WO2017143956A1 - Crystal form sodium salt of rebaudioside b and preparation method and use thereof - Google Patents
Crystal form sodium salt of rebaudioside b and preparation method and use thereof Download PDFInfo
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- WO2017143956A1 WO2017143956A1 PCT/CN2017/074114 CN2017074114W WO2017143956A1 WO 2017143956 A1 WO2017143956 A1 WO 2017143956A1 CN 2017074114 W CN2017074114 W CN 2017074114W WO 2017143956 A1 WO2017143956 A1 WO 2017143956A1
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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
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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
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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
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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 sodium stevioside B sodium salt, a preparation method thereof and use thereof.
- Rebaudioside B Sodium Salt of Rebaudioside B (RBNa), the structural formula of which is shown below (Fig. 1). It is a sodium salt of the stevioside glycoside B glucoside extracted from stevia, which is about 150 times sweeter than sucrose.
- the preparation method of the sodium stevioside B sodium salt is mainly obtained by hydrolyzing stevioside A glycoside or stevioside B glycoside to form a salt.
- stevioside A has been widely used as a sweetener in beverage applications, but aqueous solution instability and post-bitter taste have been the cause of its application.
- the present invention aims to provide a novel crystalline form of sodium stevioside B sodium.
- Another object of the present invention is to provide a process for the preparation of the novel crystalline form of the sodium stevioside B sodium salt.
- a further object of the invention is to provide the use of the novel crystalline form of the sodium stevioside B sodium salt.
- a stevioside B sodium salt crystal form A having the structure shown in Figure 1, wherein the crystal form A is subjected to an X-ray powder diffraction method of Cu-K? The indicated 2 theta angles have distinct characteristic diffraction peaks at about 4.89, 6.44, 15.91, 19.63 and 29.09.
- the crystal form A 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 Form A has a differential scanning calorimetry pattern, a thermogravimetric map, a dynamic moisture adsorption pattern, and an infrared spectrum substantially as shown in Figures 3, 4, 5, and 6.
- a process for the preparation of a crystalline form A of stevioside B sodium salt as described above characterized in that it comprises the steps of:
- step (2) filtration or centrifugation of the clear solution, cooled to 0-25 ° C, a white solid precipitated, filtered, dried to obtain stevioside B sodium salt crystal form A;
- the sodium stevioside B sodium salt described in step (1) has a dry matter purity of from 100% to 50%.
- the solvent described in the step (1) or the step (2) is selected from one or more of the following: water, methanol, ethanol, acetonitrile, acetone, methyl ethyl ketone, 1-propanol, 2-propanol, butyl acetate, tributyl methyl ether, isopropyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone , 2-methyl-1-propanol, propyl acetate.
- the solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, water, or a combination thereof.
- the solvent is a mixed solvent of an alcohol and water, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, or a combination thereof.
- 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 sodium salt crystal form A provided by the invention has the advantages of simple process and easy operation, and can obtain the stevioside B sodium salt crystal form A by various methods, and the obtained product has high crystallinity. Good water solubility, high stability and good fluidity.
- Example 1 stevioside B sodium salt crystal form A hygroscopicity analysis (DVS) pattern.
- FIG. 7 Comparison of X-ray powder diffraction (XRPD) of Example 1 Steviate S-sodium salt crystal form A for half a year at 40 ° C humidity 75%.
- Figure 8 X-ray powder diffraction (XRPD) comparison chart of commercially available stevioside B sodium salt amorphous form for half a year under conditions of a humidity of 75% at 40 °C.
- XRPD X-ray powder diffraction
- the inventors have for the first time developed a crystal form A of stevioside B sodium salt through extensive and intensive research, the crystal form A has good thermal stability and non-hygroscopicity, and the preparation process is simple, efficient, and reproducible. Well, it can realize 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. It can have low solubility in it by adding an anti-solvent or compound A solvent or a mixture of such solvents to reduce the solubility of the compound of interest. 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 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.
- stevioside B glycoside 100g was added to 500mL ethanol-water (10:1) system at 25 °C, gradually added 5g sodium hydroxide, the pH of the solution was adjusted to 8.0-8.5, and stirred for 2h. After filtration, the solid after filtration was dried under vacuum at 25 ° C to obtain stevioside B sodium salt crystal form A.
- stevioside B Under the condition of 25 ° C, 100 g of stevioside B with a purity of 99% was added to 500 mL of ethanol system, and 20 g of 25% aqueous sodium hydroxide solution was gradually added dropwise, and the pH of the solution was adjusted to 8.0-8.5, stirred for 2 hours, and then filtered. The filtered solid was dried under vacuum at 25 ° C to obtain a stevioside B sodium salt crystal form A.
- stevioside A glycoside having a purity of 99% was added to a 500 mL ethanol system at 25 ° C, and 20 g of a 25% aqueous sodium hydroxide solution was gradually added dropwise thereto, and the pH of the solution was adjusted to 8.0-8.5, and the temperature was raised to 80 ° C. After stirring for 2 hours, it was cooled to room temperature to precipitate a white solid, which was filtered, and then filtered, and the solid was dried under vacuum at 25 ° C to obtain a sodium salt of stevioside B sodium salt.
- 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.
- 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 test results are shown in Figure 3. As can be seen from Figure 3, the Form A has characteristic endothermic peaks in the range of about 50-100 ° C and 110-160 ° C.
- thermogravimetric analysis It was tested by the German Netzsch TG 209F3 thermogravimetric analyzer, temperature range: 30-400 ° C, scanning rate: 10 K / min, purge gas: 25 mL / min. The test results are shown in Figure 4. It can be analyzed from Fig. 4 that the thermogravimetric analysis of the crystal form A begins to decompose at 280 ⁇ 20 °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 test results are shown in Figure 5. In the normal storage humidity range (40-80% RH), the hygroscopicity is small, only 0.4%.
