WO2018166475A1 - 甜菊糖m苷晶型及制备方法和用途 - Google Patents

甜菊糖m苷晶型及制备方法和用途 Download PDF

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WO2018166475A1
WO2018166475A1 PCT/CN2018/079010 CN2018079010W WO2018166475A1 WO 2018166475 A1 WO2018166475 A1 WO 2018166475A1 CN 2018079010 W CN2018079010 W CN 2018079010W WO 2018166475 A1 WO2018166475 A1 WO 2018166475A1
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stevioside
glycoside
crystal form
glycoform
preparation
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French (fr)
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朱理平
梅雪锋
黄颖
王建荣
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ZHUCHENG HAOTIAN PHARM CO Ltd
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ZHUCHENG HAOTIAN PHARM CO Ltd
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Priority to JP2019551388A priority Critical patent/JP6896877B2/ja
Priority to EP18767849.5A priority patent/EP3597656B1/en
Priority to US16/494,681 priority patent/US11059843B2/en
Publication of WO2018166475A1 publication Critical patent/WO2018166475A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/256—Polyterpene radicals
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
    • A23L27/30—Artificial sweetening agents
    • A23L27/33—Artificial sweetening agents containing sugars or derivatives
    • A23L27/36—Terpene glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of sweeteners, in particular to a novel crystal form of stevioside M glycoside, a preparation method thereof and use thereof.
  • Stevia is native to the Amanbai Mountains bordering Brazil in Paraguay, South America. It is a plant with high sweetness.
  • the white powdered stevioside extracted from stevia is a natural, high-sweet, zero-calorie sweetener and natural sugar substitute.
  • Stevia is the third-best-selling product in the international high-intensity sweetener market.
  • the first generation of stevia is dominated by mixed sugars, but it is often accompanied by a bitter taste.
  • the second-generation stevioside is mainly composed of high-purity stevioside A glycoside, and has been widely used in foods, health care products and medicines. With the increasing popularity of stevioside A, other glycosides in stevia have also received increasing attention.
  • stevioside compounds which are used on the market include, in addition to stevioside A, stevioside B, stevioside C, stevioside D and stevioside.
  • stevioside D glycoside and stevioside M glycoside have the best taste, and have no post-bitter taste of stevioside A glycoside, and have been approved by the FDA as a novel sweetener.
  • Stevioside M glycosides also known as rebaudioside M or rebaudioside X, Reb M
  • Patent CN 104151378 A discloses a method of purifying stevioside M glycoside. However, due to the low content of natural stevioside M glycosides, most studies on stevioside M glycosides have turned to enzyme conversion or synthesis processes. Patent CN 104726523 A discloses a method for producing stevioside M glycoside using stevioside A glycosides and sucrose as raw materials using tomato UDP-glycosyltransferase and potato sucrose synthase.
  • Patent CN 104163839 A discloses a method in which a stevioside C-glycoside is used as a substrate and a substitution reaction with a compound R1 under the action of silver carbonate to obtain an intermediate Ac-Reb M, followed by hydrolysis to obtain a product stevioside M glycoside.
  • Patent CN 103397064 A discloses a substrate comprising stevioside A glycoside or stevioside D-glucoside as a substrate in the presence of a glucose-based donor, in UDP-glucosyltransferase and/or containing UDP-glucose A method of reacting a recombinant cell of a transferase to form a stevioside M glycoside.
  • the above method has the disadvantages of high production cost, harsh reaction conditions, and difficulty in preparing high-purity stevioside M glycoside.
  • Crystal Stevioside M glycosides have poor water solubility and solubility qualities in beverage formulations.
  • the stevioside M glycoside having a content of 75% to 90% has a solubility in water of from 0.1% to 0.15% at room temperature.
  • Patent CN 105722533 A reports the improvement of stevioside M glycoside solubility by a combination of stevioside D glycoside and at least one surfactant.
  • an amorphous composition of stevioside M glycoside and stevioside D glycoside can increase the solubility of stevioside M glycoside by 0.3% (w/w).
  • the water solubility of the stevioside M glycoside is slightly increased, the stability of the composition is unpleasant due to its amorphous nature.
  • crystal forms may cause differences in color, morphology, stability, hygroscopicity and solubility, which in turn affect the storage conditions, appearance and mouthfeel of the food.
  • the crystal form of the stevioside compound has a great influence on its mouthfeel, stability, moisture permeability and solubility.
