WO2023174422A1 - 高纯度结晶d-塔格糖，包含其的组合物，以及制备方法和用途 - Google Patents

高纯度结晶d-塔格糖，包含其的组合物，以及制备方法和用途 Download PDF

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WO2023174422A1
WO2023174422A1 PCT/CN2023/082252 CN2023082252W WO2023174422A1 WO 2023174422 A1 WO2023174422 A1 WO 2023174422A1 CN 2023082252 W CN2023082252 W CN 2023082252W WO 2023174422 A1 WO2023174422 A1 WO 2023174422A1
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tagatose
crystallized
crystallization
cooling
crystalline
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PCT/CN2023/082252
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English (en)
French (fr)
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马延和
龚俊波
石婷
韩丹丹
李元
陈明洋
王东博
王影
Original Assignee
中国科学院天津工业生物技术研究所
天津大学
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Publication of WO2023174422A1 publication Critical patent/WO2023174422A1/zh

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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
    • 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
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • 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
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/02—Monosaccharides

Definitions

  • the invention belongs to the technical field of crystal products, and specifically relates to a high-purity D-tagatose existing in crystalline form, a composition containing the D-tagatose, and corresponding preparation methods and uses.
  • D-Tagatose is a six-carbon ketose with the molecular formula C 6 H 12 O 6 . It is both the epimer of D-fructose and the ketose of D-galactose (aldose). isomer. It is a rare naturally occurring monosaccharide, mainly found in dairy products such as yogurt and milk powder. Its sweetness characteristics are similar to sucrose, but the calories generated are only one-third of sucrose, so it is called a low-calorie sweetener. D-tagatose was officially approved as a generally recognized as safe (GRAS) food by the U.S. Food and Drug Administration (FDA) in 2001, and was approved by the European Union for marketing in Europe in 2005. D-tagatose has important functions such as low caloric value, zero glycemic index, blood sugar inactivation, caries-free, prebiotic effect and antioxidant activity, and has been widely used in food, beverages, dental care products and other fields.
  • GRAS generally recognized as safe
  • FDA
  • the inventors conducted research on the crystallization of D-tagatose, completed the present invention, and provided a method suitable for industrial production. And the obtained crystalline D-tagatose has large crystal particles, complete structure, good fluidity, is not easy to agglomerate, and has high purity, a composition containing the crystalline D-tagatose, and a method for preparing the crystalline D-tagatose. methods and practical uses.
  • the present invention provides crystalline D-tagatose, the angle of repose of which is below 40°, preferably below 37°, and more preferably below 35°.
  • the purity of the crystalline D-tagatose is above 98%, preferably above 98.5%, more preferably above 99%.
  • the particle size of the crystallized D-tagatose is above 150 ⁇ m, preferably above 200 ⁇ m, more preferably above 250 ⁇ m.
  • the aspect ratio of the crystalline D-tagatose is 1.0 to 4.0, preferably 1.2 to 2.0, more preferably 1.3 to 1.6.
  • the bulk density of the crystallized D-tagatose is above 0.7g/mL, preferably above 0.75g/mL, and more preferably above 0.85g/mL.
  • the present invention provides a method for preparing crystallized D-tagatose in the first aspect, which includes the following steps:
  • step 2) Perform solid-liquid separation of the massecuite of crystallized D-tagatose described in step 1) to obtain crude crystallized D-tagatose;
  • step 3 Dry the crude crystallized D-tagatose described in step 2) to obtain crystallized D-tagatose.
  • the purity of the solution containing D-tagatose in step 1) is 80 wt% or more, preferably 85 wt% or more, and more preferably 90 wt% or more.
  • the D-tagatose saturated solution in step 1) is a saturated solution at 40°C to 70°C, preferably a saturated solution at 50°C to 65°C, and more preferably a saturated solution at 58°C to 62°C. solution.
  • the crystallization in step 1) is selected from at least one of the following methods: cooling crystallization, evaporation crystallization and anti-solvent crystallization.
  • the temperature cooling is linear cooling or segmented cooling.
  • the linear cooling includes a cooling stage, wherein the starting temperature is 58°C to 62°C, the ending temperature is below 20°C, and the cooling rate is 0.5 to 2.0°C/h, preferably 0.7 to 1.0°C/h.
  • the segmented cooling includes three cooling stages, wherein: the starting temperature of the first cooling stage is 58°C to 62°C, and the ending temperature is 54°C to 58°C; the starting temperature of the second cooling stage is is 54°C ⁇ 58°C, and the end temperature is 48°C ⁇ 52°C; the starting temperature of the third cooling stage is 48°C ⁇ 52°C, and the ending temperature is 25°C ⁇ 35°C; the cooling speed of each cooling stage is different. Independently, it is 0.35 ⁇ 0.70°C/h, preferably 0.42 ⁇ 0.65°C/h, more preferably 0.55 ⁇ 0.60°C/h; more preferably, each of the cooling stages also independently includes a constant temperature treatment at the respective end temperature. , wherein the time of each constant temperature treatment is independently 90 to 150 min, preferably 90 to 120 min.
  • the evaporation is vacuum evaporation.
  • the vacuum degree of the vacuum evaporation is 0.02-0.1MPa, preferably 0.03-0.05MPa, and the time is 9-35h, preferably 15-30h.
  • the anti-solvent is an organic solvent, preferably an alcohol solvent, and more preferably a C 1 -C 4 fatty alcohol solvent.
  • the volume of the antisolvent accounts for more than 80% of the total volume of the system after adding it.
  • the addition rate of the antisolvent is 0.1 to 0.3 mL/min.
  • step 1) adding D-tagatose seed crystals to the D-tagatose saturated solution.
  • the amount of D-tagatose seed crystal added is 5% to 15% of the mass of D-tagatose in the saturated solution of D-tagatose, preferably 8% to 15%, and more preferably 10%. ⁇ 15%.
  • the size of the D-tagatose seed crystal is 100-300 ⁇ m, preferably 100-200 ⁇ m, more preferably 150-200 ⁇ m.
  • step 1) After adding the D-tagatose seed crystal in step 1), a crystal growing step is also included.
  • the crystal growing time is 1 to 5 hours, preferably 1 to 4 hours, and more preferably 2 to 3 hours.
  • each step in step 1) is performed independently optionally under stirring conditions.
  • the stirring speed is 100-500 rpm, preferably 200-300 rpm.
  • the solid-liquid separation in step 2) is selected from at least one of the following methods: centrifugation and filtration.
  • the centrifugal speed is 2000-4000 rpm, preferably 3000 rpm, and the centrifugal time is 10-30 min, preferably 15 min.
  • the filtration is suction filtration.
  • the drying in step 3) is selected from any one of the following methods: fluidized bed drying, air blast drying and vacuum drying. More preferably, the drying temperature is 40°C to 55°C and the drying time is 12 to 24 hours.
  • the preparation method of the present invention also includes the following steps: repeating steps 1) and 2) at least once, each time subjecting the liquid obtained by solid-liquid separation in the previous step 2) to secondary crystallization.
  • the crystallizations described in each step 1) are the same or different from each other.
  • the solid-liquid separations in step 2) are the same or different from each other each time.
  • the crude crystallized D-tagatose obtained each time is dried individually or in combination.
  • preparation method of the present invention also includes the following steps:
  • step 3 Perform recrystallization, solid-liquid separation and drying of the crystallized D-tagatose described in step 3).
  • the recrystallization in step 4) is selected from at least one of the following methods: cooling crystallization and anti-solvent crystallization.
