WO2015113369A1 - Cristal du glycoside stévioside a, son procédé de préparation et ses utilisations - Google Patents

Cristal du glycoside stévioside a, son procédé de préparation et ses utilisations Download PDF

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Publication number
WO2015113369A1
WO2015113369A1 PCT/CN2014/080908 CN2014080908W WO2015113369A1 WO 2015113369 A1 WO2015113369 A1 WO 2015113369A1 CN 2014080908 W CN2014080908 W CN 2014080908W WO 2015113369 A1 WO2015113369 A1 WO 2015113369A1
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Prior art keywords
stevioside
crystal
suspension
preparation
solvent
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PCT/CN2014/080908
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English (en)
Chinese (zh)
Inventor
朱理平
梅雪峰
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诸城市浩天药业有限公司
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Publication of WO2015113369A1 publication Critical patent/WO2015113369A1/fr

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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
    • C07H1/06—Separation; Purification
    • 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

Definitions

  • the invention relates to the field of chemical pharmacy, in particular to a novel stevioside A glycoside crystal, a preparation method and use thereof. Background technique
  • the polymorphism phenomenon refers to a phenomenon in which a solid matter is arranged in two or more different spatial arrangements to form a solid state having different physicochemical properties.
  • polymorphs include multi-component crystal forms such as organic solvates, hydrates, and the like.
  • Drug polymorphism is widespread in drug development and is an inherent property of organic small molecule compounds. Theoretically, small molecule drugs can have an infinite number of crystal packing methods—polymorphs. Studies have shown that the number of drug polymorphs found is directly proportional to the time and resources of the research they are investigating. Like Lipitor, the world's highest-selling drug to date, there are as many as 35 patents for patent protection.
  • Polymorphism is not only controlled by internal factors such as the spatial structure and functional group properties of molecules, intramolecular and intermolecular interactions, but also by drug synthesis process design, crystallization and purification conditions, formulation excipient selection, and formulation process. Route and granulation methods, as well as storage conditions, packaging materials and other factors. Different crystal forms have different colors, melting points, dissolution, dissolution properties, chemical stability, reactivity, mechanical stability, etc. These physicochemical properties or processability sometimes directly affect the safe and effective performance of the drug. Therefore, crystal research and control has become an important research content in the drug development process.
  • Crystallization studies include two stages of crystal discovery and crystal form optimization.
  • the crystal discovery stage a variety of crystallization methods are used, such as melt crystallization, solution evaporation, rapid cooling and suspension crystallization, by changing the crystallization conditions, solvent , external factors affecting the crystallization of the drug, such as temperature, speed and ratio of suspended solvent.
  • High-throughput sample preparation platform is used to prepare hundreds of crystallization tests simultaneously, using micro sample preparation techniques and analytical testing methods. New crystal forms were prepared and discovered.
  • solid characterization methods such as X-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy, etc.
  • the physicochemical properties of the crystal form should be studied by DSC, TGA, DVS, HPLC, etc., and the hygroscopicity, chemical stability, physical state stability, and processability of different crystal forms were compared. Finally, the most preferred solid form is selected for development.
  • Stevioside A glycoside is a kauriene diterpene glycoside, a leaf from the asteraceae herb stevia A new natural sweetener from Zhongjing, native to Brazil and Paraguay. According to the international sweetener industry, stevioside has been widely used in the production of food, beverages and seasonings in Asia, North America, South America and the European Union. China is the world's leading producer of stevia.
  • Stevia has the characteristics of high sweetness and low heat energy. Its sweetness is 200-300 times that of sucrose, and the calorific value is only 1/300 of sucrose. It has been proved by a large number of scientific experiments that stevioside A glycosides are non-toxic and have no side effects, and are an ideal sweetener for replacing sucrose. In addition, stevioside can be widely used in food, beverage, seasoning, brewing, medicine and other industries.
  • Stevia form 1, form 2, form 3A, form 3B, amorphous form and preparation thereof are reported in the patent US 20070292582 - A1; Form 1, Form 2 and Solubility are reported in the patent WO20101 18218A1.
  • Very high crystal form 3 and its preparation method wherein the crystal form 2 is the same as the crystal form 1 reported in the patent US 20070292582 - A1, and the crystal form after the crystal form 1 is dried is the same as the US 20070292582 - A 1 crystal form 3A, 3B .