  • the patents CN 103739639 A and CN 103739640 A report two crystal forms of stevioside A glycoside, wherein the crystalline form 7 has the advantages of good mouthfeel and low wettability, and the crystalline form 9 has the advantages of high stability and high water solubility.
  • the stevioside D-glycoside form A disclosed in the patent CN 105037458 A has the advantages of high crystallinity, good water solubility and high chemical stability. At present, studies on the crystal forms of stevioside A, stevioside B, stevioside C and stevioside D have been reported, and the crystal form of the best stevioside M glycoside has never been reported.
  • the present invention aims to provide a novel crystalline form of stevioside M.
  • Another object of the present invention is to provide a process for the preparation of the novel stevioside M glycoform.
  • a further object of the invention is to provide the use of the novel stevioside M glycoforms.
  • a stevioside M-glycoside Form A wherein the Form A uses an X-ray powder diffraction method of Cu-K ⁇ , the 2 ⁇ angle expressed in degrees is about 4.30, 6.57, There are distinct characteristic diffraction peaks at 8.04, 16.31, 17.57 and 20.91.
  • the crystal form A has an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1 , the 2 ⁇ value expressed in degrees, and the error range is ⁇ 1°,
  • XRPD X-ray powder diffraction
  • the Form A has a differential scanning calorimetry pattern as shown in Figure 2, with characteristic endothermic peaks in the interval of about 30-160 ° C and 210-250 ° C.
  • thermogravimetric analysis of Form A begins to decompose at 250 ⁇ 20 °C.
  • the crystalline form A has a dynamic moisture adsorption profile as shown in FIG. In the range of 0-40% relative humidity, the mass percentage of moisture absorption is 0-9.4%; in the range of 40-80% relative humidity, the mass percentage of moisture absorption is 9.4-14.0%.
  • the infrared spectrum of the crystal form A is at least 3391 cm -1 , 2922 cm -1 , 1727 cm -1 , 1639 cm -1 , 1446 cm -1 , 1365 cm -1 , 1228 cm -1 , 1202 cm -1 , 1074 cm -1, 1032cm -1, 991cm -1, 891cm -1, 637cm -1 , and having a characteristic peak at 560cm -1, the error range of ⁇ 2cm -1.
  • a method for producing a Stevioside M glycoside Form A as described above which is one or more of a suspension method, a solution evaporation method or a cooling method.
  • a mixed crystallization process comprising the following steps:
  • the stevioside M glycoside dry matter purity described in step (1) is in the range of 20-100%.
  • the solvent described in the step (1) is: methanol, ethanol, 1-propanol, acetonitrile, acetone, methyl ethyl ketone, methyl acetate, ethyl formate, ethyl acetate, methyl t-butyl.
  • ether, tetrahydrofuran, nitromethane, and toluene, or a mixed solvent of the above solvent and water is: methanol, ethanol, 1-propanol, acetonitrile, acetone, methyl ethyl ketone, methyl acetate, ethyl formate, ethyl acetate, methyl t-butyl.
  • the composition is selected from the group consisting of a food composition, a beverage composition, a nutraceutical composition, and a pharmaceutical composition.
  • the preparation method of the stevioside M glycoside crystal form A provided by the invention has the advantages of simple process and easy operation, and the obtained product has high crystallinity, low hygroscopicity and high stability.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TG) diagram of the stevioside M glycoside form A provided by the present invention
  • Figure 4 is a graph showing the hygroscopicity analysis (DVS) of the stevioside M glycoside form A provided by the present invention.
  • Figure 5 is an infrared (IR) diagram of the stevioside M glycoform A form provided by the present invention.
  • Figure 6 is a comparison diagram of the stevioside M glycoform A, the crystalline form B and the amorphous hygroscopicity (DVS) provided by the present invention
  • XRPD X-ray powder diffraction
  • Figure 8 is a comparison diagram of X-ray powder diffraction (XRPD) of the stevioside M glycoside Form B provided by the present invention before and after drying;
  • XRPD X-ray powder diffraction
  • Figure 10 is a high performance liquid chromatography (HPLC) comparison chart of the stevioside M glycoside form A provided by the present invention stored at 40 ° C and a relative humidity of 75% for half a year;
  • HPLC high performance liquid chromatography
  • Figure 11 is a powder dissolution profile of the stevioside M glycoside Form A provided by the present invention.