  • the temperature cooling is a linear temperature cooling.
  • the linear cooling includes a cooling stage, in which the starting temperature is 58°C to 62°C, the ending temperature is below 20°C, and the cooling rate is 0.7°C to 1.0°C/h.
  • the anti-solvent is an organic solvent, preferably an alcohol solvent, and more preferably a C 1 -C 4 fatty alcohol solvent.
  • the volume of the antisolvent accounts for more than 80% of the total volume of the system after adding it.
  • the dropping speed of the anti-solvent is 0.1-0.3 mL/min.
  • the solid-liquid separation described in step 4) is filtration, preferably suction filtration.
  • the drying in step 4) is vacuum drying, preferably at 40°C to 55°C for 12 to 24 hours.
  • step 4) also includes the step of adding D-tagatose seed crystals before the recrystallization.
  • the added amount of the D-tagatose seed crystal is 7% to 15% of the mass of D-tagatose in the recrystallization system.
  • the size of the D-tagatose seed crystal is 100-150 ⁇ m.
  • the invention provides a composition comprising the crystalline D-tagatose of the first aspect.
  • the composition further comprises at least one food, cosmetic and/or pharmaceutically acceptable excipient.
  • the present invention provides uses of the crystalline D-tagatose in the first aspect and the composition in the third aspect in the preparation of food, cosmetics and/or pharmaceuticals.
  • the crystallized D-tagatose of the present invention has a massive crystal habit and a rectangular hexahedron or a structure close to it. Since the crystal structure of the present invention belongs to the orthorhombic crystal system, the uniformity and solidity of the crystal are increased. By detecting the angle of repose, bulk density and agglomeration rate, It is found that the crystallized D-tagatose of the present invention has the characteristics of being difficult to agglomerate or agglomerate and having good fluidity. In addition, judging from the particle size distribution results, the crystallized D-tagatose of the present invention has a more uniform particle size distribution.
  • the crystallized D-tagatose of the present invention has a more excellent product morphology, better fluidity and less agglomeration properties, which is conducive to improving D-tagatose. Quality of sugar products.
  • the crystallized D-tagatose of the present invention is more uniform, the strength of the crystallization is increased, and the flow performance is increased, on the one hand, the amount of crystallized D-tagatose lost together with the mother liquor during centrifugal separation of the crystals is reduced, and on the other hand, the amount of crystallized D-tagatose lost together with the mother liquor is reduced. Breakage of crystalline particles during drying and transfer (crystalline particles may become micronized after breakage and may dissolve relatively easily, thus negatively affecting the quality of the final product).
  • the crystallized D-tagatose of the present invention has higher fluidity than commercially available D-tagatose products, and due to less agglomeration and easy dispersion and handling, it is easier to store, thereby reducing the crystallized D-tagatose product. Storage and transportation costs of sugar. Therefore, the crystallized D-tagatose of the present invention is more suitable for large-scale production.
  • the crystallization method of the present invention can be used to freely adjust the particle size of the crystallized D-tagatose product to obtain a crystallized D-tagatose product with more excellent product morphology, better fluidity and less agglomeration properties; and these methods It can be easily realized industrially, so it is more conducive to the industrial production of crystallized D-tagatose.
  • Figure 1 A is an optical microscope photo of commercially available D-tagatose products, the scale bar is 200 ⁇ m; B is the particle size distribution result of commercially available D-tagatose products.
  • Figure 2 A is an optical microscope photo of the crystallized D-tagatose prepared in Example 1, the scale bar is 200 ⁇ m; B is the particle size distribution result of the crystallized D-tagatose prepared in Example 1.
  • Figure 3 A is an optical microscope photo of the primary crystallized crystalline D-tagatose prepared in Example 2, the scale bar is 200 ⁇ m; B is the particle size distribution result of the primary crystallized crystalline D-tagatose prepared in Example 2 ; C is an optical microscope photo of the secondary crystallized crystalline D-tagatose prepared in Example 2, the scale bar is 200 ⁇ m; D is the particle size distribution result of the secondary crystallized crystalline D-tagatose prepared in Example 2 .
  • Figure 4 A is an optical microscope photo of the crystallized D-tagatose obtained in Example 3, the scale bar is 200 ⁇ m; B is the particle size distribution result of the crystallized D-tagatose obtained in Example 3.
  • Figure 5 A is an optical microscope photo of the primary crystallized crystalline D-tagatose prepared in Example 4, the scale bar is 200 ⁇ m; B is the particle size distribution result of the primary crystallized crystalline D-tagatose prepared in Example 4 ; C is an optical microscope photo of the crystallized D-tagatose secondary crystallized in Example 4, the scale bar is 200 ⁇ m; D is the particle size distribution result of the crystallized D-tagatose secondary crystallized in Example 4.
  • Figure 6 A is an optical microscope photo of the primary crystallized crystalline D-tagatose prepared in Example 5, the scale bar is 200 ⁇ m; B is the particle size distribution result of the primary crystallized crystalline D-tagatose prepared in Example 5 ; C is an optical microscope photo of the recrystallized crystalline D-tagatose prepared in Example 5, and the scale bar is 200 ⁇ m; D is the particle size distribution result of the recrystallized crystalline D-tagatose prepared in Example 5.
  • Figure 7 A is an optical microscope photo of the primary crystallized crystalline D-tagatose prepared in Example 6, the scale bar is 200 ⁇ m; B is the particle size distribution result of the primary crystallized crystalline D-tagatose prepared in Example 6 ; C is an optical microscope photo of the secondary crystallized crystalline D-tagatose prepared in Example 6, the scale bar is 200 ⁇ m; D is the particle size distribution result of the secondary crystallized crystalline D-tagatose prepared in Example 6 ; E is an optical microscope photo of the recrystallized crystalline D-tagatose prepared in Example 6, the scale bar is 200 ⁇ m; F is the particle size distribution result of the recrystallized crystalline D-tagatose prepared in Example 6.
  • D-tagatose in the present invention refers to a reducing, low-calorie monosaccharide with the molecular formula of C 6 H 12 O 6 and the following structural formula.
  • Fischer-type chain structures Haworth-type six-membered ring structures including ⁇ -type and ⁇ -type are also included in the scope of D-tagatose.
  • crystalline D-tagatose in the present invention refers to the crystallized product of D-tagatose solution or D-tagatose in the crystalline (or crystalline) form, where D-tagatose Sugar molecules are arranged in regular repeating structures rather than amorphous solid lumps without repeating structures.
  • solution containing D-tagatose can be any solution (such as an aqueous solution, an aqueous alcohol solution, an aqueous nitrile solution, etc.), as long as D-tagatose can be dissolved or scattered among them.
  • the solute (D-tagatose) content of a solution containing D-tagatose can reach more than 80% (w/w), more than 85% (w/w), more than 90% (w/w), 91 % (w/w) or more, 92% (w/w) or more, 93% (w/w) or more, 94% (w/w) or more, 95% (w/w) or more, 96% (w/w) ) or above, 97% (w/w) or above, 98% (w/w) or above or 99% (w/w) or above, but the present invention is not limited thereto.
  • D-tagatose saturated solution refers to a solution obtained when D-tagatose as a solute cannot continue to dissolve in a certain amount of solvent at a certain temperature.
  • D-tagatose seed crystal in the present invention refers to fine crystals mainly composed of D-tagatose, and the size of the seed crystal can reach less than 300 ⁇ m.
