WO2017143956A1

WO2017143956A1 - Crystal form sodium salt of rebaudioside b and preparation method and use thereof

Info

Publication number: WO2017143956A1
Application number: PCT/CN2017/074114
Authority: WO
Inventors: 朱理平; 梅雪峰; 黄颖; 王建荣
Original assignee: 诸城市浩天药业有限公司
Priority date: 2016-02-27
Filing date: 2017-02-20
Publication date: 2017-08-31
Also published as: CN105669794A; CN105669794B

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

Stevia glycoside B sodium salt crystal form, preparation method and use thereof

Technical field

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.

Background technique

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.

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.

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.

Summary of the invention

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.

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.

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:

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.

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) 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) 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) 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;

In another preferred embodiment, the sodium stevioside B sodium salt described in step (1) has a dry matter purity of from 100% to 50%.

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.

In another preferred embodiment, the solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, water, or a combination thereof.

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.

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.

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.

In another preferred embodiment, 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.

DRAWINGS

Figure 1. Structural formula of Example 1 Stevia Indole B sodium salt crystal form A.

Figure 2. X-ray powder derived (XRPD) pattern of the crystalline form A of Stevioside B sodium salt of Example 1.

Figure 3. Differential Scanning Calorimetry (DSC) plot of Example 1 Steviain B sodium salt Form A.

Figure 4. Thermogravimetric analysis (TG) plot of Example 1 Steviain B sodium salt Form A.

Figure 5. Example 1 stevioside B sodium salt crystal form A hygroscopicity analysis (DVS) pattern.

Figure 6. Infrared (IR) image of Example 1 Stevia Indole B sodium salt Form A.

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%.

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.

Figure 9. Example 1 powder dissolution profile of stevioside B sodium salt crystal form A in water at 25 °C.

detailed description

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.

Terminology

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.

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.).

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.

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."

As used herein, the term "room temperature" generally refers to 4-30 ° C, preferably 20 ± 5 ° C.

Compound of the invention

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.

crystallization

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.

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.

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.

combination

The present invention also provides a composition comprising a crystalline form A compound of the invention, i.e., a sweetener composition.

In a preferred embodiment of the invention, the composition comprises a variety of different products such as food compositions, beverage compositions, and pharmaceutical compositions.

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%.

Other sweeteners such as lactose, fructose, sucrose, glucose, trehalose or combinations thereof may also be included in the sweetener compositions of the present invention.

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.

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.

The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified.

Embodiment 1

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.

Embodiment 2

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.

Embodiment 3

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.

Embodiment 4

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.

Embodiment 5

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.

Embodiment 6

Example 7

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.

Example eight

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.

Example nine

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.

Example ten

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.

Embodiment 11

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.

Example twelve

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.

Example thirteen

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.

Embodiment 14

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.

Example fifteen

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.

Example sixteen

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.

Example seventeen

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.

Example 18

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.

Example 19

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.

Example twenty

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.

Embodiment 21

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.

Example twenty two

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.

Example twenty-three

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.

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 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.

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 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 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. 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.

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:

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. 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:

The raw material of stevioside B sodium salt (amorphous) used in the above examples was provided by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.

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

A stevioside B-sodium salt crystal form A, characterized in that the structure is as shown in the following formula I,

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.
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°.
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:
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) the crystal form A has a differential scanning calorimetry map substantially as shown in FIG. 3;

(2) the crystal form A has a thermogravimetric map substantially as shown in FIG. 4;

(3) said Form A has a dynamic moisture adsorption pattern substantially as shown in Figure 5;

(4) The crystal form A has an infrared spectrum substantially as shown in Fig. 6.
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) providing a sodium salt of stevioside B and a solvent;

(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) The stevioside B sodium salt crystal form A is isolated from the suspension solution.
The method for preparing the stevioside B sodium salt crystal form A according to claim 5, wherein the step (3) comprises:

(3-1) filtering the suspension solution to obtain stevioside B sodium salt crystal form A; and/or

(3-2) centrifuging the suspension solution to obtain stevioside B sodium salt crystal form A; and/or

(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.
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%.
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.
A composition comprising the stevioside B sodium salt crystal form A according to any one of claims 1 to 4.
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.