  • the present inventors have for the first time developed a stevioside M glycoside crystal form A by extensive and intensive research.
  • the crystal form A has high crystallinity, good chemical stability, low hygroscopicity, and simple and efficient preparation process, and repeatability. 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 2°, for example about X°, and represents X ⁇ 2°, preferably X ⁇ 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.”
  • 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 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 M glycoside having a substance purity of 99.5% was added to 100 mL of acetone, and after stirring for 12 hours, it was filtered to obtain a white solid, and the white solid was dried under vacuum at 25 ° C to obtain stevioside M-form A.
  • stevioside M glycoside having a purity of 99.5% was added to 100 mL of acetonitrile, and after stirring for 24 hours, it was filtered to obtain a white solid, which was dried under vacuum at 25 ° C to give stevioside M.
  • stevioside M-glycoside form A having a substance purity of 99.5% was added to 100 mL of water, and after stirring for 12 hours, it was filtered to obtain a white solid to obtain stevioside M-form B.
  • XRPD X-ray powder diffraction analysis
  • DSC differential scanning calorimetry
  • TG thermogravimetric analysis
  • DVS dynamic moisture adsorption analysis
  • the diffraction pattern obtained from a particular crystal form is often characteristic. Due to differences in crystallization conditions, particle size, relative content of the mixture, and other test conditions, the diffraction pattern may produce a preferred orientation effect, resulting in a change in the relative intensity of certain bands (especially at low angles) in the spectrum. Therefore, the relative intensities of the diffraction peaks are not characteristic for the crystals that are targeted, and it is more important to note the position of the peaks rather than their relative intensities when determining whether they are the same as the known crystal forms.
  • DVS analysis It was measured by British SMS instrument company DVS Intrinsic type dynamic moisture adsorption instrument, measuring temperature: 25 ° C; relative humidity: 0-95%. The analysis results are shown in Figure 4.
  • the stevioside M glucoside Form A prepared in the above examples was significantly less hygroscopic than the stevioside M glycoside amorphous form and crystalline form B at 25 ° C and 40% RH.
  • the comparison results are shown in Figure 6 and Table 1. At the same time, the stevioside M glycoform A is less hygroscopic than amorphous in normal storage (40%-80% RH).
  • the stevioside M-glycoside form A prepared in the above examples was subjected to XRPD analysis after drying at 105 ° C for one day, and the analysis results are shown in Fig. 7 . It can be seen from Fig. 7 that the crystal form is unchanged, and the crystal form has good stability under high temperature conditions.
  • the stevioside M glycoside form B is extremely unstable under high temperature conditions, and is amorphous after drying for one day at 105 ° C.
  • the analysis results are shown in Fig. 8.
  • the stevioside M-glycoside form A prepared in the above examples was stored at 25 ° C and RH 60% for half a year, and the analysis results are shown in Fig. 9. It can be seen from Fig. 9 that the crystal form is unchanged, indicating that the crystal form has good physical stability under normal storage conditions.
  • HPLC analysis It was determined using a 1260 infinity liquid chromatograph from Agilent Technologies, Inc., USA.
  • Sample solution preparation method accurately weigh 25-50 mg of stevioside M glycoside sample, put it into a 25 ml volumetric flask, then add water-acetonitrile (7:3, v/v) solution, dissolve and dilute 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.
  • Detector 210 nm UV detection.
  • the elution gradient is as follows:
  • the analysis results are shown in Figure 10.
  • the stevioside M glycoside form A prepared in the above examples has good chemical stability, and the HPLC analysis shows that the content is reduced by less than 0.2% after storage for half a year at 40 ° C and RH 75%. This crystal form shows good chemical stability under high humidity conditions.
  • the stevioside M glycoside form A prepared in the above examples has good reproducibility and is water-soluble, and has a maximum solubility of about 3 mg/mL, and an equilibrium solubility of about 2 mg/mL at 24 hours.
  • the powder dissolution profiles of the two batches of Stevioside M glycoform A prepared by the examples are shown in Figure 11.
  • the water solubility of Form A is similar to that of the stevioside D-stevioside M glycoside amorphous composition (about 3 mg/mL) reported in Patent CN 105722533 A, and can stably increase the water solubility by 2-3 times.
  • the stevioside M glycoside material used in the above examples was supplied by Shandong Zhucheng Haotian Pharmaceutical Co., Ltd.

