WO2017050171A1 - 吡咯并喹啉醌钠盐的晶型及其制备方法和用途 - Google Patents

吡咯并喹啉醌钠盐的晶型及其制备方法和用途 Download PDF

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WO2017050171A1
WO2017050171A1 PCT/CN2016/099013 CN2016099013W WO2017050171A1 WO 2017050171 A1 WO2017050171 A1 WO 2017050171A1 CN 2016099013 W CN2016099013 W CN 2016099013W WO 2017050171 A1 WO2017050171 A1 WO 2017050171A1
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pyrroloquinoline quinone
crystal form
disodium salt
water
ray powder
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English (en)
French (fr)
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杨志清
张亮
张相洋
施珍娟
赵敏
罗海荣
骆红英
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浙江海正药业股份有限公司
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Priority to CN201680041932.8A priority Critical patent/CN108026091B/zh
Priority to US15/762,895 priority patent/US10364244B2/en
Publication of WO2017050171A1 publication Critical patent/WO2017050171A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • 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
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use
    • 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 present invention relates to novel crystal forms of pyrroloquinoline quinone sodium salt, to a process for the preparation of the novel crystal forms, and to their use in the fields of medicine, functional foods and cosmetics.
  • Pyrroloquinoline quinone chemical name is 4,5-dihydro-4,5-dioxo-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid, also known as methaxatin It has the following structural formula:
  • Pyrroloquinoline quinone is a small molecule compound found in microorganisms. It is widely distributed in various tissues and organs of human body and is called the 14th vitamin. It is widely used in medicine, functional food and cosmetics.
  • pyrroloquinoline quinone can improve the immune function of the human body in an all-round way. It can be used in the medical field to prevent liver damage, reduce free radical damage to the human body, regulate various nervous system diseases, promote amino acid absorption, promote synthetic growth factors, and prevent and treat. Alzheimer's disease, promotes the synthesis of glutathione, and has a strong anti-cancer function.
  • pyrroloquinoline can be used as a health food having an anti-aging effect; in the field of cosmetics, it is an anti-allergic effect and a skin-beautifying effect.
  • crystal forms can have different physical and chemical properties; including melting point, chemical stability, apparent solubility, dissolution rate, optical and mechanical properties, etc., and these physicochemical properties directly determine a certain
  • the crystal form of pyrroloquinoline quinone obtained by the prior art method is unstable, and has high hygroscopicity. In the temperature range of normal temperature storage, the humidity changes greatly, the solid state is not ideal, and is not suitable for processing (filtration, Drying, tableting), which is detrimental to the application and storage of pyrroloquinoline sodium salt.
  • the present invention includes, but is not limited to, the following documents: JP-A-2005-530786, JP-A-2011-246442, and JP-A-2007-269769
  • Some crystal forms of pyrroloquinoline quinone have been disclosed in the bulletin, International Publication No. 2011/007633, Japanese Patent Publication No. 7-113024, CN201280028888.9, but it is still necessary to develop properties superior to known crystals.
  • the present invention provides a crystal form having lower wettability, a wettability of less than 0.3% at 75% RH, preferably no hygroscopicity.
  • the invention aims to provide a crystal form with high crystallinity, high product purity, low residual solvent, easy to filter, dry and store, and environmentally friendly and pollution-free process.
  • a novel crystalline form I of pyrroloquinoline quinone disodium salt which is characterized in the X-ray powder diffraction (XRPD) pattern at the following 2 theta diffraction angle Peaks: 8.0 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 11.2 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 15.8 ⁇ 0.2 °, 22.4 ⁇ 0.2 °, 25.5 ⁇ 0.2 °, 27.7 ⁇ 0.2 °.
  • the crystalline form I of the pyrroloquinoline quinone disodium salt of the present invention has characteristic peaks at the following 2 ⁇ diffraction angles: 16.9 ⁇ 0.2°, 18.2 ⁇ 0.2°, 20.6. ⁇ 0.2°, 21.5 ⁇ 0.2°, 23.7 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.3 ⁇ 0.2°, 28.1 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pyrroloquinoline quinone disodium salt crystal form I of the present invention has a 2 ⁇ angle, a d value, and a characteristic peak relative intensity as shown in Table 1 below. data:
  • the pyrroloquinoline quinone disodium salt crystal form I of the present invention has an X-ray powder diffraction pattern as shown in FIG.
  • the crystal form I of the pyrroloquinoline quinone disodium salt of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 3502.68 cm -1 , 3075.00 cm -1 , 1745.31 cm -1 , 1720.24 cm -1 .
  • the infrared absorption spectrum of the pyrroloquinoline quinone disodium salt crystal form I of the present invention is still about 1431.23 cm -1 , 1398.99 cm -1 , 1144.92 cm -1 , There is a characteristic peak at 1082.92 cm -1 .
  • the pyrroloquinoline quinone disodium salt crystal form I of the present invention has an infrared spectrum as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form I of the present invention has a differential scanning calorimetry (DSC) pattern as shown in FIG.
  • thermogravimetric analysis (TGA) pattern as shown in FIG.
  • a novel Form II of pyrroloquinoline quinone disodium salt which is characterized in the X-ray powder diffraction (XRPD) pattern at the following 2 theta diffraction angle Peaks: 7.8 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 11.1 ⁇ 0.2 °, 22.2 ⁇ 0.2 °, 27.5 ⁇ 0.2 °.
  • the crystalline form II of the pyrroloquinoline quinone disodium salt of the present invention has characteristic peaks at the following 2 ⁇ diffraction angles: 8.9 ⁇ 0.2°, 15.6 ⁇ 0.2°, 18.0. ⁇ 0.2°, 23.5 ⁇ 0.2°, 28.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pyrroloquinoline quinone disodium salt crystal form II of the present invention has the 2 ⁇ , d, and relative intensity data shown in Table 2 below:
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention has an X-ray powder diffraction spectrum as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 1710.04 cm -1 , 1667.65 cm -1 , 1610.08 cm -1 , and 1541.60 cm -1 .
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention is still about 3349.74 cm -1 , 3122.28 cm -1 , 3074.36 cm -1 , 2560.88 cm -1 , There are characteristic peaks at 2360.30cm -1 , 1740.02cm -1 , 1397.72cm -1 , and 888.38cm -1 .
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention has an infrared spectrum as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention has a DSC pattern as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form II of the present invention has a TGA pattern as shown in FIG.
