WO2017012572A1 - 一种甜菊糖d苷晶型a、其制备方法及其应用 - Google Patents

一种甜菊糖d苷晶型a、其制备方法及其应用 Download PDF

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WO2017012572A1
WO2017012572A1 PCT/CN2016/090898 CN2016090898W WO2017012572A1 WO 2017012572 A1 WO2017012572 A1 WO 2017012572A1 CN 2016090898 W CN2016090898 W CN 2016090898W WO 2017012572 A1 WO2017012572 A1 WO 2017012572A1
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stevioside
solvent
glycoside
drying
glycoform
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PCT/CN2016/090898
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English (en)
French (fr)
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朱理平
梅雪锋
黄颖
王建荣
张奇
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诸城市浩天药业有限公司
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Priority to US15/747,072 priority Critical patent/US10611789B2/en
Priority to EP16827263.1A priority patent/EP3327025B1/en
Priority to JP2018522843A priority patent/JP2018526431A/ja
Publication of WO2017012572A1 publication Critical patent/WO2017012572A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • 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
    • A23L19/00—Products from fruits or vegetables; Preparation or treatment thereof
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/02—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation containing fruit or vegetable juices
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A23L2/60—Sweeteners
    • 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
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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]
    • 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
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • 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
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • A23L27/33—Artificial sweetening agents containing sugars or derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of sweeteners, and in particular relates to a stevioside D-glycoside form A, a preparation method thereof and application thereof.
  • Polymorphism means that the same elements or molecules are spatially arranged in different ways to form different solid forms, such as diamond and graphite.
  • the difference in the arrangement may be due to the difference in the manner in which the spatial elements or molecules are stacked, or the formation of different conformational isomers due to the structural flexibility of the molecules themselves, resulting in a difference in spatial arrangement.
  • This difference in arrangement results in different solubility, physical and chemical stability, reactivity, mechanical stability and morphology of the different crystal forms.
  • a crystalline drug or food product may undergo a change in solid state during processing or storage. This is mainly due to the fact that the preparation process often involves various processes for the drug substance, which are generally derived from mechanical compression, grinding, compression molding or tableting processes, freezing, drying, melting, and the like.
  • drugs or foods may absorb water during storage, interact with oxygen in the air, decompose impurities and interact with excipients.
  • Changes in crystal form may result in changes in various solid-state chemistry-related properties such as lattice volume, density, viscosity, surface tension, hardness, crystal morphology, color, refractive index, melting point, heat of dissolution, solubility, dissolution rate, stability , hygroscopicity and chemical reaction properties, etc.
  • different crystal forms may result in changes in drug dissolution, dissolution properties, pharmacokinetics, and bioavailability, which in turn affect the efficacy and safety of the drug.
  • different crystal forms may lead to changes in color, morphology, stability and hygroscopicity, which in turn affect food storage conditions, mouthfeel and sensory evaluation. Therefore, comparing the hygroscopicity, chemical stability, and processability of different crystal forms, and then selecting the optimal crystal form, is crucial in the development of food and drugs.
  • Stevioside D-glycoside is a stevioside compound extracted from stevia, which is about 200 times sweeter than sucrose and is considered to be a potent sweetener.
  • stevioside A has been widely used as a sweetener in beverage applications, but has a problem of poor mouthfeel, while stevioside D glycoside has better sugar characteristics and more than stevioside A glycoside. The ideal taste.
  • stevioside D glycoside can be used to improve the mouthfeel and flavor of existing sweeteners, especially stevioside natural sweeteners.
  • the improved sweetener has a similar taste to sucrose, has no post-bitter taste and astringency, and does not introduce any artificial synthetic ingredients and energy components, and maintains the natural and non-energy characteristics of stevioside and stevioside A glycoside.
  • stevioside D has low water solubility (300 to 450 ppm) at room temperature, its application in food, beverage, seasoning, brewing, medicine and the like is limited.
  • One of the objects of the present invention is to provide a stevioside D-glycoform A which has good crystallinity, good water solubility and high chemical stability.