- IR analysis It was detected at room temperature by Nicolet-Magna FT-IR750 infrared spectrometer from Nico, USA, and the detection range was: wave number of 4000-500 cm -1 .
- the test results are shown in Figure 6.
- the infrared spectrum of Form A at least 3384cm -1, 2947cm -1, 2856cm -1 , 1664cm -1, 1539cm -1, 1460cm -1, 1400cm -1, 1352cm -1, 1254cm -1, 1126cm -1, Characteristic peaks at 1076 cm -1 , 1034 cm -1 , 997 cm -1 and 652 cm -1 with an error range of ⁇ 2 cm -1 .
- 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 sodium salt sample, put it into a 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution to dissolve and volume. 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 B sodium salt crystal form A prepared in the above examples is slightly hygroscopic under conventional storage conditions (40%-80% RH), while the commercially available amorphous form has hygroscopicity.
- the hygroscopicity of the stevioside B sodium salt crystal form A is significantly lower than that of the commercially available amorphous form.
- the stevioside B sodium salt 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. 7. From Fig. 7, it can be seen that the crystal form is unchanged, crystal Good stability. The amorphous stability sold on the market is extremely poor, and it is easy to absorb moisture under high humidity conditions (the hygroscopicity is 29.4 times that of the crystal form A), thereby causing the knot unity block, and the analysis result is shown in Fig. 8.
- the stevioside B sodium salt crystal form A obtained in the above examples has good reproducibility. And the water solubility is high and stable, about 180 mg/mL. The analysis results are shown in Figure 9.
- the stevioside B sodium salt crystal form A obtained in the above examples has good fluidity with respect to commercially available amorphous form.
- the average particle size of the stevioside B sodium salt crystal form A is greater than the commercially available amorphous form.
- the bulk density and bulk density of the stevioside B sodium salt crystal form A are higher than the commercially available amorphous, indicating that the compressibility is superior to the commercially available amorphous shape, and it is easier to prepare the sugar tablet.
- the raw material of stevioside B sodium salt (amorphous) used in the above examples was provided by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.
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Abstract
The present invention relates to a naturally-extracted high potency sweetener rebaudioside, and particularly relates to a novel crystal form of a sodium salt of rebaudioside B and a preparation method thereof. The novel crystal form is comprehensively characterized using means of solid chemical analysis such as XRD, DSC, TGA, DVS, and the like, with the finding that the novel crystal form has the characteristics of a high crystallinity, stable physico-chemical properties, good water solubility, low hygroscopicity, and high flowability. The novel crystal form therefore has superior physico-chemical properties and is suitable for a wider range of applications. A preparation method of a novel crystal form A of the sodium salt of rebaudioside B is simple, easily controlled, and reproducible to provide a steady supply of the target crystal form.
Description
本发明涉及甜味剂领域,尤其涉及一种甜菊糖B苷钠盐的新晶型及其制备方法和用途。The invention relates to the field of sweeteners, in particular to a novel crystal form of sodium stevioside B sodium salt, a preparation method thereof and use thereof.
甜菊糖B苷钠盐(Sodium Salt of Rebaudioside B,RBNa),其结构式如下所示(图1)。其是一种从甜叶菊中提取的甜菊糖苷类化合物甜菊糖B苷的钠盐,甜度约为蔗糖的150倍。甜菊糖B苷钠盐的制备方法主要是通过氢氧化钠水解甜菊糖A苷或甜菊糖B苷成盐得到。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,但水溶液不稳定性和后苦味的口感一直是影响其应用的原因。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。此外,在专利US 20130267693 A1中报道了甜菊糖B苷四个多晶型。但是,由于甜菊糖B苷在室温下的水溶性低(小于0.5mg/mL),而限制了其使用。甜菊糖B苷钠盐具有与其相当的口感,同时具有极高的水溶性,而被应用于在食品、饮料、调味料、酿酒、医药等行业的应用。目前,市面上的甜菊糖B苷钠盐均是无定形,但是无定形具有不稳定,极易吸湿结块等缺陷。Sodium Salt of Rebaudioside B (RBNa), the structural formula of which is shown below (Fig. 1). It is a sodium salt of the stevioside glycoside B glucoside extracted from stevia, which is about 150 times sweeter than sucrose. The preparation method of the sodium stevioside B sodium salt is mainly obtained by hydrolyzing stevioside A glycoside or stevioside B glycoside to form a salt. Among the stevioside compounds, stevioside A has been widely used as a sweetener in beverage applications, but aqueous solution instability and post-bitter taste have been the cause of its application. 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. Furthermore, four polymorphic forms of stevioside B glycoside are reported in the patent US 20130267693 A1. However, since stevioside B has low water solubility (less than 0.5 mg/mL) at room temperature, its use is limited. Stevioside sodium glucoside has a taste comparable to that of the stevioside sodium salt, and is highly water-soluble, and is used in applications in food, beverage, seasoning, brewing, medicine, and the like. At present, the sodium stevioside B sodium salt in the market is amorphous, but the amorphous shape is unstable, and it is easy to absorb moisture and agglomerate.
