WO2016197980A1 - 一种黄芩苷a晶型、其制备方法及其应用 - Google Patents

一种黄芩苷a晶型、其制备方法及其应用 Download PDF

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WO2016197980A1
WO2016197980A1 PCT/CN2016/085479 CN2016085479W WO2016197980A1 WO 2016197980 A1 WO2016197980 A1 WO 2016197980A1 CN 2016085479 W CN2016085479 W CN 2016085479W WO 2016197980 A1 WO2016197980 A1 WO 2016197980A1
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crystal form
baicalin
form according
crystal
dried
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PCT/CN2016/085479
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English (en)
French (fr)
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朱理平
梅雪锋
王建荣
王晓娟
朱冰清
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诸城市浩天药业有限公司
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Publication of WO2016197980A1 publication Critical patent/WO2016197980A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P7/10—Antioedematous agents; Diuretics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/06—Benzopyran radicals
    • C07H17/065—Benzo[b]pyrans
    • C07H17/07—Benzo[b]pyran-4-ones

Definitions

  • the invention belongs to the technical field of medicinal chemistry, in particular to a crystal form of baicalin A, a preparation method thereof and application thereof.
  • polymorphism phenomenon refers to a phenomenon in which solid materials are arranged in two or more different spatial arrangements to form solid states having different physicochemical properties.
  • polymorphs include multi-component crystalline forms such as organic solvates, hydrates, and the like.
  • Drug polymorphism is widespread in drug development and is an inherent property of organic small molecule compounds. Theoretically, small molecule drugs can have an infinite number of crystal packing methods - polymorphs. Studies have shown that the number of drug polymorphs found is directly proportional to the time and resources of the research they are investigating. Like Lipitor, the world's highest-selling drug to date, there are as many as 35 patents for patent protection. Polymorphism is not only controlled by the internal structure of the molecule itself, functional group properties, intramolecular and intermolecular interactions, but also by drug synthesis process design, crystallization and purification conditions, formulation excipient selection, formulation process Route and granulation methods, as well as storage conditions, packaging materials and other factors.
  • crystal form research and control has become an important research content in the drug development process.
  • the crystal form study includes two stages of crystal discovery and crystal form optimization.
  • the crystal discovery stage a variety of crystallization methods such as melt crystallization, solution volatilization, rapid cooling and suspension crystallization are employed, by changing the crystallization conditions and solvent. , external factors affecting the crystallization of the drug, such as temperature, speed and ratio of suspended solvent, using a high-throughput sample preparation platform, preparing hundreds of crystallization tests at the same time, using micro sample preparation techniques and analytical testing methods to prepare and discover new crystal forms. .
  • Baicalin is a flavonoid extracted from the root of Astragalus membranaceus. It has significant biological activity, has antibacterial, diuretic, anti-inflammatory, anti-metamorphic and antispasmodic effects, and has a strong anti-cancer effect. And other physiological effects, so it can be used for both medicine and cosmetics.
  • the main component of Astragalus membranaceus is baicalin, up to 9%-14%.
  • Baicalin is the main raw material for preparing Chinese patent medicines such as Shuanghuanglian Oral Liquid, Yinhuang Soft Capsule and Yinhuang Tablet.
  • baicalin Due to its fat solubility and poor water solubility, baicalin has poor absorption in vivo, low bioavailability (orally bioavailability of 2.2-30%), and unstable drug efficacy, which limits clinical application.
  • Baicalin has a polymorphic phenomenon, but there are no reports of crystallographic patents.
  • the invention adopts a new crystal nucleation mode and crystallization conditions to prepare a new crystal form of baicalin: A crystal form. It has been found that the new crystal form has small hygroscopicity, good stability, and can form a regular crystal form, which is beneficial to the improvement of the process and physical and chemical properties of the drug, and improves the performance of the drug.
  • One of the objects of the present invention is to provide a crystal form of baicalin A which has low hygroscopicity, good stability, and regular crystal form.
