯血症、家族性高胆甾醇血症、心血管疾病、心绞痛、局部缺血、心肌缺血、心肌梗死、再灌注损伤、血管成形术后再狭窄、高血压、糖尿病性血管并发症、肥胖症、内毒素血症或代谢综合症的方法，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安塞曲匹晶型1或由本发明制备方法得到的安塞曲匹晶型1或其药物组合物。所述患者是指包括人类在内的哺乳动物。通常本发明安塞曲匹晶型1的日剂量为0.01～100毫克/千克体重，优选作为单次日剂量或每日分为二至六次给药或采用控释剂型。
附图说明
图1为根据WO2006014413A1制备的安塞曲匹无定型物的XRPD图谱。
图2为根据WO2013064188A1制备的安塞曲匹晶型B的XRPD图谱。
图3为根据WO2013064188A1制备的安塞曲匹晶型B的PLM图谱。
图4为根据WO2013064188A1制备的安塞曲匹晶型B的TGA图。
图5为本发明安塞曲匹晶型1的XRPD图谱。
图6为本发明安塞曲匹晶型1的PLM图谱。
图7为本发明安塞曲匹晶型1的TGA图谱。
图8为根据WO2013064188A1制备的安塞曲匹晶型B在40℃、75％RH条件下放置0天和15天的XRPD图谱(图中从下至上对应0天和15天)。
图9为本发明安塞曲匹晶型1在40℃、75％RH条件下放置0天和15天的XRPD图谱(图中从下至上对应0天和15天)。
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型、其制备方法和应用。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
检测仪器及方法：
X射线粉末衍射(XPRD)所使用的仪器为Bruker D8Advance Diffractometer，配置有θ-2θ测角仪、Mo单色仪、Lynxeye探测器。采集软件是Diffrac Plus XRD Commander。仪器在使用前用仪器自带的标准品(一般为刚玉)校准。检测条 件为：2θ扫描角度范围3～40°，步长0.02°，速度0.2秒/步。检测过程：采用铜靶波长为1.54nm的Ka X-射线，在40kV和40mA的操作条件下，样品在室温下测试，把需要检测的样品放在有机玻片上。除非特别说明，样品在检测前未经研磨。
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XP-500E偏振光显微镜的载物台上，选择合适的放大倍数观测样品的形貌并拍照。
热重分析(TGA)数据采自于TA Instruments Q500 TGA，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取5～15mg样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/分钟的升温速度在40毫升/分钟干燥N2保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的重量变化。
高效液相分析(HPLC)数据采自于Waters 2695/2487，仪器控制软件和分析软件是Empower。采用C18色谱柱，250mm×4.6mm,5μm，柱温25℃，波长220nm，流速1.0ml/min，进样量10μl，运行时间20min。流动相A为水，流动相B为乙腈，HPLC梯度条件见表1。
表1HPLC梯度条件
Figure PCTCN2015070597-appb-000004
单冲压片机，压片压力为5MPa，片剂直径为10mm。
如无特别说明，实施例均在室温条件下操作。
如无特别说明，实施例中所用的各种试剂均为商购获得。
制备例1
根据专利文献WO2006014413A1实施例73的合成方法合成安塞曲匹无定型物。具体为：将(4S,5R)-5-[3,5-二(三氟甲基)苯基]-3-[2-碘-5-(三氟甲基)苄基]-4-甲基-1,3-噁唑烷-2-酮(50mg；0.084mmol)、(4-氟-5-异丙基-2-甲氧基苯基)硼酸(22mg；0.105mmol)、乙酸钯(6mg；0.0103mmol)和碳酸钾(29mg；0.257mmol)在5∶1的丙酮/水(6mL)混合物中加热回流1小时。真空除去丙酮，将残余物用水(10mL)稀释，用二氯甲烷(3×10mL)萃取。将合并的萃取液用(10mL)盐水洗 涤，用硫酸钠干燥，过滤，并真空浓缩。将残余物通过快速色谱法纯化(0-25％乙酸乙酯/己烷梯度)，获得所述安塞曲匹无定型物。
1H-NMR数据与文献报道一致。XRPD图谱如图1所示，显示为无定型物。
制备例2
根据专利文献WO2013064188A1实施例1的方法制备安塞曲匹晶型B。具体为：取制备例1制备的安塞曲匹无定型物12.9mg放入5mL反应瓶中，加入50μL的乙醇∶水＝95∶5(V/V)和200μL乙醇使其溶清，加入100μL水形成悬浮液，于室温约19-25℃下搅拌一天，再转移至3℃下搅拌4周，过滤，室温干燥过夜，得所述安塞曲匹晶型B，共10mg，摩尔收率为77.5％。
XRPD图谱如图2所示，显示与WO2013064188A1公开的安塞曲匹晶型B一致。