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Abstract

本发明涉及甜菊糖M苷晶型及制备方法和用途，具体地，涉及一种天然提取的高倍甜味剂甜菊糖M苷晶型A、制备方法及其应用。通过对该新晶型进行了全面表征，发现该新晶型具有结晶度高，稳定性好、吸湿性小等优点，适于更加广泛的运用领域。本发明涉及的制备方法简单，易于操作，选择性多，重现性好，可以稳定地获得目标晶型。

Description

甜菊糖M苷晶型及制备方法和用途 技术领域
本发明涉及甜味剂领域，尤其涉及一种甜菊糖M苷的新晶型及其制备方法和用途。
背景技术
甜叶菊原产于南美巴拉圭与巴西接壤的阿曼拜山脉，是一种具有高倍甜味的植物。从甜叶菊中提取的白色粉末状甜菊糖苷，是一种纯天然、高甜度、零卡路里的甜味剂、天然代糖。甜菊糖是国际高倍甜味剂市场上第三大畅销的产品。第一代甜菊糖以混合糖为主，但是其常常伴随着苦涩的口感。第二代甜菊糖以高纯的甜菊糖A苷为主，已经被广泛用于食品、保健品和药品中。随着甜菊糖A苷不断的普及，甜叶菊中的其他苷类化合物也逐渐受到重视。目前，市场上开始使用的甜菊糖苷类化合物除了甜菊糖A苷外，还有甜菊糖B苷、甜菊糖C苷、甜菊糖D苷和甜菊糖M苷。其中，甜菊糖D苷和甜菊糖M苷的口感最好，并没有甜菊糖A苷的后苦味，已被FDA批准作为新型甜味剂使用。
甜菊糖M苷(还被称为莱鲍迪苷M或莱鲍迪苷X，Reb M)，(13-[(2-O-β-D-吡喃葡萄糖基-3-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基)氧基]对映贝壳杉-16-烯-19-酸-[(2-O-β-D-吡喃葡萄糖基-3-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基)酯]是从甜叶菊中分离出的。
甜菊糖M苷以微量(按重量计为0.05％-0.5％)存在于甜叶菊中。专利CN 104151378 A公开了一种提纯甜菊糖M苷的方法。但由于天然的甜菊糖M苷含量甚微，所以对甜菊糖M苷的研究大多转向了酶转化或合成工艺上。专利CN 104726523 A公开了利用番茄UDP-糖基转移酶和土豆蔗糖合成酶，以甜菊糖A苷和蔗糖为原料生产甜菊糖M苷的方法。专利CN 104163839 A公开了以甜菊糖C苷为底物，在碳酸银的作用下与化合物R1发生取代反应，得到中间体Ac-Reb M，再进行水解得到产品甜菊糖M苷的方法。专利CN 103397064 A公开了一种以甜菊糖A苷或甜菊糖D苷为底物，使所述底物在葡萄糖基供体存在下，在UDP-葡萄糖基转移酶和/或含有UDP-葡萄糖基转移酶的重组细胞的催化下反应生成甜菊糖M苷的方法。上述方法存在生产成本高、反应条件苛刻，难以制备高纯甜菊糖M苷等缺点。
晶体甜菊糖M苷在饮料配制品中具有差的水溶性和溶解品质。含量为75％-90％的甜菊糖M苷在室温条件下水中溶解度在0.1％-0.15％之间。专利CN 105722533 A报道了通过与甜菊糖D苷和至少一种表面活性剂组合的方法来提高甜菊糖M苷溶解度。其中，甜菊糖M苷和甜菊糖D苷的无定形组合物，可以提高甜菊糖M苷溶解度达0.3％(w/w)。虽然，甜菊糖M苷的水溶性得到少量提高，但是由于组合物为无定形，而使得其稳定性令人堪忧。
众所周知，晶型不同，可能导致颜色、形态、稳定性、吸湿性和溶解性存在差异，进而影响食品的储存条件、外观和口感。甜菊糖类化合物的晶型不同对其口感、稳定性、引湿性和溶解度有很大的影响。专利CN 103739639 A和CN 103739640 A报道了甜菊糖A苷的两种晶型，其中晶型7具有口感好和引湿性低的优势，晶型9具有稳定性高和水溶性高的优势。专利CN 105037458 A公开的甜菊糖D苷晶型A具有结晶度高、水溶性好和化学稳定性高的优点。目前，关于甜菊糖A苷、甜菊糖B苷、甜菊糖C苷、甜菊糖D苷的晶型研究均有报道，而口感最好的甜菊糖M苷的晶型从未报道过。
本领域迫切需要提供一种性能更好的甜菊糖M苷的晶型，例如结晶度好、水溶性好、化学稳定性高、口感好的新晶型。同时，迫切需要提供上述晶型的制备方法和用途。
发明内容
本发明旨在提供一种新的甜菊糖M苷晶型。
本发明的另一个目的是提供所述新的甜菊糖M苷晶型的制备方法。
