WO2017161987A1 - 甜菊双糖苷晶型及制备方法和用途 - Google Patents

甜菊双糖苷晶型及制备方法和用途 Download PDF

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WO2017161987A1
WO2017161987A1 PCT/CN2017/074117 CN2017074117W WO2017161987A1 WO 2017161987 A1 WO2017161987 A1 WO 2017161987A1 CN 2017074117 W CN2017074117 W CN 2017074117W WO 2017161987 A1 WO2017161987 A1 WO 2017161987A1
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crystal form
stevia
diglucoside
disaccharide
methyl
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PCT/CN2017/074117
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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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    • 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
    • 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
    • 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

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  • the invention relates to the field of sweeteners, in particular to a novel crystal form of stevioside and its preparation method and use.
  • Stevia belongs to the small Compositae family and is native to the Amanbai Mountains bordering Brazil in Paraguay, South America. The leaves contain glycocalyx 150-300 times sweeter than sucrose. It is used as a low-calorie food instead of synthetic sugar, and is used to treat diabetes, obesity, heart disease and control of pediatric worms.
  • Stevioside refers to the white powdery stevioside produced from stevia, which is a natural, high-sweet, zero-calorie (zero calorific value) food additive (sweetener) and natural sugar substitute. Stevioside is not absorbed by the human small intestine, but is converted to stevioside which is not absorbed by the body. Stevia is the “third source of sugar” after sucrose and beet sugar, and it is also the third best-selling high-intensity sweetener product of international high-intensity sweeteners.
  • stevioside There are nine sweet ingredients in stevia that have been identified: stevioside, steviol glycoside, stevioside A-stevia glycoside F and dugrise A. They are all glycosidic compounds with the same aglycone-stevioside; the only difference is that the type, number and configuration of the binding sugars on the glycosidic linkages are different. Because they are all sweet sugar glycosides, collectively known as stevioside. Among them, the stevioside is a stevioside compound having a sweetness of about 100 times that of sucrose. Steviolbioside (STB), its structural formula is shown in Figure 1.
  • stevioside The highest content of stevia dry leaves is stevioside, followed by stevioside A and stevioside C.
  • stevioside A has a better taste than stevioside, it has been widely used as a sweetener in beverages, foods, and health care products.
  • the polymorphism of stevioside A has been extensively studied, and the literature is entitled “Single Crystal Growth and Structure Determination of the Natural “High Potency” Sweetener Rebaudioside A” and the patents US 20070292582 A1, WO 2010118218 A1, CN103739639 A and CN 103739640 A
  • the polymorphism of stevioside A glycoside has been reported. Studies on these polymorphs have found that different crystal forms not only affect their physical stability, solubility, appearance, but also their mouthfeel and sweetness.
  • Stevia diglucoside has a parent structure similar to stevioside A glycoside, which may have different polymorphic phenomena. The presence of different polymorphic phenomena may affect product quality.
  • a crystalline form having excellent properties such as a new crystal form having high crystallinity, low hygroscopicity, and high stability.
  • a method and use for the preparation of the above crystal forms there is an urgent need to provide a method and use for the preparation of the above crystal forms.
  • the present invention aims to provide a novel crystalline form of stevioside.
  • Another object of the present invention is to provide a process for the preparation of the novel crystalline form of stevioside.
  • a further object of the invention is to provide the use of said novel steviol glycoside crystalline form.
  • a Stevia diglucoside crystal form A which uses an X-ray powder diffraction method of Cu-K ⁇ , the 2 ⁇ angle expressed in degrees being about 4.72, 7.20, 12.24 There are distinct characteristic diffraction peaks at 13.40, 14.16, 14.74, 16.54, 17.04, 18.18 and 18.98.
  • the crystal form A 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 A has a characteristic endothermic peak in the range of about 50-150 ° C and 250-280 ° C.
  • thermogravimetric analysis of Form A begins to decompose at 270 ⁇ 10 °C.
  • the crystalline form A has a dynamic moisture adsorption (DVS) pattern as shown in FIG. 5, and the mass percentage of absorbed moisture is in the range of 0-4.2% in the range of 0-20% relative humidity.
  • the relative humidity is in the range of 20-40%, the mass percentage of moisture absorption is 4.2-9.5%, and the relative humidity is 40% or more, and the mass percentage of absorbed moisture is small.
  • the Stevia disaccharide crystal form A has a topographical feature as shown in FIG.
  • a process for the preparation of a Stevia diglucoside crystal form A as described above characterized in that it comprises one or more of the following steps:
  • Suspension mixing the stevioside disaccharide with a solvent for 0.1-48 h in a temperature range from zero degrees to the boiling point of the solvent to obtain a suspension solution;
  • step (2) filtration or centrifugation of the clear solution, cooled to 0-50 ° C, a white solid precipitated, filtered, dried to obtain Stevia disaccharide crystal form A;
  • Step (2) The clear solution after filtration or centrifugation is volatilized at a temperature range from zero to the boiling point of the solvent to precipitate a white solid, which is dried to obtain a Stevia disaccharide crystal form A.
  • the dendrilous glycoside dry matter purity described in step (1) is in the range of 50-100%.
  • the solvent described in the step (1) is selected from one or more of the following: water, 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.
  • the composition is selected from the group consisting of a food composition, a beverage composition, and a pharmaceutical composition.
  • the preparation method of the Stevia diglucoside crystal form A provided by the invention has the advantages of simple process and easy operation, and the Stevia diglucoside crystal form A can be obtained by various methods, and the obtained product has high crystallinity, low hygroscopicity and stability. high.
  • FIG. 1 is a structural diagram of the Stevia diglucoside crystal form A provided by the present invention.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Figure 5 is a graph showing the hygroscopicity analysis (DVS) of the Stevia diglucoside crystal form A provided by the present invention.
  • Figure 6 is a polarized photograph of the Stevia disaccharide crystal form A provided by the present invention.
  • XRPD X-ray powder diffraction
  • Figure 8 is a comparison diagram of X-ray powder diffraction (XRPD) of the Stevia diglucoside crystal form A provided by the present invention stored at 40 ° C and a relative humidity of 75% for half a year;
  • XRPD X-ray powder diffraction
  • Fig. 9 is a high performance liquid phase (HPLC) comparison chart of the steviol glycoside crystal form A provided by the present invention stored at 40 ° C and a relative humidity of 75% for half a year.
  • HPLC liquid phase
  • the present inventors have for the first time developed a Stevia diglucoside crystal form A by extensive and intensive research.
  • the crystal form A has high crystallinity, low hygroscopicity, good stability, simple preparation 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.
  • compound of the invention or “form of the invention” or “compound of the form A of the invention”, as used herein, is used interchangeably to mean having the compound of formula I as described in the first aspect of the invention having said X A crystalline compound of a characteristic peak of a ray diffraction.
  • the compounds of the invention are useful as sweeteners.
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. This can be done in a number of ways, for example by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods.
  • the solubility of the compound of interest can be reduced by the addition of an antisolvent or a solvent in which the compound has a low solubility or a mixture of such solvents. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest at elevated temperatures In a solvent, an appropriate volume of anti-solvent is then added in a controlled manner to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • the present invention also provides a composition comprising a crystalline form A compound of the 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.
  • the steviol glycoside crystal form A prepared in the above examples was subjected to X-ray powder diffraction analysis (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), dynamic moisture adsorption analysis (DVS) and the like.
  • 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 Stevia diglucoside crystal form A has a characteristic endothermic peak in the range of about 50-150 ° C and 250-280 ° 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.
  • the Stevia diglucoside crystal form A prepared in the above examples is slightly hygroscopic, has a hygroscopicity of only 1% under normal storage (40%-80% RH), and has low hygroscopicity relative to other sugars.
  • Polarized photo It was tested by XPV-400E polarized light microscope of Shanghai Changfang Optical Instrument Co., Ltd., and the test magnification was 5 times. The analysis results are shown in Figure 6. The polarized photograph shows that the Stevia disaccharide crystal form A obtained in the above examples is a columnar crystal and has good morphology characteristics.
  • the Stevia diglucoside crystal form A 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. 7 . It can be seen from Fig. 7 that the crystal form is unchanged and the crystal form stability is good.
  • the Stevia diglucoside crystal form A 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. 8. It can be seen from Fig. 8 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 sample 25-50 mg of steviol diglucoside, put it into a 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution, dissolve and dilute to the mark.
  • 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 Stevia diglucoside crystal form A obtained in the above examples has good reproducibility and is water-soluble and stable at about 0.16 mg/mL.