  • the technical solution of the present invention is:
  • baicalin A crystal form having an X-ray powder diffraction at a diffraction angle of 4.99, 5.65, 6.99, 8.21, 8.64, 9.95, 11.78, 11.98, 12.61, 14.94, 16.33, 17.38, 18.52, 20.76, 21.26, 21.68, 24.94, 26.64, 28.80, 29.97 degrees with characteristic peaks.
  • the X-ray powder diffraction pattern of Form A is substantially as shown in FIG.
  • the differential scanning calorimetry pattern of Form A is substantially as shown in FIG.
  • the differential scanning calorimetry of the crystalline form has a characteristic melting peak at 220 ⁇ 1 °C.
  • the infrared pattern of the crystal form has characteristic peaks at least at 1754, 1731, 1659, 1602, 1574, 1473, 1367, 1075 cm -1 .
  • the infrared spectrum of the crystal form A is substantially as shown in FIG.
  • thermogravimetric analysis pattern of the crystal form A is basically as shown in FIG.
  • the hygroscopicity analysis pattern of the crystal form A is basically as shown in FIG.
  • the thermal weight loss analysis of the crystal form has a decomposition temperature of 220 ⁇ 1 ° C, and there is no weight loss before the decomposition temperature.
  • the crystalline form is an unsolvate or a non-hydrate.
  • the second object of the present invention is to provide a method for preparing a baicalin A crystal form, comprising the steps of:
  • the preparation method comprises the following steps:
  • the base is sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • the acid is concentrated hydrochloric acid, hydrochloric acid or sulfuric acid.
  • the volume ratio of the solid to the methanol is 1:10.
  • the third object of the present invention is to provide the application of baicalin A crystal form in bacteriostatic, anti-inflammatory, diuretic, anti-metamorphosis, antispasmodic and anti-cancer drugs.
  • a fourth object of the present invention is to provide a baicalin A crystal form having an X-ray powder diffraction represented by a 2 ⁇ angle at diffraction angles of 4.99 ° ⁇ 0.1 °, 5.65 ° ⁇ 0.1 °, and 8.21 ° ⁇ 0.1°, 14.94° ⁇ 0.1°, 18.52° ⁇ 0.1°, and 21.68° ⁇ 0.1°.
  • the crystal form is a non-hydrate, and the X-ray powder diffraction pattern of the Form A is substantially as shown in FIG.
  • a fifth object of the present invention is to provide a method of treatment comprising the step of administering to a subject in need thereof the baicalin A crystal form of the first aspect of the invention.
  • the treatment is for bacteriostatic, anti-inflammatory, diuretic, anti-metamorphic, antispasmodic, and anti-cancer.
  • the invention provides a baicalin A crystal form and a preparation method thereof, the preparation method thereof is simple in operation, the crystal form has small hygroscopicity, has good stability, and can form a regular crystal form, thereby facilitating the process of the medicine. And the improvement of physical and chemical properties, improve the performance of the drug.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of the baicalin A crystal form provided by the present invention.
  • DSC differential scanning calorimetry
  • IR infrared spectrum
  • Figure 5 is a graph showing the hygroscopicity analysis (DVS) of the baicalin A crystal form provided by the present invention.
  • Figure 6 is an X-ray powder diffraction (XRPD) pattern of the stability of 1, 2, 4, and 6 weeks of the baicalin A crystal form provided by the present invention.
  • XRPD X-ray powder diffraction
  • Form A of the present invention whose X-ray powder diffraction expressed in terms of 2 ⁇ angle is expressed in the form of a characteristic peak ⁇ x° at a diffraction angle peak, where x ⁇ 0.2°, preferably, x is 0.05°, 0.1° or 0.2°.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) the crystalline form A of the first aspect of the invention, and (b) a pharmaceutically acceptable carrier.
  • the "active ingredient" in the pharmaceutical composition of the present invention means a compound of the formula (I) according to the present invention.
  • safety and effective amount is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet or an injection.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • composition capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate,
  • the administration form of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration forms include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compounds of the invention may be administered alone or in combination with other therapeutic agents.