PLM图谱如图3所示，显示为细小颗粒晶体，易团聚。
TGA图谱如图4所示，显示为无水物。
实施例1
取制备例1制备的安塞曲匹无定型物50.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于3℃条件下搅拌15天，过滤，室温真空干燥过夜，得到47.3mg安塞曲匹晶型1，摩尔收率为94.6％。XRPD图谱如图5所示，为安塞曲匹晶型1。
PLM图谱如图6所示，显示为块状晶体。
TGA图谱如图7所示，显示为无水物。
实施例2
将实施例1中“正庚烷”替换为“正己烷”，其它实验操作同实施例1，得到46.0mg安塞曲匹晶型1。
实施例3
将实施例1中“正庚烷”替换为“甲基环己烷”，其它实验操作同实施例1，得到46.2mg安塞曲匹晶型1。
实施例4
取制备例1制备的安塞曲匹无定型物20.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于3℃条件下搅拌15天，过滤，室温真空干燥过夜，得到18.1mg安塞曲匹晶型1，摩尔收率为90.5％。
实施例5
取制备例1制备的安塞曲匹无定型物100.0mg放入5mL反应瓶中，加入2mL 水形成悬浮液，再加入0.05mL正庚烷，于3℃条件下搅拌15天，过滤，室温真空干燥过夜，得到92.3mg安塞曲匹晶型1，摩尔收率为92.3％。
实施例6
取制备例1制备的安塞曲匹无定型物200.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于5℃条件下搅拌15天，过滤，室温真空干燥过夜，得到172.8mg安塞曲匹晶型1，摩尔收率为86.4％。
实施例7
取制备例1制备的安塞曲匹无定型物50.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.04mL正庚烷，于3℃条件下搅拌20天，过滤，室温真空干燥过夜，得到45.6mg安塞曲匹晶型1，摩尔收率为91.2％。
实施例8
取制备例1制备的安塞曲匹无定型物50.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.1mL正庚烷，于3℃条件下搅拌15天，过滤，室温真空干燥过夜，得到40.8mg安塞曲匹晶型1，摩尔收率为81.6％。
实施例9
取制备例1制备的安塞曲匹无定型物50.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于10℃条件下搅拌15天，过滤，室温真空干燥过夜，得到43.6mg安塞曲匹晶型1，摩尔收率为87.2％。
实施例10
取制备例1制备的安塞曲匹无定型物55.0mg放入5mL反应瓶中，加入2.1mL水形成悬浮液，再加入0.06mL正庚烷，于1℃条件下搅拌15天，过滤，室温真空干燥过夜，得到49.3mg安塞曲匹晶型1，摩尔收率为89.6％。
实施例11
取制备例1制备的安塞曲匹无定型物70.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于2℃条件下搅拌10天，过滤，室温真空干燥过夜，得到64.5mg安塞曲匹晶型1，摩尔收率为92.1％。
实施例12
取制备例1制备的安塞曲匹无定型物55.0mg放入5mL反应瓶中，加入2.1mL水形成悬浮液，再加入0.06mL正庚烷，于3℃条件下搅拌7天，过滤，室温真空干燥过夜，得到45.9mg安塞曲匹晶型1，摩尔收率为83.4％。
实施例13
取制备例1制备的安塞曲匹无定型物80mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.05mL正庚烷，于3℃条件下搅拌30天，过滤，室温真空 干燥过夜，得到72.3mg安塞曲匹晶型1，摩尔收率为90.4％。
实施例14
取制备例1制备的安塞曲匹无定型物50.0mg放入5mL反应瓶中，加入2mL水形成悬浮液，再加入0.1mL正庚烷，于3℃条件下搅拌2天，过滤，室温真空干燥过夜，得到39.8mg安塞曲匹晶型1，摩尔收率为79.6％。
实施例2～14制备的样品具有与实施例1样品相同或相似的XRPD图谱、PLM图谱和TGA图谱(未示出)，说明实施例2～14样品和实施例1样品是相同的晶型。
实施例15
胶囊剂配方如表2所示。
表2胶囊剂配方
Figure PCTCN2015070597-appb-000005
胶囊剂的制备方法：室温下，按照表2配方，以1000粒的规模将本发明制备的安塞曲匹晶型1与羟丙基纤维素、交联羧甲基纤维素钠以及乳糖用混合机混匀成混合粉，将十二烷基硫酸钠溶于水形成0.5％的水溶液，加入到上述混合物中，制备得到湿颗粒，将颗粒干燥后装入胶囊，制得相应的胶囊剂。
实施例16
片剂配方如表3所示。
表3片剂配方
Figure PCTCN2015070597-appb-000006
片剂的制备方法：室温下，按照表3配方，以1000片的规模将本发明制备的 安塞曲匹晶型1与微晶纤维素、乳糖、交联羧甲基纤维素钠、胶体二氧化硅用混合机混匀成混合粉，将十二烷基硫酸钠溶于水形成0.5％的水溶液，加入到上述混合物中，制备得到湿颗粒，将湿颗粒干燥，加入硬脂酸镁混匀后在单冲压片机中进行压片，制得相应片剂。
对比例1
