WO2017161985A1 - 甜菊糖b苷晶型及制备方法和用途 - Google Patents

甜菊糖b苷晶型及制备方法和用途 Download PDF

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WO2017161985A1
WO2017161985A1 PCT/CN2017/074115 CN2017074115W WO2017161985A1 WO 2017161985 A1 WO2017161985 A1 WO 2017161985A1 CN 2017074115 W CN2017074115 W CN 2017074115W WO 2017161985 A1 WO2017161985 A1 WO 2017161985A1
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stevioside
glycoform
glycoside
crystal form
crystal
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PCT/CN2017/074115
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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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    • 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
    • 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
    • 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
    • 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 B glycoside, a preparation method thereof and use thereof.
  • Stevia is a small compositae native to the Amanbai Mountains bordering Brazil in Paraguay, South America.
  • stevioside B glycoside is a stevioside compound having a sweetness of about 150 times that of sucrose.
  • Rebaudioside B (RB) the structural formula of which is shown in Figure 1 below.
  • stevioside A In stevia extract, stevioside A has been widely used as a sweetener in beverages, foods, and health care products. However, stevioside A has a natural mild bitterness or grassy taste, which cannot be completely removed or masked by the prior art, which makes it difficult for the beverage and food industry to completely replace stevia with stevia.
  • a study in the journal "Journal of Agricultural and Food Chemistry” entitled “Human Psychometric and Taste Receptor Responses to Steviol Glycosides” showed that stevioside B glycoside is similar to stevioside A glycoside, but its bitterness is similar. To be slightly weaker.
  • stevioside B has a taste superior to that of stevioside A, and can be used as a sweetener.
  • Patent CN 104602543 A reports the combination of stevioside B glycoside with other sugars in food and beverage applications. Due to the low content in the stevia leaves, the current preparation method of stevioside B glycosides is mainly obtained by hydrolyzing stevioside A glycoside by sodium hydroxide. The stevioside B glycoside has very low water solubility at room temperature, thereby limiting its use.
  • amorphous in the product may result in moisture agglomeration agglomeration during storage and transportation.
  • the four crystal forms did not improve the water solubility of the stevioside B glycoside.
  • the present invention aims to provide a novel crystalline form of stevioside B.
  • Another object of the present invention is to provide a process for the preparation of the novel stevioside B genotype.
  • a further object of the invention is to provide the use of the novel stevioside B-glycoform.
  • a stevioside B glycoform wherein the crystal form G uses an X-ray powder diffraction method of Cu-K ⁇ , the 2 ⁇ angle expressed in degrees is about 3.93, 13.45, There are distinct characteristic diffraction peaks at 16.62, 18.33, 19.90, 23.95 and 28.02.
  • the crystal form G has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 2, the Bragg 2 ⁇ angle, the interplanar spacing d and the relative intensity (percentage of the strongest rays) are expressed as follows:
  • the differential scanning calorimetry of Form G has a distinct endothermic peak at 60-140 ° C, 150-180 ° C, and 200-240 ° C.
  • thermogravimetric analysis of the Form G begins to decompose at 270 ⁇ 10 °C.
  • the crystal form G 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 to 2.5% in the range of 0 to 45% relative humidity.
  • the relative humidity is in the range of 45-55%, the mass percentage of moisture absorption is 2.5-5.1%, and the relative mass fluctuation range of 55% or more is relatively small.
  • the crystal form G has a topographical feature as shown in FIG.
  • a process for the preparation of stevioside B-glycoform form G as described above characterized in that it comprises one or more of the following steps:
  • step (2) filtration or centrifugation of the clear solution, cooled to 0-50 ° C, a white solid precipitated, filtered, that is, stevioside B glycoside form G;
  • Step (2) The clear solution after filtration or centrifugation is volatilized at a temperature ranging from zero degrees to the boiling point of the solvent to precipitate a white solid, thereby obtaining a stevioside B glycoside form G.
  • the stevioside B 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.
  • the method further comprises drying the isolated stevioside B glycoform form G.
  • 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 B glycoside form G provided by the invention has the advantages of simple process and easy operation, and the stevioside B glycoside form G can be obtained by various methods, and the obtained product has high crystallinity and low hygroscopicity. High stability and good water solubility.
  • Figure 1 is a structural diagram of the stevioside B glycoform form G
  • Figure 2 is an X-ray powder diffraction (XRPD) pattern of stevioside B glycoform form G;
  • Figure 3 is a differential scanning calorimetry (DSC) chart of stevioside B glycoform form G;
  • FIG. 4 is a thermogravimetric analysis (TG) diagram of stevioside B glycoform form G
  • Figure 5 is a graph showing the hygroscopicity analysis (DVS) of stevioside B glycoform
  • Figure 6 is a polarized photograph of the stevioside B glycoform form G
  • Figure 7 is a comparison diagram of X-ray powder diffraction (XRPD) of stevioside B glycoform form G before and after drying;
  • Figure 8 is a comparison chart of X-ray powder diffraction (XRPD) of stevioside B glycoform form G 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 chromatography (HPLC) comparison chart of stevioside B glycoform form G stored at 40 ° C and a relative humidity of 75% for half a year.