  • the ratio of material to liquid is g (solid): mL (liquid).
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, hydrochloric acid is added, the pH is adjusted to 1.5, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding potassium hydroxide aqueous solution, adjust the pH to 7.2, then add calcium chloride, stir evenly, then add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, hydrochloric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, concentrated hydrochloric acid is added, the pH is adjusted to 2.0, and after the stirring is stopped, the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid is put into a crystallization tank, methanol is added at a ratio of 1:10, and the mixture is stirred for 1 hour, centrifuged, and the wet product after centrifugation is dried to obtain a baicalin A crystal form, which is a yellow crystalline powder.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, concentrated hydrochloric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid is put into a crystallization tank, methanol is added at a ratio of 1:10, and the mixture is stirred for 1 hour, centrifuged, and the wet product after centrifugation is dried to obtain a baicalin A crystal form, which is a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding potassium hydroxide aqueous solution, adjust the pH to 7.5, then add calcium chloride, stir evenly, then add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, sulfuric acid is added, the pH is adjusted to 1.5, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding potassium hydroxide aqueous solution, adjust the pH to 7.2, then add calcium chloride, stir evenly, then add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, hydrochloric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, sulfuric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding potassium hydroxide aqueous solution, adjust the pH to 7.0, then add calcium chloride, stir evenly, add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, concentrated hydrochloric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid is put into a crystallization tank, methanol is added at a ratio of 1:10, and the mixture is stirred for 1 hour, centrifuged, and the wet product after centrifugation is dried to obtain a baicalin A crystal form, which is a yellow crystalline powder.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, sulfuric acid is added, the pH is adjusted to 1.5, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding lithium hydroxide aqueous solution, adjust the pH to 7.5, then add calcium chloride, stir evenly, then add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, sulfuric acid is added, the pH is adjusted to 2.0, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and passed.
  • the filtered and dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid crude Take 10 g of baicalin solid crude, dissolve it by adding lithium hydroxide aqueous solution, adjust the pH to 7.5, then add calcium chloride, stir evenly, then add glacial acetic acid to adjust the floc until particles appear, and let stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, hydrochloric acid is added, the pH is adjusted to 1.5, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • baicalin solid 10 g was taken, dissolved in aqueous sodium hydroxide solution, adjusted to pH 7.2, then calcium chloride was added, stirred well, and then glacial acetic acid was added to adjust the floc until particles appeared, and the precipitate was allowed to stand for 5 hours.
  • the supernatant after removal of the precipitate is stirred, the rotation speed is controlled at 10 rpm, the temperature is ⁇ 90 ° C, sulfuric acid is added, the pH is adjusted to 1.8, the stirring is stopped, and the precipitation is kept for 2 hours; the precipitate is filtered, dried, and filtered.
  • the dried solid was put into a crystallization tank, methanol was added at a ratio of 1:10, and the mixture was stirred for 1 hour, centrifuged, and the wet product after centrifugation was dried to obtain a baicalin A crystal form, which was a yellow crystalline powder.
  • the invention provides a baicalin A crystal form by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared (IR) and hygroscopicity analysis (DVS). Characterization by solid state methods.
  • XRPD X-ray powder diffraction
  • TG thermogravimetric analysis
  • DSC differential scanning calorimetry
  • IR infrared
  • DVD hygroscopicity analysis
  • the voltage is 40 kV
  • the current is 40 mA
  • the scanning speed is 12 degrees/min
  • the step size is 0.02 degrees
  • each step takes 0.1 second.
  • the analysis results are shown in Figure 1.
  • the solid sample of baicalin A prepared in Example 1 was subjected to thermogravimetric analysis using a thermogravimetric analyzer of the German TG Scientific Model Instrument Co., Ltd. TG209F3, and the atmosphere was nitrogen gas, and the heating rate was 10 degrees/min.
  • the analysis results are shown in Figure 2. As can be seen in Figure 2, the crystalline form is a non-hydrate or an unsolvate.
