WO2017161986A1 - 甜菊糖c苷晶型及制备方法和用途 - Google Patents

甜菊糖c苷晶型及制备方法和用途 Download PDF

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WO2017161986A1
WO2017161986A1 PCT/CN2017/074116 CN2017074116W WO2017161986A1 WO 2017161986 A1 WO2017161986 A1 WO 2017161986A1 CN 2017074116 W CN2017074116 W CN 2017074116W WO 2017161986 A1 WO2017161986 A1 WO 2017161986A1
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stevioside
glycoform
glycoside
methyl
acetate
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PCT/CN2017/074116
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English (en)
French (fr)
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朱理平
梅雪峰
黄颖
王建荣
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诸城市浩天药业有限公司
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Publication of WO2017161986A1 publication Critical patent/WO2017161986A1/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
    • C07H15/256—Polyterpene radicals
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar 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 relates to the field of sweeteners, in particular to a novel crystal form of stevioside C glycoside, a preparation method thereof and use thereof.
  • Stevia is a plant with high sweetness and is native to the Amanbai Mountains bordering Brazil in Paraguay, South America.
  • Stevioside refers to the white powdery stevioside extracted from stevia, which is a natural, high-sweet, zero-calorie sweetener and natural sugar substitute.
  • stevia is the third-best-selling high-intensity sweetener product on the international high-intensity sweetener market.
  • the first generation of stevia is dominated by mixed sugars, but it is often accompanied by a bitter taste.
  • the current second-generation stevioside is mainly composed of high-purity stevioside A glycoside, and has been widely used in beverages, foods, and health care products.
  • Patent CN 105037458 A discloses a polymorph of stevioside D glycosides.
  • Patent US 20130267693 A1 discloses four crystal forms of stevioside B glycoside.
  • Patent US 8030481 B2 discloses solvates and hydrates of stevioside.
  • stevioside C glycoside has a bitter taste, which seriously affects the taste and quality of stevia products.
  • stevioside C glycoside is used in medicine in Japan for clinical application.
  • stevioside C glucoside can be used as a sweetness enhancer, which can significantly reduce the amount of sucrose used, and thus has attracted more and more attention.
  • the present invention aims to provide a novel crystalline form of stevioside C.
  • Another object of the present invention is to provide a process for the preparation of the novel stevioside C-glycoform.
  • a further object of the invention is to provide the use of the novel stevioside C-glycoform.
  • a stevioside C-glycan form V which uses an X-ray powder diffraction method of Cu-K ⁇ , the 2 ⁇ angle expressed in degrees is about 3.77, 12.87, There are distinct characteristic diffraction peaks at 14.96, 18.16, 19.58 and 20.92.
  • the crystal form V has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 2, the 2 ⁇ value expressed in degrees, and the error range is ⁇ 1°,
  • XRPD X-ray powder diffraction
  • the differential scanning calorimetry of Form V has a characteristic endothermic peak in the interval of about 50-150 ° C and 210-250 ° C.
  • thermogravimetric analysis of Form V begins to decompose at 250 ⁇ 20 °C.
  • the crystal form V has a dynamic moisture adsorption (DVS) pattern as shown in FIG. 5, and the mass percentage of moisture absorbed in the range of 0-40% relative humidity is 0-1.7%.
  • the relative humidity is in the range of 40-80%, and the mass percentage of moisture absorption is 1.7-2.9%.
  • the stevioside C glycoside dry matter purity described in step (1) is in the range of 40-100%.
  • the solvent described in the step (1) is water or water and one or more mixed solvents of the following: methanol, ethanol, 1-propanol, 2-propanol, 3- Methyl-1-butanol, 2-methyl-1-propanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl formate, ethyl acetate, butyl acetate, propyl acetate, Isopropyl acetate, isobutyl acetate, tributyl methyl ether, tetrahydrofuran, nitromethane, toluene.
  • a use of the stevioside C-glycoform V of the invention as described above for the preparation of a food, a drink and a pharmaceutical is provided.
  • the composition is selected from the group consisting of a food composition, a beverage composition, and a pharmaceutical composition.
  • the preparation method of the stevioside C-glycoside form V provided by the invention has the advantages of simple process and easy operation, and the obtained product has high crystallinity, low hygroscopicity and high stability.