  • the technical solution of the present invention is:
  • a stevioside D-glycoform A which uses X-ray powder diffraction analysis measured by Cu-K ⁇ ray, the 2 ⁇ value expressed in degrees, and the error range is ⁇ 1°,
  • the relative spacing between the indicated interplanar spacing d and the diffraction peaks expressed as a percentage has the following characteristics:
  • the Form A is analyzed by X-ray powder diffraction obtained by Cu-K ⁇ ray measurement, and the 2 ⁇ value expressed by degrees is at least 4.53, 6.38, 12.76, 13.52, 17.48, 17.96, 20.07, and 22.63. Obvious characteristic diffraction peaks.
  • the differential scanning calorimetry of Form A has a distinct endothermic peak at 50 °C - 120 °C.
  • thermogravimetric analysis of Form A began to decompose at 275 ⁇ 10 ° C and there was significant weight loss at the beginning of the experiment.
  • the crystal form A has a dynamic moisture adsorption (DVS) pattern as shown in FIG.
  • DVS dynamic moisture adsorption
  • the IR spectra of Form A at least 3384cm -1, 2946cm -1, 2915cm -1 , 1735cm -1, 1660cm -1, 1449cm -1, 1366cm -1, with characteristic peaks at 1074cm -1 .
  • the second object of the present invention is to provide a preparation method of stevioside D-glycoside Form A which is simple in process, easy to handle, has good crystallinity and high stability.
  • the technical solution of the present invention is:
  • a method for preparing stevioside D-glycoside Form A which is a suspension method, a solution volatilization method or a cooling method.
  • the suspension method comprises the following steps:
  • the solution volatilization method comprises the following steps:
  • the cooling method comprises the following steps:
  • the stevioside D glycoside has a substance purity of 50-100%.
  • the stevioside D glycoside is mixed with the solvent in a manner of stirring, shaking or vortexing.
  • the solvent is one or more selected from the group consisting of water, methanol, ethanol, acetonitrile, tetrahydrofuran, acetone, methyl ethyl ketone, ethyl acetate, ethyl formate, 1-propanol, and 2-propanol.
  • the drying is one or two or more drying methods of natural drying, blast drying, vacuum drying, freeze drying, air flow drying, microwave drying, infrared drying, or high frequency drying.
  • a third object of the present invention is to provide a use of stevioside D-glycoform A in foods, beverages and pharmaceuticals.
  • the preparation method of the stevioside D-glycoside crystal form A provided by the invention has the advantages of simple process, easy operation and high selectivity, and the stevioside D-glycoside crystal form A can be obtained by various methods, and the obtained product has good crystallinity. It has good water solubility and high chemical stability.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TG) diagram of the stevioside D-glycoside form A provided by the present invention
  • DVS dynamic moisture adsorption
  • Figure 5 is an infrared (IR) diagram of the stevioside D glycoside form A provided by the present invention.
  • FIG. 6 is a comparison diagram of X-ray powder diffraction (XRPD) of the stevioside D-glycoside form A provided by the present invention under conditions of relative humidity lower than 32%;
  • XRPD X-ray powder diffraction
  • XRPD X-ray powder diffraction
  • Fig. 8 is a high performance liquid phase (HPLC) comparison chart of the stevioside D glycoform A of the present invention stored at 25 ° C and a relative humidity of 60% for half a year.
  • HPLC liquid phase
  • Stevioside D-crystal form A can be obtained by vacuum drying at 25 ° C, respectively.
  • stevioside D glycoside with 60% purity of the substance was added to 100 mL of 50% ethanol-methanol (v/v) system at 60 ° C, stirred for 1 h, and filtered to obtain a filtrate and a white solid, filtrate and white solid.
  • the stevioside D-glycoform A can be obtained by naturally drying at 50 ° C.
  • Stevioside D-crystal form A can be obtained by drying naturally at 50 °C.
  • stevioside D glycoside having a purity of 100% was added to 200 mL of ultrapure water at 90 ° C, stirred for 5 h, and then centrifuged to obtain a supernatant and a white solid. The supernatant and the white solid were respectively at 50 ° C. Naturally dry, stevioside D-glycoform A can be obtained.
  • Stevia D D-form A can be obtained.
  • stevioside D glycoside with 100% purity of the substance was added to 600 mL of acetonitrile at 90 ° C. After vortexing for 0.1 h, the stevioside D glycoside was completely dissolved to obtain a clear solution, and the clear solution was naturally volatilized at 90 ° C. That is, stevioside D glycoform A is obtained.