  • the term "cultivating crystals" in the present invention refers to a process or method that promotes the precipitation of crystallizable substances from their supersaturated solvents and the formation of crystals under certain conditions.
  • the term "purity" in the present invention refers to the purity of a substance (such as crystalline D-tagatose in the present invention) expressed in percentage content, which can be analyzed by, for example, X-ray powder diffraction (XRPD), Differential scanning calorimetry (DSC) analysis, infrared spectroscopy (IR) analysis, high performance liquid chromatography (HPLC) analysis, liquid chromatography/mass spectrometry (LC/MS) analysis and other methods can be obtained.
  • XRPD X-ray powder diffraction
  • DSC Differential scanning calorimetry
  • IR infrared spectroscopy
  • HPLC high performance liquid chromatography
  • LC/MS liquid chromatography/mass spectrometry
  • particle size refers to the size of a substance in the form of particles (such as crystalline tagatose in the present invention).
  • particle size of spherical particles is expressed by diameter.
  • the particle size of cubic particles is expressed by the side length.
  • the diameter of a sphere with the same behavior as the particle can be used as the equivalent diameter of the particle.
  • the specific particle size can be determined by a particle size analyzer, optical microscope (OM) or Scanning electron microscopy (SEM) measurement.
  • angle of repose or “angle of repose” in the present invention refers to the free surface of a powder accumulation formed by granular substances (such as crystalline tagatose in the present invention) in a gravitational field. In the limit state of equilibrium, the distance between the free surface and the horizontal plane angle. The smaller the angle of repose, the better the fluidity of the powder. There are two methods for measuring the angle of repose: injection method and discharge method.
  • the term "aspect ratio" in the present invention refers to the length ratio between the long diameter and the short diameter of the particulate matter (such as crystalline D-tagatose in the present invention), and the aspect ratio can roughly reflect the particle.
  • the aspect ratio can be determined by measuring the long diameter and short diameter of D-tagatose crystals using an optical microscope, and then calculating the ratio.
  • the term "bulk density” in the present invention refers to the measured mass of the powder formed from the granular material (such as crystallized D-tagatose in the present invention) when it is put into a container and its mass.
  • the ratio to the volume of the container (such as the actual volume after tapping). The greater the bulk density, the better the fluidity of the powder.
  • the specific bulk density can be measured by a powder tap density meter.
  • parameter results such as crystal system, space group, unit cell parameters, and number of molecules per unit cell can be obtained through X-ray single crystal diffraction.
  • the above method can adopt parameter settings used in routine operations in this field, and can be adjusted or changed as appropriate according to the specific physical and chemical properties of the substance to be tested.
  • crystallographic parameters of the crystallized D-tagatose of the present invention are as follows:
  • the crystallized D-tagatose of the present invention can have an angle of repose (e.g., measured by funnel expulsion method) below 40°, such as 40°, 38°, 36°, 34°, or any other An angle.
  • angle of repose e.g., measured by funnel expulsion method
  • the above-mentioned angle of repose can reach below 37°, such as 37°, 36°, 35°, 34° or any other angle.
  • the above-mentioned angle of repose can reach below 35°, such as 35°, 34°, 33°, 31° or any other angle.
  • the purity of the crystalline D-tagatose of the present invention can reach more than 98%, such as 98.0%, 98.5%, 99.0%, 99.5%, or any other purity.
  • the above-mentioned purity can reach more than 98.5%, such as 98.5%, 98.8%, 99.0%, 99.5% or any other purity.
  • the above-mentioned purity can reach more than 99%, such as 99.0%, 99.2%, 99.5%, 99.8% or any other purity.
  • the crystalline D-tagatose of the present invention may have a particle size (eg, measured by SEM) of more than 150 ⁇ m, such as any particle size in the range of 150 to 1200 ⁇ m.
  • the above-mentioned particle size can reach more than 200 ⁇ m, such as any particle size in the range of 200 to 1000 ⁇ m.
  • the above-mentioned particle size can reach 250 ⁇ m or more, such as any particle size from 250 to 800 ⁇ m (especially 300 to 700 ⁇ m).
  • the crystallized D-tagatose of the present invention has a relatively regular external morphology, and its aspect ratio can reach 1.0 ⁇ 4.0, 1.0 ⁇ 3.0, 1.0 ⁇ 2.5, 1.0 ⁇ 2.4, 1.0 ⁇ 2.3, 1.0 ⁇ 2.2, 1.0 ⁇ 2.1 or 1.0 ⁇ 2.0, such as 1.0, 1.2, 1.3, 1.4, 1.5, 1.6, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 3.0, 4.0, 5.0 or any other ratio.
  • the above aspect ratio can reach 1.2 ⁇ 2.0, 1.2 ⁇ 1.9, 1.2 ⁇ 1.8, 1.2 ⁇ 1.7, 1.2 ⁇ 1.6, 1.2 ⁇ 1.5, 1.2 ⁇ 1.4 or 1.2 ⁇ 1.3, such as 1.2, 1.3 , 1.4, 1.5, 1.6, 2.0 or any other ratio.
  • the above-mentioned aspect ratio can reach 1.3-1.6, 1.3-1.5 or 1.3-1.4, such as 1.3, 1.4, 1.5, 1.6 or any other ratio.
  • the bulk density of the crystalline D-tagatose of the present invention (for example, measured by a powder tap density meter) can reach more than 0.7g/mL, such as 0.70, 0.71, 0.72, 0.73, 0.74 , 0.75, 0.76, 0.80, 0.85, 0.90g/mL or any other density.
  • the above bulk density can reach above 0.75g/mL, such as 0.75, 0.76, 0.80, 0.85, 0.90g/mL or any other density.
  • the above-mentioned bulk density can reach above 0.85g/mL, such as 0.85, 0.86, 0.87, 0.89, 0.90, 0.92g/mL or any other density.
  • the preparation method of crystallized D-tagatose of the present invention mainly proceeds through crystallization, solid-liquid separation, drying and other process steps to finally obtain the corresponding product.
  • the crystalline D-tagatose of the present invention can be prepared by the following method, which includes:
  • step 2) Perform solid-liquid separation of the massecuite of crystallized D-tagatose described in step 1) to obtain crude crystallized D-tagatose;
  • step 3 Dry the crude crystallized D-tagatose described in step 2) to obtain crystallized D-tagatose.
  • the purity of the solution containing D-tagatose can be above 80wt%, such as 80wt%, 85wt%, 90wt%, 91wt%, 92wt%, 93wt%, 94wt%, 95wt%, 96wt%, 97wt%, 98wt%, 99wt% or any other purity.
  • the purity of the solution containing D-tagatose can be above 85wt%, such as 85wt%, 90wt%, 91wt%, 92wt%, 93wt% , 94wt%, 95wt%, 96wt%, 97wt%, 98wt%, 99wt% or any other purity.
  • the purity of the solution containing D-tagatose can be above 90wt%, such as 90wt%, 91wt%, 92wt%, 93wt%, 94wt% , 95wt%, 96wt%, 97wt%, 98wt%, 99wt% or any other purity.
  • the above-mentioned purity can be achieved by at least one of the following separation and/or purification methods, such as membrane separation and impurity removal, activated carbon decolorization, ion exchange desalting and continuous chromatography purification.
  • the above separation and/or purification method can be applied to any crude solution containing D-tagatose, such as D-tagatose reaction liquid prepared by a chemical catalytic reaction system, or prepared by a biological catalytic reaction system.