不同晶型的同一化合物在溶解度、溶出速率、熔点、密度、硬度、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。对于甜味剂来说,对其进行多晶型研究也是至关重要的。例如甜菊糖A苷,其多晶型现象已得到深入研究,且不同晶型具有显著性能差异。专利US20070292582_A1报道了甜菊糖A苷晶型1、晶型2、晶型3A、晶型3B及其制备方法。专利WO2010118218_A1报道了三种晶型,其中晶型3具有溶解度高的优势。专利CN 103739639 A和CN103739640 A分别报道了晶型9和晶型7,其中晶型7具有稳定性好的优势。同时,其多晶型现象在文献中也被报道过。在《Crystal Growth&Design》中一篇名为“Single Crystal Growth and Structure Determination of the Natural“High Potency”Sweetener Rebaudioside A”的文章中报道了其四种晶型,其中晶型Form III为不稳定的甲醇四水合物。与甜菊糖A苷具有同样母体结构的甜菊糖B苷钠盐也可能具有多晶型现象。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。如何通过对其进行系统的多晶型研究,推荐最优晶型来避免市售无定形的不稳定性,在甜菊糖B苷钠盐的早期开发与开发阶段具有重大意义。
The same compound of different crystal forms has significant differences in solubility, dissolution rate, melting point, density, hardness, appearance and bioavailability, which affects its stability and bioavailability. The study of drug polymorphism has become an indispensable part of pharmaceutical processes and new drug formulations. For sweeteners, it is also critical to conduct polymorphic studies. For example, stevioside A glycoside has been studied intensively, and different crystal forms have significant performance differences. Patent US20070292582_A1 reports stevioside A glycoforms 1, crystal form 2, crystal form 3A, crystal form 3B and a preparation method thereof. Patent WO2010118218_A1 reports three crystal forms in which Form 3 has the advantage of high solubility. The patents CN 103739639 A and CN103739640 A report Form 9 and Form 7, respectively, wherein Form 7 has the advantage of good stability. At the same time, its polymorphism has also been reported in the literature. In the article "Single Crystal Growth and Structure Determination of the Natural" High Potency "Sweetener Rebaudioside A" in Crystal Growth & Design, four crystal forms are reported, in which Form III is unstable methanol. Hydrate. The stevioside B-sodium salt having the same parent structure as stevioside A glycoside may also have a polymorphic phenomenon. Different crystal forms not only affect its physical stability, solubility, appearance, but also its taste and sweetness. How to systematically study the polymorphism and recommend the best crystal form to avoid the instability of commercially available amorphous, which is of great significance in the early stage of development and development of stevioside B sodium salt.
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、稳定性高、吸湿性小的新晶型。同时,迫切需要提供上述晶型的制备方法和用途。There is an urgent need in the art to provide a crystal form having better properties, such as a new crystal form having high crystallinity, good water solubility, high stability, and low hygroscopicity. At the same time, there is an urgent need to provide a method and use for the preparation of the above crystal forms.
发明内容Summary of the invention
本发明旨在提供一种新的甜菊糖B苷钠盐晶型。The present invention aims to provide a novel crystalline form of sodium stevioside B sodium.
本发明的另一个目的是提供所述新的甜菊糖B苷钠盐晶型的制备方法。Another object of the present invention is to provide a process for the preparation of the novel crystalline form of the sodium stevioside B sodium salt.
本发明的再一个目的是提供所述新的甜菊糖B苷钠盐晶型的用途。A further object of the invention is to provide the use of the novel crystalline form of the sodium stevioside B sodium salt.
在本发明的第一方面,提供了一种甜菊糖B苷钠盐晶型A,其结构如式图1所示,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4.89,6.44,15.91,19.63和29.09处有明显的特征衍射峰。In a first aspect of the invention, there is provided a stevioside B sodium salt crystal form A having the structure shown in Figure 1, wherein the crystal form A is subjected to an X-ray powder diffraction method of Cu-K? The indicated 2 theta angles have distinct characteristic diffraction peaks at about 4.89, 6.44, 15.91, 19.63 and 29.09.
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,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:In another preferred embodiment, the crystal form A has an X-ray powder diffraction (XRPD) pattern as shown in Fig. 2, the Bragg 2θ angle, the interplanar spacing d and the relative intensity (percentage of the strongest rays) are expressed as follows:
在另一优选例中,所述晶型A具有基本上如图3、4、5、6所示的差示扫描量热分析图谱、热失重图谱、动态水分吸附图谱和红外图谱。
In another preferred embodiment, the Form A has a differential scanning calorimetry pattern, a thermogravimetric map, a dynamic moisture adsorption pattern, and an infrared spectrum substantially as shown in Figures 3, 4, 5, and 6.
在本发明的第二方面,提供了一种如上所述的甜菊糖B苷钠盐晶型A的制备方法,其特征在于,该方法包括以下步骤:In a second aspect of the invention, there is provided a process for the preparation of a crystalline form A of stevioside B sodium salt as described above, characterized in that it comprises the steps of:
(1)在室温至溶剂沸点温度条件下,将甜菊糖B苷钠盐与溶剂混合0.1-48h,得到混悬溶液;(1) mixing stevioside B sodium salt with a solvent for 0.1 to 48 hours at room temperature to the boiling point of the solvent to obtain a suspension solution;
(2)在室温至溶剂沸点温度条件下,将混悬溶液过滤或离心,得到白色固体,干燥即得甜菊糖B苷钠盐晶型A;(2) The suspension solution is filtered or centrifuged at room temperature to the boiling point of the solvent to obtain a white solid, which is dried to obtain a crystalline form A of stevioside B sodium salt;
(3)步骤(2)过滤或离心后的澄清溶液,冷却至0-25℃,析出白色固体,过滤,干燥即得甜菊糖B苷钠盐晶型A;(3) step (2) filtration or centrifugation of the clear solution, cooled to 0-25 ° C, a white solid precipitated, filtered, dried to obtain stevioside B sodium salt crystal form A;
在另一优选例中,步骤(1)中所述的甜菊糖B苷钠盐干物质纯度在100%到50%。In another preferred embodiment, the sodium stevioside B sodium salt described in step (1) has a dry matter purity of from 100% to 50%.
在另一优选例中,步骤(1)或步骤(2)中所述的溶剂选自下述的一种或一种以上:水、甲醇、乙醇、乙腈、丙酮、甲乙酮、1-丙醇、2-丙醇、乙酸丁酯、三丁甲基乙醚、乙酸异丙酯、乙酸乙酯、甲酸乙酯、乙酸异丁酯、乙酸甲酯、3-甲基-1-丁醇、甲基异丁酮、2-甲基-1-丙醇、乙酸丙酯。In another preferred embodiment, the solvent described in the step (1) or the step (2) is selected from one or more of the following: water, methanol, ethanol, acetonitrile, acetone, methyl ethyl ketone, 1-propanol, 2-propanol, butyl acetate, tributyl methyl ether, isopropyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone , 2-methyl-1-propanol, propyl acetate.