  • XRPD X-ray powder diffraction analysis
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • DVS dynamic moisture adsorption analysis
  • IR Infrared analysis
  • the diffraction pattern obtained from a particular crystal form is often characteristic. Due to differences in crystallization conditions, particle size, relative content of the mixture, and other test conditions, the diffraction pattern may produce a preferred orientation effect, resulting in a change in the relative intensity of certain bands (especially at low angles) in the spectrum. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystals that are targeted, and it is more important to note the position of the peaks rather than their relative intensities when determining whether they are the same as the known crystal forms.
  • DVS analysis It was measured by British SMS instrument company DVS Intrinsic type dynamic moisture adsorption instrument, measuring temperature: 25 ° C; relative humidity: 0-95%. The analysis results are shown in Figure 4.
  • the stevioside D-glycoside form A prepared in the above examples was subjected to XRPD analysis at 25 ° C and RH ⁇ 30%, and the analysis results are shown in Fig. 6. From Fig. 6, it can be seen that the crystal form is unchanged, and the crystal form is unchanged. Good stability.
  • the stevioside D-glycoform A prepared in the above examples was stored at 25 ° C and RH 60% for half a year, and the analysis results are shown in Fig. 7. From Fig. 7, it can be seen that the crystal form is unchanged and the crystal form is stable. Good sex.
  • HPLC analysis It was determined using a 1260 infinity liquid chromatograph from Agilent Technologies, Inc., USA.
  • Sample solution preparation method accurately weigh 25-50 mg of stevioside D glycoside sample, put it into a 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution, dissolve and dilute to the scale .
  • Arrangement method of sodium phosphate buffer (specification: 10 mmol/L, pH: 2.6): 2.76 g of sodium dihydrogen phosphate was dissolved in 2 liters of water, and phosphoric acid was added to adjust the pH to 2.6.