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Abstract

本发明涉及天然提取的高倍甜味剂甜菊糖苷，具体涉及甜菊双糖苷的新晶型、制备方法及其应用。运用XRPD、DSC、TGA、DVS等固体化学分析手段对该新晶型进行了全面表征，发现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。本发明涉及的制备方法简单，易于操作，选择性多，重现性好，可以稳定地获得目标晶型。

Description

甜菊双糖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，尤其涉及一种甜菊双糖苷的新晶型及其制备方法和用途。
背景技术
甜叶菊属于小菊科植物，原产于南美巴拉圭与巴西接壤的阿曼拜山脉。叶中含有糖甙甜度为蔗糖的150-300倍。用它做低热食品，代替合成糖料，并用于治疗糖尿病、肥胖病、心脏病及防治小儿虫齿等。甜菊糖是指从甜叶菊中提取生产的白色粉末状甜菊糖苷，是一种纯天然、高甜度、零卡路里(零热值)的食品添加剂(甜味剂)、天然代糖。甜菊糖在人体内并不被人体小肠吸收，而是转换为不会被人体吸收的甜菊糖醇。甜菊糖是继蔗糖、甜菜糖之后的“第三糖源”,同时也是如今国际高倍甜味剂的第三大畅销的高倍甜味剂产品。
现已确定的甜叶菊中的甜味成分有9种：甜菊苷、甜菊双糖苷、甜菊糖A苷-甜菊糖F苷和杜克苷A。它们均属苷类化合物，具有相同苷元—甜菊醇；区别仅在于苷键上结合糖的种类、数量和构型具有差异性。因为它们都是带有甜味的苷类化合物，统称为甜菊糖。其中，甜菊双糖苷是一种甜度约为蔗糖100倍的甜菊糖苷类化合物。甜菊双糖苷(Steviolbioside，STB)，其结构式如下图1所示。
甜叶菊干叶中含量最高的是甜菊苷，其次是甜菊糖A苷和甜菊糖C苷。当然，不同地区产的甜叶菊中这些甜味成分的比例会发生变化，但大体的趋势是如此的。由于甜菊糖A苷相对于甜菊苷来说口感更佳，而被作为甜味剂已经被广泛用于饮料、食品和保健品中。甜菊糖A苷的多晶型现象已经得到了广泛的研究，文献名为“Single Crystal Growth and Structure Determination of the Natural“High Potency”Sweetener Rebaudioside A”和专利US 20070292582 A1、WO 2010118218 A1、CN103739639 A和CN 103739640 A对甜菊糖A苷的多晶型现象均有报道。通过对这些多晶型研究发现：不同晶型不仅会影响其物理稳定性、溶解度、外观，甚至会影响其口感和甜度。
甜菊双糖苷具有与甜菊糖A苷相似的母体结构，其可能存在不同的多晶型现象。不同多晶型现象的存在可能影响产品品质。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双糖苷晶型。
本发明的另一个目的是提供所述新的甜菊双糖苷晶型的制备方法。
本发明的再一个目的是提供所述新的甜菊双糖苷晶型的用途。
在本发明的第一方面，提供了一种甜菊双糖苷晶型A，所述晶型A使用Cu-Kα的X-射线粉末衍射方法，以度表示的2θ角在约为4.72，7.20，12.24，13.40，14.16，14.74，16.54，17.04，18.18和18.98处有明显的特征衍射峰。
在另一优选例中，所述晶型A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 PCTCN2017074117-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％
4.72 18.7 100
7.20 12.3 21
8.50 10.4 7
12.24 7.2 38
13.40 6.6 43
14.16 6.3 13
14.74 6.0 44
15.76 5.6 7
16.12 5.5 28
16.54 5.4 14
17.04 5.2 15
18.18 4.9 27
18.98 4.7 20
20.12 4.4 15
22.14 4.0 6
22.68 3.9 14
23.14 3.8 8
24.34 3.7 9
24.62 3.6 7
25.78 3.5 9
26.22 3.4 6
32.58 2.7 7
。
在另一优选例中，所述晶型A的差示扫描量热分析在约50-150℃和250-280℃区间内有特征吸热峰。
在另一优选例中，所述晶型A的热失重分析在270±10℃开始分解。
在另一优选例中，所述晶型A有如图5所示的动态水分吸附(DVS)图谱，在相对湿度为0-20％范围内，其吸收水分的质量百分数在0-4.2％，在相对湿度为20-40％范围内，其吸收水分的质量百分数在4.2-9.5％，在相对湿度40％以上，其吸收水分的质量百分数波动范围较小。
在另一优选例中，所述甜菊双糖苷晶型A有如图6所示形貌特征。
在本发明的第二方面，提供了一种如上所述的甜菊双糖苷晶型A的制备方法，其特征在于，该方法包括以下步骤的一种或一种以上：
(1)混悬：在零度至溶剂沸点温度范围内，将甜菊双糖苷与溶剂混合0.1-48h，得到混悬溶液；
(2)过滤：在零度至溶剂沸点温度范围内，将混悬溶液过滤或离心，得到白色固体，干燥即得甜菊双糖苷晶型A；
(3)冷却：步骤(2)过滤或离心后的澄清溶液，冷却至0-50℃，析出白色固体，过滤，干燥即得甜菊双糖苷晶型A；
(4)挥发：步骤(2)过滤或离心后的澄清溶液，置于零度至溶剂沸点温度范围内挥发，析出白色固体，干燥即得甜菊双糖苷晶型A。
在另一优选例中，步骤(1)中所述的甜菊双糖苷干物质纯度在50-100％范围内。
在另一优选例中，步骤(1)中所述的溶剂选自下述的一种或一种以上：水、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双糖苷晶型A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双糖苷晶型A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。
本发明提供的甜菊双糖苷晶型A的制备方法，其工艺简单、易于操作、可通过多种方法制得甜菊双糖苷晶型A，且制得的产品结晶度高、吸湿性低、稳定性高。
附图说明
图1是本发明提供的甜菊双糖苷晶型A的结构图；
图2是本发明提供的甜菊双糖苷晶型A的X-射线粉末衍(XRPD)图；
图3是本发明提供的甜菊双糖苷晶型A的差示扫描量热分析(DSC)图；
图4是本发明提供的甜菊双糖苷晶型A的热失重分析(TG)图；
图5是本发明提供的甜菊双糖苷晶型A吸湿性分析(DVS)图；
图6是本发明提供的甜菊双糖苷晶型A的偏光照片；
图7是本发明提供的甜菊双糖苷晶型A在干燥前后的X-射线粉末衍射(XRPD)比较图；