  • the obtained tagatose reaction liquid (such as the reaction liquid of lactose enzymatic hydrolysis and isomerization reaction, the reaction liquid of amylase enzymatic hydrolysis reaction, the reaction liquid of cellulose enzymatic hydrolysis reaction, the fermentation liquid of fermentation production, etc.).
  • the saturated solution of D-tagatose in step 1) of the above method, can be a saturated solution at 40°C to 70°C, such as 40°C, 45°C, 50°C, 55°C, Saturation at 60°C, 65°C, 70°C or any other temperature within the above range solution.
  • the saturated solution of D-tagatose in step 1) of the above method, can be a saturated solution at 50°C to 65°C, such as 50°C, 52°C, 55°C, 58°C , 60°C, 62°C, 65°C or any other saturated solution within the above range.
  • the saturated solution of D-tagatose in step 1) of the above method, can be a saturated solution at 58°C to 62°C, such as 58°C, 59°C, 60°C, 61°C , 62°C or any other temperature within the above range.
  • Controlling the temperature of the saturated solution of D-tagatose and maintaining this temperature during the optional addition of seed crystals and/or crystal growth will reduce the degree of supersaturation in the early stages of crystallization and further avoid the possibility of explosive nucleation.
  • step 1) of the above method crystallization can be achieved by cooling (cooling), evaporating (volatilizing) and/or adding an anti-solvent.
  • any one of the above crystallization methods can be used alone (for example, cooling alone, evaporation alone, etc.), or two or more methods can be used in combination (for example, two or more methods can be used in combination). Different cooling procedures, using a combination of cooling and adding anti-solvent, etc.).
  • step 1) of the above method crystallization can be achieved by cooling crystallization.
  • linear cooling can be used for cooling crystallization.
  • the entire linear cooling process only includes one cooling stage, during which a single cooling rate (for example, 0.5 to 2.0°C/h, preferably 0.7 to 1.0°C/h, or any other speed within the above range, such as 0.7°C/h, 0.8 °C/h, 0.9°C/h or 1.0°C/h) from the starting temperature (for example, 58°C ⁇ 62°C, or any other temperature within the above range, such as 58°C, 59°C, 60°C, 61°C or 62°C) to the termination temperature (for example, below 20°C, or any other temperature within the above range, such as 20°C, 18°C, 15°C, 12°C or 10°C).
  • a single cooling rate for example, 0.5 to 2.0°C/h, preferably 0.7 to 1.0°C/h, or any other speed within the above range, such as 0.7°C/h, 0.8 °C/h, 0.9°C/
  • linear cooling can be used for cooling and crystallization, from 58°C to 62°C to below 20°C at a cooling rate of 0.5°C to 2.0°C/h.
  • staged cooling can be used for cooling and crystallization.
  • the entire segmented cooling process may include more than two (for example, two, three, four, five or any other number within the above range, preferably three) cooling stages.
  • the cooling rates of each cooling stage can be the same as each other, different from each other, or different from each other.
  • the above cooling rate can be 0.35 ⁇ 0.70°C/h (for example, 0.35°C/h, 0.40°C/h, 0.46°C/h, 0.50°C/h, 0.60°C/h, 0.70°C/h or any other speed within the above range), preferably 0.42 to 0.65°C/h ( For example, 0.42°C/h, 0.46°C/h, 0.50°C/h, 0.60°C/h, 0.65°C/h or any other speed within the above range), more preferably 0.55 to 0.60°C/h (for example, 0.55°C /h, 0.40°C/h, 0.46°C/h, 0.50°C/h, 0.60°C/h, 0.70°C/h or any other speed within the above range); the first cooling stage can be started by the starting temperature (for example, 58°C ⁇ 62°C, or any other temperature within the above range, such as 58°C, 59°C, 60°C, 61°C or 62°C) to
  • each cooling stage can also independently include a constant temperature treatment step at the respective cooling end point, wherein the time of each constant temperature treatment step can be independently 90 to 150 minutes (for example, 90, 100, 110, 120, 130, 140, 150 min or any other time within the above range), preferably 90 to 120 min (such as 90, 100, 110 or 120 min or any other time within the above range).
  • the time of each constant temperature treatment step can be independently 90 to 150 minutes (for example, 90, 100, 110, 120, 130, 140, 150 min or any other time within the above range), preferably 90 to 120 min (such as 90, 100, 110 or 120 min or any other time within the above range).
  • three stages of cooling can be used for cooling and crystallization; in the first cooling stage, the temperature is reduced from 58°C to 62°C to 54°C to 58°C at a cooling rate of 0.35 to 0.70°C/h. , followed by constant temperature treatment for 90-150min; in the second cooling stage, the cooling rate is 0.42 ⁇ 0.60°C/h from 54°C ⁇ 58°C to 48°C ⁇ 52°C, and then constant temperature treatment for 90 ⁇ 150min; in the third cooling stage In this stage, the temperature is reduced from 48°C to 52°C to 25°C to 35°C at a cooling rate of 0.55°C/h to 0.65°C/h, followed by constant temperature treatment for 90 to 150 minutes.
  • step 1) of the above method crystallization can be achieved by evaporative crystallization.
  • vacuum evaporation can be used for evaporative crystallization.
  • the entire evaporation process is under certain vacuum conditions.
  • a suitable degree of vacuum can adjust the evaporation rate of water in the system to be evaporated, thereby avoiding the occurrence of fine crystals and polycrystals in the product.
  • a suitable evaporation time can adjust the level of water content in the system, thus On the premise of ensuring the yield, avoid the system being too viscous and causing crystal sticking and polycrystals.
  • a suitable vacuum degree can be 0.02 to 0.1MPa (for example, 0.02, 0.03, 0.05, 0.08, 0.1MPa or any other vacuum degree within the above range), preferably 0.03 to 0.05MPa (for example, 0.03, 0.035, 0.04, 0.045 , 0.05MPa or any other vacuum degree within the above range).
  • a suitable time can be 9 to 35h (for example, 9, 10, 15, 20, 25, 30, 35h or any other time within the above range), preferably 15 to 30h (for example, 15, 18, 20, 22, 25, 28, 30h or any other time within the above range).
  • step 1) of the above method crystallization can be achieved by anti-solvent crystallization.
  • anti-solvent crystallization can use organic solvents (for example, alcohols, nitriles, etc.) as anti-solvents.
  • organic solvents for example, alcohols, nitriles, etc.
  • anti-solvent crystallization can use alcoholic solvents (for example, aliphatic alcohols, aromatic alcohols, etc.) as anti-solvents.
  • alcoholic solvents for example, aliphatic alcohols, aromatic alcohols, etc.
  • anti-solvent crystallization can use C 1 -C 4 fatty alcohol solvents (for example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc.) as anti-solvent, preferably methanol and/or Or ethanol is used as the anti-solvent, and ethanol is more preferably used as the anti-solvent.
  • C 1 -C 4 fatty alcohol solvents for example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, etc.
  • the amount of antisolvent added can account for more than 80% of the total amount after addition (for example, 80%, 85%, 90%, 95% or any other amount within the above range). Proportion).
  • the antisolvent is added (for example, dropped) at a rate of 0.1 to 0.3 mL/min (for example, 0.1, 0.15, 0.2, 0.25, 0.3 mL/min or any other within the above range). speed).
  • the preparation method of the present invention can also add D-tagatose seed crystals to the saturated solution of D-tagatose before crystallization.
  • the seed crystals can be ground, screened, and rinsed (rinsing will cause the surface of the seed crystals to change It is made smooth and flat to reduce the possibility of crystal sticking), and then sieved.