  • the solid sample of baicalin A prepared in Example 1 was subjected to differential scanning calorimetry, which was detected by a DSC 8500 differential calorimeter from Elmer, USA, and the atmosphere was nitrogen, and the heating rate was 10 degrees Celsius / minute.
  • the analysis results are shown in Figure 3. As can be seen from Fig. 2 and Fig. 3, the crystal form was decomposed while being melted at 220 ⁇ 1 °C.
  • the solid sample of baicalin A prepared in Example 1 was subjected to infrared spectroscopy, and was detected at room temperature by Nicolet-Magna FT-IR 750 infrared spectroscopy analyzer of Nikola, USA, and the detection range was 4000-350 cm -1 . Wave number. The analysis results are shown in Figure 4.
  • the baicalin A solid sample prepared in Example 1 was subjected to hygroscopicity analysis.
  • the analysis results are shown in Figure 5. It can be seen from Fig. 5 that the higher the relative humidity, the higher the water content, the relative humidity is 0-75%, the water absorption of the crystal form is lower and the growth is slow, and the relative humidity is 75-90%, and the water absorption rate is The increase is faster, and even when the relative humidity is 90%, the water absorption rate is 4.5% or less, indicating that the crystal form has low hygroscopicity.
  • Examples 2-12 were also subjected to X-ray powder diffraction, and the XRD patterns of the crystal forms of Examples 2-12 were identical to those of the crystal form A obtained in Example 1, indicating that the crystal forms obtained in Examples 2-12 were also Baicalin A crystal form.
  • Example 2 Same as Example 1, except that ethanol was used instead of methanol.
  • the obtained solid was amorphous, and the baicalin crystal form A could not be obtained.
  • Example 2 Same as Example 1, except that isopropyl alcohol was used instead of methanol.
  • the obtained solid was amorphous, and the baicalin crystal form A could not be obtained.
  • Baicalin A crystal form is also baicalin, and baicalin has antibacterial, anti-inflammatory, diuretic, anti-metamorphic, antispasmodic and anti-cancer effects. As the above effects have been disclosed, baicalin A crystal form is in the above-mentioned diseases. The application will not be described here.