  • a novel Form III of pyrroloquinoline quinone disodium salt which is characterized in the X-ray powder diffraction (XRPD) pattern at the following 2 theta diffraction angle Peaks: 7.4 ⁇ 0.2 °, 8.6 ⁇ 0.2 °, 14.0 ⁇ 0.2 °, 14.6 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 21.4 ⁇ 0.2 °, 26.0 ⁇ 0.2 °, 27.3 ⁇ 0.2 °, 28.5 ⁇ 0.2 °.
  • XRPD X-ray powder diffraction
  • the X-ray powder diffraction pattern of the pyrroloquinoline quinone disodium salt crystal form III of the present invention has the 2 ⁇ , d and relative intensity data shown in Table 3 below:
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention has an X-ray powder diffraction spectrum as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 3446.06 cm -1 , 1721.16 cm -1 , 1680.19 cm -1 , and 1613.68 cm -1 . 1541.14cm -1 , 1496.91cm -1 , 1349.99cm -1 , 1243.04cm -1 , 940.32cm -1 , 722.10cm -1 , 562.47cm -1 , 424.89cm -1 have absorption peaks.
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention has a characteristic peak at about 1077.39 cm -1 , 801.05 cm -1 , and 749.60 cm -1 .
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention has an infrared spectrum as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention has a DSC pattern as shown in FIG.
  • the pyrroloquinoline quinone disodium salt crystal form III of the present invention has a TGA pattern as shown in FIG.
  • a novel Form IV of pyrroloquinoline quinone monosodium salt which is characterized in the X-ray powder diffraction (XRPD) pattern at the following 2 theta diffraction angle Peaks: 7.8 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 15.7 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 20.6 ⁇ 0.2 °, 27.7 ⁇ 0.2 °, 28.4 ⁇ 0.2 °.
  • the pyrroloquinoline quinone monosodium salt crystal form IV of the present invention has characteristic peaks at the following 2 ⁇ diffraction angles: 18.0 ⁇ 0.2°, 22.3 ⁇ 0.2°, 23.6 ⁇ 0.2°, 25.4 ⁇ 0.2°, 25.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pyrroloquinoline quinone monosodium salt form IV of the present invention has the 2 ⁇ , d, and relative intensity data shown in Table 4 below:
  • the pyrroloquinoline quinone monosodium salt form IV of the present invention has an X-ray powder diffraction pattern as shown in FIG.
  • the pyrroloquinoline quinone monosodium salt crystal form IV of the present invention can be characterized by an infrared absorption spectrum measured by KBr tableting, which is about 3503.09 cm -1 , 3074.74 cm -1 , 1744.71 cm -1 , and 1720.37 cm -1 .
  • the pyrroloquinoline quinone monosodium salt crystal form IV of the present invention has an infrared spectrum as shown in FIG.
  • the pyrroloquinoline quinone monosodium salt form IV of the present invention has a DSC pattern as shown in FIG.
  • the pyrroloquinoline quinone monosodium salt crystal form IV of the present invention has a TGA pattern as shown in FIG.
  • the weight-to-volume ratio (g/ml) of the pyrroloquinoline quinone to the mixed solvent is preferably 1:10-1:400, more preferably 1:50-1:200.
  • the state of the crystallization liquid described in (1) may be clarified or suspended; the temperature thereof is controlled from 15 ° C to 60 ° C, preferably from 25 ° C to 50 ° C.
  • a process for the preparation of the pyrroloquinoline quinone disodium salt crystal form II comprising: the pyrroloquinoline quinone disodium salt crystal form I at 30 ° C - Form II can be obtained by drying at 60 ° C under vacuum.
  • the weight-to-volume ratio (g/ml) of the pyrroloquinoline quinone to the mixed solvent is preferably 1:200 to 1:400.
  • the volume ratio of ethanol to water is 1:1 to 3:1; the crystallization temperature is controlled to be 0 to 20 ° C, preferably 5 to 15 ° C.
  • the state of the crystallization liquid described in (1) may be clarified or suspended; the temperature thereof is controlled from 15 ° C to 60 ° C, preferably from 25 ° C to 50 ° C.
  • the unit of the weight-to-volume ratio of the pyrroloquinoline quinone to the corresponding solvent may be g/ml, Kg/L or the like, depending on the specific operation scale.
  • a pharmaceutical composition in a third aspect of the invention, there is provided a pharmaceutical composition, a cosmetic composition, a functional food or a nutrient comprising the novel crystalline form of the invention and their use in the fields of medicine, functional foods and cosmetics.
  • the pyrroloquinoline quinone starting material used in the process of the invention is commercially available or can be prepared according to known methods.
  • the solvent to be used in the present invention is not particularly limited, and a commercially available conventional solvent can be used.
  • stirring described in the process of the present invention may be carried out by conventional methods in the art, for example, stirring means including magnetic stirring, mechanical stirring; unless otherwise stated.
  • the X-ray powder diffraction apparatus (XRPD) and the test conditions of the present invention are: X-diffraction instrument model Rigaku D/max-2200Cu target; operation method: scanning speed 4 ° / min, scanning step width 0.01 °.
  • the infrared spectrophotometer and the test conditions of the invention are: infrared spectrophotometer model: BRWKER JECTOR 22; operation method: KBr tableting method, scanning range 400-4000 cm -1 .
  • DSC test conditions are as follows: DSC detector model: NETZSCH DSC200 F3 Jaia; operation method: heating rate 10 ° C / min, temperature range: 30-250 ° C.
  • the present invention relates to the thermogravimetric analysis (TGA) test conditions: TGA detector model: PerkinElmer TGA400; operating method: heating rate 10 ° C / min, temperature range: 30-300 ° C.
  • TGA detector model PerkinElmer TGA400
  • operating method heating rate 10 ° C / min, temperature range: 30-300 ° C.
  • microscope test conditions involved in the present invention are: microscope model: OLYMPUS CX31; operation method: eyepiece 10x, objective lens 10x.
  • the liquid phase test conditions of the invention are as follows: the column is Yuexu LP-C18 4.6 ⁇ 250 mm, 5 ⁇ m; phase A: 5 mM potassium dihydrogen phosphate, pH is adjusted to 2.2 with phosphoric acid; phase B: pure acetonitrile; detection wavelength: 251 nm Flow rate: 1.0 ml/min; injection amount: 10 ⁇ l; column temperature: 30 ° C, liquid phase conditions are shown in Table 5:
  • the present invention also provides a picture of the crystal of pyrroloquinoline quinone sodium salt under the microscope, as shown in FIG. 17, wherein the pyrroloquinoline quinone disodium salt crystal form I crystal is a diamond shape, and the crystal form II is The crystal form I is prepared by drying, and the crystal habit has not changed.