  • Figure 1 is a structural diagram of stevioside C glycoside
  • Figure 2 is an X-ray powder diffraction (XRPD) pattern of stevioside C glycoform form V;
  • Figure 3 is a differential scanning calorimetry (DSC) chart of stevioside C glycoform form V;
  • FIG. 4 is a thermogravimetric analysis (TG) diagram of stevioside C glycoform form V;
  • Figure 5 is a graph showing the hygroscopicity analysis (DVS) of stevioside C glycoform form V;
  • Figure 6 is a comparison chart of X-ray powder diffraction (XRPD) of stevioside C glycoform form V before and after drying;
  • Figure 7 is a comparison chart of X-ray powder diffraction (XRPD) of stevioside C-form crystal form V stored at 40 ° C and a relative humidity of 75% for half a year;
  • XRPD X-ray powder diffraction
  • Fig. 8 is a high-performance liquid phase (HPLC) comparison chart of the stevioside C-form crystal form V stored at 40 ° C and a relative humidity of 75% for half a year.
  • HPLC high-performance liquid phase
  • the inventors have for the first time developed a stevioside C-glycoform form V through extensive and in-depth research.
  • the crystal form V has high crystallinity, low hygroscopicity, good stability, simple process and easy operation, and can be realized. Large-scale industrial production. On the basis of this, the present invention has been completed.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the term "about” means that the recited value varies by no more than 0.2, for example about X, which represents X ⁇ 0.2, preferably X ⁇ 0.1.
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • room temperature generally refers to 4-30 ° C, preferably 20 ⁇ 5 ° C.
  • the terms "compound of the invention” or “form of the invention” or “compound of the form V of the invention” are used interchangeably and mean that the compound of formula I described in the first aspect of the invention has said X A crystalline compound of a characteristic peak of a ray diffraction.
  • the compounds of the invention are useful as sweeteners.
  • the present invention also provides a composition comprising a Form V compound of the present invention, i.e., a sweetener composition.
  • the composition comprises a variety of different products such as food compositions, beverage compositions, and pharmaceutical compositions.
  • the content (wt%) of the compound of the invention is from 0.1 to 99%, preferably from 1 to 90%, more preferably, based on the total weight of the sweetener composition or product. Ground, 2-50%.
  • sweeteners such as lactose, fructose, sucrose, glucose, trehalose or combinations thereof may also be included in the sweetener compositions of the present invention.
  • the sweetener composition contains no sucrose or a small amount of sucrose, and in the sweetener composition, the sucrose content (wt%) ⁇ 5, preferably ⁇ 2, more preferably ⁇ 1.
  • XRPD X-ray powder diffraction analysis
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • DFS dynamic moisture adsorption 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.
  • DSC analysis It was tested by a DSC 8500 differential scanning calorimeter from Elmer, USA, with a nitrogen atmosphere at a heating rate of 10 degrees Celsius/minute. The analysis results are shown in Figure 3. It can be analyzed from Fig. 3 that the stevioside C glycoform form V has a characteristic endothermic peak in the range of about 50-150 ° C and 210-250 ° C.
  • 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 5. It can be analyzed from Fig. 5 that the stevioside C-glycan form V is in the range of 0-40% relative humidity, and the mass of water absorption is 100. The fraction is in the range of 0-1.7%; in the range of 40-80% relative humidity, the mass percentage of moisture absorbed is between 1.7 and 2.9%.
  • the stevioside C-glycoform form V prepared in the above examples has a lower hygroscopicity than the crystalline form I reported in the patent US 20150064117 A1, and the comparison results are shown in Table 1.
  • the stevioside C-glycosidic form V prepared in the above examples was subjected to XRPD analysis after drying at 105 ° C for one day, and the analysis results are shown in Fig. 6. It can be seen from Fig. 6 that the crystal form is unchanged, and the crystal form has good stability under high temperature conditions.
  • the stevioside C-glycosidic form V prepared in the above examples was stored at 40 ° C and RH 75% for half a year, and the analysis results are shown in Fig. 7. It can be seen from Fig. 7 that the crystal form is unchanged, indicating that the crystal form has good physical stability under high humidity conditions.
  • 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 C-glycoside sample, put it into 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution, dissolve and dilute to 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 C-glycoform form V obtained in the above examples has good reproducibility and is water-soluble and stable, about 0.65 mg/mL.