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Abstract

本发明涉属于药物化学技术领域，尤其涉及一种黄芩苷A晶型、其制备方法及其应用，所述晶型以2θ角度表示的X-射线粉末衍射在衍射角为4.99，5.65，6.99，8.21，8.64，9.95，11.78，11.98，12.61，14.94，16.33，17.38，18.52，20.76，21.26，21.68，24.94，26.64，28.80，29.97度处具有特征峰；该晶型的制备方法包括以下步骤：溶解复盐沉淀、酸析和重结晶；本发明其制备方法操作简单，晶型吸湿性小，具有良好的稳定性，并可形成规整的晶体型态，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。

Description

一种黄芩苷A晶型、其制备方法及其应用 技术领域
本发明属于药物化学技术领域，尤其涉及一种黄芩苷A晶型、其制备方法及其应用。
背景技术
多晶型现象是指固体物质以两种或两种以上的不同空间排列方式，形成的具有不同物理化学性质的固体状态的现象。在药物研究领域，多晶型包括了有机溶剂化物、水合物等多组分晶体形式。
药物多晶型现象在药物开发过程中广泛存在，是有机小分子化合物固有的特性。理论上小分子药物可以有无限多的晶体堆积方式-多晶型，研究表明，药物多晶型的发现数量与其投入的研究的时间和资源成正比例。如世界上迄今为止销售额最高的药物-Lipitor，申请专利保护的晶型就多达35种。多晶型现象不光受到分子本身的空间结构和官能基团性能，分子内和分子间的相互作用等内在因素的控制，它还受药物合成工艺设计、结晶和纯化条件、制剂辅料选择、制剂工艺路线和制粒方法、以及储存条件、包装材料等诸方面因素的影响。不同晶型具有不同的颜色、熔点、溶解、溶出性能、化学稳定性、反应性、机械稳定性等，这些物理化学性能或可加工性能有时直接影响到药物的安全、有效性能。因此，晶型研究和控制成为药物研发过程中的重要研究内容。
晶型研究包括晶体发现和晶型优选的两个阶段，在晶体发现阶段，主要采用多种结晶手段，如熔融结晶、溶液挥发、快速冷却和混悬法的结晶方法，通过改变结晶条件、溶剂、温度、速度和混悬溶剂比例等影响药物结晶的外部因素，采用高通量样品制备平台，同时制备数百次结晶试验，运用微量样品制备技术和分析测试手段，制备和发现新的晶型。在晶型优选阶段，要对于新的晶型工艺放大和制备条件摸索，采用多种固体表征手段，如x-射线衍射，固体核磁共振，拉曼光谱，红外光谱等手段晶型晶体表征，另外，要采用DSC、TGA、DVS、HPLC等对晶型进行物化性能研究，比较不同晶型的吸湿性、化学稳定、物理状态稳定性、可加工性等进行研究。最后选择最为优选的固体形态进行开发。
黄芩苷(Baicalin)的化学名为：
(5,6-Dihydroxy-4-oxygen-2-phenyl-4H-1-benzopyran-7-beta-D-glucopyranoseacid)，其化学结构式如下：
Figure PCTCN2016085479-appb-000001
黄芩苷(Baicalin)是从黄芩根中提取分离出来的一种黄酮类化合物,具有显著的生物活性，具有抑菌、利尿、抗炎、抗变态及解痉作用，并且具有较强的抗癌反应等生理效能，因此既可用于医药，也可用于化妆品。黄芩中的主要成分是黄芩苷，高达9％-14％，黄芩苷是制备双黄连口服液、银黄软胶囊、银黄片等中成药的主要原料药。
因黄芩苷脂溶性、水溶性差等原因造成其在体内吸收差、生物利用度低(口服生物利用度2.2-30％)、药效不稳定，限制了临床应用。
黄芩苷具有多晶型现象，但暂无晶型专利的报道。
本发明在综合采用新的结晶成核方式和结晶条件的基础上，研究制备了一种黄芩苷的新晶型：A晶型。研究发现，该新晶型吸湿性小，稳定性好，并能形成规整的晶体型态，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。
发明内容
本发明的目的之一在于：本发明第一方面提供一种吸湿性小、稳定性好、晶体型态规整的黄芩苷A晶型。
为解决上述技术问题，本发明的技术方案是：
一种黄芩苷A晶型，所述晶型以2θ角度表示的X-射线粉末衍射在衍射角为4.99，5.65，6.99，8.21，8.64，9.95，11.78，11.98，12.61，14.94，16.33，17.38，18.52，20.76，21.26，21.68，24.94，26.64，28.80，29.97度处具有特征峰。
作为一种改进，所述晶型A的X射线粉末衍射图谱基本如图1所示。
作为一种改进，所述晶型A的差示扫描量热分析图谱基本如图3所示。
作为一种改进，所述晶型的差示扫描量热分析在220±1℃有特征熔融峰。作为一种改进，所述晶型的红外图谱至少在1754,1731,1659,1602,1574,1473,1367,1075cm-1处具有特征峰。
作为一种改进，所述晶型A的红外图谱基本如图4所示。
作为一种改进，所述晶型A的热失重分析图谱基本如图2所示。
作为一种改进，所述晶型A的吸湿性分析图谱基本如图5所示。
作为一种改进，所述晶型的热失重分析的分解温度为220±1℃，在所述分解温度之前未有失重。
作为一种改进，所述晶型为非溶剂合物或非水合物。