  • the crystal form IV is consistent with the crystal form I. From the figure, the crystal habit rule of the crystal form I can be seen, the solid fluidity is good, and it is easy to filter and dry. In addition, the crystallized crystal has high purity, poor hygroscopicity, good stability, and easy storage.
  • Example 1 is an X-ray powder diffraction spectrum of crystal form I of pyrroloquinoline quinone disodium salt obtained in Example 1.
  • Example 2 is an infrared absorption spectrum of crystal form I of pyrroloquinoline quinone disodium salt obtained in Example 1.
  • Example 3 is a DSC chart of the crystal form I of the pyrroloquinoline quinone disodium salt obtained in Example 1.
  • Example 4 is a TGA pattern of the crystalline form I of the pyrroloquinoline quinone disodium salt obtained in Example 1.
  • Figure 5 is an X-ray powder diffraction spectrum of the pyrroloquinoline quinone disodium salt crystal form II obtained in Example 9.
  • Fig. 6 is an infrared absorption spectrum of crystal form II of pyrroloquinoline quinone disodium salt obtained in Example 9.
  • Example 7 is a DSC chart of the crystal form II of pyrroloquinoline quinone disodium salt obtained in Example 9.
  • Figure 8 is a TGA spectrum of the crystal form II of pyrroloquinoline quinone disodium salt obtained in Example 9.
  • Figure 9 is an X-ray powder diffraction spectrum of crystal form III of pyrroloquinoline quinone disodium salt obtained in Example 11.
  • Fig. 10 is an infrared absorption spectrum of crystal form III of pyrroloquinoline quinone disodium salt obtained in Example 11.
  • Figure 11 is a DSC chart of the crystal form III of pyrroloquinoline quinone disodium salt obtained in Example 11.
  • Figure 12 is a TGA spectrum of the crystalline form III of the pyrroloquinoline quinone disodium salt obtained in Example 11.
  • Figure 13 is an X-ray powder diffraction pattern of the pyrroloquinoline quinone monosodium salt crystal form IV obtained in Example 14.
  • Fig. 14 is an infrared absorption spectrum of crystal form IV of pyrroloquinoline quinone monosodium salt obtained in Example 14.
  • Figure 15 is a DSC chart of the crystalline form IV of pyrroloquinoline quinone monosodium salt obtained in Example 14.
  • Figure 16 is a TGA chart of the crystalline form IV of pyrroloquinoline quinone monosodium salt obtained in Example 14.
  • Figure 17 is a picture of the crystal of pyrroloquinoline quinone sodium salt.
  • the crude pyrroloquinoline quinone used in the present invention is pyrroloquinoline quinone trisodium salt, which can be obtained by a conventional method in the art, for example, by the patent document CN101228963B or the document J. Am. Chem. Soc., 1981, 103. The method of 5599-5600 is made.
  • pyrroloquinoline quinone trisodium salt solution in Example 1 and Example 14 A pyrroloquinoline quinone fermentation broth was prepared by the method of Japanese Patent No. 2751183, which adjusted the pH to 9 -10, after column treatment (adding sample to silica gel column, silica gel 200-300 mesh, eluting alcohol-soluble impurities with ethanol, eluting the material with water, and extracting the purified sample solution), the obtained solution is pyrroloquine.
  • the crystal form I of pyrroloquinoline quinone disodium salt of Example 1 was dried at 60 ° C for 8 hours to obtain a new crystal form, and the X-ray powder diffraction, infrared, DSC and TGA spectra of the crystal form are shown in FIG. 5 . -9, which is named in the present invention as pyrroloquinoline quinone disodium salt crystal form II.
  • the pyrroloquinoline quinone disodium salt crystal form I of Example 2 was dried at 30 ° C for 8 hours to obtain pyrroloquinoline quinone disodium salt crystal form II.
  • Example 10 The X-ray powder diffraction spectrum of the product obtained in Example 10 was the same as that of Example 9, and the description thereof will not be repeated here.
  • Hygroscopicity test The watch glass was placed in an environment of a temperature of 25 ° C and a humidity of 75% for 24 hours, and then 1 g of the following samples were weighed, and quickly placed in an environment of a temperature of 25 ° C and a humidity of 75% for 24 hours to fully absorb moisture. The results are as follows:
  • Form I, Form III and Form IV are not hygroscopic, and the stability is good, and Form II is second.
  • CN201080031945 has the strongest hygroscopicity. Therefore, the new crystal form developed by the present invention is not easy to exchange substances with the outside, and can maintain good stability.
  • the crystal form I, the crystal form II and the form IV of the present invention are rhomboid, the crystal form III is needle-like, and the crystal form I, the crystal form II, the crystal form III and the crystal form.
  • Type IV crystal habit rules easy to filter, wash, can effectively reduce the residue of the solution in the solid, effectively improve the purity of the product, reduce solvent residue, facilitate drying, small specific surface area per unit volume, low surface energy, and environment The contact surface is small, which is conducive to material stability.
  • the crystal form I and the crystal form II of the invention can be used without using an organic solvent, thereby effectively avoiding solvent residue in the sample, reducing production cost, and reducing solvent recovery cost, and the process is more green and environmentally friendly.
  • the inventors of the present invention have found a new crystal form of pyrroloquinoline quinone disodium salt of the present invention through extensive research, which has good solubility, simple crystallization process, easy operation, low pollution, and industrial production. Further, the crystalline drug of the present invention has the advantages of high product purity, excellent physicochemical properties, good chemical stability, and processability (filtration, drying, dissolution, and tableting).