本发明的再一个目的是提供所述新的甜菊糖M苷晶型的用途。
在本发明的第一方面，提供了一种甜菊糖M苷晶型A，所述晶型A使用Cu-Kα的X-射线粉末衍射方法，以度表示的2θ角在约为4.30、6.57、8.04、16.31、17.57和20.91处有明显的特征衍射峰。
在另一优选例中，所述晶型A有如图1所示的X-射线粉末衍射(XRPD)图，以度表示的2θ值、误差范围为±1°，以
Figure PCTCN2018079010-appb-000001
表示的晶面间距d和以百分数表示的衍射峰的相对强度具有如下特征：
2θ角 d 相对强度％
3.51 25.12 14.4
4.30 20.54 63.7
5.27 16.75 17.7
6.57 13.44 54.4
8.04 10.99 100.0
13.43 6.59 28.8
14.61 6.06 39.9
16.31 5.43 59.5
17.57 5.04 87.7
18.34 4.83 40.8
19.25 4.61 22.5
19.75 4.49 32.1
20.91 4.24 42.6
22.56 3.94 31.5
23.67 3.76 19.5
3.51 25.12 14.4
4.30 20.54 63.7
5.27 16.75 17.7
6.57 13.44 54.4
8.04 10.99 100.0
13.43 6.59 28.8
在另一优选例中，所述晶型A有如图2所示的差示扫描量热分析图谱，在约30-160℃和210-250℃区间内有特征吸热峰。
在另一优选例中，所述晶型A的热失重分析在250±20℃开始分解。
在另一优选例中，所述晶型A有如图4所示的动态水分吸附图谱。在相对湿度为0-40％范围内，其吸收水分的质量百分数在0-9.4％；在相对湿度为40-80％范围内，其吸收水分的质量百分数在9.4-14.0％。
在另一优选例中，所述晶型A的红外光谱至少在3391cm -1、2922cm -1、1727cm -1、1639cm -1、1446cm -1、1365cm -1、1228cm -1、1202cm -1、1074cm -1、1032cm -1、991cm -1、891cm -1、637cm -1和560cm -1处具有特征峰，误差范围为±2cm -1。
在本发明的第二方面，提供了一种如上所述的甜菊糖M苷晶型A的制备方法，所述制备方法为混悬法、溶液挥发法或冷却法的一种或两种以上的混合结晶方法，包括以下步骤：
(1)混悬：在0-100℃温度范围内，将甜菊糖M苷与溶剂混合0.1-48h，得到混悬溶液；
(2)冷却：步骤(1)中的混悬溶液趁热过滤，滤液冷却至0-30℃温度范围内，直至析出大量的白色固体，得到混悬溶液；
(3)挥发：步骤(1)中的混悬溶液过滤后，在0-100℃温度范围内挥发，真空压力小于或等于0.1MPa，直至析出大量的白色固体，得到混悬溶液；
(4)过滤：在0-100℃温度范围内，将步骤(1)、(2)或(3)中的混悬溶液过滤或离心，得到白色固体，干燥即得甜菊糖M苷晶型A。
在另一优选例中，步骤(1)中所述的甜菊糖M苷干物质纯度在20-100％范围内。
在另一优选例中，步骤(1)中所述的溶剂为：甲醇、乙醇、1-丙醇、乙腈、丙酮、甲乙酮、乙酸甲酯、甲酸乙酯、乙酸乙酯、甲基叔丁基醚、四氢呋喃、硝基甲烷、甲苯中的一种或两种以上，或是上述溶剂与水的混合溶剂。
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M苷晶型A在制备食品、保健品及药品中的用途。
在另一优选例中，提供了一种如上所述的本发明提供的甜菊糖M苷晶型A在组合物中的用途。
在另一优选例中，所述的组合物选自下组：食品组合物、饮料组合物、保健品组合物和药品组合物。
本发明提供的甜菊糖M苷晶型A的制备方法，其工艺简单、易于操作，且制得的产品结晶度高、吸湿性低、稳定性高。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是本发明提供的甜菊糖M苷晶型A的X-射线粉末衍射(XRPD)图；
图2是本发明提供的甜菊糖M苷晶型A的差示扫描量热分析(DSC)图；
图3是本发明提供的甜菊糖M苷晶型A的热失重分析(TG)图；
图4是本发明提供的甜菊糖M苷晶型A吸湿性分析(DVS)图；