  • HPLC liquid chromatography
  • 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 G 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 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.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • 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 in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent 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 G 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.
  • XRPD X-ray powder diffraction 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. As can be seen from Fig. 3, the stevioside B glycoform form G has a distinct endothermic peak at 60 to 140 ° C, 150 to 180 ° C and 200 to 240 ° 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 B glycoform G has a relative humidity of 0-45%, a mass percentage of moisture absorption of 0-2.5%, and a relative humidity of 45-55%. The mass percentage of moisture absorption is 2.5-5.1%; when the relative humidity is 55% or more, the mass percentage of moisture absorption fluctuates less.
  • 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 stevioside B glycoside form G prepared in the above examples is a rhombohedral crystal and has good morphological characteristics.
  • stevioside B glycoside form G prepared in the above examples was subjected to XRPD analysis after drying, 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 stevioside B glycoside G 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 weigh 25-50 mg of stevioside B glycoside sample into 25 ml of volume In a measuring flask, a solution of water-acetonitrile (7:3, v/v) was then added to dissolve and bring to volume.
  • 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 B glycoside form G prepared in the above examples has good reproducibility. And the water solubility is high and stable, about 0.5 mg / mL, significantly higher than the crystalline form 1-4 reported in US 20130267693 A1.
  • the analysis results are shown in Table 1:
  • the stevioside B glycoform form G prepared in the above examples is slightly hygroscopic under conventional storage conditions (45-80% RH).
  • the hygroscopicity of stevioside B genotype G is significantly lower than that of crystalline form 1-4 reported in US 20130267693 A1, and it is not easy to absorb moisture and agglomerate.
  • Table 2 The results of the analysis are shown in Table 2 below:
  • the stevioside B glycoside raw material used in the above examples was supplied by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.

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Abstract

本发明涉及天然提取的高倍甜味剂甜菊糖苷，具体涉及甜菊糖B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、水溶性好、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

甜菊糖B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B苷的新晶型及其制备方法和用途。
背景技术
甜叶菊是一种小菊科植物，原产于南美巴拉圭与巴西接壤的阿曼拜山脉。现已确定的甜叶菊甜味成分有9种：甜菊苷、甜菊糖双糖、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(steviol)；区别仅在于苷键上结合糖的种类、数量和构型。因为它们都是带有甜味的苷类化合物，统称为甜菊糖(Steviol Glycosides)。其中，甜菊糖B苷是一种甜度约为蔗糖150倍的甜菊糖苷类化合物。甜菊糖B苷(Rebaudioside B，RB)，其结构式如下图1所示。
在甜叶菊提取物中，甜菊糖A苷作为甜味剂已经被广泛用于饮料、食品和保健品中。但是，甜菊糖A苷带有天然的轻微苦味或青草味，现有技术还无法完全去除或者掩盖，这使得饮料和食品行业还不敢轻易地完全用甜菊糖来简单替代白糖。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B苷相对于甜菊糖A苷，其甜度差不多，但是苦味要略弱。所以，甜菊糖B苷具有优于甜菊糖A苷的口感，而可以作为甜味剂使用。专利CN 104602543 A报道了甜菊糖B苷与其他糖的组合物在食品及饮料应用。由于在甜菊叶中的含量较低，所以目前甜菊糖B苷的制备方法主要是通过氢氧化钠水解甜菊糖A苷得到。在室温条件下甜菊糖B苷的水溶性极低，从而限制了其使用。