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Abstract

提供了吡咯并喹啉醌钠盐的晶型I、晶型II、晶型III和晶型IV以及它们的制备方法。还提供了含有上述晶型的药物组合物、化妆品组合物、功能性食品或营养剂。这些晶型在溶解性、晶体稳定性、吸湿性等方面具有优异的性质。

Description

吡咯并喹啉醌钠盐的晶型及其制备方法和用途 技术领域
本发明涉及吡咯并喹啉醌钠盐的新晶型以及所述新晶型的制备方法、以及它们在的医药、功能性食品及化妆品领域中的用途。
背景技术
吡咯并喹啉醌化学名称为4,5-二氢-4,5-二氧代-1H-吡咯并[2,3-f]喹啉-2,7,9-三羧酸，又名methaxatin；其具有如下结构式：
Figure PCTCN2016099013-appb-000001
吡咯并喹啉醌是从微生物中发现的小分子化合物，广泛分布于人体的各组织器官中，被称为第十四种维生素；并广泛应用于医药、功能性食品及化妆品领域。例如：吡咯并喹啉醌能全面提高人体免疫功能，在医药领域中可用于防治肝损伤、减少自由基对人体的伤害、调理各种神经系统疾病、促进氨基酸的吸收、促进合成生长因子、防治老年痴呆症、促进合成谷胱甘肽、具有极强的抗癌功能。此外，在食品领域中，吡咯并喹啉可作为具有抗衰老效果的保健食品；在化妆品领域中，它是具有抗过敏作用、有美肌效果的物质。
对于多晶型化合物而言，不同的晶型可以具有不同的物理和化学性质；包括熔点、化学稳定性、表观溶解度、溶解速率、光学和机械性质等，而这些物理化学性能直接决定了某种特定晶型在药品、功能性食品、化妆品等领域中的使用效果。比如：现有技术方法获得的吡咯并喹啉醌钠盐的结晶晶型不稳定、吸湿性大，在常温储存的温度范围内，湿度变化幅度大，固体状态不理想，不适于加工(过滤、干燥、压片)，从而对吡咯并喹啉醌钠盐的应用和储存不利。现有技术中对吡咯并喹啉醌钠盐的晶型进行了一些改进，如：在专利CN201080031945中，其克服了一些文献报道中的结晶性低、残留溶剂高等缺点，但是同样具有吸湿性；而CN201210452297.6中的晶型A虽然吸湿性有所改善，为65％-85％RH下的引湿性小于3％，优选小于0.6％，但还是无法满足对晶型吸湿性要求较高的制剂工艺的需求。
因此，尽管在现有技术(除上述列举的两篇文献外，还包括但不限于下述文献：日本特开2005-530786号公报、日本特开2011-246442号公报、日本特开2007-269769号公报、国际公开第2011/007633、日本特公平7-113024号公报、CN201280028888.9)中，已经披露了吡咯并喹啉醌的一些晶型，但仍有必要开发出性能优于已知晶型，且具有广阔应用前景的新晶型。与现有技术相比，本发明提供的晶型引湿性更低，在75％RH下的引湿性小于0.3％，优选无引湿性。
本发明旨在提供一种结晶度高、产品纯度高，残留溶剂低，易于过滤、干燥、储存的晶型和环保无污染的工艺。
发明内容
本发明第一方面的目的在于提供具有卓越的化学和物理稳定性，且在溶解性、晶型稳定性、吸湿性和加工(过滤、干燥、压片)适应性方面具有优异性质的吡咯并喹啉醌钠盐的新晶型。本发明第二方面的目的在于提供所述吡咯并喹啉醌钠盐新晶型的制备方法以及第三方面的目的在于提供包含这些新晶型的药物组合物、化妆品组合物、功能性食品或营养剂以及它们在医药、功能性食品和化妆品领域中的用途。
在本发明的第一方面中，提供了一种吡咯并喹啉醌二钠盐的新晶型I，该晶型I在X-射线粉末衍射(XRPD)图谱中在以下2θ衍射角处有特征峰：8.0±0.2°、10.9±0.2°、11.2±0.2°、15.1±0.2°、15.8±0.2°、22.4±0.2°、25.5±0.2°、27.7±0.2°。
进一步的，在本发明的另一实施方案中，本发明的吡咯并喹啉醌二钠盐的晶型I还在以下2θ衍射角处有特征峰：16.9±0.2°、18.2±0.2°、20.6±0.2°、21.5±0.2°、23.7±0.2°、26.0±0.2°、27.3±0.2°、28.1±0.2°、28.5±0.2°、29.8±0.2°。
在本发明的一个具体实施方案中，本发明的吡咯并喹啉醌二钠盐晶型I的X-射线粉末衍射谱图具有如下述表1所示的2θ角、d值和特征峰相对强度数据：
表1
Figure PCTCN2016099013-appb-000002
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型I具有如图1所示的X-射线粉末衍射谱图。
本发明的吡咯并喹啉醌二钠盐晶型I，可以用KBr压片测得的红外吸收图谱表征，其在约3502.68cm-1、3075.00cm-1、1745.31cm-1、1720.24cm-1、1662.49cm-1、1607.36cm-1、1542.24cm-1、1505.77cm-1、1372.28cm-1、1300.29cm-1、1280.01cm-1、1260.47cm-1、1220.80cm-1、1202.86cm-1、1176.23cm-1、971.91cm-1、940.36cm-1、886.67cm-1、812.19cm-1、792.93cm-1、770.80cm-1、747.86cm-1、702.98cm-1、610.52cm-1、538.17cm-1、430.94cm-1处有吸收峰。
进一步地，在本发明的另一实施方案中，本发明的吡咯并喹啉醌二钠盐晶型I的红外吸收谱图还在约1431.23cm-1、1398.99cm-1、1144.92cm-1、1082.92cm-1处有特征峰。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型I具有如图2所示的红外谱图。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型I具有如图3所示的差示扫描量热分析(DSC)图谱。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型I具有如图4所示的热重分析(TGA)图谱。
在本发明的第一方面中，提供了一种吡咯并喹啉醌二钠盐的新晶型II，该晶型II在X-射线粉末衍射(XRPD)图谱中在以下2θ衍射角处有特征峰：7.8±0.2°、10.8±0.2°、11.1±0.2°、22.2±0.2°、27.5±0.2°。
进一步的，在本发明的另一实施方案中，本发明的吡咯并喹啉醌二钠盐的晶型II还在以下2θ衍射角处有特征峰：8.9±0.2°、15.6±0.2°、18.0±0.2°、23.5±0.2°、28.2±0.2°。
在本发明的一个具体实施方案中，本发明的吡咯并喹啉醌二钠盐晶型II的X-射线粉末衍射谱图具有如下表2所示的2θ、d和相对强度数据：
表2