  • an article entitled “Single Crystal Growth and Structure Determination of the Natural " High Potency " Sweetener Rebaudioside A” in Crystal Growth & Design magazine reported the methanol tetrahydrate Form III. , the crystal form is unstable.
  • Form 1 in the patent US 20070292582 - A 1 corresponding to Form I in this article
  • Form II corresponds to Form 3A
  • Form IV corresponds to US 20070292582 - A1 Form 2.
  • the present invention aims to provide a novel stevioside A glycoside crystal.
  • Another object of the present invention is to provide a process for the preparation of the novel stevioside A glycoside crystal.
  • a further object of the invention is to provide the use of said novel stevioside A glycoside crystals.
  • a Stevia A glycoform wherein the structure is as shown in Formula I,
  • the X-ray powder diffraction (XRPD) pattern of the Form 9 has characteristic peaks at the following 2 ⁇ 0.1° angles: 4.748, 9.511, 11.767, 13 23.428;
  • the X-ray powder diffraction (XRPD) pattern of Form 9 has characteristic peaks at the following 2 ⁇ ⁇ 0.1° angles: 4.86, 6.00, 8.82, 9.02, 9.64, 11.90, 13.68, 14.13 14.79, 15.86, 16.40, 17.31, 18.06, 18.70, 19.33, 21.27, 21.76, 22.83, 23.47, 25.30, 25.76.
  • the crystal form 9 has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • XRPD X-ray powder diffraction
  • the crystalline form 9 differential scanning calorimetry has no characteristic endothermic peak at 50-250 °C.
  • the solvent in the step (1) is tetrahydrofuran, and/or n-heptane.
  • the stirring speed in the step (2) is 60-600 rpm; and the stirring time is 2 hours - 2 days.
  • step (3) suspension 2 is filtered, solvent washed and dried to obtain stevioside crystal 9; the solvent is selected from low boiling point ether.
  • the drying in the step (3) is dried at 50 ° C or dried under reduced pressure.
  • a use of the stevioside A glycoside form 9 provided by the invention as described above for the preparation of a food or a medicament is provided. Accordingly, the present invention provides a crystal form having better properties, such as a new crystal form having high crystallinity, good solubility, and high stability.
  • Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the stevioside A glycoside form 9 obtained in the examples.
  • Fig. 2 is a graph showing the thermogravimetric analysis (TG) of the stevioside A glycoside form 9 obtained in the examples.
  • Fig. 3 is a differential scanning calorimetry (DSC) chart of the stevioside A glycoform form 9 obtained in the examples.
  • Fig. 4 is a dynamic water vapor adsorption (DVS) diagram of the stevioside A glycoform form 9 obtained in the examples.
  • composition refers to when applied to a body. (human or animal), the pharmacy that can be induced by local and/or systemic effects And/or a compound or composition that is physiologically reactive.
  • room temperature means 15-30 ° C, preferably 20-25 ° C.
  • the inventors further studied the properties of the stevioside A glycoside using a variety of methods and instruments.
  • X-ray powder diffraction also known as “X-ray polycrystalline diffraction (XRPD)
  • XRPD X-ray polycrystalline diffraction
  • An X-ray powder diffractometer is used to generate a series of diffraction patterns when X-rays are transmitted through the crystal. The different diffraction lines and their intensities in the spectrum are determined by the atomic groups of a certain structure, thereby determining the specific crystal structure of the crystal.
  • Methods for determining X-ray powder diffraction of crystals are known in the art. For example, using a Bmker D8 Advanced model X-ray powder diffractometer, a copper radiation target is used to acquire the spectrum at a scan rate of 2° per minute.
  • the stevioside A genotype 9 of the present invention has a specific crystal morphology and has a specific characteristic peak in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the XRPD pattern of the stevioside A glycoform form 9 of the present invention has eight strong peaks at the following 2 ⁇ ⁇ 0.1° angles: 4.748, 9.511, 11.767, 13.598, 14.038, 17.224, 19.242 , 23.428;
  • the stevioside form
  • DSC Differential calorimetric scanning analysis
  • a DSC scan of the crystal can be obtained by using a DSC Q20 differential scanning calorimeter at a temperature rise rate of 10 °C per minute from 25 °C to 300 °C.
  • the stevioside A glycoside form 9 differential scanning calorimetry obtained by the method of the present invention is measured by DSC to have no characteristic endothermic peak at 50-250 ° C, preferably the sweetness of the present invention.
  • Inulin A glycoform form 9 has a DSC pattern substantially identical to that of Figure 3.
  • TG Thermal Weightlessness Analysis
  • a dynamic moisture adsorber can be used.
  • the stevioside A glycoside form 9 obtained by the method of the present invention has a TG pattern substantially identical to that of Figure 2 as measured by TG.
  • Dynamic Water Vapor Adsorption is a “Dynamic Water Vapor Adsorption” (DVS) instrument that measures the hygroscopicity of a sample. Methods for its determination are known in the art. For example, Surface Measurement Systems, Ltd. instruments can be used to collect data from 5% to 95% humidity at 25 degrees Celsius. The weight deviation under each humidity is not more than ⁇ 0.02% within lOmin. .
  • the stevioside A glycoside form 9 of the present invention has a specific stability and is advantageous for preservation.