图5是本发明提供的甜菊糖M苷晶型A红外(IR)图；
图6是本发明提供的甜菊糖M苷晶型A、晶型B与无定形的吸湿性(DVS)比较图；
图7是本发明提供的甜菊糖M苷晶型A在干燥前后的X-射线粉末衍射(XRPD)比较图；
图8是本发明提供的甜菊糖M苷晶型B在干燥前后的X-射线粉末衍射(XRPD)比较图；
图9是本发明提供的甜菊糖M苷晶型A在25℃、相对湿度60％的条件下储存半年的X-射线粉末衍射(XRPD)比较图；
图10是本发明提供的甜菊糖M苷晶型A在40℃、相对湿度75％的条件下储存半年的高效液相(HPLC)比较图；
图11是本发明提供的甜菊糖M苷晶型A的粉末溶出曲线。
具体实施方式
本发明人通过广泛而深入的研究，首次研发出一种甜菊糖M苷晶型A，所述的晶型A结晶度高，化学稳定性好、吸湿性小，且制备工艺简单高效，重复性好，可实现规模化工业生产。在此基础上，完成了本发明。
术语说明
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
对于用2θ角表示的特征衍射峰，术语“约”表示列举的值变动不多于2°，例如约为X°，则表示X±2°，较佳地X±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”。
本发明化合物
如本文所用，术语“本发明化合物”或“本发明晶型”或“本发明晶型A化合物”可互换使用，指本发明第一方面中所述的具有式I化合物的具有所述X-射线衍射特征峰的结晶化合物。本发明化合物可用作甜味剂。
组合物
本发明还提供了含有本发明晶型A化合物的组合物，即甜味剂组合物。
在本发明的一种优选实施方式中，所述组合物包括食品组合物、饮料组合物、和药品组合物等各种不同产品。
在一优选实施方式中，以所述甜味剂组合物或产品的总重计，所述本发明化合物的含量(wt％)为0.1-99％，较佳地，1-90％，更佳地，2-50％。
在本发明的甜味剂组合物中，还可含有其他甜味剂，例如乳糖、果糖、蔗糖、葡萄糖、海藻糖或其组合。
在一优选实施方式中，所述甜味剂组合物不含蔗糖或含少量的蔗糖，并且在所述甜味剂组合物中，所述蔗糖的含量(wt％)≤5，较佳地≤2，更佳地≤1。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例一
在室温条件下，将20g物质纯度为99.5％的甜菊糖M苷加入100mL丙酮中，搅拌12h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例二
在室温条件下，将20g物质纯度为99.5％的甜菊糖M苷加入100mL乙腈中，搅拌24h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例三
在50℃条件下，将20g物质纯度为99.5％的甜菊糖M苷加入100mL乙醇中， 搅拌1h后，过滤得到白色固体，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例四
在50℃条件下，将10g物质纯度为50.2％的甜菊糖M苷加入1.5L甲醇中，搅拌1h，过滤后的滤液放置在25℃、真空压力低于0.5MPa条件下挥发，直至溶剂体积小于50mL，过滤，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例五
在50℃条件下，将10g物质纯度为50.2％的甜菊糖M苷加入1L乙醇中，搅拌1h，过滤后的滤液放置在50℃条件下挥发，直至溶剂体积小于50mL，过滤，白色固体于50℃下鼓风干燥，得甜菊糖M苷晶型A。
实施例六
在50℃条件下，将10g物质纯度为40％的甜菊糖M苷加入900mL乙醇-水(2:1,v/v)溶液中，搅拌0.5h，过滤后的滤液放置在50℃、真空压力低于0.5MPa条件下挥发，直至溶剂体积小于50mL，过滤，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例七
在80℃条件下，将10g物质纯度为60％的甜菊糖M苷加入500mL乙醇-水(1:1,v/v)溶液中，搅拌0.5h，趁热过滤后的滤液自然降温至室温，静置12h析出大量固体后，过滤，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例八