Figure PCTCN2016099013-appb-000003
Figure PCTCN2016099013-appb-000004
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型II具有如图5所示的X-射线粉末衍射谱图。
本发明的吡咯并喹啉醌二钠盐晶型II，可以用KBr压片测得的红外吸收图谱表征，其在约1719.04cm-1、1667.65cm-1、1610.08cm-1、1541.60cm-1、1503.07cm-1、1279.55cm-1、1222.19cm-1、1142.30cm-1、1079.27cm-1、963.60cm-1、938.81cm-1、792.11cm-1、771.05cm-1、702.30cm-1、609.59cm-1、535.29cm-1、429.20cm-1、411.27cm-1处有吸收峰。
进一步地，在本发明的另一实施方案中，本发明的吡咯并喹啉醌二钠盐晶型II还在约3499.74cm-1、3122.28cm-1、3074.36cm-1、2560.88cm-1、2360.30cm-1、1744.02cm-1、1397.72cm-1、888.38cm-1处有特征峰。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型II具有如图6所示的红外谱图。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型II具有如图7所示的DSC图谱。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型II具有如图8所示的TGA图谱。
在本发明的第一方面中，提供了一种吡咯并喹啉醌二钠盐的新晶型III，该晶型II在X-射线粉末衍射(XRPD)图谱中在以下2θ衍射角处有特征峰：7.4±0.2°、8.6±0.2°、14.0±0.2°、14.6±0.2°、19.9±0.2°、21.4±0.2°、26.0±0.2°、27.3±0.2°、28.5±0.2°。
本发明的吡咯并喹啉醌二钠盐晶型III的X-射线粉末衍射谱图具有如下表3所示的2θ、d和相对强度数据：
表3
Figure PCTCN2016099013-appb-000005
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型III具有如图9所示的X-射线粉末衍射谱图。
本发明的吡咯并喹啉醌二钠盐晶型III，可以用KBr压片测得的红外吸收图谱表征，其在约3446.06cm-1、1721.16cm-1、1680.19cm-1、1613.68cm-1、1541.14cm-1、1496.91cm-1、 1349.99cm-1、1243.04cm-1、940.32cm-1、722.10cm-1、562.47cm-1、424.89cm-1处有吸收峰。
进一步地，在本发明的另一实施方案中，本发明的吡咯并喹啉醌二钠盐晶型III还在约1077.39cm-1、801.05cm-1、749.60cm-1、处有特征峰。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型III具有如图10所示的红外谱图。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型III具有如图11所示的DSC图谱。
非限制性地，本发明的吡咯并喹啉醌二钠盐晶型III具有如图12所示的TGA图谱。
在本发明的第一方面中，提供了一种吡咯并喹啉醌一钠盐的新晶型IV，该晶型IV在X-射线粉末衍射(XRPD)图谱中在以下2θ衍射角处有特征峰：7.8±0.2°、10.8±0.2°、15.1±0.2°、15.7±0.2°、16.9±0.2°、18.2±0.2°、20.6±0.2°、27.7±0.2°、28.4±0.2°。
进一步的，在本发明的另一实施方案中，本发明的吡咯并喹啉醌一钠盐晶型IV还在以下2θ衍射角处有特征峰：18.0±0.2°、22.3±0.2°、23.6±0.2°、25.4±0.2°、25.8±0.2°。
在本发明的一个具体实施方案中，本发明的吡咯并喹啉醌一钠盐晶型IV的X-射线粉末衍射谱图具有如下表4所示的2θ、d和相对强度数据：
表4
Figure PCTCN2016099013-appb-000006
非限制性地，本发明的吡咯并喹啉醌一钠盐晶型IV具有如图13所示的X-射线粉末衍射谱图。
本发明的吡咯并喹啉醌一钠盐晶型IV，可以用KBr压片测得的红外吸收图谱表征，其在约3503.09cm-1、3074.74cm-1、1744.71cm-1、1720.37cm-1、1664.30cm-1、1606.88cm-1、 1544.10cm-1、1505.39cm-1、1398.65cm-1、1301.22cm-1、1280.13cm-1、1259.72cm-1、1202.57cm-1、1176.96cm-1、1144.49cm-1、1082.30cm-1、970.03cm-1、939.56cm-1、793.39cm-1、770.25cm-1、748.91cm-1、717.95cm-1、608.86cm-1、536.98cm-1、430.96cm-1处有吸收峰。
非限制性地，本发明的吡咯并喹啉醌一钠盐晶型IV具有如图14所示的红外谱图。
非限制性地，本发明的吡咯并喹啉醌一钠盐晶型IV具有如图15所示的DSC图谱。
非限制性地，本发明的吡咯并喹啉醌一钠盐晶型IV具有如图16所示的TGA图谱。
在本发明的第二方面中，提供了所述吡咯并喹啉醌二钠盐晶型I的制备方法，所述方法包括：
(1)将吡咯并喹啉醌作为溶质，纯水或乙醇/水为溶剂；
(2)调节pH至1-2；
(3)搅拌析晶；
(4)继续调节pH至3-4；
(5)过滤，得到吡咯并喹啉醌二钠盐晶型I。
当使用水或乙醇/水作为溶剂时，吡咯并喹啉醌与该混合溶剂的重量体积比(g/ml)优选1:10-1:400，更优选1:50-1:200。其中，(1)中描述的结晶液状态可为澄清或混悬；其温度控制在15℃-60℃，优选25℃-50℃。
在本发明的第二方面中，还提供了所述吡咯并喹啉醌二钠盐晶型II的制备方法，所述方法包括：将吡咯并喹啉醌二钠盐晶型I在30℃-60℃真空条件下烘干可得晶型II。
在本发明的第二方面中，还提供了所述吡咯并喹啉醌二钠盐晶型III的制备方法，所述方法包括：
(1)将吡咯并喹啉醌加入到乙醇/水的混合溶剂中；
(2)搅拌，升温溶解；
(3)过滤、降温、调节pH至3-4；
(4)析晶；
(5)过滤，得到吡咯并喹啉醌二钠盐晶型III。
当使用乙醇/水作为溶剂时，吡咯并喹啉醌与该混合溶剂的重量体积比(g/ml)优选1:200-1:400。乙醇与水的体积比为1：1-3：1；其结晶温度控制在0～20℃，优选5～15℃。