  • the inventors showed by the DVS spectrum that in the conventional storage environment (40% - 80% RH), Form 9 has no or almost no hygroscopicity.
  • the DVS pattern of the resulting stevioside A glycoform 9 is substantially identical to that of Figure 4.
  • the present invention provides a method of preparing the stevioside A form 9, wherein the method comprises the steps of:
  • the first step is to carry out the suspension, that is, mixing the stevioside and the solvent at room temperature to obtain a suspension 1; the second step is stirring, that is, the suspension 1 obtained in the first step is stirred to obtain a suspension 2;
  • the third step is to obtain a crystal, which is obtained by filtering the suspension 2 obtained in the second step, and then drying to obtain a stevioside crystal 9 crystal.
  • the solvent involved in the first step is tetrahydrofuran and/or n-heptane.
  • the volume ratio of tetrahydrofuran to n-heptane is 2: 1-1: 0, preferably pure tetrahydrofuran (1:0).
  • the stirring speed involved in the second step is preferably 60-600 rpm; the stirring time is preferably 2 hours - 2 days, more preferably 2 hours - 10 hours.
  • the suspension 2 is filtered, and the solid portion is washed with a solvent and then dried.
  • the drying is preferably dried at 50 ° C or dried under reduced pressure.
  • the solvent used for washing in the third step is selected from low boiling point ether.
  • the invention further relates to a composition comprising a novel crystalline form of Stevia A glycoside provided by the present invention, said composition comprising an effective amount of Stevia A glycoside Form 9 and a food/pharmaceutically acceptable carrier.
  • a composition comprising a novel crystalline form of Stevia A glycoside provided by the present invention, said composition comprising an effective amount of Stevia A glycoside Form 9 and a food/pharmaceutically acceptable carrier.
  • the term “containing” or “including” includes “comprising”, “consisting essentially of”, and “consisting of”.
  • effective amount refers to an amount which is functional or active against a human and/or animal and which is acceptable to humans and/or animals.
  • the "pharmaceutically acceptable carrier” is selected from the group consisting of: a filler, a disintegrant, a lubricant, a glidant, an effervescent agent, a flavoring agent, a coating material, an excipient, or a gentle/ Controlled release agent.
  • the pharmaceutically acceptable carrier may contain a liquid such as water, saline, glycerol and ethanol.
  • auxiliary substances such as fillers, disintegrants, lubricants, glidants, effervescent agents, wetting or emulsifying agents, flavoring agents, pH buffering substances and the like may also be present in these carriers.
  • these materials can be formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous carrier medium wherein the pH is usually from about 5 to about 8, preferably, the pH is from about 6 to about 8.
  • the pH is usually from about 5 to about 8
  • the pH is from about 6 to about 8.
  • the new crystal form provided by the present invention has high crystallinity, remarkable solubility, and a certain degree of improvement in chemical and physical stability.
  • the new crystal form provided by the invention has good chemical and physical stability, and the crystal form formed is regular, which is beneficial to the process treatment of stevioside A glycoside and industrial application.
  • the method for preparing new stevioside A glycoforms provided by the invention is simple and easy to industrialize. Production.
  • the invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.
  • the unit of weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight of the solute in a 100 ml solution.
  • XRPD All XRPD spectra of this patent are detected by the Brooke D8 Advance X-ray diffractometer at room temperature, 2 angstrom scans from 3 degrees to 40 degrees, Cu K , scanning speed: 0. ⁇ / step.
  • the specific crystal form of the diffraction spectrum obtained from the crystalline compound is often characteristic, and the relative intensity of the band (especially at low angles) may be due to crystallization conditions.
  • DSC All DSC spectra of this patent were measured by a DSC 8500 differential scanning calorimeter from Elmer, Platinum, USA, with an atmosphere of nitrogen and a heating rate of 10 degrees Celsius per minute.
  • DVS All of the dynamic moisture adsorption (DVS) experimental data of this patent were measured by the British SMS instrument company DVS Intrinsic type dynamic moisture adsorber. Measurement conditions: Temperature: 25 Relative humidity range: 5%-95%. The raw stevioside in the following examples was purchased from Zhucheng Haotian Pharmaceutical Co., Ltd. Example 1
  • sample solution Accurately weigh 50-100 mg of stevioside sample, put it into a 50 ml volumetric flask, and then add 7:3 water acetonitrile solution to dissolve to 50 ml mark. Detection procedure: 5 ⁇ l of the sample solution was injected under the following conditions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline 9 du glycoside stévioside A, dont la structure est représentée par la formule I. Le diagramme de diffraction X sur poudre (XRPD) de la forme cristalline 9 présente les pics caractéristiques suivants aux angles 2θ ± 0,1 degrés : 4,748, 9,511, 11,767, 13,598, 14,038, 17 224, 19,242, et 23,428.
PCT/CN2014/080908 2014-01-30 2014-06-27 Cristal du glycoside stévioside a, son procédé de préparation et ses utilisations WO2015113369A1 (fr)