在另一优选例中,所述的溶剂选自下组:甲醇、乙醇、1-丙醇、2-丙醇、水、或其组合。In another preferred embodiment, the solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, water, or a combination thereof.
在另一优选例中,所述的溶剂为醇与水的混合溶剂,其中所述的醇选自下组:甲醇、乙醇、1-丙醇、2-丙醇、或其组合。In another preferred embodiment, the solvent is a mixed solvent of an alcohol and water, wherein the alcohol is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, or a combination thereof.
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苷钠盐晶型A在制备食品和药品中的用途。In a third aspect of the invention, there is provided a use of the stevioside B-sodium salt crystal form A of the invention as described above for the preparation of a food or a medicament.
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苷钠盐晶型A在组合物中的用途。In another preferred embodiment, there is provided a use of the stevioside B sodium salt crystalline form A provided by the present invention as described above in a composition.
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。In another preferred embodiment, the composition is selected from the group consisting of a food composition, a beverage composition, and a pharmaceutical composition.
本发明提供的甜菊糖B苷钠盐晶型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糖B苷钠盐晶型A,且制得的产品结晶度高、水溶性好、稳定性高、流动性好。The preparation method of the stevioside B sodium salt crystal form A provided by the invention has the advantages of simple process and easy operation, and can obtain the stevioside B sodium salt crystal form A by various methods, and the obtained product has high crystallinity. Good water solubility, high stability and good fluidity.
图1.实施例1甜菊糖B苷钠盐晶型A的结构式。Figure 1. Structural formula of Example 1 Stevia Indole B sodium salt crystal form A.
图2.实施例1甜菊糖B苷钠盐晶型A的X-射线粉末衍(XRPD)图。Figure 2. X-ray powder derived (XRPD) pattern of the crystalline form A of Stevioside B sodium salt of Example 1.
图3.实施例1甜菊糖B苷钠盐晶型A的差示扫描量热分析(DSC)图。Figure 3. Differential Scanning Calorimetry (DSC) plot of Example 1 Steviain B sodium salt Form A.
图4.实施例1甜菊糖B苷钠盐晶型A的热失重分析(TG)图。
Figure 4. Thermogravimetric analysis (TG) plot of Example 1 Steviain B sodium salt Form A.
图5.实施例1甜菊糖B苷钠盐晶型A吸湿性分析(DVS)图。Figure 5. Example 1 stevioside B sodium salt crystal form A hygroscopicity analysis (DVS) pattern.
图6.实施例1甜菊糖B苷钠盐晶型A的红外(IR)图。Figure 6. Infrared (IR) image of Example 1 Stevia Indole B sodium salt Form A.
图7.实施例1甜菊糖B苷钠盐晶型A在40℃湿度75%的条件下,储存半年的X-射线粉末衍射(XRPD)比较图。Figure 7. Comparison of X-ray powder diffraction (XRPD) of Example 1 Steviate S-sodium salt crystal form A for half a year at 40 ° C humidity 75%.
图8.市售的甜菊糖B苷钠盐无定形在40℃湿度75%的条件下,储存半年的X-射线粉末衍射(XRPD)比较图。Figure 8. X-ray powder diffraction (XRPD) comparison chart of commercially available stevioside B sodium salt amorphous form for half a year under conditions of a humidity of 75% at 40 °C.
图9.实施例1甜菊糖B苷钠盐晶型A在25℃的条件下,水中的粉末溶出曲线。Figure 9. Example 1 powder dissolution profile of stevioside B sodium salt crystal form A in water at 25 °C.
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苷钠盐晶型A,所述的晶型A具备良好的热稳定性和非吸湿性,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。The inventors have for the first time developed a crystal form A of stevioside B sodium salt through extensive and intensive research, the crystal form A has good thermal stability and non-hygroscopicity, and the preparation process is simple, efficient, and reproducible. Well, it can realize large-scale industrial production. On the basis of this, the present invention has been completed.
术语说明Terminology
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。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.
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)。As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
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°。For a characteristic diffraction peak represented by a 2 theta angle, 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.
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”。As used herein, 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."
如本文所用,术语“室温”一般指4-30℃,较佳地指20±5℃。As used herein, the term "room temperature" generally refers to 4-30 ° C, preferably 20 ± 5 ° C.
本发明化合物Compound of the invention
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。The term "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.
结晶crystallization
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。可通过加入抗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。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. It can have low solubility in it by adding an anti-solvent or compound
A solvent or a mixture of such solvents to reduce the solubility of the compound of interest. 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.
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。If 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.
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抗溶剂,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。Optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed. In addition, 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.
组合物combination
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。The present invention also provides a composition comprising a crystalline form A compound of the invention, i.e., a sweetener composition.
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。In a preferred embodiment of the invention, the composition comprises a variety of different products such as food compositions, beverage compositions, and pharmaceutical compositions.
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%。In a preferred embodiment, 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%.
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。Other sweeteners such as lactose, fructose, sucrose, glucose, trehalose or combinations thereof may also be included in the sweetener compositions of the present invention.
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。In a preferred embodiment, 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.
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。The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It is understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.
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。The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified.
实施例一Embodiment 1
在25℃条件下,将25g物质纯度为100%的甜菊糖B苷钠盐加入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苷钠盐晶型A。25 g of sodium stevioside B sodium salt having a purity of 100% was added to 100 mL of methanol at 25 ° C, and after stirring for 12 hours, the filtrate and the white solid were filtered, and the filtrate and the white solid were vacuum dried at 25 ° C, respectively. Stevioside B sodium salt crystal form A.