在本发明的第二方面中，还提供了所述吡咯并喹啉醌一钠盐晶型IV的制备方法，所述方法包括：
(1)将吡咯并喹啉醌作为溶质，纯水或乙醇/水为溶剂；
(2)调节pH至1-2；
(3)搅拌析晶；
(4)过滤，得到吡咯并喹啉醌一钠盐晶型IV。
其中，(1)中描述的结晶液状态可为澄清或混悬；其温度控制在15℃-60℃，优选25℃-50℃。
上述方法中，所述吡咯喹啉醌与相应溶剂的重量体积比的单位可以为g/ml、Kg/L等，视具体的操作规模而定。
在本发明的第三方面中，提供了包含本发明的新晶型的药物组合物、化妆品组合物、功能性食品或营养剂以及它们在医药、功能性食品和化妆品领域中的用途。
本发明方法中所使用的吡咯并喹啉醌原料可以商购获得，或者按照已知方法制备。本发明所使用的溶剂没有特别的限制，可采用商购的常规溶剂。
本发明方法中所述的“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌；另有说明除外。
本发明所涉及的X-射线粉末衍射仪器(XRPD)及测试条件为：X-衍射仪器型号Rigaku D/max-2200Cu靶；操作方法：扫描速度4°/min，扫描步宽0.01°。
本发明所涉及的红外分光广度仪及测试条件为：红外分光光度仪型号：BRWKER JECTOR 22；操作方法：采用KBr压片法，扫描范围400-4000cm-1。
本发明涉及的差示扫描量热分析(DSC)测试条件为：DSC检测仪型号为：NETZSCH DSC200 F3 Jaia；操作方法：升温速率10℃/min，温度范围：30-250℃。
本发明涉及的热重分析(TGA)测试条件为：TGA检测仪型号为：PerkinElmer TGA400；操作方法：升温速率10℃/min，温度范围：30-300℃。
本发明涉及的显微镜测试条件为：显微镜型号为：OLYMPUS CX31；操作方法：目镜10x，物镜10x。
本发明涉及的液相测试条件为：色谱柱为月旭LP-C18 4.6×250mm，5μm；A相：5mM磷酸二氢钾，用磷酸调节pH至2.2；B相：纯乙腈；检测波长：251nm；流速：1.0ml/min；进样量：10μl；柱温：30℃，液相条件如表5所示：
表5
t(min) A(％) B(％)
0.0min 93 7％
2.0min 93 7％
15.0min 85 15％
30.0min 75 25％
31.0min 70 30％
40.0min 70 30％
40.1min 93 7％
59.0min 93 7％
应当强调的是，本发明技术方案中所涉及的数值或数值端点，其含义或意在保护的范围并不局限于该数字本身。本领域技术人员能够理解，它们包含了那些已被本领域广为接受的可允许的误差范围，例如：实验误差、测量误差、统计误差和随机误差等，而这些误差范围均包含在本发明的范围之内。
另外，本发明还提供了显微镜下的吡咯并喹啉醌钠盐的晶习图片，如图17所示，其中，吡咯并喹啉醌二钠盐晶型I晶习为菱形，晶型II由晶型I烘干制得，晶习未发生改变，晶型IV与晶型I的晶习一致，从图中可看出晶型I的晶习规则，固体流动性好，易于过滤、干燥，另外，结晶出的晶体纯度高，吸湿性差，稳定性好，易于保存。
附图说明
图1为实施例1所得吡咯并喹啉醌二钠盐晶型I的X-射线粉末衍射谱。
图2为实施例1所得吡咯并喹啉醌二钠盐晶型I的红外吸收光谱。
图3为实施例1所得吡咯并喹啉醌二钠盐晶型I的DSC图谱。
图4为实施例1所得吡咯并喹啉醌二钠盐晶型I的TGA图谱。
图5为实施例9所得吡咯并喹啉醌二钠盐晶型II的X-射线粉末衍射谱。
图6为实施例9所得吡咯并喹啉醌二钠盐晶型II的红外吸收光谱。
图7为实施例9所得吡咯并喹啉醌二钠盐晶型II的DSC图谱。
图8为实施例9所得吡咯并喹啉醌二钠盐晶型II的TGA图谱。
图9为实施例11所得吡咯并喹啉醌二钠盐晶型III的X-射线粉末衍射谱。
图10为实施例11所得吡咯并喹啉醌二钠盐晶型III的红外吸收光谱。
图11为实施例11所得吡咯并喹啉醌二钠盐晶型III的DSC图谱。
图12为实施例11所得吡咯并喹啉醌二钠盐晶型III的TGA图谱。
图13为实施例14所得吡咯并喹啉醌一钠盐晶型IV的X-射线粉末衍射图谱。
图14为实施例14所得吡咯并喹啉醌一钠盐晶型IV的红外吸收光谱。
图15为实施例14所得吡咯并喹啉醌一钠盐晶型IV的DSC图谱。
图16为实施例14所得吡咯并喹啉醌一钠盐晶型IV的TGA图谱。
图17为吡咯并喹啉醌钠盐的晶习图片。
具体实施方式
下列实施例进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
本发明所用的吡咯并喹啉醌粗品为吡咯并喹啉醌三钠盐，其可以使用本领域常规方法制得：例如通过专利文献CN101228963B或文献J.Am.Chem.Soc.,1981,103,5599～5600中的方法制得。
实施例1及实施例14中的吡咯并喹啉醌三钠盐溶液的制备：通过专利文献日本特许第2751183号公报中的方法制得到吡咯并喹啉醌发酵液，该发酵液调节pH至9-10，再经过柱处理(将样品加入硅胶柱，硅胶200-300目，用乙醇洗脱醇溶性杂质，再用水洗脱物料，接纯化后的样品溶液)后，得到的溶液为吡咯并喹啉醌三钠盐溶液。
实施例
实施例1
将吡咯并喹啉醌三钠盐溶液100g(HPLC纯度>98％，浓度0.7％)，升温至40℃，持续搅拌30min，调节pH至1.0-2.0；过滤，得到澄清滤液，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶12h，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到0.45g晶体，HPLC测得其纯度为99.1％，X-射线粉末衍射检测表明为新晶型。
该晶型的X-射线粉末衍射、红外、DSC以及TGA谱图详见图1-4，在本发明中将其命名为吡咯并喹啉醌二钠盐晶型I。
实施例2
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，升温至60℃，持续搅拌30min，溶解；过滤，调节pH至1.0-2.0；过滤，得到澄清滤液，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶48h，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到0.62g晶体，HPLC测得其纯度为98.8％，X-射线粉末衍射检测表明为晶型I。
实施例3