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CN201410044437.5A CN103739639B (zh) 2014-01-30 2014-01-30 一种甜菊糖a苷晶体及其制备方法和用途

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CN103739639B (zh) * 2014-01-30 2016-10-19 诸城市浩天药业有限公司 一种甜菊糖a苷晶体及其制备方法和用途
CN106866757B (zh) 2017-03-16 2020-06-26 诸城市浩天药业有限公司 甜菊糖m苷晶型及制备方法和用途
CN112156183B (zh) * 2020-08-21 2021-07-30 浙江皇冠科技有限公司 一种CpG复合佐剂及作为新型冠状病毒疫苗佐剂的用途

Citations (3)

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CN101812096A (zh) * 2010-04-21 2010-08-25 赣州菊隆高科技实业有限公司 一种超声波结晶莱鲍迪甙a的方法
CN102766177A (zh) * 2012-06-06 2012-11-07 天津北洋百川生物技术有限公司 结晶法提高甜菊糖中莱鲍迪甙a含量的方法
CN103739639A (zh) * 2014-01-30 2014-04-23 诸城市浩天药业有限公司 一种甜菊糖a苷晶体及其制备方法和用途

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US9012626B2 (en) * 2006-06-19 2015-04-21 The Coca-Cola Company Rebaudioside a composition and method for purifying rebaudioside a
CN101472487B (zh) * 2006-06-19 2013-05-01 可口可乐公司 甜菊双糖苷a组合物及其纯化方法
WO2010118218A1 (fr) * 2009-04-09 2010-10-14 Cargill, Incorporated Composition d'édulcorant comprenant une forme de rébaudioside a à solubilité élevée et procédé de fabrication

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812096A (zh) * 2010-04-21 2010-08-25 赣州菊隆高科技实业有限公司 一种超声波结晶莱鲍迪甙a的方法
CN102766177A (zh) * 2012-06-06 2012-11-07 天津北洋百川生物技术有限公司 结晶法提高甜菊糖中莱鲍迪甙a含量的方法
CN103739639A (zh) * 2014-01-30 2014-04-23 诸城市浩天药业有限公司 一种甜菊糖a苷晶体及其制备方法和用途

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