  • the stevioside D-glycoside form A prepared in the above examples has good chemical stability, and the HPLC analysis shows that the purity after the half year of storage is less than 0.5% compared with the raw material.
  • the stevioside D-glycoform A prepared in the above examples has good reproducibility. And the water solubility is good, about 0.6mg/mL.
  • the stevioside D glycoside raw material used in the above examples was provided by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.
  • a health drink consisting of the following raw materials: ⁇ 25g, astragalus 15g, walnut 5g, stevioside D-glycoform A 1g, yam 8g and lotus seed core 2g.
  • a purple potato dessert consisting of the following raw materials: purple potato 250g, raisin 20g, red date 20g, sweet-scented osmanthus 5g, lily 5g and stevioside D-glycody form A 25g.
  • a purple potato dessert consisting of the following raw materials: acetaminophen 80g, pseudoephedrine hydrochloride 7g, chlorpheniramine maleate 0.3g, starch 20g, sodium carboxymethylcellulose 8g, stevioside D-glycoform A 8g and magnesium stearate 3g.

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Abstract

提供一种甜菊糖D苷（Rebaudioside D）晶型A、其制备方法及应用。所述甜菊糖D苷晶型A使用Cu-Kα射线测量得到的X射线粉末衍摄射分析，以度表示的2θ值至少在4.53、6.38、12.76、13.52、17.48、17.96、20.07和22.63处有明显的特征衍射峰。所述的制备方法为混悬法、溶剂挥发法或冷却法，工艺简单，便于操作。所述甜菊糖D苷晶型A产品结晶度好、水溶性好、化学稳定性高。

Description

一种甜菊糖D苷晶型A、其制备方法及其应用 技术领域
本发明属于甜味剂技术领域，尤其涉及一种甜菊糖D苷晶型A、其制备方法及其应用。
背景技术
多晶型是指相同元素或分子在空间上以不同方式排列而形成不同的固体形态，如金刚石和石墨。这种排列方式的差异可以来自空间元素或分子的堆积方式不同，也可能是由于分子本身的结构柔韧性而形成不同的构象异构体，进而导致的空间排列方式差异。而这种排列方式的差异会导致不同晶型具有不同的溶解性、物理及化学稳定性、反应性、机械稳定性和形貌。
晶态药物或食品可能在加工过程或储存中发生固体状态的改变。这主要是由于制备过程常常涉及到对于原料药的各种工艺处理，这些外界刺激一般来自机械压挤、研磨、压制成型或压片过程、冷冻、干燥、熔融等。另外，药品或食品在储存过程中可能吸收水分，与空气中的氧气作用，分解杂质以及与辅料的作用等等。
晶型的改变可能导致各种固态化学相关的性能发生变化，如晶格体积、密度、粘度、表面张力、硬度、晶体形态、颜色、折光率、熔点、溶解热、溶解度、溶出速率、稳定性、吸湿性和化学反应性能等等。重要的是，晶型不同，可能导致药物的溶解、溶出性能、药物动力学和生物利用度发生改变，进而影响药物的疗效和安全性能。同时，在食品方面，晶型不同，可能导致颜色、形态、稳定性和吸湿性发生改变，进而影响食品的储存条件、口感和感官评价。所以，比较不同晶型的吸湿性、化学稳定性、可加工性，进而选择最优的晶型，在食品与药物研发过程中是至关重要的。
甜菊糖D苷(Rebaudioside D，RD)，其结构式如下图所示：
Figure PCTCN2016090898-appb-000001
甜菊糖D苷是一种从甜叶菊中提取的甜菊糖苷类化合物，甜度约为蔗糖的200倍，被认为是很有潜力的甜味剂。在甜菊糖苷类化合物中，甜菊糖A苷已经被广泛用作饮料应用中的甜味剂，但具有口感不好的问题，而甜菊糖D苷具有比甜菊糖A苷更好的糖特征和更理想的味道。