在50℃条件下，将10g物质纯度为80％的甜菊糖M苷加入1L乙醇-水(1:1,v/v)溶液中，搅拌0.5h，趁热过滤后的滤液以1℃/h的降温速率降至30℃，析出固体后，过滤，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例九
在80℃条件下，将10g物质纯度为60％的甜菊糖M苷加入500mL乙醇-水(1:1,v/v)溶液中，搅拌0.5h，向趁热过滤后的滤液内加入0.1g物质纯度为95％的甜菊糖M苷，随后自然降温至室温，静置12h析出固体后，过滤，白色固体于25℃下真空干燥，得甜菊糖M苷晶型A。
实施例十
在室温条件下，将20g物质纯度为99.5％的甜菊糖M苷晶型A加入100mL水 中，搅拌12h后，过滤得到白色固体，即得甜菊糖M苷晶型B。
对上述实施例制得的甜菊糖M苷晶型A进行X-射线粉末衍射分析(XRPD)、差示扫描量热分析(DSC)、热失重分析(TG)、动态水分吸附分析(DVS)等。
XRPD分析：其采用德国布鲁克仪器有限公司Bruker D8 advance型的衍射仪于室温进行检测，采用Cu–Kα射线
Figure PCTCN2018079010-appb-000002
2θ角扫描从3度到40度，扫描速度为0.2度/秒。其分析结果见图1。XRPD谱图显示上述实施例制得的甜菊糖M苷晶型A具有良好的结晶度。
在样品粉末X-射线粉末衍射图谱中，由特定晶型得到的衍射谱图往往是特征性的。因为结晶条件、粒径、混合物的相对含量和其它测试条件的差异，衍射谱图可能会产生择优取向效果，从而导致谱图中某些谱带(尤其是在低角度)的相对强度发生变化。因此，衍射峰的相对强度对所针对的晶体并非是特征性的，判断是否与已知的晶型相同时，更应该注意的是峰的位置而不是它们的相对强度。另外，判断晶型是否一样时应注意保持整体观念，因为并不是一条衍射线代表一个物相，而是一套特定的“d-I/I1”数据才代表某一物相。还应指出的是，在混合物的鉴定中，由于含量下降等因素会造成部分衍射线的缺失，此时，无需依赖高纯试样中观察到的全部谱带，甚至一条谱带也可能对给定的晶体是特征性的。
DSC分析：其采用美国铂金埃尔默公司的DSC 8500型差示扫描量热仪进行检测，气氛为氮气，加热速度为10摄氏度/分钟。其分析结果见图2。
TG分析：其采用德国耐驰公司的Netzsch TG 209F3型热重分析仪检测，温度范围：30-400℃，扫描速率：10K/min，吹扫气：25mL/min。其分析结果见图3。
DVS分析：其采用英国SMS仪器公司DVS Intrinsic型动态水分吸附仪进行测定，测定温度：25℃；相对湿度：0-95％。其分析结果见图4。上述实施例制得的甜菊糖M苷晶型A在25℃ 40％RH条件下吸湿性明显低于甜菊糖M苷无定形和晶型B，比较结果见图6和表1。同时，甜菊糖M苷晶型A在正常储存(40％-80％RH)条件下吸湿性低于无定形。
表1
Figure PCTCN2018079010-appb-000003
Figure PCTCN2018079010-appb-000004
对上述实施例制得的甜菊糖M苷晶型A，在105℃条件下干燥一天后进行XRPD分析，其分析结果见图7。从图7中可以看出其晶型不变，晶型在高温条件下稳定性好。而甜菊糖M苷晶型B在高温条件下极其不稳定，在105℃条件下干燥一天后为无定形，其分析结果见图8。
对上述实施例制得的甜菊糖M苷晶型A，在25℃、RH 60％条件下储存半年，其分析结果见图9。从图9中可以看出其晶型不变，说明该晶型在正常储存条件下物理稳定性好。
HPLC分析：其采用美国安捷伦科技有限公司的1260infinity液相色谱仪测定。样品溶液配制方法：精确称量25-50毫克甜菊糖M苷样品，放入25毫升的容量瓶中，然后加入水-乙腈(7：3，v/v)溶液，进行溶解并定容至刻度。磷酸钠缓冲液(规格：10mmol/L，pH值：2.6)的配置方法：将2.76克磷酸二氢钠溶解到2升水中，加入磷酸，将pH值调至2.6。色谱柱：Phenomenex公司的Luna 5μ C18(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。洗脱梯度如下：