  • step 1) may include the following steps: concentrating the solution containing D-tagatose into a saturated solution of D-tagatose, and then adding D-tagatose to the saturated solution of D-tagatose.
  • Tagatose crystals are seeded, and then crystallized by cooling (for example, linear cooling, segmented cooling) to obtain a massecuite of crystallized D-tagatose.
  • step 1) may include the following steps: concentrating the solution containing D-tagatose into a saturated solution of D-tagatose, and then adding D-tagatose to the saturated solution of D-tagatose.
  • Tagatose crystals are seeded and then crystallized by evaporation (eg, vacuum evaporation) to obtain a massecuite of crystallized D-tagatose.
  • step 1) may include the following steps: concentrating the solution containing D-tagatose into a saturated solution of D-tagatose, and then adding D-tagatose to the saturated solution of D-tagatose.
  • Tagatose crystals are seeded and then crystallized from an antisolvent (e.g., ethanol) to obtain a massecuite of crystallized D-tagatose.
  • an antisolvent e.g., ethanol
  • a sufficient amount of seed crystals can provide sufficient growth surface for the crystallization system, thereby reducing the possibility of pseudocrystals and polycrystals.
  • adding a sufficient amount of seed crystals can promptly consume the supersaturation generated during the cooling process and reduce explosive nucleation. possibility.
  • the amount of D-tagatose seed crystals added is 5% to 15% of the mass of D-tagatose in the saturated solution of D-tagatose (for example, 5%, 8%, 10 %, 12%, 14%, 15% or any other ratio within the above range), preferably 8% to 15% (for example, 8%, 9%, 10%, 12%, 14%, 15% or the above range) any other ratio within the above range), more preferably 10% to 15% (for example, 10%, 11%, 12%, 13%, 14%, 15% or any other ratio within the above range).
  • the size of D-tagatose seed crystals can be 100-300 ⁇ m (for example, 100-120 ⁇ m, 100-150 ⁇ m, 120-180 ⁇ m, 150-200 ⁇ m, 200-250 ⁇ m, 250-300 ⁇ m or any other size within the above range).
  • the size of D-tagatose seed crystals can be 100-200 ⁇ m (for example, 100-120 ⁇ m, 100-150 ⁇ m, 120-180 ⁇ m, 150-200 ⁇ m or any other within the above range size).
  • the size of D-tagatose seed crystals can be 150-200 ⁇ m (for example, 150-160 ⁇ m, 160-180 ⁇ m, 180-200 ⁇ m, 150-200 ⁇ m or any other within the above range size).
  • the preparation method of the present invention can also grow crystals after adding D-tagatose seed crystals and before crystallization.
  • the crystal growth time can be 1 to 5 hours (for example, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 hours or any other time within the above range).
  • the crystal growth time can be 1 to 4 hours (for example, 1, 1.5, 2, 2.5, 3, 3.5, 4 hours or any other time within the above range).
  • the crystal growth time may be 2 to 3 hours (for example, 2, 2.5, 3 hours or any other time within the above range).
  • each step in step 1) can be carried out independently and optionally under stirring conditions; if carried out under stirring conditions, the stirring speed can be 100 to 500 rpm (for example, 100, 200 , 300, 400, 500 rpm or any other speed within the above range), preferably 200 to 300 rpm (for example, 200, 220, 250, 280, 300 rpm or any other speed within the above range).
  • the stirring speed can be 100 to 500 rpm (for example, 100, 200 , 300, 400, 500 rpm or any other speed within the above range), preferably 200 to 300 rpm (for example, 200, 220, 250, 280, 300 rpm or any other speed within the above range).
  • step 2) of the above method solid-liquid separation can be achieved by methods such as centrifugation and/or filtration.
  • the above solid-liquid separation methods can be used alone (for example, centrifugation alone, filtration alone, etc.) or in combination (for example, centrifugation followed by filtration, etc.).
  • step 2) of the above method solid-liquid separation can be achieved by centrifugation.
  • the rotation speed of centrifugation can be 2000-4000 rpm (for example, 2000, 2500, 3000, 3500, 4000 rpm or any other rotation speed within the above range), and the centrifugation time can be 10-30 min (for example, 10 , 15, 20, 25, 30min or any other time within the above range).
  • step 2) of the above method solid-liquid separation can be achieved by filtration.
  • the filtration may be suction filtration.
  • drying can be achieved by fluidized bed drying, blast drying or vacuum drying.
  • drying may be air drying.
  • drying may be vacuum drying.
  • the drying temperature may be 40°C to 55°C (for example, 40°C, 45°C, 50°C, 55°C or above). any other temperature within the above range), the time is 12 to 24h (for example, 12, 15, 18, 24h or any other time within the above range).
  • the present invention also provides an improved method based on the above basic method including steps 1) to 3).
  • the improved method may include the following steps: repeating steps 1) and 2) in the basic method at least once, each time subjecting the liquid obtained by solid-liquid separation in the previous step 2) to secondary crystallization.
  • steps 1) and 2) in the basic method are recorded as one unit, the improved method may include at least two units.
  • the steps of concentration, crystallization, optional addition of seed crystals, crystal growth and other steps in step 1) of different units may be the same as each other, may be different, or may be different from each other.
  • the solid-liquid separation steps in step 2) of different units may be the same as each other, may be different, or may be different from each other.
  • the crude crystallized D-tagatose obtained through different units can be dried individually (the drying steps each time can be the same, different, or different), or can be combined and dried uniformly.
  • the improvement scheme may include the following steps: repeat steps 1) and 2) in the basic method once, and subject the liquid obtained by solid-liquid separation in the previous step 2) to secondary crystallization, wherein: The crystallization steps in step 1) before and after are the same (such as cooling and crystallization), the solid-liquid separation steps in step 2) are the same (such as filtration, especially suction filtration), and the crystallization D-
  • the crude tagatose is dried separately (for example, uniformly vacuum dried).
  • the improvement scheme may include the following steps: repeat steps 1) and 2) in the basic method once, and carry out secondary crystallization of the liquid obtained by solid-liquid separation in the previous step 2), wherein :
  • the crystallization steps in step 1) before and after are different (such as cooling crystallization and anti-solvent crystallization), and the solid-liquid separation steps in step 2) before and after are the same (such as filtration, especially suction filtration).
  • the crystalline D-tagatose crude product obtained is dried separately (for example, air drying and vacuum drying are used respectively).
  • the present invention also provides another improved method based on the above basic method including steps 1) to 3).
  • the improved method may include the following steps: 4) Recrystallizing, solid-liquid separation and drying the D-tagatose crystallized in step 3).
  • the recrystallization in step 4) can be performed by cooling (such as linear cooling) and/or adding an anti-solvent (such as an organic solvent, preferably an alcohol solvent, more preferably a C 1 -C 4 fatty alcohol) solvent, more preferably ethanol) and other methods.
  • an anti-solvent such as an organic solvent, preferably an alcohol solvent, more preferably a C 1 -C 4 fatty alcohol
  • the above recrystallization method can be used alone (for example, adding an antisolvent alone) or in combination (for example, adding an antisolvent after cooling down).
  • the specific process parameters of cooling and adding anti-solvent are the same as or similar to the basic method.
  • the solid-liquid separation in step 4) can be achieved by filtration (such as suction filtration) and other methods.
  • filtration such as suction filtration
  • the specific process parameters of the above filtration are the same or similar to the basic method.