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，升温至40℃，持续搅拌30min，溶解；过滤，降温至15℃，调节pH至1.0-2.0；升温至45℃下搅拌析晶12h，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到0.61g晶体，HPLC测得其纯度为99.2％，X-射线粉末衍射检测表明为晶型I。
实施例4
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，降温至15℃，调节PH至1.0-2.0；搅拌12h，调节PH至3.0-4.0；搅拌，过滤，30℃下真空干燥，得0.61g晶体，HPLC测得其纯度为99.0％，X-射线粉末衍射检测表明为晶型I。
实施例5
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，100ml乙醇升温至50℃，持续搅拌30min，溶解；过滤，降温至15℃，调节pH至1.0-2.0；升温至45℃下搅拌析晶12h，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到0.80g晶体，HPLC测得其纯度为99.2％，X-射线粉末衍射检测表明为晶型I。
实施例6
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，300ml乙醇升温至30℃，调节pH至1.0-2.0；搅拌12h，调节pH至3.0-4.0；搅拌，过滤，45℃下真空干燥，得到0.85g晶体，HPLC测得其纯度为99.1％，X-射线粉末衍射检测表明为晶型I。
实施例7
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，10ml乙醇，降温至15℃，调节pH至1.0-2.0；搅拌12h，调节pH至3.0-4.0；搅拌，过滤，35℃下真空干燥，得到0.75g晶体，HPLC测得其纯度为98.7％，X-射线粉末衍射检测表明为晶型I。
实施例8
将吡咯并喹啉醌粗品1Kg(HPLC纯度>98％)溶于100L水中，100L乙醇升温至50℃，持续搅拌30min，溶解；过滤，降温至15℃，调节pH至1.0-2.0；升温至45℃下搅拌析晶12h，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到800g晶体，HPLC测得其纯度为99.1％，X-射线粉末衍射检测表明为晶型I。
实施例2-8所得产物的X-射线粉末衍射谱图与实施例1相同，在此不再重复示出。
实施例9
将实施例1中吡咯并喹啉醌二钠盐晶型I在60℃下烘干8小时得到新晶型，该晶型的X-射线粉末衍射、红外、DSC以及TGA谱图详见图5-9，在本发明中将其命名为吡咯并喹啉醌二钠盐晶型II。
实施例10
将实施例2中吡咯并喹啉醌二钠盐晶型I在30℃下烘干8小时得吡咯并喹啉醌二钠盐晶型II。
实施例10所得产物的X-射线粉末衍射谱图与实施例9相同，在此不再重复示出。
实施例11
将吡咯并喹啉醌粗品100g(HPLC纯度>98％)溶于10L水中，10L乙醇升温至50℃，持续搅拌30min，溶解；过滤，降温至10℃，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到900g晶体，HPLC测得其纯度为98.7％，XRPD检测为新晶型，该晶型的X-射线粉末衍射、红外、DSC以及TGA谱图详见图9-12，在本发明中将其命名为吡咯并喹啉醌二钠盐晶型III。
实施例12
将吡咯并喹啉醌粗品100g(HPLC纯度>98％)溶于10L水中，30L乙醇升温至50℃，持续搅拌30min，溶解；过滤，降温至20℃，调节pH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得到920g晶体，HPLC测得其纯度为98.7％，XRPD检测为晶型III。
实施例13
将吡咯并喹啉醌粗品100g(HPLC纯度>98％)溶于10L水中，20L乙醇升温至50℃，持续搅拌30min，溶解；过滤，降温至0℃，调节PH至3.0-4.0；搅拌，过滤，25℃下真空干燥，得930g晶体，HPLC测得其纯度为98.7％，XRPD检测为晶型III。
实施例14
将吡咯并喹啉醌三钠盐溶液100g(HPLC纯度>98％，浓度0.7％)，升温至40℃，持续搅拌30min，调节pH至1.0-2.0；过滤，得到澄清滤液，滤液以10℃/h的速率降温至25℃， 并在25℃下搅拌析晶12h，过滤，25℃下真空干燥，得到0.9g晶体，HPLC测得其纯度为99.4％，X-射线粉末衍射检测表明为新晶型。
该晶型的X-射线粉末衍射、红外、DSC以及TGA谱图详见图13-16，在本发明中将其命名为吡咯并喹啉醌一钠盐晶型IV。
实施例15
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，升温至60℃，持续搅拌30min，溶解；过滤，调节PH至1.0-2.0；过滤，得到澄清滤液，滤液以10℃/h的速率降温至25℃，并在25℃下搅拌析晶48h，过滤，25℃下真空干燥，得0.72g晶体，HPLC测得其纯度为99.1％，X-射线粉末衍射检测表明为晶型IV。
实施例16
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，升温至40℃，持续搅拌30min，溶解；过滤，降温至15℃，调节PH至1.0-2.0；搅拌12h，过滤，25℃下真空干燥，得0.71g晶体，HPLC测得其纯度为99.2％，X-射线粉末衍射检测表明为晶型IV
实施例17
将吡咯并喹啉醌粗品1g(HPLC纯度>98％)溶于100ml水中，降温至15℃，调节PH至1.0-2.0；搅拌12h，过滤，30℃下真空干燥，得0.88g晶体，HPLC测得其纯度为99.0％，X-射线粉末衍射检测表明为晶型IV
实施例15-17所得产物的X-射线粉末衍射谱图与实施例14相同，在此不再重复示出。
实施例18
吸湿性试验。测试条件：将表面皿放置在温度25℃，湿度为75％的环境中24h，然后称量下述样品各1g，快速放入温度25℃，湿度为75％的环境中24h充分吸湿。结果如下：
Figure PCTCN2016099013-appb-000007
由上述试验数据可以看出：晶型I、晶型III、晶型IV不吸湿，稳定性良好，晶型II次之，CN201080031945晶型吸湿性最强。所以，本发明开发的新晶型不易与外界进行物质交换，能保持较好的稳定性。
另外，由图17中的晶习图片可以看出本发明的晶型I、晶型II和晶型IV呈菱形，晶型III成针状，晶型I、晶型II、晶型III和晶型IV的晶习规则，易于过滤、洗涤、能有效减少溶液在固体中的残留，有效提高了产品的纯度，降低溶剂残留，利于干燥，单位体积内的比表面积小，表面能低，与环境接触面小，有利于物质稳定。此外，本发明的晶型I与晶型II在制备过程中可以不使用有机溶剂，从而有效的避免了样品中的溶剂残留，降低了生产成本，减少了溶剂回收成本，该工艺更绿色环保。