在杂志《Journal of Agricultural and Food Chemistry》中的一篇名为“Human Psychometric and Taste Receptor Responses to Steviol Glycosides”中的研究表明，甜菊糖D苷相对于甜菊糖A苷、甜菊糖B苷、甜菊糖C苷、甜菊糖E苷及甜菊糖F苷来说，甜度最强，而后苦味较弱。
此外，在专利CN 102894325 A中报道了，甜菊糖D苷可用于改善现有甜味剂，尤其是甜菊糖苷类天然甜味剂的口感和风味。改善后的甜味剂具有与蔗糖相似的口感，无后苦味、涩味，未引入任何人工合成成分和能量成分，保持了甜菊苷和甜菊糖A苷纯天然、无能量的特点。但是，由于甜菊糖D苷在室温下的水溶性低(300至450ppm)，而限制了其在食品、饮料、调味料、酿酒、医药等行业的应用。虽然，甜菊糖D苷的制备和提取方法分别在CN 104159908 A和CN 103709215 A中被报道。但是，甜菊糖D苷的晶型从未被报道过。晶型不同，可能导致颜色、形态、稳定性、吸湿性和溶解性存在差异，进而影响食品的储存条件、口感和感官评价。制备方法不同，得到的晶型不可预测。因此，优化并控制条件得到最优晶型，在食品与药物研发过程中是至关重要的。
本领域迫切需要提供一种性能更好的甜菊糖D苷的晶型，例如结晶度好、水溶性好、化学稳定性高的新晶型。同时，迫切需要提供上述晶型的制备方法和用途。
发明内容
本发明的目的之一在于：提供一种结晶度好、水溶性好、化学稳定性高的甜菊糖D苷晶型A。
为解决上述技术问题，本发明的技术方案是：
一种甜菊糖D苷晶型A，所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析，以度表示的2θ值、误差范围为±1°，以
Figure PCTCN2016090898-appb-000002
表示的晶面间距d和以百分数表示的衍射峰的相对强度具有如下特征：
2θ d 相对强度％
4.53 19.5129 39.7
6.38 13.8374 46.4
10.37 8.5210 33.9
12.76 6.9319 54.9
13.52 6.5432 52.0
15.11 5.8596 27.8
16.45 5.3858 25.3
17.48 5.0695 100.0
17.96 4.9363 98.7
18.36 4.8291 21.0
18.64 4.7571 36.2
20.07 4.4197 73.7
20.49 4.3300 39.8
22.63 3.9259 57.0
24.18 3.6775 27.6
24.79 3.5891 23.8
26.19 3.4005 20.7
作为一种改进，所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析，以度表示的2θ值至少在4.53、6.38、12.76、13.52、17.48、17.96、20.07和22.63处有明显的特征衍射峰。
作为一种改进，所述晶型A的差示扫描量热分析在50℃-120℃有明显吸热峰。
作为一种改进，所述晶型A的热失重分析，在275±10℃开始分解，且在实验开始阶段有明显失重。
作为一种改进，所述晶型A有如图4所示的动态水分吸附(DVS)图谱，在相 对湿度为0-40％范围内，其吸收水分的质量百分数在0-3.4％，在相对湿度为40-100％范围内，其吸收水分的质量百分数在3.4-7.1％。
作为一种改进，所述晶型A的红外图谱至少在3384cm-1,2946cm-1,2915cm-1,1735cm-1,1660cm-1,1449cm-1,1366cm-1,1074cm-1处具有特征峰。
本发明的目的之二在于：提供一种工艺简单、易于操作、产品结晶度好和稳定性高的甜菊糖D苷晶型A的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种甜菊糖D苷晶型A的制备方法，所述制备方法为混悬法、溶液挥发法或冷却法。
优选的，所述混悬法包括以下步骤：
(1)在零度至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；
(2)在零度至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到白色固体；
(3)将所述白色固体，在零度至溶剂沸点温度的条件下干燥，即得甜菊糖D苷晶型A。
优选的，所述溶液挥发法包括以下步骤：
(1)在零度至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；
(2)在零度至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到澄清溶液；
(3)将步骤(1)中所述混悬溶液或步骤(2)中所述澄清溶液，在零度至溶剂沸点温度的条件下挥发，即得甜菊糖D苷晶型A。
优选的，所述冷却法包括以下步骤：
(1)在室温至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；
(2)在室温至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到澄清溶液；