本发明的目的之二在于：提供一种黄芩苷A晶型的制备方法，包括步骤：
(1)提供一个黄芩苷和甲醇的混合物，所述黄芩苷与甲醇的料液比为1g:(5-15mL)；和
(2)加热所述混合物至回流温度±5℃，进行析晶，从而得到所述黄芩苷A晶型。
作为一种改进，所述制备方法包括以下步骤：
(1)溶解后复盐沉淀：将黄芩苷固体粗品打成液体状，加入碱，调pH为7.0-7.5，加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物至出现颗粒，静置5小时后去除沉淀；
(2)酸析：将步骤(1)中的澄清液加热至温度≥90℃，加入酸，调pH为1.5-2.0，停止搅拌，保温沉淀2小时；
(3)重结晶：将步骤(2)中的沉淀进行过滤、干燥，将过滤、干燥后的固体投入结晶罐，加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得。
作为一种改进，步骤(1)中，所述碱为氢氧化钠、氢氧化钾或氢氧化锂。
作为一种改进，步骤(2)中，所述酸为浓盐酸、盐酸或硫酸。
作为一种改进，步骤(3)中，所述固体与所述甲醇的体积比为1:10。
本发明的目的之三在于：提供黄芩苷A晶型在抑菌、抗炎、利尿、抗变态、解痉及抗癌药物中的应用。
本发明的目的之四在于：提供一种黄芩苷A晶型，所述晶型以2θ角度表示的X-射线粉末衍射在衍射角为4.99°±0.1°、5.65°±0.1°、8.21°±0.1°、14.94°±0.1°、18.52°±0.1°和21.68°±0.1°。
作为一种改进，所述晶型为非水合物，并且所述A晶型的X射线粉末衍射图谱基本如图1所示。
本发明的目的之五在于：提供了一种治疗方法，包括步骤：给需要的对象施用本发明第一方面中的黄芩苷A晶型。
在另一优选例中，所述治疗用于抑菌、抗炎、利尿、抗变态、解痉及抗癌。
由于采用了上述技术方案，本发明的有益效果是：
本发明提供的一种黄芩苷A晶型及其制备方法，其制备方法操作简单，晶型吸湿性小，具有良好的稳定性，并可形成规整的晶体型态，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。
附图说明
图1是本发明提供的黄芩苷A晶型的X-射线粉末衍射(XRPD)图。
图2是本发明提供的黄芩苷A晶型的热失重分析(TG)图。
图3是本发明提供的黄芩苷A晶型的差示扫描量热分析(DSC)图。
图4是本发明提供的黄芩苷A晶型的红外光谱(IR)图。
图5是本发明提供的黄芩苷A晶型的吸湿性分析(DVS)图。
图6是本发明提供的黄芩苷A晶型的1、2、4、6周的稳定性的X-射线粉末衍射(XRPD)图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
本发明的晶型A，其以2θ角度表示的X-射线粉末衍射在衍射角峰值以特征峰±x°的形式表示，其中x≤0.2°，较佳地，x为0.05°、0.1°或0.2°。
药物组合物
本发明提供一种药物组合物，所述组合物包含(a)本发明第一方面所述的晶型A，以及(b)药学上可接受的载体。
本发明所述药物组合物中的“活性成分”是指本发明所述的式(I)化合物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。
通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片或一支注射针剂。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2016085479-appb-000002
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括但不限于：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。 它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明化合物可以单独给药，或者与其他治疗药物联合给药。
测试方法
XRD(X-射线粉末衍射)方法：仪器型号：Bruker D8advance
TG(热重分析)方法：仪器型号：Netzsch TG 209F3
DSC(差示扫描量热法)方法：Perkin Elmer DSC 1200
DVS方法：SMS DVS Intrinsic
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
下述实施例中，料液比单位均为g(固)：mL(液)。
实施例1
取10g黄芩苷固体粗品，加入氢氧化钠水溶液溶解，并调pH为7.0，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入盐酸，调pH为1.5，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例2
取10g黄芩苷固体粗品，加入氢氧化钾水溶液溶解，调pH为7.2，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入盐酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例3