图8是本发明提供的甜菊双糖苷晶型A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9是本发明提供的甜菊双糖苷晶型A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双糖苷晶型A，所述的晶型A结晶度高、吸湿性低、稳定性好，且制备工艺简单、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A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。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入反溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization,第三版,J W Mullens,Butterworth-Heineman Ltd.，1993,ISBN 0750611294。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解 在溶剂中，随后通过受控方式加入适当体积的反溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
组合物
本发明还提供了含有本发明晶型A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％的甜菊双糖苷加入100mL甲醇中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊双糖苷晶型A。
实施例二
在50℃条件下，将30g物质纯度为99.5％的甜菊双糖苷加入100mL甲醇中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊双糖苷晶型A。
实施例三
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入100mL甲醇中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊双糖苷晶型A。
实施例四
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入50mL乙醇中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊双糖苷晶型A。
实施例五
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入50mL乙醇中，搅拌1h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊双糖苷晶型A。
实施例六
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入50mL乙醇中，搅拌1h后，过滤得到白色固体，白色固体于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例七
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入600mL乙醇中，搅拌1h后，趁热过滤后的澄清溶液，快速冷却至室温，静置12h，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例八
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，快速冷却至室温，静置12h，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例九
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，以0.1℃/min的降温速率降至室温，静置10h，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例十
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，以0.1℃/min的降温速率降至室温，静置10h，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例十一
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，以0.5℃/min的降温速率降至室温，静置10h，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例十二
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，于50℃条件下自然挥发，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例十三
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，于25℃减压挥发，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
实施例十四
在50℃条件下，将40g物质纯度为80％的甜菊双糖苷加入1000mL乙醇-水(1:1，v:v)中，搅拌30min后，趁热过滤后的澄清溶液，于25℃减压挥发，析出大量晶体，过滤后于50℃下鼓风干燥，得甜菊双糖苷晶型A。
对上述实施例制得的甜菊双糖苷晶型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)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 PCTCN2017074117-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双糖苷晶型A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：所述的甜菊双糖苷晶型A在约50-150℃和250-280℃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：所述的甜菊双糖苷晶型A在270±10℃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。上述实施例制得的甜菊双糖苷晶型A略有吸湿性，在正常储存(40％-80％RH)条件下吸湿性仅为1％，相对于其他糖类来说，吸湿性较低。
偏光照片：其采用上海长方光学仪器有限公司的XPV-400E偏光显微镜进行实验，测试放大倍数：5倍。其分析结果见图6。偏光照片显示，上述实施例制得的甜菊双糖苷晶型A为柱状晶体，具有良好的形貌特征。
对上述实施例制得的甜菊双糖苷晶型A，在105℃条件下干燥一天后进行XRPD分析，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。
对上述实施例制得的甜菊双糖苷晶型A，在40℃、RH 75％条件下储存半年，其分析结果见图8。从图8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毫克甜菊双糖苷样品，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9。上述实施例制得的甜菊双糖苷晶型A，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双糖苷晶型A，具有很好的重现性，并且水溶性稳定，约为0.16mg/mL。
上述实施例中所用的甜菊双糖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 (12)