(3)将步骤(1)中所述混悬溶液或步骤(2)中所述澄清溶液，冷却至-20-30℃，析出白色固体，过滤，干燥，即得甜菊糖D苷晶型A。
作为一种改进，所述甜菊糖D苷的物质纯度为50-100％。
作为一种改进，所述甜菊糖D苷与所述溶剂的混合方式为搅拌、振荡或涡旋。
作为一种改进，所述溶剂为水、甲醇、乙醇、乙腈、四氢呋喃、丙酮、甲乙酮、乙酸乙酯、甲酸乙酯、1-丙醇、2-丙醇中的一种或两种以上。
作为一种改进，所述干燥为自然干燥、鼓风干燥、真空干燥、冷冻干燥、气流干燥、微波干燥、红外线干燥或高频率干燥中的一种或两种以上干燥方式。
本发明的目的之三在于：提供一种甜菊糖D苷晶型A在食品、饮料及药品中的应用。
由于采用了上述技术方案，本发明的有益效果是：
本发明提供的甜菊糖D苷晶型A的制备方法，其工艺简单、易于操作、选择性较多，可通过多种方法制得甜菊糖D苷晶型A，且制得的产品结晶度好、水溶性好、化学稳定性高。
附图说明
图1是本发明提供的甜菊糖D苷晶型A的X-射线粉末衍射(XRPD)图；
图2是本发明提供的甜菊糖D苷晶型A的差示扫描量热分析(DSC)图；
图3是本发明提供的甜菊糖D苷晶型A的热失重分析(TG)图；
图4是本发明提供的甜菊糖D苷晶型A的动态水分吸附(DVS)图；
图5是本发明提供的甜菊糖D苷晶型A的红外(IR)图；
图6是本发明提供的甜菊糖D苷晶型A的在相对湿度低于32％的条件下的X-射线粉末衍射(XRPD)比较图；
图7是本发明提供的甜菊糖D苷晶型A的在25℃、相对湿度60％的条件下储存半年的X-射线粉末衍射(XRPD)比较图；
图8是本发明提供的甜菊糖D苷晶型A的在25℃、相对湿度60％的条件下储存半年的高效液相(HPLC)比较图。
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。
实施例一
在25℃条件下，将25g物质纯度为100％的甜菊糖D苷加入100mL超纯水中，静置12h后，过滤得到滤液和白色固体，滤液和白色固体分别于25℃下真空干燥，均可得甜菊糖D苷晶型A。
实施例二
在25℃条件下，将25g物质纯度为100％的甜菊糖D苷加入150mL 60％的乙醇-水(v/v)体系中，静置12h后，过滤得到滤液和白色固体，滤液和白色固体分别于25℃下真空干燥，均可得甜菊糖D苷晶型A。
实施例三
在50℃条件下，将31.5g物质纯度为80％的甜菊糖D苷加入150mL 60％的乙醇-水(v/v)体系中，静置12h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下鼓风干燥，均可得甜菊糖D苷晶型A。
实施例四
在50℃条件下，将31.5g物质纯度为80％的甜菊糖D苷加入100mL 50％的乙醇-甲醇(v/v)体系中，静置12h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下鼓风干燥，均可得甜菊糖D苷晶型A。
实施例五
在60℃条件下，将31.5g物质纯度为60％的甜菊糖D苷加入100mL 50％的乙醇-甲醇(v/v)体系中，搅拌1h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例六
在60℃条件下，将31.5g物质纯度为60％的甜菊糖D苷加入100mL 50％的乙醇-甲醇(v/v)体系中，涡旋3h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例七
在60℃条件下，将50g物质纯度为50％的甜菊糖D苷加入100mL 50％的乙醇-甲醇(v/v)体系中，振荡5h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例八
在90℃条件下，将25g物质纯度为100％的甜菊糖D苷加入200mL超纯水中，搅拌5h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例九
在90℃条件下，将25g物质纯度为100％的甜菊糖D苷加入200mL超纯水中，搅拌5h后，离心，得到上清液和白色固体，上清液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例十
在90℃条件下，将25g物质纯度为100％的甜菊糖D苷加入300mL超纯水中，搅拌5h后，得混悬液，将混悬液于90℃下自然干燥，即得甜菊糖D苷晶型A。
实施例十一
在90℃条件下，将4g物质纯度为100％的甜菊糖D苷加入600mL超纯水中，搅拌5h后，甜菊糖D苷全部溶解，得澄清溶液，将澄清溶液于90℃下自然挥干，即得甜菊糖D苷晶型A。
实施例十二
在90℃条件下，将4g物质纯度为100％的甜菊糖D苷加入600mL超纯水中，搅拌5h后，甜菊糖D苷全部溶解，得澄清溶液，反应体系降温至25℃，析出白色固体，离心，得到上清液和白色固体，上清液和白色固体分别于50℃下自然干燥，均可得甜菊糖D苷晶型A。
实施例十三