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Abstract

天然提取的高倍甜味剂甜菊糖苷，具体涉及甜菊糖C苷的新晶型、制备方法及其应用。该新晶型具有结晶度高，稳定性好、吸湿性小等优点，适于更加广泛的运用领域。制备方法简单，易于操作，选择性多，重现性好，可以稳定地获得目标晶型。

Description

甜菊糖C苷晶型及制备方法和用途 技术领域
本发明涉及甜味剂领域，尤其涉及一种甜菊糖C苷的新晶型及其制备方法和用途。
背景技术
甜叶菊是一种具有高倍甜味的植物，原产于南美巴拉圭与巴西接壤的阿曼拜山脉。甜菊糖是指从甜叶菊中提取的白色粉末状甜菊糖苷，是一种纯天然、高甜度、零卡路里的甜味剂、天然代糖。目前，甜菊糖是国际高倍甜味剂市场上第三大畅销的高倍甜味剂产品。第一代甜菊糖以混合糖为主，但是其常常伴随着苦涩的口感。目前的第二代甜菊糖以高纯的甜菊糖A苷为主，已经被广泛用于饮料、食品和保健品中。随着甜菊糖A苷不断的普及，甜叶菊中的其他苷类化合物也逐渐受到重视。文章名为“Human Psychometric and Taste Receptor Responses to Steviol Glycosides”就比较了甜叶菊中各成分的口感。专利CN 105037458 A公开了一种甜菊糖D苷的多晶型。专利US 20130267693 A1公开了甜菊糖B苷的四种晶型。专利US 8030481B2公开了甜菊苷的溶剂合物及水合物。甜菊糖C苷相对于其他苷类化合物，苦涩味较重，严重影响了甜菊糖产品的口感和品质。但是，研究发现其具有抗肿瘤、降血压、降血脂、减肥等功效。目前，甜菊糖C苷在日本被制成药品在临床上进行应用。同时，甜菊糖C苷可以作为甜味增强剂，能显著降低蔗糖的使用量，因而越来越受到人们的关注。
目前，对甜菊糖C苷的研究大多集中在制备工艺，如专利CN 103965271 A和CN 102030788 A。专利US 20150064117 A1报道了甜菊糖C苷的晶型I。但是，晶型I具有很严重的吸湿性大和结晶度差等缺陷，所以本领域迫切需要提供一种性能很好的晶型，例如结晶度高、吸湿性小、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
本发明旨在提供一种新的甜菊糖C苷晶型。
本发明的另一个目的是提供所述新的甜菊糖C苷晶型的制备方法。
本发明的再一个目的是提供所述新的甜菊糖C苷晶型的用途。
在本发明的第一方面，提供了一种甜菊糖C苷晶型V，所述晶型V使用Cu-Kα的X-射线粉末衍射方法，以度表示的2θ角在约为3.77，12.87，14.96，18.16，19.58和20.92处有明显的特征衍射峰。
在另一优选例中，所述晶型V有如图2所示的X-射线粉末衍射(XRPD)图，以度表示的2θ值、误差范围为±1°，以
Figure PCTCN2017074116-appb-000001
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角 d 相对强度％
3.77 23.4 56
9.78 9.0 35
11.21 7.9 24
12.51 7.1 24
12.87 6.9 60
13.11 6.8 33
13.81 6.4 21
14.35 6.2 34
14.96 5.9 100
16.75 5.3 31
17.81 5.0 24
18.16 4.9 57
18.51 4.8 33
19.58 4.5 59
20.42 4.3 23
20.92 4.2 76
22.02 4.0 20
22.64 3.9 20
23.82 3.7 26
24.46 3.6 24
29.47 3.0 37
在另一优选例中，所述晶型V的差示扫描量热分析在约50-150℃和210-250℃区间内有特征吸热峰。
在另一优选例中，所述晶型V的热失重分析在250±20℃开始分解。
在另一优选例中，所述晶型V有如图5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0-1.7％，在相对湿度为40-80％范围内，其吸收水分的质量百分数在1.7-2.9％。
在本发明的第二方面，提供了一种如上所述的甜菊糖C苷晶型V的制备方法，其特征在于，该方法包括以下步骤：
(1)混悬：在0-100℃温度范围内，将甜菊糖C苷与溶剂混合0.1-48h，得到混悬溶液；
(2)过滤：在0-100℃温度范围内，将混悬溶液过滤或离心，得到白色固体，干燥即得甜菊糖C苷晶型V。
在另一优选例中，步骤(1)中所述的甜菊糖C苷干物质纯度在40-100％范围内。
在另一优选例中，步骤(1)中所述的溶剂为水或水与下述的一种或一种以上的混合溶剂：甲醇、乙醇、1-丙醇、2-丙醇、3-甲基-1-丁醇、2-甲基-1-丙醇、乙腈、丙酮、甲乙酮、甲基异丁酮、乙酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、乙酸丙酯、乙酸异丙酯、乙酸异丁酯、三丁甲基乙醚、四氢呋喃、硝基甲烷、甲苯。
在本发明的第三方面，提供了一种如上所述的本发明提供的甜菊糖C苷晶型V在制备食品、饮料及药品中的用途。
在另一优选例中，提供了一种如上所述的本发明提供的甜菊糖C苷晶型V在组合物中的用途。
在另一优选例中，所述的组合物选自下组：食品组合物、饮料组合物、和药品组合物。
本发明提供的甜菊糖C苷晶型V的制备方法，其工艺简单、易于操作，且制得的产品结晶度高、吸湿性低、稳定性高。