  1. 一种甜菊双糖苷晶型A，其特征在于，其结构如下式I所示，
    Figure PCTCN2017074117-appb-100001
    并且，所述晶型A使用Cu-Kα射线测得的X-射线粉末衍射分析，以度表示的2θ角，在约4.72，约12.24，约13.40，约14.74，和约16.12处具有3个、4个或5个特征衍射峰。
  2. 根据权利要求1所述的甜菊双糖苷晶型A，其特征在于，所述晶型A还具有一个或多个选自下组的特征衍射峰：4.72±0.1°、7.20±0.1°、12.24±0.1°、13.40±0.1°、14.74±0.1°、16.12±0.1°、17.04±0.1°、18.18±0.1°、18.98±0.1°和20.12±0.1°。
  3. 根据权利要求1所述的甜菊双糖苷晶型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 PCTCN2017074117-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 PCTCN2017074117-appb-100003
    Figure PCTCN2017074117-appb-100004
  4. 根据权利要求1所述的甜菊双糖苷晶型A，其特征在于，差示扫描量热分析在约50-150℃和250-280℃区间内有特征吸热峰。
  5. 根据权利要求1所述的甜菊双糖苷晶型A，其特征在于，热失重分析在270±10℃开始分解。
  6. 根据权利要求1所述的甜菊双糖苷晶型A，其特征在于，动态水分吸附图谱基本上如图5所示，在相对湿度为0-20％范围内，其吸收水分的质量百分数在0-4.2％，在相对湿度为20-40％范围内，其吸收水分的质量百分数在4.2-9.5％，在相对湿度40％以上，其吸收水分的质量百分数波动范围较小。
  7. 权利要求1-6所述的甜菊双糖苷晶型A的制备方法，其特征在于，该方法包括以下步骤：
    (1)提供甜菊双糖苷与溶剂；
    (2)将甜菊双糖苷与溶剂混合，对混合液进行结晶处理，从而形成含有甜菊双糖苷晶型A的混悬溶液；和
    (3)从所述的混悬溶液中分离得到甜菊双糖苷晶型A。
  8. 根据权利要求7所述的甜菊双糖苷晶型A的制备方法，其特征在于，所述步骤(3)包括：
    (3-1)对所述的混悬溶液进行过滤，获得甜菊双糖苷晶型A；和/或
    (3-2)对所述的混悬溶液进行离心，获得甜菊双糖苷晶型A；和/或
    (3-3)对过滤或离心后的澄清溶液进行降温处理，从而析出甜菊双糖苷晶型A，分离以获得甜菊双糖苷晶型A；
    (3-4)对过滤或离心后的澄清溶液的溶剂进行挥发处理，从而析出甜菊双糖苷晶型A，分离以获得甜菊双糖苷晶型A。
  9. 根据权利要求7所述的甜菊双糖苷晶型A的制备方法，其特征在于，步骤(1)中所述的甜菊双糖苷干物质纯度在50-100％范围内。
  10. 根据权利要求7所述的甜菊双糖苷晶型A的制备方法，其特征在于，步骤(1)中所述的溶剂选自下述的一种或一种以上：水、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。
  11. 一种组合物，其特征在于，所述组合物含有如权利要求1-6任一项所述的甜菊双糖苷晶型A。
  12. 根据权利要求1-6任一项所述的甜菊双糖苷晶型A及其制备方法在食品、饮料及药品中的用途。
PCT/CN2017/074117 2016-03-24 2017-02-20 甜菊双糖苷晶型及制备方法和用途 WO2017161987A1 (zh)

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