实施例二
Embodiment 2
在25℃条件下,将25g物质纯度为100%的甜菊糖B苷钠盐加入100mL乙醇中,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苷钠盐晶型A。25 g of sodium stevioside B sodium salt having a purity of 100% was added to 100 mL of ethanol at 25 ° C, and after stirring for 12 hours, the filtrate and the white solid were filtered, and the filtrate and the white solid were vacuum dried at 25 ° C, respectively. Stevioside B sodium salt crystal form A.
实施例三Embodiment 3
在25℃条件下,将25g物质纯度为100%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)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苷钠盐晶型A。25 g of sodium stevioside B sodium salt having a purity of 100% was added to 100 mL of ethanol-water (10:1) system at 25 ° C. After stirring for 12 h, the filtrate and white solid were filtered, and the filtrate and white solid were respectively Drying under vacuum at 25 ° C gave stevioside B sodium salt crystal form A.
实施例四Embodiment 4
在25℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌12h后,过滤得到滤液和白色固体,白色固体于25℃下真空干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 25 ° C, stirred for 12h, and filtered to obtain a filtrate and a white solid at 25 ° C Drying in vacuo gave stevioside B sodium salt crystal form A. The filtrate can be recovered.
实施例五 Embodiment 5
在35℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌12h后,过滤得到滤液和白色固体,白色固体于25℃下真空干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 35 ° C. After stirring for 12 hours, the filtrate and white solid were filtered, and the white solid was at 25 ° C. Drying in vacuo gave stevioside B sodium salt crystal form A. The filtrate can be recovered.
实施例六Embodiment 6
在35℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌12h后,过滤得到滤液和白色固体,白色固体于25℃下真空干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 35 ° C. After stirring for 12 hours, the filtrate and white solid were filtered, and the white solid was at 25 ° C. Drying in vacuo gave stevioside B sodium salt crystal form A. The filtrate can be recovered.
实施例七Example 7
在35℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌48h后,过滤得到滤液和白色固体,白色固体于25℃下真空干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 35 ° C, stirred for 48h, and filtered to obtain a filtrate and a white solid at 25 ° C Drying in vacuo gave stevioside B sodium salt crystal form A. The filtrate can be recovered.
实施例八Example eight
在35℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌48h后,过滤得到滤液和白色固体,白色固体于25℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 35 ° C, stirred for 48h, and filtered to obtain a filtrate and a white solid at 25 ° C The blast was dried to obtain the stevioside B-sodium salt crystal form A. The filtrate can be recovered.
实施例九Example nine
在35℃条件下,将42g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌48h后,过滤得到滤液和白色固体,白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。42g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 35 ° C, stirred for 48h, and filtered to obtain a filtrate and a white solid at 50 ° C The blast was dried to obtain the stevioside B-sodium salt crystal form A. The filtrate can be recovered.
实施例十Example ten
在50℃条件下,将51g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌1h后,过滤,澄清滤液以1℃/min的降温速率降温至25℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠
盐晶型A。滤液可回收。51g of sodium stevioside B sodium salt with a purity of 60% was added to 100mL ethanol-water (10:1) system at 50 ° C, stirred for 1 h, filtered, and the filtrate was clarified to cool at a cooling rate of 1 ° C / min. At 25 ° C, a white solid precipitated, and the white solid was filtered and dried at 50 ° C to obtain sodium stevioside B sodium.
Salt crystal form A. The filtrate can be recovered.
实施例十一Embodiment 11
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌1h后,过滤,澄清滤液以1℃/min的降温速率降温至25℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。64g of 60% pure stevioside B sodium salt was added to 100mL ethanol-water (10:1) system at 60 ° C, stirred for 1 h, filtered, and the filtrate was clarified to cool at a cooling rate of 1 ° C / min. At 25 ° C, a white solid was precipitated, and the white solid was filtered and dried at 50 ° C to give crystals of the sodium salt of stevioside B sodium salt. The filtrate can be recovered.
实施例十二Example twelve
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液以1℃/min的降温速率降温至25℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。64g of 60% pure stevioside B sodium salt was added to 100mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, and the filtrate was clarified to cool at a cooling rate of 1 ° C / min. At 25 ° C, a white solid was precipitated, and the white solid was filtered and dried at 50 ° C to give crystals of the sodium salt of stevioside B sodium salt. The filtrate can be recovered.
实施例十三Example thirteen
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液以10℃/min的降温速率降温至25℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。64g of 60% pure stevioside B sodium salt was added to 100mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, and the filtrate was clarified to cool at a cooling rate of 10 ° C / min. At 25 ° C, a white solid was precipitated, and the white solid was filtered and dried at 50 ° C to give crystals of the sodium salt of stevioside B sodium salt. The filtrate can be recovered.
实施例十四Embodiment 14
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入100mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液以10℃/min的降温速率降温至10℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。64g of 60% pure stevioside B sodium salt was added to 100mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, and the filtrate was clarified to cool at a cooling rate of 10 ° C / min. At 10 ° C, a white solid precipitated, and the white solid was filtered and dried at 50 ° C to give crystals of sodium ste The filtrate can be recovered.
实施例十五Example fifteen
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入90mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液以10℃/min的降温速率降温至10℃,析出白色固体,过滤后白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。滤液可回收。64g of 60% pure stevioside B sodium salt was added to 90mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, and the filtrate was clarified to cool down at a cooling rate of 10 ° C / min. At 10 ° C, a white solid precipitated, and the white solid was filtered and dried at 50 ° C to give crystals of sodium ste The filtrate can be recovered.
实施例十六Example sixteen
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入90mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液于60℃常压挥发,析出白色固体,当溶液总体积达到20mL时,过滤,白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。64g of 60% pure stevioside B sodium salt was added to 90mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, clarified filtrate was volatilized at 60 ° C, white precipitated The solid, when the total volume of the solution reached 20 mL, was filtered, and the white solid was air-dried at 50 ° C to obtain a stevioside B sodium salt crystal form A.