  • drying in step 4) can be achieved by vacuum drying or other methods.
  • the specific process parameters of the above vacuum drying are the same or similar to the basic method.
  • step 4) may also include adding D-tagatose seed crystals before recrystallization.
  • the specific process parameters for adding seed crystals are the same as or similar to the basic method.
  • whether a basic method or an improved method is used to prepare crystallized D-tagatose usually depends on the solution containing D-tagatose as the raw material and whether the finally obtained crystallized D-tagatose meets the corresponding requirements. , and can be selected and adjusted according to the actual situation.
  • composition refers to a mixture composed of two or more components (or ingredients), which includes the main ingredient (such as the crystalline D-tagatose of the present invention) and One or more excipients (or minor ingredients), which may be food be of a nutritionally, cosmetically and/or pharmaceutically acceptable type.
  • pharmaceutically acceptable excipients refers to pharmaceutical excipients that are compatible with the active pharmaceutical ingredients and are not harmful to the subject, including (but not limited to) diluents (or fillers), binders, Disintegrants, lubricants, wetting agents, thickeners, glidants, flavoring agents, olfactory agents, preservatives, antioxidants, pH regulators, solvents, co-solvents, surfactants, etc.
  • compositions of the invention may comprise crystalline D-tagatose of the invention.
  • composition of the present invention may further comprise at least one food, cosmetic and/or pharmaceutically acceptable excipient.
  • the composition of the present invention may be a food composition, which may comprise the crystallized D-tagatose of the present invention, and preferably may further comprise at least one food acceptable excipient. .
  • composition of the present invention may be a cosmetic composition, which may comprise the crystalline D-tagatose of the present invention, preferably also at least one cosmetically acceptable Excipients.
  • the composition of the present invention may be a pharmaceutical composition, which may comprise the crystalline D-tagatose of the present invention, and preferably may further comprise at least one pharmaceutically acceptable excipient. .
  • Both the crystalline D-tagatose of the present invention and the composition of the present invention can be used to prepare products suitable for use in specific scenarios, such as food, cosmetics, medicines, etc. Therefore, the present invention also provides the use of the crystalline D-tagatose and compositions of the present invention in the preparation of food, cosmetics and/or pharmaceuticals.
  • Crystallized D-tagatose was prepared according to the method of Example 1 in Chinese patent application CN112592378A, and a crystallized D-tagatose comparative product was obtained.
  • the relevant quality parameter measurements of the crystallized D-tagatose comparative product prepared in the comparative example are detailed in Table 1.
  • S2 Centrifuge the crystallized D-tagatose massecuite obtained in S1 for 15 minutes at 3000 rpm for solid-liquid separation to obtain crude crystallized D-tagatose.
  • Detector Differential refractive index detector.
  • the microscopic picture and particle size distribution of the crystallized D-tagatose prepared in Example 1 are shown in Figure 2.
  • the results show that the particle size range of the crystallized D-tagatose prepared in Example 1 is 250-859 ⁇ m.
  • the aspect ratio is finally calculated to be 1.3 (as shown in the table shown in 1).
  • the crystallographic parameters of the obtained crystallized D-tagatose were determined: the single crystal structure of D-tagatose was measured at 190K (relying on liquid nitrogen to maintain low temperature) using Mo-K ⁇ radiation on a Rigaku Saturn 70 CCD diffractometer. and graphite monochromator for analysis. Integration and scaling of intensity data are achieved through the SAINT program. These structures were solved directly with SHELXS-97 and refined with the full matrix least squares method of SHELXL-2014. Non-hydrogen atoms are refined anisotropically. Hydrogen atoms are placed in calculated positions and refined through isotropy.
  • S2' Separate the massecuite of crystallized D-tagatose obtained in S1' through solid-liquid separation by suction filtration to obtain crude crystallized D-tagatose primary crystallization and mother liquor after primary crystallization, and recover the mother liquor.
  • Example 2 Using the same HPLC analysis conditions as in Example 1, the purity of the prepared primary crystallized crystallized D-tagatose and secondary crystallized crystallized D-tagatose was measured. The results showed that the primary crystallized D-tagatose prepared in Example 2 The purity of the crystallized D-tagatose was 99.8%; the purity of the secondary crystallized D-tagatose was 99.1%.
  • the microscope picture and particle size distribution of the crystallized D-tagatose prepared in Example 2 are shown in Figure 3.
  • the results show that the particle size range of the primary crystallized D-tagatose prepared in Example 2 is 200-760 ⁇ m.
  • the aspect ratio is finally calculated to be 1.6.
  • the secondary crystallized crystallized D-tagatose has a particle size range of 170-700 ⁇ m.
  • the long diameter and short diameter of the D-tagatose crystal were measured using a microscope, and the aspect ratio was finally calculated to be 1.5 (as shown in Table 1).
  • S2 Centrifuge the crystallized D-tagatose massecuite obtained in S1 for 15 minutes at 3000 rpm for solid-liquid separation to obtain crude crystallized D-tagatose.
  • the purity of the prepared crystalline D-tagatose was measured using the same analysis method as in Example 1. The results showed that the purity of the crystalline D-tagatose prepared in Example 3 was 99.4%.
  • the microscopic picture and particle size distribution of the crystallized D-tagatose prepared in Example 3 are shown in Figure 4.
  • the results show that the particle size range of the crystallized D-tagatose prepared in Example 3 is 180-770 ⁇ m.
  • the aspect ratio is finally calculated to be 1.5 (as shown in the table shown in 1).
  • S5" The massecuite of crystallized D-tagatose obtained in S4" is separated into solid and liquid by suction filtration to obtain the crude secondary crystallization of crystallized D-tagatose and the mother liquor after secondary crystallization, and use rotation The evaporator recovers the ethanol in the mother liquor.
  • Example 4 Using the same HPLC analysis conditions as in Example 1, the prepared primary crystallized crystallized D-tagatose and secondary crystallized crystallized The purity of D-tagatose was measured, and the results showed that the purity of the primary crystallized crystallized D-tagatose prepared in Example 4 was 99.8%, and the purity of the secondary crystallized crystallized D-tagatose was 99.3%.
  • the microscopic picture and particle size distribution of the crystallized D-tagatose prepared in Example 4 are shown in Figure 5.
  • the results show that the particle size range of the primary crystallized D-tagatose prepared in Example 4 is 200-790 ⁇ m.
  • the aspect ratio is finally calculated to be 1.4.
  • the particle size range of the secondary crystallized D-tagatose is 250-750 ⁇ m.
  • the aspect ratio is finally calculated to be 1.5 (as shown in Table 1) .
  • the purity of the prepared primary crystallized crystalline D-tagatose was measured using the same HPLC analysis conditions as in Example 1. The results showed that the purity of the primary crystallized crystalline D-tagatose prepared in Example 5 was 98.2%.
  • the microscopic picture and particle size distribution of the primary crystallized crystallized D-tagatose prepared in Example 5 are shown in Figures 6A and 6B.
  • the results show that the particle size range of the primary crystallized D-tagatose prepared in Example 5 is 20-860 ⁇ m.
  • the aspect ratio is finally calculated to be 2.1.
  • Experimental results show that the primary crystallization crystals prepared in Example 5 are easy to aggregate, the particle size distribution is uneven, and many broken crystals appear. This shows that other components besides D-tagatose act as impurities that interfere with the growth of crystallized D-tagatose.
  • the purity of the prepared recrystallized crystalline D-tagatose was measured using the same HPLC analysis conditions as in Example 1. The results showed that the purity of the recrystallized crystalline D-tagatose prepared in Example 5 was 99.5 %.