取10g黄芩苷固体粗品，加入氢氧化锂水溶液溶解，调pH为7.4，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入浓盐酸，调pH为2.0，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例4
取10g黄芩苷固体粗品，加入氢氧化钠水溶液溶解，调pH为7.5，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入浓盐酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例5
取10g黄芩苷固体粗品，加入氢氧化钾水溶液溶解，调pH为7.5，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入硫酸，调pH为1.5，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例6
取10g黄芩苷固体粗品，加入氢氧化钾水溶液溶解，调pH为7.2，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入盐酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例7
取10g黄芩苷固体粗品，加入氢氧化锂水溶液溶解，调pH为7.0，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入硫酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例8
取10g黄芩苷固体粗品，加入氢氧化钾水溶液溶解，调pH为7.0，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入浓盐酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例9
取10g黄芩苷固体粗品，加入氢氧化锂水溶液溶解，调pH为7.0，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入硫酸，调pH为1.5，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例10
取10g黄芩苷固体粗品，加入氢氧化锂水溶液溶解，调pH为7.5，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入硫酸，调pH为2.0，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过 滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例11
取10g黄芩苷固体粗品，加入氢氧化锂水溶液溶解，调pH为7.5，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入盐酸，调pH为1.5，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
实施例12
取10g黄芩苷固体粗品，加入氢氧化钠水溶液溶解，调pH为7.2，然后加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物直至出现颗粒，静置沉淀5小时。
将去除沉淀后的上清液进行搅拌，控制转速10转/分，温度≥90℃，加入硫酸，调pH为1.8，停止搅拌后，保温沉淀2小时；将沉淀进行过滤、干燥，将过滤、干燥后的固体，投入结晶罐，按料液比1:10加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得到黄芩苷A晶型，为黄色结晶性粉末。
本发明提供的一种黄芩苷A晶型，通过X-射线粉末衍射(XRPD)、热失重分析(TG)、差示扫描量热分析(DSC)、红外(IR)以及吸湿性分析(DVS)等固态方法表征。
对实施例1制得的黄芩苷A晶型固体样品进行X-射线粉末衍射分析，其采用德国布鲁克仪器有限公司Bruker D8advance型的衍射仪，采用Cu–Kα射线(λ＝1.5418
Figure PCTCN2016085479-appb-000003
)，电压为40千伏，电流为40毫安，扫描速度为12度/分钟，步径为0.02度，每步用时0.1秒。其分析结果见图1。
对实施例1制得的黄芩苷A晶型固体样品进行热失重分析，其采用德国耐驰科学仪器有限公司TG209F3型热重分析仪，气氛为氮气，升温速率为10度/分钟。其分析结果见图2。从图2中可以看出，该晶型为非水合物或非溶剂合物。
对实施例1制得的黄芩苷A晶型固体样品进行差示扫描量热分析，其采用美国铂金埃尔默公司的DSC 8500差示量热仪检测，气氛为氮气，加热速度为10摄氏度/分钟。其分析结果见图3。从图2和图3中可以看出，该晶型在220±1℃，熔融的同时进行分解。
对实施例1制得的黄芩苷A晶型固体样品进行红外光谱分析，其采用美国尼高力公司的Nicolet-Magna FT-IR 750红外光谱分析仪于室温检测，检测范围为4000-350cm-1波数。其分析结果见图4。