在90℃条件下，将4g物质纯度为100％的甜菊糖D苷加入600mL超纯水中，振荡24h后，甜菊糖D苷全部溶解，得澄清溶液，反应体系降温至30℃，析出白色固体，形成混悬液，混悬液于30℃真空干燥，甜菊糖D苷晶型A。
实施例十四
在90℃条件下，将5g物质纯度为100％的甜菊糖D苷加入600mL超纯水中，振荡24h后，过滤，得到澄清溶液，将澄清溶液降温至30℃，析出白色固体，过滤，白色固体于30℃真空干燥，得甜菊糖D苷晶型A。
实施例十五
在90℃条件下，将5g物质纯度为100％的甜菊糖D苷加入600mL超纯水中，振荡24h后，过滤，得到澄清溶液，将澄清溶液降温至10℃，析出白色固体，过滤，上清液于于30℃真空干燥，得甜菊糖D苷晶型A。
实施例十六
在0℃条件下，将25g物质纯度为100％的甜菊糖D苷加入100mL超纯水中，静置48h后，过滤得到滤液和白色固体，滤液和白色固体分别于25℃下真空干燥，均可得甜菊糖D苷晶型A。
实施例十七
在90℃条件下，将4g物质纯度为100％的甜菊糖D苷加入600mL乙腈中，涡旋0.1h后，甜菊糖D苷全部溶解，得澄清溶液，将澄清溶液于90℃下自然挥发，即得甜菊糖D苷晶型A。
实施例十八
在70℃条件下，将7g物质纯度为100％的甜菊糖D苷加入600mL2-丁醇中，振荡30h后，过滤，得到澄清溶液，将澄清溶液降温至-20℃，析出白色固体，过滤，白色固体于30℃真空干燥，得甜菊糖D苷晶型A。
实施例十九
在80℃条件下，将6g物质纯度为100％的甜菊糖D苷加入500mL超纯水中，涡旋2h后，过滤，得到澄清溶液，将澄清溶液降温至0℃，析出白色固体，过滤，白色固体于50℃真空干燥，得甜菊糖D苷晶型A。
对上述实施例制得的甜菊糖D苷晶型A进行X-射线粉末衍射分析(XRPD)、差示扫描量热分析(DSC)、热失重分析(TG)、动态水分吸附分析(DVS)、红外分析(IR)等。
XRPD分析：其采用德国布鲁克仪器有限公司Bruker D8 advance型的衍射仪于室温进行检测，采用Cu–Kα射线
Figure PCTCN2016090898-appb-000003
2θ角扫描从3度到40度，扫描速度为0.2度/秒。其分析结果见图1。
在样品粉末X-射线粉末衍射图谱中，由特定晶型得到的衍射谱图往往是特征性的。因为结晶条件、粒径、混合物的相对含量和其它测试条件的差异，衍射谱图可能会产生择优取向效果，从而导致谱图中某些谱带(尤其是在低角度)的相对强度发生变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的位置而不是它们的相对强度。另外，判断晶型是否一样时应注意保持整体观念，因为并不是一条衍射线代表一个物相，而是一套特定的“d-I/I1”数据才代表某一物相。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
DSC分析：其采用美国铂金埃尔默公司的DSC 8500型差示扫描量热仪进行检测，气氛为氮气，加热速度为10摄氏度/分钟。其分析结果见图2。
TG分析：其采用德国耐驰公司的Netzsch TG 209F3型热重分析仪检测，温度范围：30-400℃，扫描速率：10K/min，吹扫气：25mL/min。其分析结果见图3。
DVS分析：其采用英国SMS仪器公司DVS Intrinsic型动态水分吸附仪进行测定，测定温度：25℃；相对湿度：0-95％。其分析结果见图4。
IR分析：其采用美国尼高力公司的Nicolet-Magna FT-IR750红外光谱仪于室温进行检测，检测范围为：4000-500cm-1的波数。其分析结果见图5。
对上述实施例制得的甜菊糖D苷晶型A，在25℃、RH≤30％条件下进行XRPD分析，其分析结果见图6，从图6中可以看出其晶型不变，晶型稳定性好。
对上述实施例制得的甜菊糖D苷晶型A，在25℃、RH 60％条件下储存半年，其分析结果见图7，从图7中可以看出其晶型不变，晶型稳定性好。
HPLC分析：其采用美国安捷伦科技有限公司的1260infinity液相色谱仪测定。样品溶液配制方法：精确称量25-50毫克甜菊糖D苷样品，放入25毫升的容量瓶中，然后加入水-乙腈(7：3，v/v)溶液，进行溶解并定容至刻度。磷酸钠缓冲液(规格：10mmol/L，pH值：2.6)的配置方法：将2.76克磷酸二氢钠溶解到2升水中，加入磷酸，将pH值调至2.6。色谱柱：Phenomenex公司的Luna 5μC18(2)100A型色谱柱。进样量：5μl。流速：1.0mL/min。柱温：40℃。检测器：210nm紫外检测。流动相：乙腈和磷酸钠缓冲液(规格：10mmol/L，pH值：2.6)的比例为32：68。其分析结果见图8。
上述实施例制得的甜菊糖D苷晶型A，具有好的化学稳定性，HPLC分析显示放置半年后其纯度与原料相比，变化小于0.5％。
上述实施例制得的甜菊糖D苷晶型A，具有很好的重现性。并且水溶性好，约为0.6mg/mL。
上述实施例中所用的甜菊糖D苷原料由山东诸城浩天药业有限公司提供。
实施例二十
一种保健饮品
一种保健饮品，其是由以下原料组成：枸杞25g、黄芪15g、核桃5g、甜菊糖D苷晶型A 1g、山药8g和莲子芯2g。
实施例二十一
一种紫薯甜品