同一化合物的不同晶型在溶解度、溶出速率、熔点、外观及生物有效性等方面有显著差异，从而影响其稳定性和生物利用度。药物多晶型现象的研究已经成为制药工艺及新药制剂确定前必不可少的重要部分。对于甜菊糖B苷来说，对其进行多晶型研究也是至关重要的。专利US 20130267693 A1中报道了甜菊糖B苷晶型1、晶型2、晶型3、晶型4及其制备方法。但从X-射线粉末衍射图谱及偏光照片来看，该四种晶型结晶度差并含有部分无定形。对于吸湿性高的糖苷类化合物来说，产品中的无定形可能导致在储存及运输过程中吸湿结块结团。同时，该四种晶型并未改善甜菊糖B苷的水溶性。
本领域迫切需要提供一种性能更好的晶型，例如结晶度高、水溶性好、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B苷晶型。
本发明的另一个目的是提供所述新的甜菊糖B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B苷晶型的用途。
在本发明的第一方面，提供了一种甜菊糖B苷晶型G，所述晶型G使用Cu-Kα的X-射线粉末衍射方法，以度表示的2θ角在约为3.93，13.45，16.62，18.33，19.90，23.95和28.02处有明显的特征衍射峰。
在另一优选例中，所述晶型G有如图2所示的X-射线粉末衍射(XRPD)图，其布拉格2θ角，晶面间距d和相对强度(最强射线的百分数)表示如下：
Figure PCTCN2017074115-appb-000001
在另一优选例中，所述晶型G的差示扫描量热分析在60～140℃、150～180℃和200～240℃有明显吸热峰。
在另一优选例中，所述晶型G的热失重分析在270±10℃开始分解。
在另一优选例中，所述晶型G有如图5所示的动态水分吸附(DVS)图谱，在相对湿度为0-45％范围内，其吸收水分的质量百分数在0-2.5％，在相对湿度为45-55％范围内，其吸收水分的质量百分数在2.5-5.1％，在相对湿度55％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，所述晶型G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糖B苷晶型G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，将甜菊糖B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，即得甜菊糖B苷晶型G；
(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，即得甜菊糖B苷晶型G；
(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，即得甜菊糖B苷晶型G。
在另一优选例中，步骤(1)中所述的甜菊糖B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。
在另一优选例中，还包括对分离得到甜菊糖B苷晶型G进行干燥处理。
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B苷晶型G在制备食品和药品中的用途。
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B苷晶型G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B苷晶型G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糖B苷晶型G，且制得的产品结晶度高、吸湿性低、稳定性高、水溶性好。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例) 中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1甜菊糖B苷晶型G的结构图；
图2甜菊糖B苷晶型G的X-射线粉末衍(XRPD)图；
图3甜菊糖B苷晶型G的差示扫描量热分析(DSC)图；
图4甜菊糖B苷晶型G的热失重分析(TG)图；
图5甜菊糖B苷晶型G吸湿性分析(DVS)图；
图6甜菊糖B苷晶型G的偏光照片；
图7甜菊糖B苷晶型G在干燥前后的X-射线粉末衍射(XRPD)比较图；
图8甜菊糖B苷晶型G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甜菊糖B苷晶型G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B苷晶型G，所述的晶型G结晶度高、吸湿性低、稳定性高、水溶性好，且制备工艺简单高效，重复性好，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G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。
假如期望盐的形成与结晶同时发生，如果盐在反应介质中比原料溶解度小，那么加入适当的酸或碱可导致所需盐的直接结晶。同样，在最终想要的形式比反应物溶解度小的介质中，合成反应的完成可使最终产物直接结晶。
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G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，否则百分比和份数按重量计算。
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100％的甜菊糖B苷加入100mL甲醇中，搅拌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，均得甜菊糖B苷晶型G。
实施例二
在50℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL甲醇中，搅拌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，均得甜菊糖B苷晶型G。
实施例三
在室温条件下，将40g物质纯度为50％的甜菊糖B苷加入100mL甲醇中，搅拌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，均得甜菊糖B苷晶型G。
实施例四
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入70mL 30％的甲醇-水(v/v)体系中，搅拌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，均得甜菊糖B苷晶型G。
实施例五
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入50mL 50％的甲醇-水(v/v)体系中，搅拌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，均得甜菊糖B苷晶型G。
实施例六
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入50mL 50％的乙醇-水(v/v)体系中，搅拌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，均得甜菊糖B苷晶型G。
实施例七
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入50mL 50％的乙醇-水(v/v)体系中，搅拌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，均得甜菊糖B苷晶型G。
实施例八
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入50mL 50％的乙 醇-水(v/v)体系中，搅拌48h后，过滤得到滤液和白色固体，滤液和白色固体分别于50℃下真空干燥，均得甜菊糖B苷晶型G。
实施例九
在室温条件下，将20g物质纯度为100％的甜菊糖B苷加入200mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液快速冷却至5℃，析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液快速冷却至室温，析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十一