实施例十七Example seventeen
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入90mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液于30℃常压挥发,析出白色固体,当溶液总体积达到20mL时,过滤,白色固体于50℃下鼓风干燥,得甜菊糖B
苷钠盐晶型A。64g of sodium stevioside B sodium salt with a purity of 60% was added to a 90mL ethanol-water (10:1) system at 60 ° C, stirred for 2 hours, filtered, and the filtrate was clarified at 30 ° C to volatilize at room temperature to precipitate white. Solid, when the total volume of the solution reaches 20mL, it is filtered, and the white solid is blast dried at 50 ° C to obtain stevioside B.
Sodium glycoside crystal form A.
实施例十八Example 18
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入90mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液于30℃减压挥发,析出白色固体,当溶液总体积达到20mL时,过滤,白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。64g of 60% pure stevioside B sodium salt was added to 90mL ethanol-water (10:1) system at 60 ° C, stirred for 2h, filtered, clarified filtrate was evaporated under reduced pressure at 30 ° C, white precipitated The solid, when the total volume of the solution reached 20 mL, was filtered, and the white solid was air-dried at 50 ° C to obtain a stevioside B sodium salt crystal form A.
实施例十九Example 19
在60℃条件下,将64g物质纯度为60%的甜菊糖B苷钠盐加入90mL乙醇—水(10:1)体系中,搅拌2h后,过滤,澄清滤液于20℃减压挥发,析出白色固体,当溶液总体积达到20mL时,过滤,白色固体于50℃下鼓风干燥,得甜菊糖B苷钠盐晶型A。64g of sodium stevioside B sodium salt with a purity of 60% was added to a 90mL ethanol-water (10:1) system at 60 ° C, stirred for 2 hours, filtered, and the filtrate was clarified and evaporated under reduced pressure at 20 ° C to precipitate white. The solid, when the total volume of the solution reached 20 mL, was filtered, and the white solid was air-dried at 50 ° C to obtain a stevioside B sodium salt crystal form A.
实施例二十Example twenty
在25℃条件下,将100g物质纯度为95%的甜菊糖B苷加入500mL乙醇—水(10:1)体系中,逐渐加入5g氢氧化钠,将溶液pH调至8.0-8.5,搅拌2h后,过滤,过滤后固体于25℃真空干燥,得甜菊糖B苷钠盐晶型A。100g of 95% pure stevioside B glycoside was added to 500mL ethanol-water (10:1) system at 25 °C, gradually added 5g sodium hydroxide, the pH of the solution was adjusted to 8.0-8.5, and stirred for 2h. After filtration, the solid after filtration was dried under vacuum at 25 ° C to obtain stevioside B sodium salt crystal form A.
实施例二十一Embodiment 21
在25℃条件下,将100g物质纯度为99%的甜菊糖B苷加入500mL乙醇—水(10:1)体系中,逐渐加入5g氢氧化钠,将溶液pH调至8.0-8.5,搅拌2h后,过滤,过滤后固体于25℃真空干燥,得甜菊糖B苷钠盐晶型A。100g of 99% pure stevioside B glycoside was added to 500mL ethanol-water (10:1) system at 25 °C, gradually added 5g sodium hydroxide, the pH of the solution was adjusted to 8.0-8.5, and stirred for 2h. After filtration, the solid after filtration was dried under vacuum at 25 ° C to obtain stevioside B sodium salt crystal form A.
实施例二十二Example twenty two
在25℃条件下,将100g物质纯度为99%的甜菊糖B苷加入500mL乙醇体系中,逐渐滴入20g 25%的氢氧化钠水溶液,将溶液pH调至8.0-8.5,搅拌2h后,过滤,过滤后固体于25℃真空干燥,得甜菊糖B苷钠盐晶型A。Under the condition of 25 ° C, 100 g of stevioside B with a purity of 99% was added to 500 mL of ethanol system, and 20 g of 25% aqueous sodium hydroxide solution was gradually added dropwise, and the pH of the solution was adjusted to 8.0-8.5, stirred for 2 hours, and then filtered. The filtered solid was dried under vacuum at 25 ° C to obtain a stevioside B sodium salt crystal form A.
实施例二十三Example twenty-three
在25℃条件下,将100g物质纯度为99%的甜菊糖A苷加入500mL乙醇体系中,逐渐滴入20g 25%的氢氧化钠水溶液,将溶液pH调至8.0-8.5,升温至80℃,搅拌2h后,冷却至室温析出白色固体,过滤,过滤后固体于25℃真空干燥,得甜菊糖B苷钠盐晶型A。100 g of stevioside A glycoside having a purity of 99% was added to a 500 mL ethanol system at 25 ° C, and 20 g of a 25% aqueous sodium hydroxide solution was gradually added dropwise thereto, and the pH of the solution was adjusted to 8.0-8.5, and the temperature was raised to 80 ° C. After stirring for 2 hours, it was cooled to room temperature to precipitate a white solid, which was filtered, and then filtered, and the solid was dried under vacuum at 25 ° C to obtain a sodium salt of stevioside B sodium salt.
对上述实施例制得的甜菊糖B苷钠盐晶型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。X-ray powder diffraction analysis (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TG), dynamic moisture adsorption analysis (DVS) of the stevioside B sodium salt crystal form A prepared in the above examples. ), infrared analysis (IR), etc.
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),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 analysis: It was tested at room temperature using a Bruker D8advance type diffractometer from Bruker Instruments, Germany, using Cu–Kα ray (λ=1.5418). The 2θ angle scan is from 3 degrees to 40 degrees, and the scanning speed is 0.2 degrees/second. The analysis results are shown in Figure 2.