一种紫薯甜品，其是由以下原料组成：紫薯250g、葡萄干20g、红枣20g、桂花5g、百合5g和甜菊糖D苷晶型A 25g。
实施例二十二
一种治疗儿童感冒药
一种紫薯甜品，其是由以下原料组成：对乙酰氨基酚80g、盐酸伪麻黄碱7g、马来酸氯苯那敏0.3g、淀粉20g、羧甲基纤维素钠8g、甜菊糖D苷晶型A 8g和硬脂酸镁3g。
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 (9)

  1. 一种甜菊糖D苷晶型A，其特征在于，所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析，以度表示的2θ值、误差范围为±1°，具有3个或3个以上选自下组的特征衍射峰：4.53、6.38、12.76、13.52、17.48、17.96、20.07和22.63。
  2. 如权利要求1所述的甜菊糖D苷晶型A，其特征在于，所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析，以度表示的2θ值、误差范围为±1°，以
    Figure PCTCN2016090898-appb-100001
    表示的晶面间距d和以百分数表示的衍射峰的相对强度具有如下特征：
    2θ d 相对强度％ 4.53 19.5129 39.7 6.38 13.8374 46.4 10.37 8.5210 33.9 12.76 6.9319 54.9 13.52 6.5432 52.0 15.11 5.8596 27.8 16.45 5.3858 25.3 17.48 5.0695 100.0 17.96 4.9363 98.7 18.36 4.8291 21.0 18.64 4.7571 36.2 20.07 4.4197 73.7 20.49 4.3300 39.8 22.63 3.9259 57.0 24.18 3.6775 27.6 24.79 3.5891 23.8 26.19 3.4005 20.7。
  3. 如权利要求1所述的甜菊糖D苷晶型A，其特征在于，所述晶型A具有选自下组的一个或多个特征：
    (1)所述晶型A具有基本上如图2所示的差示扫描量热分析图谱
    (2)所述晶型A具有基本上如图3所示的热失重分析图谱；
    (3)所述晶型A具有基本上如图4所示的动态水分吸附图谱；和/或
    (4)所述晶型A具有基本上如图5所示的红外图谱。
  4. 一种甜菊糖D苷晶型A的制备方法，其特征在于，所述制备方法为混悬法、溶液挥发法或冷却法。
  5. 如权利要求4所述的甜菊糖D苷晶型A的制备方法，其特征在于，所述混悬法包括以下步骤：
    (1)在零度至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；其中，所述溶剂选自下组：水、甲醇、乙醇、乙腈、四氢呋喃、丙酮、甲乙酮、乙酸乙酯、甲酸乙酯、1-丙醇、2-丙醇、或其组合；
    (2)在零度至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到白色固体；
    (3)将所述白色固体，在零度至溶剂沸点温度的条件下干燥，即得甜菊糖D苷晶型A。
  6. 如权利要求4所述的甜菊糖D苷晶型A的制备方法，其特征在于，所述溶液挥发法包以下步骤：
    (1)在零度至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；其中，所述溶剂选自下组：水、甲醇、乙醇、四氢呋喃、乙腈、或其组合；
    (2)在零度至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到澄清溶液；
    (3)将步骤(1)中所述混悬溶液或步骤(2)中所述澄清溶液，在零度至溶剂沸点温度的条件下挥发，即得甜菊糖D苷晶型A。
  7. 如权利要求4所述的甜菊糖D苷晶型A的制备方法，其特征在于，所述冷却法包括以下步骤：
    (1)在室温至溶剂沸点温度的条件下，将甜菊糖D苷与所述溶剂混合0.1-48h，得到混悬溶液；其中，所述溶剂选自下组：水、甲醇、乙醇、2-丁醇、或其组合；
    (2)在室温至溶剂沸点温度的条件下，将所述混悬溶液过滤或离心，得到澄清溶液；
    (3)将步骤(1)中所述混悬溶液或步骤(2)中所述澄清溶液，冷却至-20-30℃，析出白色固体，过滤，干燥，即得甜菊糖D苷晶型A。
  8. 如权利要求4-7任一项所述的甜菊糖D苷晶型A的制备方法，其特征在于，所述干燥为自然干燥、鼓风干燥、真空干燥、冷冻干燥、气流干燥、微波干燥、红外线干燥或高频率干燥中的一种或两种以上干燥方式。
  9. 如权利要求1-3任一项所述的甜菊糖D苷晶型A在食品、饮料及药品中的应用。
PCT/CN2016/090898 2015-07-23 2016-07-21 一种甜菊糖d苷晶型a、其制备方法及其应用 WO2017012572A1 (zh)

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