  • the microscopic images and particle size distribution of the recrystallized crystalline D-tagatose prepared in Example 5 are shown in Figures 6C and 6D.
  • the results show that, The particle size range of the recrystallized D-tagatose prepared in Example 5 is 200-850 ⁇ m.
  • the aspect ratio is finally calculated to be 1.4 (as shown in Table 1 shown).
  • S1' Perform separation steps such as decolorization, desalting, and chromatographic separation on the reaction solution of the enzymatic hydrolysis of starch to obtain a D-tagatose solution with a purity of 97%, and then concentrate it into a saturated D-tagatose solution at 60°C.
  • a stirring speed of 200 rpm add D-tagatose seed crystals to the saturated solution (the amount added is 8% of the mass of D-tagatose in the saturated solution, the seed size is 100-120 ⁇ m), grow the crystals for 3 hours, and then Cool to 20°C at a cooling rate of 1.0°C/h to obtain crystallized D-tagatose massecuite.
  • S2' Perform solid-liquid separation of the crystallized D-tagatose massecuite obtained in S1' by suction filtration to obtain the primary crystallized product of crystallized D-tagatose and the mother liquor after primary crystallization, and recover the mother liquor. .
  • the mother liquor after primary crystallization is subjected to secondary crystallization.
  • Example 6 Using the same HPLC analysis conditions as in Example 1, the purity of the prepared primary crystallized and secondary crystallized D-tagatose was measured. The results showed that the primary crystallized crystallized D-tagatose prepared in Example 6 The purity is 99.6%; the purity of the secondary crystallized D-tagatose is 98.0%.
  • the microscopic images and particle size distribution of the primary crystallized and secondary crystallized D-tagatose prepared in Example 6 are shown in Figures 7A, 7B, 7C and 7D.
  • the results show that the particle size range of the primary crystallized D-tagatose prepared in Example 6 is 130-586 ⁇ m.
  • the aspect ratio is finally calculated to be 1.7.
  • the particle size range of the secondary crystallized D-tagatose is 8-290 ⁇ m.
  • the aspect ratio is finally calculated to be 2.3 (as shown in Table 1) .
  • S6' Dissolve the once-crystallized crystallized D-tagatose obtained in S5' at 60°C and concentrate it into a solution with a sugar content of 60%; then slowly cool the above solution to 30°C and stabilize it for 30 minutes.
  • S7' Perform solid-liquid separation of the crystalline D-tagatose massecuite obtained in S5' by suction filtration to obtain crystallized D-tagatose recondensation. Crystallize the crude product and the recrystallized mother liquor, and use a rotary evaporator to recover the ethanol in the mother liquor.
  • the purity of the prepared recrystallized crystalline D-tagatose was measured using the same HPLC analysis conditions as in Example 1. The results showed that the purity of the recrystallized crystalline D-tagatose prepared in Example 6 was 99.6 %.
  • the specific measurement method is as follows: D-tagatose naturally falls from a funnel at a certain height to a horizontal plate until no more crystals flow out of the funnel, and then the angle between the inclined surface of the crystal and the horizontal plate is measured, which is the rest. horn.
  • the specific measurement method is as follows: Accurately weigh 2g of D-tagatose sample on an analytical balance, then add it to a 5mL graduated cylinder, fix the graduated cylinder to the tap density meter and vibrate for 10 minutes, and then read the volume after vibration.
  • the sample mass is equal to The ratio of volumes is the bulk density.
  • the bulk densities of commercially available D-tagatose products, crystallized D-tagatose prepared in comparative examples, and crystallized D-tagatose prepared in Examples 1-5 are as shown in Table 1.
  • Experimental results show that the crystallized D-tagatose prepared in Examples 1-6 has a higher bulk density than the crystallized D-tagatose prepared by commercial products and comparative examples (such as the crystallized D-tagatose prepared in Example 1
  • the bulk density of D-tagatose is 1.5 times that of commercially available D-tagatose products), indicating that the crystallized D-tagatose prepared in Examples 1-6 has better fluidity than the commercially available product.
  • the higher bulk density reduces the cracking of crystalline particles during the drying and transfer processes of the crystallized D-tagatose prepared in Examples 1-6, which is beneficial to improving the operating environment during the preparation of crystallized D-tagatose.
  • the specific measurement method is as follows: accurately weigh 5g of the sample with an analytical balance and spread it flat in a glass dish. Weigh the sample and glass dish as a whole on an electronic balance. Gently shake the glass dish to make the sample evenly distributed and in continuous contact without overlapping. Then put it into a constant temperature and humidity box, set the temperature to 25°C, and the humidity to about 60%-30%. Cycle it every 6 hours and repeat the cycle 5 times. After the cycle is completed, pick out the agglomerated samples and weigh them. The mass ratio of the agglomerated sample to the initial sample is the agglomeration rate.
  • the crystallized D-tagatose of the present invention has a more uniform particle size distribution.
  • the crystallized D-tagatose of the present invention has the characteristics of being difficult to agglomerate or agglomerate and having good fluidity.
  • the tagatose product of the present invention has a more excellent product morphology, better fluidity and less agglomeration properties, which is conducive to improving the quality of D-tagatose products. quality.