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。In the sample powder X-ray powder diffraction pattern, 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. In addition, care should be taken to maintain the overall concept when determining whether the crystal form is the same, because not a diffraction line represents a phase, but a specific set of "d-I/I1" data represents a phase. It should also be noted that in the identification of the mixture, some of the diffraction lines are missing due to factors such as a decrease in content. At this time, it is not necessary to rely on all the bands observed in the high-purity sample, and even one band may be given. The crystals are characteristic.
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。其测试结果见图3。从图3中可以看出,所述晶型A在约50-100℃和110-160℃区间内有特征吸热峰。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 test results are shown in Figure 3. As can be seen from Figure 3, the Form A has characteristic endothermic peaks in the range of about 50-100 ° C and 110-160 ° C.
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。其测试结果见图4。从图4中可以分析得出:所述晶型A的热失重分析在280±20℃开始分解。TG analysis: It was tested by the German Netzsch TG 209F3 thermogravimetric analyzer, temperature range: 30-400 ° C, scanning rate: 10 K / min, purge gas: 25 mL / min. The test results are shown in Figure 4. It can be analyzed from Fig. 4 that the thermogravimetric analysis of the crystal form A begins to decompose at 280 ± 20 °C.
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%。其测试结果见图5,在常规储存湿度范围内(40-80%RH),吸湿性小,仅为0.4%。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 test results are shown in Figure 5. In the normal storage humidity range (40-80% RH), the hygroscopicity is small, only 0.4%.
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。其测试结果见图6。所述晶型A的红外光谱至少在3384cm-1、2947cm-1、2856cm-1、1664cm-1、1539cm-1、1460cm-1、1400cm-1、1352cm-1、1254cm-1、1126cm-1、1076cm-1、1034cm-1、997cm-1和652cm-1处具有特征峰,误差范围为±2cm-1。IR analysis: It was detected at room temperature by Nicolet-Magna FT-IR750 infrared spectrometer from Nico, USA, and the detection range was: wave number of 4000-500 cm -1 . The test results are shown in Figure 6. The infrared spectrum of Form A at least 3384cm -1, 2947cm -1, 2856cm -1 , 1664cm -1, 1539cm -1, 1460cm -1, 1400cm -1, 1352cm -1, 1254cm -1, 1126cm -1, Characteristic peaks at 1076 cm -1 , 1034 cm -1 , 997 cm -1 and 652 cm -1 with an error range of ± 2 cm -1 .
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苷钠盐样品,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。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 sodium salt sample, put it into a 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution to dissolve and volume. 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. Column: Phenomenex Luna 5μC18(2) 100A column. Injection volume: 5 μl. Flow rate: 1.0 mL/min. Column temperature: 40 ° C. Detector: 210 nm UV detection. Mobile phase: The ratio of acetonitrile and sodium phosphate buffer (specification: 10 mmol/L, pH: 2.6) was 32:68.
上述实施例制得的甜菊糖B苷钠盐晶型A在常规储存条件(40%-80%RH)下略有吸湿性,而市售的无定形有引湿性。甜菊糖B苷钠盐晶型A的吸湿性明显低于市售的无定形。分析结果如下表:The stevioside B sodium salt crystal form A prepared in the above examples is slightly hygroscopic under conventional storage conditions (40%-80% RH), while the commercially available amorphous form has hygroscopicity. The hygroscopicity of the stevioside B sodium salt crystal form A is significantly lower than that of the commercially available amorphous form. The results of the analysis are as follows:
对上述实施例制得的甜菊糖B苷钠盐晶型A,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,晶型稳定性好。而市面上销售的无定形的稳定性极差,极易在高湿条件下吸湿(吸湿性为晶型A的29.4倍),从而导致结团结块,其分析结果见图8。The stevioside B sodium salt 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. 7. From Fig. 7, it can be seen that the crystal form is unchanged, crystal Good stability. The amorphous stability sold on the market is extremely poor, and it is easy to absorb moisture under high humidity conditions (the hygroscopicity is 29.4 times that of the crystal form A), thereby causing the knot unity block, and the analysis result is shown in Fig. 8.
上述实施例制得的甜菊糖B苷钠盐晶型A,具有很好的重现性。并且水溶性高并且稳定,约为180mg/mL。其分析结果见图9。The stevioside B sodium salt crystal form A obtained in the above examples has good reproducibility. And the water solubility is high and stable, about 180 mg/mL. The analysis results are shown in Figure 9.
上述实施例制得的甜菊糖B苷钠盐晶型A相对于市售的无定形,具有很好的流动性。甜菊糖B苷钠盐晶型A的平均粒径大于市售的无定形。同时,甜菊糖B苷钠盐晶型A的松密度及堆密度均高于市售的无定形,说明其可压性优于市售的无定形,更易于制备糖片。分析结果如下表:The stevioside B sodium salt crystal form A obtained in the above examples has good fluidity with respect to commercially available amorphous form. The average particle size of the stevioside B sodium salt crystal form A is greater than the commercially available amorphous form. At the same time, the bulk density and bulk density of the stevioside B sodium salt crystal form A are higher than the commercially available amorphous, indicating that the compressibility is superior to the commercially available amorphous shape, and it is easier to prepare the sugar tablet. The results of the analysis are as follows:
上述实施例中所用的甜菊糖B苷钠盐原料(无定形)由山东诸城浩天药业有限公司提供。The raw material of stevioside B sodium salt (amorphous) used in the above examples was provided by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.
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。
The above is only the preferred embodiment of the present invention, and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection of the present invention. Within the scope.
Claims (10)
- 一种甜菊糖B苷钠盐晶型A,其特征在于,其结构如下式I所示,A stevioside B-sodium salt crystal form A, characterized in that the structure is as shown in the following formula I,并且,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4.89,约6.44,约15.91,约19.63和约29.09处具有3个、4个或5个特征衍射峰。Further, the crystal form A has an X-ray powder diffraction method of Cu-Kα, and has a 2θ angle expressed by degrees, and has 3, 4, or 5 at about 4.89, about 6.44, about 15.91, about 19.63, and about 29.09. Characteristic diffraction peaks.