称取各20.0mg的本发明制备的安塞曲匹晶型1和制备例2制备的现有技术的安塞曲匹晶型B，置于40℃、75％相对湿度条件下15天。分别检测放置0天和15天样品的XRPD图谱。
XRPD图谱检测结果显示：现有技术的安塞曲匹晶型B在放置15天后转变为无定型物且呈玻璃态，结果见图8；本发明安塞曲匹晶型1的晶型未发生改变，结果见图9。说明本发明的安塞曲匹晶型1具有更好的晶型稳定性。
对比例2
称取各20.0mg的本发明制备的安塞曲匹晶型1、制备例1制备的现有技术的安塞曲匹无定型物和制备例2制备的现有技术的安塞曲匹晶型B，置于65℃、80％相对湿度和光照强度为7000±500lx照度的条件下，放置15天。分别检测放置0天和15天样品的HPLC纯度，结果见表4。
表4HPLC纯度检测结果
Figure PCTCN2015070597-appb-000007
表4的HPLC纯度检测结果显示：在高温、高湿、强光的条件下，现有技术的安塞曲匹无定型物和现有技术的安塞曲匹晶型B在放置15天后纯度由99.0％和99.2％分别降至95.4％和96.6％，纯度分别下降3.6％和2.6％；本发明的安塞曲匹晶型1纯度在放置15天后纯度由99.1％降至98.6％，纯度下降0.5％。说明本发明的安塞曲匹晶型1具有更好的稳定性。
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。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (10)

  1. 结构式如下所示的安塞曲匹晶型1，
    Figure PCTCN2015070597-appb-100001
    其特征在于，使用Cu-Kα辐射，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.9±0.2°、6.9±0.2°、16.3±0.2°、17.4±0.2°、18.3±0.2°和20.6±0.2°。
  2. 根据权利要求1所述的安塞曲匹晶型1，其特征在于，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：5.9±0.2°、6.9±0.2°、7.6±0.2°、13.6±0.2°、15.3±0.2°、16.3±0.2°、17.4±0.2°、18.3±0.2°、20.6±0.2°、21.1±0.2°、22.3±0.2°、25.7±0.2°和27.7±0.2°。
  3. 根据权利要求2所述的安塞曲匹晶型1，其特征在于，所述安塞曲匹晶型1的X-射线粉末衍射图在以下衍射角2θ处具有特征峰及其相对强度：
    Figure PCTCN2015070597-appb-100002
    Figure PCTCN2015070597-appb-100003
  4. 权利要求1～3中任一项所述的安塞曲匹晶型1的制备方法，包括如下步骤：形成安塞曲匹无定型物在水中的悬浮液，再加入C6～C7烷烃，其中C6～C7烷烃与水的体积比为1∶50～1∶20，搅拌析晶，得到所述安塞曲匹晶型1。
  5. 根据权利要求4所述的安塞曲匹晶型1的制备方法，其特征在于，所述C6～C7烷烃选自正庚烷、正己烷、甲基环己烷或其混合物，优选为正庚烷；所述C6～C7烷烃与水的体积比为1∶40～1∶35。
  6. 根据权利要求4或5所述的安塞曲匹晶型1的制备方法，其特征在于，所述析晶的温度为1℃～10℃，优选为1℃～3℃；所述析晶的时间为2天～30天，优选为7天～15天。
  7. 根据权利要求6所述的安塞曲匹晶型1的制备方法，其特征在于，安塞曲匹无定型物与水的质量体积比为10mg:1mL～100mg:1mL，优选为25mg:1mL～50mg:1mL。
  8. 一种药物组合物，其特征在于，所述药物组合物包含治疗和/或预防有效量的权利要求1～3中任一项所述的安塞曲匹晶型1或权利要求4～7中任一项所述制备方法得到的安塞曲匹晶型1，以及至少一种药学上可接受的赋形剂。
  9. 权利要求1～3中任一项所述的安塞曲匹晶型1或权利要求4～7中任一项所述制备方法得到的安塞曲匹晶型1在制备治疗和/或预防动脉粥样硬化、冠心病、中风、外周血管疾病、异常血脂症、高β-脂蛋白血症、高α-脂蛋白血症、高胆固醇血症、高甘油三酯血症、家族性高胆甾醇血症、心血管疾病、心绞痛、局部缺血、心肌缺血、心肌梗死、再灌注损伤、血管成形术后再狭窄、高血压、糖尿病性血管并发症、肥胖症、内毒素血症或代谢综合症的药物中的用途。
  10. 一种治疗和/或预防动脉粥样硬化、冠心病、中风、外周血管疾病、异常血脂症、高β-脂蛋白血症、高α-脂蛋白血症、高胆固醇血症、高甘油三酯血症、家族性高胆甾醇血症、心血管疾病、心绞痛、局部缺血、心肌缺血、心肌梗死、再灌注损伤、血管成形术后再狭窄、高血压、糖尿病性血管并发症、肥胖症、内毒素血症或代谢综合症的方法，其特征在于，所述方法包括给予需要的患者治疗和/或预防有效量的权利要求1～3中任一项所述的安塞曲匹晶型1、权利要求4～7中任一项所述制备方法得到的安塞曲匹晶型1或者权利要求8所述的药物组合物。
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