对实施例1制得的黄芩苷A晶型固体样品进行吸湿性分析。其分析结果见图5。从图5中可以看出，相对湿度越大，其含水率越高，在相对湿度0-75％，该晶型的吸水率较低且增加缓慢，在相对湿度75-90％，其吸水率增加较快，即使在相对湿度90％时，其吸水率也在4.5％以下，说明该晶型的吸湿性小。
对实施例2-12的晶型同样进行了X-射线粉末衍射，实施例2-12晶型的XRD图谱与实施例1所得晶型A图谱一致，表明实施例2-12所得晶型也为黄芩苷A晶型。
实施例13
黄芩苷A晶型的稳定性实验
实验条件：将实施例1制得的黄芩苷A晶型样品放入加速稳定性箱，40℃/75％相对湿度条件下储存，分别在1,2,4,6周取出部分样品粉末衍射测试。
从图6中可以看出该晶型具有良好的稳定性。
对比例1
同实施例1，不同之处在于，用乙醇替代甲醇。所得固体为无定形，无法制得黄芩苷晶型A。
对比例2
同实施例1，不同之处在于，用异丙醇替代甲醇。所得固体为无定形，无法制得黄芩苷晶型A。
黄芩苷A晶型同样是黄芩苷，而黄芩苷具有抑菌、抗炎、利尿、抗变态、解痉及抗癌的作用，由于上述作用已经公开，黄芩苷A晶型在上述疾病药物中的应用在此就不再赘述。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (18)

  1. 一种黄芩苷A晶型，其特征在于:所述晶型以2θ角度表示的X-射线粉末衍射在衍射角为4.99，5.65，6.99，8.21，8.64，9.95，11.78，11.98，12.61，14.94，16.33，17.38，18.52，20.76，21.26，21.68，24.94，26.64，28.80，29.97度处具有特征峰。
  2. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的X射线粉末衍射图谱基本如图1所示。
  3. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的差示扫描量热分析在220±1℃有特征熔融峰。
  4. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的差示扫描量热分析图谱基本如图3所示。
  5. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的红外图谱至少在1754cm-1,1731cm-1,1659cm-1,1602cm-1,1574cm-1,1473cm-1,1367cm-1,1075cm-1处具有特征峰。
  6. 如权利要求1所述的黄芩苷A晶型，所述A晶型的红外图谱基本如图4所示。
  7. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的热失重分析的分解温度为220℃±1℃，在所述分解温度之前未有失重。
  8. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型的热失重分析图谱基本如图2所示。
  9. 如权利要求1所述的黄芩苷A晶型，其特征在于:所述A晶型为非溶剂合物或非水合物。
  10. 一种黄芩苷A晶型，其特征在于:所述A晶型以2θ角度表示的X-射线粉末衍射在衍射角为4.99°±0.1°、5.65°±0.1°、8.21°±0.1°、14.94°±0.1°、18.52°±0.1°和21.68°±0.1°。
  11. 如权利要求10所述的黄芩苷A晶型，其特征在于:所述A晶型为非水合物，并且所述A晶型的X射线粉末衍射图谱基本如图1所示。
  12. 一种制备权利要求1或10所述黄芩苷A晶型的方法，包括步骤：
    (1)提供一个黄芩苷和甲醇的混合物，所述黄芩苷与甲醇的料液比为1g:(5-15mL)；和
    (2)加热所述混合物至回流温度±5℃，进行析晶，从而得到所述黄芩苷A晶型。
  13. 一种黄芩苷A晶型的制备方法，其特征在于：所述制备方法包括以下步 骤：
    (1)溶解复盐沉淀：取黄芩苷固体粗品，加入碱溶解，调pH为7.0-7.5，加入氯化钙，搅拌均匀，再加入冰乙酸调絮状物至出现颗粒，静置沉淀5小时；
    (2)酸析：将步骤(1)中的沉淀进行搅拌，控制转速10转/分，温度≥90℃，加入酸，调pH为1.5-2.0，停止搅拌，保温沉淀2小时；
    (3)重结晶：将步骤(2)中的沉淀进行过滤、干燥，将过滤、干燥后的固体投入结晶罐，加入甲醇，搅拌回流1小时，离心，将离心后的湿品干燥，即得。
  14. 如权利要求13所述的黄芩苷A晶型的制备方法，其特征在于：步骤(1)中，所述碱为氢氧化钠、氢氧化钾或氢氧化锂。
  15. 如权利要求13所述的黄芩苷A晶型的制备方法，其特征在于：步骤(2)中，所述酸为浓盐酸、盐酸或硫酸。
  16. 如权利要求13所述的黄芩苷A晶型的制备方法，其特征在于：步骤(3)中，所述固体与所述甲醇的体积比为1:10。
  17. 一种药物组合物，所述组合物包含(a)权利要求1或10所述的黄芩苷A晶型，以及(b)药学上可接受的载体。
  18. 一种权利要求1或10所述的黄芩苷A晶型的用途，用于制备抑菌、抗炎、利尿、抗变态、解痉及抗癌的药物。
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