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液以1℃/h的降温速率冷却至室温，析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十二
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液以10℃/h的降温速率冷却至室温，并在室温条件下静置2h，析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十三
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液在室温条件下敞口自然挥发，待析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十四
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液在室温，氮气流量为25mL/min条件下挥发，待析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十五
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液在室温，真空度为0.05MPa条件下挥发，待析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
实施例十六
在90℃条件下，将20g物质纯度为100％的甜菊糖B苷加入100mL 50％的乙醇-水(v/v)体系中，搅拌48h后，过滤得到的滤液在室温，真空度为0.05MPa条件下挥发，待析出大量晶体，过滤，晶体干燥，得甜菊糖B苷晶型G。
对上述实施例制得的甜菊糖B苷晶型G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 PCTCN2017074115-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B苷晶型G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中可以看出，甜菊糖B苷晶型G在60～140℃、150～180℃和200～240℃有明显吸热峰。
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B苷晶型G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。从图5中可以分析得出：甜菊糖B苷晶型G在相对湿度为0-45％范围内，其吸收水分的质量百分数在0-2.5％；在相对湿度为45-55％范围内，其吸收水分的质量百分数在2.5-5.1％；在相对湿度55％以上，其吸收水分的质量百分数波动范围较小。
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糖B苷晶型G为菱型晶体，具有良好的形貌特征。
对上述实施例制得的甜菊糖B苷晶型G，在干燥后进行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糖B苷晶型G，在40℃、RH75％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毫克甜菊糖B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糖B苷晶型G，具有好的化学稳定性，HPLC分析显示在40℃、RH75％条件下储存半年后,其纯度仍高达98.3％。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B苷晶型G，具有很好的重现性。并且水溶性高并且稳定，约为0.5mg/mL，明显高于US 20130267693 A1中报道的晶型1-4。其分析结果如下表1：
表1
Figure PCTCN2017074115-appb-000003
上述实施例制得的甜菊糖B苷晶型G，在常规储存条件(45-80％RH)下略有吸湿性。甜菊糖B苷晶型G的吸湿性明显低于US 20130267693 A1中报道的晶型1-4,不易吸湿结块。分析结果如下表2:
表2
Figure PCTCN2017074115-appb-000004
Figure PCTCN2017074115-appb-000005
上述实施例中所用的甜菊糖B苷原料由山东诸城浩天药业有限公司提供。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，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B苷晶型G，其特征在于，其结构式如下式I所示，
    Figure PCTCN2017074115-appb-100001
    并且，所述晶型G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3.93，约13.45，约16.62，约18.33和约19.90处具有3个、4个或5个特征衍射峰。
  2. 根据权利要求1所述的甜菊糖B苷晶型G，其特征在于，所述晶型G还具有一个或多个选自下组的特征衍射峰：3.93±0.1°、13.45±0.1°、16.62±0.1°、18.33±0.1°、19.90±0.1°、23.95±0.1°和28.02±0.1°。
  3. 根据权利要求1所述的甜菊糖B苷晶型G，其特征在于，所述晶型G有基本如图2所示的X-射线粉末衍射(XRPD)图谱，其布拉格2θ角，晶面间距d和相对强度(最强射线的百分数)表示如下：
    Figure PCTCN2017074115-appb-100002
    Figure PCTCN2017074115-appb-100003
  4. 根据权利要求1所述的甜菊糖B苷晶型G，其特征在于，所述晶型G还具有选自下组的一个或多个特征：
    (1)所述晶型G具有基本上如图3所示的差示扫描量热分析图谱；
    (2)所述晶型G具有基本上如图4所示的热失重图谱；
    (3)所述晶型G具有基本上如图5所示的动态水分吸附图谱。
  5. 根据权利要求1-4中任一所述的甜菊糖B苷晶型G的制备方法，其特征在于，该方法包括以下步骤：
    (1)提供甜菊糖B苷与溶剂；
    (2)将甜菊糖B苷与溶剂混合，对混合液进行结晶处理，从而形成含有甜菊糖B苷晶型G的混悬溶液；和
    (3)从所述的混悬溶液中分离得到甜菊糖B苷晶型G。
  6. 根据权利要求5所述的甜菊糖B苷晶型G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，获得甜菊糖B苷晶型G；和/或
    (3-2)对所述的混悬溶液进行离心，获得甜菊糖B苷晶型G；和/或
    (3-3)对过滤或离心后的澄清溶液进行降温处理，从而析出甜菊糖B苷晶型G，分离以获得甜菊糖B苷晶型G；和/或
    (3-4)对过滤或离心后的澄清溶液的溶剂进行挥发处理，从而析出甜菊糖B苷晶型G，分离以获得甜菊糖B苷晶型G。
  7. 根据权利要求5所述的甜菊糖B苷晶型G的制备方法，其特征在于，步骤(1)中所述的甜菊糖B苷干物质纯度在50-100％范围内。
  8. 根据权利要求5所述的甜菊糖B苷晶型G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。
  9. 一种组合物，其特征在于，所述组合物含有如权利要求1-4任一项所述的甜菊糖B苷晶型G。
  10. 根据权利要求1-4任一项所述的甜菊糖B苷晶型G及其制备方法在食品、饮料及药品中的用途。
PCT/CN2017/074115 2016-03-24 2017-02-20 甜菊糖b苷晶型及制备方法和用途 WO2017161985A1 (zh)

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