综上所述，本发明的发明人经过大量研究发现了本发明的吡咯并喹啉醌二钠盐新晶型，其溶解性良好、结晶工艺简单、便于操作、污染小、可实现工业化生产，而且本发明的晶型药物同时具备产品纯度高、理化性质优异、化学稳定性良好、可加工(过滤、干燥、溶出和压片)再现的优点。

Claims (18)

  1. 一种吡咯并喹啉醌二钠盐晶型I，其特征在于，使用Cu靶，其X-射线粉末衍射谱在以下2θ衍射角处具有特征峰：8.0±0.2°、10.9±0.2°、11.2±0.2°、15.1±0.2°、15.8±0.2°、22.4±0.2°、25.5±0.2°和27.7±0.2°。
  2. 如权利要求1所述的吡咯并喹啉醌二钠盐晶型I，使用Cu靶，其特征在于，其X-射线粉末衍射谱还在以下2θ衍射角处具有特征峰：16.9±0.2°、18.2±0.2°、20.6±0.2°、21.5±0.2°、23.7±0.2°、26.0±0.2°、27.3±0.2°、28.1±0.2°、28.5±0.2°和29.8±0.2°。
  3. 一种制备权利要求1-2中任一项所述的吡咯并喹啉醌二钠盐晶型I的方法，所述方法包括下述步骤：
    (1)将吡咯并喹啉醌为溶质，纯水或乙醇/水为溶剂；
    (2)调节pH至1-2；
    (3)析晶；
    (4)继续调节pH至3-4；
    (5)过滤，得到所述吡咯并喹啉醌二钠盐晶型I。
  4. 如权利要求3所述的方法，其特征在于，当使用水或乙醇/水作为溶剂时，吡咯并喹啉醌与该混合溶剂的重量体积比，以g/ml为单位，优选1:10-1:400，更优选1:50-1:200；其温度控制在15℃-60℃，优选25℃-50℃。
  5. 一种吡咯并喹啉醌二钠盐晶型II，其特征在于，使用Cu靶，其X-射线粉末衍射谱在以下2θ衍射角处具有特征峰：7.8±0.2°、10.8±0.2°、11.1±0.2°、22.2±0.2°和27.5±0.2°。
  6. 如权利要求5所述的吡咯并喹啉醌二钠盐晶型II，其特征在于，使用Cu靶，其X-射线粉末衍射谱还在以下2θ衍射角处具有特征峰：8.9±0.2°、15.6±0.2°、18.0±0.2°、23.5±0.2°和28.2±0.2°。
  7. 一种制备权利要求5-6中任一项所述的吡咯并喹啉醌二钠盐晶型II的方法，其包括将权利要求1或2中所述的吡咯并喹啉醌二钠盐晶型I在30℃-60℃真空条件下烘干得到晶型II。
  8. 一种吡咯并喹啉醌二钠盐晶型III，其特征在于，使用Cu靶，其X-射线粉末衍射谱在以下2θ衍射角处具有特征峰：7.4±0.2°、8.6±0.2°、14.0±0.2°、14.6±0.2°、19.9±0.2°、21.4±0.2°、26.0±0.2°、27.3±0.2°和28.5±0.2°。
  9. 一种制备权利要求8中所述的吡咯并喹啉醌二钠盐晶型III的方法，所述方法包括下述步骤：
    (1)将吡咯并喹啉醌加入到乙醇/水的混合溶剂中；
    (2)搅拌，升温溶解；
    (3)降温、调节pH至3-4；
    (4)析晶；
    (5)过滤，得到吡咯并喹啉醌二钠盐晶型III。
  10. 如权利要求8所述的方法，其特征在于，当使用乙醇/水作为溶剂时，吡咯并喹啉 醌与该混合溶剂的重量体积比，以g/ml为单位，为1:200-1:400；乙醇与水的体积比为1：1-3：1；其结晶温度控制在0～20℃，优选5～15℃。
  11. 一种吡咯并喹啉醌一钠盐晶型IV，其特征在于，使用Cu靶，其X-射线粉末衍射谱在以下2θ衍射角处具有特征峰：7.8±0.2°、10.8±0.2°、15.1±0.2°、15.7±0.2°和16.9±0.2°、18.2±0.2°、20.6±0.2°、27.7±0.2°、28.4±0.2°。
  12. 如权利要求11所述的吡咯并喹啉醌一钠盐晶型IV，其特征在于，使用Cu靶，其X-射线粉末衍射谱还在以下2θ衍射角处具有特征峰：18.0±0.2°、22.3±0.2°、23.6±0.2°、25.4±0.2°、25.8±0.2°。
  13. 一种制备权利要求11-12中任一项所述的吡咯并喹啉醌一钠盐晶型IV的方法，所述方法包括下述步骤：
    (1)将吡咯并喹啉醌为溶质，纯水或乙醇/水为溶剂；
    (2)调节pH至1-2；
    (3)析晶；
    (4)过滤，得到吡咯并喹啉醌一钠盐晶型IV。
  14. 如权利要求13所述的方法，其特征在于，当使用水或乙醇/水作为溶剂时，吡咯并喹啉醌与该混合溶剂的重量体积比，以g/ml为单位，优选1:10-1:400，更优选1:50-1:200；其温度控制在15℃-60℃，优选25℃-50℃。
  15. 一种含有权利要求1-14中任一项所述的吡咯并喹啉醌钠盐晶型的药物组合物。
  16. 一种含有权利要求1-14中任一项所述的吡咯并喹啉醌钠盐晶型的化妆品组合物。
  17. 一种含有权利要求1-14中任一项所述的吡咯并喹啉醌钠盐晶型的功能性食品或营养剂。
  18. 权利要求1-14中任一项所述的吡咯并喹啉醌钠盐晶型在制备药品、功能性食品、化妆品中的用途。
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CN115716825A (zh) * 2021-08-24 2023-02-28 浙江医药股份有限公司新昌制药厂 吡咯并喹啉醌二钠盐结晶、其制备方法及包含其的组合物
CN115724840A (zh) * 2021-08-26 2023-03-03 浙江医药股份有限公司新昌制药厂 涉及一种吡咯并喹啉醌三钠盐结晶、其制备方法及包含其的组合物
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CN115716825A (zh) * 2021-08-24 2023-02-28 浙江医药股份有限公司新昌制药厂 吡咯并喹啉醌二钠盐结晶、其制备方法及包含其的组合物
CN115724840A (zh) * 2021-08-26 2023-03-03 浙江医药股份有限公司新昌制药厂 涉及一种吡咯并喹啉醌三钠盐结晶、其制备方法及包含其的组合物
CN117327069A (zh) * 2023-09-27 2024-01-02 山东原力泰医药科技有限公司 吡咯并喹啉醌二钠盐晶型及其制备方法和应用
CN117327069B (zh) * 2023-09-27 2024-04-30 山东原力泰医药科技有限公司 吡咯并喹啉醌二钠盐晶型及其制备方法和应用

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