- 根据权利要求1所述的甜菊糖B苷钠盐晶型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:4.89±0.1°、6.44±0.1°、15.91±0.1°、19.63±0.1°、29.09±0.1°、14.17±0.1°、17.97±0.1°、19.42±0.1°、25.10±0.1°和30.62±0.1°。The stevioside B sodium salt crystal form A according to claim 1, wherein the crystal form A further has one or more characteristic diffraction peaks selected from the group consisting of 4.89 ± 0.1 ° and 6.44 ± 0.1 °. 15.91±0.1°, 19.63±0.1°, 29.09±0.1°, 14.17±0.1°, 17.97±0.1°, 19.42±0.1°, 25.10±0.1° and 30.62±0.1°.
- 根据权利要求1所述的甜菊糖B苷钠盐晶型A,其特征在于,所述晶型A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:The stevioside B-sodium salt crystal form A according to claim 1, wherein the crystal form A has an X-ray powder diffraction (XRPD) pattern substantially as shown in Fig. 2, and its Bragg 2θ angle, crystal The interplanar spacing d and relative intensity (percentage of the strongest rays) are expressed as follows:
- 根据权利要求1所述的甜菊糖B苷钠盐晶型A,其特征在于,所述晶型A还具有选自下组的一个或多个特征:The stevioside B sodium salt crystal form A according to claim 1, wherein the crystal form A further has one or more characteristics selected from the group consisting of:(1)所述晶型A具有基本上如图3所示的差示扫描量热分析图谱;(1) the crystal form A has a differential scanning calorimetry map substantially as shown in FIG. 3;(2)所述晶型A具有基本上如图4所示的热失重图谱;(2) the crystal form A has a thermogravimetric map substantially as shown in FIG. 4;(3)所述晶型A具有基本上如图5所示的动态水分吸附图谱;和(3) said Form A has a dynamic moisture adsorption pattern substantially as shown in Figure 5;(4)所述晶型A具有基本上如图6所示的红外图谱。(4) The crystal form A has an infrared spectrum substantially as shown in Fig. 6.
- 根据权利要求1-4中任一所述的甜菊糖B苷钠盐晶型A的制备方法,其特征在于,该方法包括以下步骤:The method for preparing the stevioside B sodium salt crystal form A according to any one of claims 1 to 4, characterized in that the method comprises the following steps:(1)提供甜菊糖B苷钠盐与溶剂;(1) providing a sodium salt of stevioside B and a solvent;(2)将甜菊糖B苷钠盐与溶剂混合,对混合液进行结晶处理,从而形成含有甜菊糖B苷钠盐晶型A的混悬溶液;和(2) mixing stevioside sodium salt with a solvent, and subjecting the mixture to crystallization treatment to form a suspension solution containing stevioside B sodium salt crystal form A;(3)从所述的混悬溶液中分离得到甜菊糖B苷钠盐晶型A。(3) The stevioside B sodium salt crystal form A is isolated from the suspension solution.
- 根据权利要求5所述的甜菊糖B苷钠盐晶型A的制备方法,其特征在于,所述步骤(3)包括:The method for preparing the stevioside B sodium salt crystal form A according to claim 5, wherein the step (3) comprises:(3-1)对所述的混悬溶液进行过滤,获得甜菊糖B苷钠盐晶型A;和/或 (3-1) filtering the suspension solution to obtain stevioside B sodium salt crystal form A; and/or(3-2)对所述的混悬溶液进行离心,获得甜菊糖B苷钠盐晶型A;和/或(3-2) centrifuging the suspension solution to obtain stevioside B sodium salt crystal form A; and/or(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苷钠盐晶型A,分离以获得甜菊糖B苷钠盐晶型A。(3-3) The clear solution after filtration or centrifugation is subjected to a temperature lowering treatment to precipitate the stevioside B sodium salt crystal form A, and is isolated to obtain the stevioside B sodium salt crystal form A.
- 根据权利要求5所述的方法,其特征在于,步骤(1)中所述的甜菊糖B苷钠盐干物质纯度在100%到50%。The method according to claim 5, wherein the sodium stevioside B sodium salt in step (1) has a dry matter purity of from 100% to 50%.
- 根据权利要求5所述的方法,其特征在于,步骤(1)或步骤(2)中所述的溶剂选自下述的一种或一种以上:水、甲醇、乙醇、乙腈、丙酮、甲乙酮、1-丙醇、2-丙醇、乙酸丁酯、三丁甲基乙醚、乙酸异丙酯、乙酸乙酯、甲酸乙酯、乙酸异丁酯、乙酸甲酯、3-甲基-1-丁醇、甲基异丁酮、2-甲基-1-丙醇、乙酸丙酯。The method according to claim 5, wherein the solvent in the step (1) or the step (2) is selected from one or more of the following: water, methanol, ethanol, acetonitrile, acetone, methyl ethyl ketone. , 1-propanol, 2-propanol, butyl acetate, tributyl methyl ether, isopropyl acetate, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol , methyl isobutyl ketone, 2-methyl-1-propanol, propyl acetate.
- 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苷钠盐晶型A。A composition comprising the stevioside B sodium salt crystal form A according to any one of claims 1 to 4.
- 根据权利要求1-4任一项所述的甜菊糖B苷钠盐晶型A及其制备方法在食品、饮料及药品中的用途。 The use of the stevioside B-sodium salt crystal form A according to any one of claims 1 to 4 and a process for the preparation thereof in foods, beverages and pharmaceuticals.
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DUBOIS, GRANT E. ET AL.: "Diterpenoid Sweeteners. Synthesis and Sensory Evaluation of Stevioside Analogues with Improved Organoleptic Properties", J. MED. CHEM., vol. 28, no. 1, 31 December 1985 (1985-12-31), pages 93 - 98, XP002543470 * |
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