附图说明
图1甜菊糖C苷的结构图；
图2甜菊糖C苷晶型V的X-射线粉末衍(XRPD)图；
图3甜菊糖C苷晶型V的差示扫描量热分析(DSC)图；
图4甜菊糖C苷晶型V的热失重分析(TG)图；
图5甜菊糖C苷晶型V吸湿性分析(DVS)图；
图6甜菊糖C苷晶型V在干燥前后的X-射线粉末衍射(XRPD)比较图；
图7甜菊糖C苷晶型V的在40℃、相对湿度75％的条件下储存半年的X-射线粉末衍射(XRPD)比较图；
图8甜菊糖C苷晶型V的在40℃、相对湿度75％的条件下储存半年的高效液相(HPLC)比较图。
具体实施方式
本发明人通过广泛而深入的研究，首次研发出一种甜菊糖C苷晶型V，所述的晶型V结晶度高、吸湿性低、稳定性好，且工艺简单、易于操作，可实现规模化工业生产。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
对于用2θ角表示的特征衍射峰，术语“约”表示列举的值变动不多于0.2°，例如约为X°，则表示X±0.2°，较佳地X±0.1°。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
本发明化合物
如本文所用，术语“本发明化合物”或“本发明晶型”或“本发明晶型V化合物”可互换使用，指本发明第一方面中所述的具有式I化合物的具有所述X-射线衍射特征峰的结晶化合物。本发明化合物可用作甜味剂。
组合物
本发明还提供了含有本发明晶型V化合物的组合物，即甜味剂组合物。
在本发明的一种优选实施方式中，所述组合物包括食品组合物、饮料组合物、和药品组合物等各种不同产品。
在一优选实施方式中，以所述甜味剂组合物或产品的总重计，所述本发明化合物的含量(wt％)为0.1-99％，较佳地，1-90％，更佳地，2-50％。
在本发明的甜味剂组合物中，还可含有其他甜味剂，例如乳糖、果糖、蔗糖、葡萄糖、海藻糖或其组合。
在一优选实施方式中，所述甜味剂组合物不含蔗糖或含少量的蔗糖，并且在所述甜味剂组合物中，所述蔗糖的含量(wt％)≤5，较佳地≤2，更佳地≤1。
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。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。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例一
在室温条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例二
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例三
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入80mL水-乙醇(1：1，v/v)中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例四
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水-四氢呋喃(1：1，v/v)中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例五
在50℃条件下，将20g物质纯度为80％的甜菊糖C苷加入100mL水中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例六
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水中，搅拌2h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例七
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水中，搅拌12h后，离心得到白色固体，白色固体于25℃下真空干燥，得甜菊糖C苷晶型V。
实施例八
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入100mL水中，搅拌12h后，离心得到白色固体，白色固体于50℃下鼓风干燥，得甜菊糖C苷晶型V。
实施例九
在50℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入90mL水中，搅拌12h后，离心得到白色固体，白色固体微波干燥，得甜菊糖C苷晶型V。
实施例十
在70℃条件下，将20g物质纯度为99.5％的甜菊糖C苷加入90mL水中，搅拌12h后，离心得到白色固体，白色固体于50℃下鼓风干燥，得甜菊糖C苷晶型V。
对上述实施例制得的甜菊糖C苷晶型V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)等。
XRPD分析：其采用德国布鲁克仪器有限公司Bruker D8advance型的衍射仪于室温进行检测，采用Cu–Kα射线(λ＝1.5418
Figure PCTCN2017074116-appb-000002
)，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2。XRPD谱图显示上述实施例制得的甜菊糖C苷晶型V具有良好的结晶度。