Figure PCTCN2018079010-appb-000005
其分析结果见图10。上述实施例制得的甜菊糖M苷晶型A，具有好的化学稳定性，HPLC分析显示在40℃、RH 75％条件下储存半年后,其含量降低小于0.2％。说明该晶型在高湿条件下化学稳定性好。
上述实施例制得的甜菊糖M苷晶型A，具有很好的重现性，并且水溶性稳定，最大溶解度约为3mg/mL，24h时的平衡溶解度约为2mg/mL。通过实施例制备的两批甜菊糖M苷晶型A的粉末溶出曲线见图11。晶型A的水溶性与专利CN 105722533 A中报道的甜菊糖D苷-甜菊糖M苷无定形组合物(约3mg/mL)差不多，均可以稳定提高水溶性2-3倍。
上述实施例中所用的甜菊糖M苷原料由山东诸城浩天药业有限公司提供。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (8)

  1. 一种甜菊糖M苷晶型A，其特征在于，其结构如下式I所示，
    Figure PCTCN2018079010-appb-100001
    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4.30、约6.57、约8.04、约16.31、约17.57和约20.91处具有3个、4个、5个或6个特征衍射峰。
  2. 根据权利要求1所述的甜菊糖M苷晶型A，其特征在于，所述晶型A有基本如图1所示的X-射线粉末衍射(XRPD)图谱，以度表示布拉格2θ角、误差范围为±1°，以
    Figure PCTCN2018079010-appb-100002
    表示的晶面间距d和以百分数表示的衍射峰的相对强度具有如下特征：
    Figure PCTCN2018079010-appb-100003
    Figure PCTCN2018079010-appb-100004
  3. 根据权利要求1所述的甜菊糖M苷晶型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：
    (1)所述晶型A具有基本上如图2所示的差示扫描量热分析图谱；
    (2)所述晶型A具有基本上如图3所示的热失重分析图谱；
    (3)所述晶型A具有基本上如图4所示的动态水分吸附图谱；和
    (4)所述晶型A具有基本上如图5所示的红外图谱。
  4. 根据权利要求1-3任一项所述的甜菊糖M苷晶型A的制备方法，其特征在于，所述制备方法为混悬法、溶液挥发法或冷却法的一种或两种以上的混合结晶方法，包括以下步骤：
    (1)混悬：在0-100℃温度范围内，将甜菊糖M苷与溶剂混合0.1-48h，得到混悬溶液；
    (2)冷却：步骤(1)中的混悬溶液趁热过滤，滤液冷却至0-30℃温度范围内，直至析出大量的白色固体，得到混悬溶液；
    (3)挥发：步骤(1)中的混悬溶液过滤后，在0-100℃温度范围内挥发，真空压力小于或等于0.1MPa，直至析出大量的白色固体，得到混悬溶液；和
    (4)过滤：在0-100℃温度范围内，将步骤(1)、(2)或(3)中的混悬溶液过滤或离心，得到白色固体，干燥即得甜菊糖M苷晶型A。
  5. 根据权利要求4所述的甜菊糖M苷晶型A的制备方法，其特征在于，步骤(1)中所述的甜菊糖M苷干物质纯度在20-100％范围内。
  6. 根据权利要求4所述的甜菊糖M苷晶型A的制备方法，其特征在于，步骤(1)中所述的溶剂为：甲醇、乙醇、1-丙醇、乙腈、丙酮、甲乙酮、乙酸甲酯、甲酸乙酯、乙酸乙酯、甲基叔丁基醚、四氢呋喃、硝基甲烷、甲苯中的一种或两种以上，或是上述溶剂与水的混合溶剂。
  7. 一种组合物，其特征在于，所述组合物含有如权利要求1-3任一项所述的甜菊糖M苷晶型A。
  8. 根据权利要求1-3任一项所述的甜菊糖M苷晶型A及其制备方法在食品、保健品及药品中的用途。
PCT/CN2018/079010 2017-03-16 2018-03-14 甜菊糖m苷晶型及制备方法和用途 Ceased WO2018166475A1 (zh)

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