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3。从图3中可以分析得出：甜菊糖C苷晶型V在约50-150℃和210-250℃区间内有特征吸热峰。
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4。从图4中可以分析得出：甜菊糖C苷晶型V在250±20℃条件下开始分解。
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5。从图5中可以分析得出：甜菊糖C苷晶型V在相对湿度为0-40％范围内，其吸收水分的质量百 分数在0-1.7％；在相对湿度为40-80％范围内，其吸收水分的质量百分数在1.7-2.9％。
上述实施例制得的甜菊糖C苷晶型V相对于专利US 20150064117 A1报道的晶型I吸湿性较低，比较结果见表1。
表1
Figure PCTCN2017074116-appb-000003
对上述实施例制得的甜菊糖C苷晶型V，在105℃条件下干燥一天后进行XRPD分析，其分析结果见图6。从图6中可以看出其晶型不变，晶型在高温条件下稳定性好。
对上述实施例制得的甜菊糖C苷晶型V，在40℃、RH 75％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，说明该晶型在高湿条件下物理稳定性好。
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C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C苷晶型V，具有好的化学稳定性，HPLC分析显示在40℃、RH 75％条件下储存半年后，其纯度仍高达98.8％。说明该晶型在高湿条件下化学稳定性好。
上述实施例制得的甜菊糖C苷晶型V，具有很好的重现性，并且水溶性稳定，约为0.65mg/mL。
上述实施例中所用的甜菊糖C苷原料由山东诸城浩天药业有限公司提供。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 (10)

  1. 一种甜菊糖C苷晶型V，其特征在于，其结构如下式I所示，
    Figure PCTCN2017074116-appb-100001
    并且，所述晶型V使用Cu-Kα的X-射线粉末衍射分析方法，以度表示的2θ角，在约3.77，约12.87，约14.96，约18.16，约19.58和约20.92处具有3个、4个、5个或6个特征衍射峰。
  2. 根据权利要求1所述的甜菊糖C苷晶型V，其特征在于，所述晶型V还具有一个或多个选自下组的特征衍射峰：3.77±0.1°、9.78±0.1°、12.87±0.1°、13.11±0.1°、14.35±0.1°、14.96±0.1°、18.16±0.1°、18.51±0.1°、19.58±0.1°、20.92±0.1°和29.47±0.1°。
  3. 根据权利要求1所述的甜菊糖C苷晶型V，其特征在于，所述晶型V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 PCTCN2017074116-appb-100002
    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：
    Figure PCTCN2017074116-appb-100003
    Figure PCTCN2017074116-appb-100004
  4. 根据权利要求1所述的甜菊糖C苷晶型V，其特征在于，差示扫描量热分析在约50-150℃和210-250℃区间内有特征吸热峰。
  5. 根据权利要求1所述的甜菊糖C苷晶型V，其特征在于，热失重分析在250±20℃开始分解。
  6. 根据权利要求1所述的甜菊糖C苷晶型V，其特征在于，动态水分吸附图谱如图5所示，在相对湿度为0-40％范围内，其吸收水分的质量百分数在0-1.7％，在相对湿度为40-80％范围内，其吸收水分的质量百分数在1.7-2.9％。
  7. 权利要求1-6所述的甜菊糖C苷晶型V的制备方法，其特征在于，该方法包括以下步骤：
    (1)在零度至溶剂沸点温度的条件下，将甜菊糖C苷与溶剂混合0.1-48h，得到混悬溶液；
    (2)在零度至溶剂沸点温度的条件下，将混悬溶液过滤或离心，得到白色固体，干燥即得甜菊糖C苷晶型V。
  8. 根据权利要求7所述的甜菊糖C苷晶型V的制备方法，其特征在于，步骤(1)中所述的甜菊糖C苷干物质纯度在40-100％范围内。
  9. 根据权利要求7所述的甜菊糖C苷晶型V的制备方法，其特征在于，步骤(1)中所述的溶剂为水或水与下述的一种或一种以上的混合溶剂：甲醇、乙醇、1-丙醇、2-丙醇、3-甲基-1-丁醇、2-甲基-1-丙醇、乙腈、丙酮、甲乙酮、甲基异丁酮、乙酸甲酯、甲酸乙酯、乙酸乙酯、乙酸丁酯、乙酸丙酯、乙酸异丙酯、乙酸异丁酯、三丁甲基乙醚、四氢呋喃、硝基甲烷、甲苯。
  10. 一种组合物，其特征在于，所述组合物含有如权利要求1-6任一项所述的甜菊糖C苷晶型V。
PCT/CN2017/074116 2016-03-24 2017-02-20 甜菊糖c苷晶型及制备方法和用途 WO2017161986A1 (zh)

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