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Abstract

本发明属于晶体产品技术领域，涉及一种高纯度结晶D-塔格糖，包含其的组合物，以及制备方法和用途。具体而言，本发明的结晶D-塔格糖的纯度在98％以上，粒度在150μm以上，纵横比为1.0～4.0，休止角在40°以下，堆密度在0.7g/mL以上，相比于市售产品具有更加优异的产品形貌、更好的流动性和不易结块的性能，有利于降低储存和运输成本。另外，本发明的结晶D-塔格糖制备方法可以自由调控产品的粒度，无需使用成本高昂的设备，易于结晶D-塔格糖的工业化生产。

Description

高纯度结晶D-塔格糖，包含其的组合物，以及制备方法和用途
本申请要求于2022年03月18日提交的申请号为202210273074.7、发明名称为“高纯度结晶D-塔格糖，包含其的组合物，以及制备方法和用途”的中国专利申请的优先权，在此通过引用将其全文并入本文。
技术领域
本发明属于晶体产品技术领域，具体涉及一种纯度高、以结晶形式存在的D-塔格糖，包含该D-塔格糖的组合物，以及相应的制备方法和用途。
背景技术
D-塔格糖(D-Tagatose)是一种六碳酮糖，分子式为C6H12O6，既是D-果糖的差向异构体，也是D-半乳糖(醛糖)的酮糖异构体。其为天然存在的一种稀有单糖，主要存在于酸乳、奶粉等乳制品中。其甜味特性与蔗糖相似，而产生的热量只有蔗糖的三分之一，所以被称之为低热量甜味剂。D-塔格糖在2001年被美国食品药品监督管理局(FDA)正式批准为普遍公认安全食品(GRAS)，2005年被欧盟批准在欧洲上市。D-塔格糖具有低热量值、零血糖生成指数、血糖钝化作用、无龋齿性、益生元作用和抗氧化活性等重要功能，已广泛用于食品、饮料、护齿产品等领域。
目前，塔格糖的生产主要有化学合成和生物转化两类方法，其中生物转化法是目前D-塔格糖的主要生产方法。然而，通过该方法制得的产品无法避免目前市售D-塔格糖产品普遍存在的问题，诸如产品形状不规则、粒度分布不均匀、流动性差、易结块等，严重影响了产品的质量。因此，亟需开发适用于工业化生产的高品质结晶D-塔格糖产品及其制备方法。
发明内容
发明要解决的问题
本发明的发明人在对D-塔格糖的结晶进行研究时发现，D-塔格糖的现有结晶条件复杂，料液粘稠，结晶困难。当结晶过程中体系粘度大或过饱和度低时，D-塔格糖晶体生长缓慢，主要表现为待结晶的溶质由溶液主体缓慢扩散到晶体表面，延缓了晶体的生长。而在结晶过程中，晶体生长速度缓慢，消耗不掉所产生的过饱和度，就会出现过饱和度的累积，导致爆发成核，产生大量细晶。这些细晶易黏附在大晶体表面形成黏晶，影响产品的感光质量与形貌，从而导致了产品形状不规则、光泽欠佳、表面粗糙、产品流动性差等问题。同时，在结晶过程中，由于体系粘度大，也容易造成母液包藏，从而影响产品的纯度与色泽。
为了改善D-塔格糖产品的质量，获得高品质的D-塔格糖晶体，发明人对D-塔格糖的结晶进行了研究，完成了本发明，并提供了一种适合工业化生产，且所得结晶颗粒大、结构完整、流动性好、不易结块、纯度高的结晶D-塔格糖，包含该结晶D-塔格糖的组合物，以及用于制备该结晶D-塔格糖的方法和实际用途。
用于解决问题的方案
第一方面，本发明提供了一种结晶D-塔格糖，其休止角在40°以下，优选在37°以下，更优选在35°以下。
优选地，所述结晶D-塔格糖的纯度在98％以上，优选在98.5％以上，更优选在99％以上。
优选地，所述结晶D-塔格糖的粒度在150μm以上，优选在200μm以上，更优选在250μm以上。
优选地，所述结晶D-塔格糖的纵横比为1.0～4.0，优选1.2～2.0，更优选1.3～1.6。
优选地，所述结晶D-塔格糖的堆密度在0.7g/mL以上，优选在0.75g/mL以上，更优选在0.85g/mL以上。
第二方面，本发明提供了第一方面中结晶D-塔格糖的制备方法，其包括如下步骤：
1)将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，析晶，得到结晶D-塔格糖的糖膏；
2)将步骤1)中所述结晶D-塔格糖的糖膏进行固液分离，得到结晶D-塔格糖粗品；
3)将步骤2)中所述结晶D-塔格糖粗品干燥，得到结晶D-塔格糖。
优选地，步骤1)中所述含有D-塔格糖的溶液的纯度为80wt％以上，优选85wt％以上，更优选90wt％以上。
优选地，步骤1)中所述D-塔格糖饱和溶液为40℃～70℃下的饱和溶液，优选为50℃～65℃下的饱和溶液，更优选为58℃～62℃下的饱和溶液。
优选地，步骤1)中所述析晶选自如下方法中的至少一种：降温析晶、蒸发析晶和反溶剂析晶。
当所述析晶包括降温析晶时，所述降温为线性降温或分段降温。优选地，所述线性降温包括一个降温阶段，其中：起始温度为58℃～62℃，终止温度为20℃以下，降温速度为0.5～2.0℃/h，优选0.7～1.0℃/h。或者，优选地，所述分段降温包括三个降温阶段，其中：第一降温阶段的起始温度为58℃～62℃，终止温度为54℃～58℃；第二降温阶段的起始温度为54℃～58℃，终止温度为48℃～52℃；第三降温阶段的起始温度为48℃～52℃，终止温度为25℃～35℃；每个所述降温阶段的降温速度各自独立地为0.35～0.70℃/h，优选0.42～0.65℃/h，更优选0.55～0.60℃/h；更优选地，每个所述降温阶段还各自独立地包括在各自终止温度下的恒温处理，其中，每个所述恒温处理的时间各自独立地为90～150min，优选90～120min。
当所述析晶包括蒸发析晶时，所述蒸发为真空蒸发。优选地，所述真空蒸发的真空度为0.02～0.1MPa，优选0.03～0.05MPa，时间为9～35h，优选15～30h。
当所述析晶包括反溶剂析晶时，所述反溶剂为有机溶剂，优选醇类溶剂，更优选C1-C4脂肪醇类溶剂。优选地，所述反溶剂的体积占将其加入后体系总体积的80％以上。优选地，所述反溶剂的添加速度为0.1～0.3mL/min。
进一步地，在步骤1)中析晶之前还包括如下步骤：向所述D-塔格糖饱和溶液中加入D-塔格糖晶种。
优选地，所述D-塔格糖晶种的添加量为所述D-塔格糖饱和溶液中D-塔格糖质量的5％～15％，优选8％～15％，更优选10％～15％。
优选地，所述D-塔格糖晶种的尺寸为100～300μm，优选100～200μm，更优选150～200μm。
更进一步地，在步骤1)中加入D-塔格糖晶种之后还包括养晶步骤。
优选地，所述养晶的时间为1～5h，优选1～4h，更优选2～3h。
优选地，步骤1)中的每个步骤各自独立地任选在搅拌条件下进行。
更优选地，所述搅拌的速度为100～500rpm，优选200～300rpm。
优选地，步骤2)中所述固液分离选自如下方法中的至少一种：离心和过滤。
当所述固液分离为离心时，所述离心的转速为2000～4000rpm，优选3000rpm，时间为10～30min，优选15min。
当所述固液分离为过滤时，所述过滤为抽滤。
优选地，步骤3)中所述干燥选自如下方法中的任意一种：流化床干燥、鼓风干燥和真空干燥。更优选地，所述干燥的温度为40℃～55℃，时间为12～24h。
进一步地，本发明的制备方法还包括如下步骤：按照步骤1)和2)重复至少一次，每次将前次步骤2)中所述固液分离得到的液体进行二次结晶。
优选地，每次步骤1)中所述析晶彼此相同或不同。
优选地，每次步骤2)中所述固液分离彼此相同或不同。
优选地，每次得到的所述结晶D-塔格糖粗品单独或合并干燥。
进一步地，本发明的制备方法还包括如下步骤：
4)将步骤3)中所述结晶D-塔格糖进行重结晶、固液分离和干燥。
优选地，步骤4)中所述重结晶选自如下方法中的至少一种：降温析晶和反溶剂析晶。
当所述重结晶包括降温析晶时，所述降温为线性降温。优选地，所述线性降温包括一个降温阶段，其中：起始温度为58℃～62℃，终止温度为20℃以下，降温速度为0.7～1.0℃/h。
当所述重结晶包括反溶剂析晶时，所述反溶剂为有机溶剂，优选醇类溶剂，更优选C1-C4脂肪醇类溶剂。优选地，所述反溶剂的体积占将其加入后体系总体积的80％以上。优选地，所述反溶剂的滴加速度为0.1～0.3mL/min。
优选地，步骤4)中所述固液分离为过滤，优选抽滤。
优选地，步骤4)中所述干燥为真空干燥，优选在40℃～55℃真空干燥12～24h。
更进一步地，步骤4)还包括在所述重结晶之前的加入D-塔格糖晶种步骤。
优选地，所述D-塔格糖晶种的添加量为重结晶体系中D-塔格糖质量的7％～15％。
优选地，所述D-塔格糖晶种的尺寸为100～150μm。
第三方面，本发明提供了一种组合物，其包含第一方面中的结晶D-塔格糖。
优选地，所述组合物还包含至少一种食品学、化妆品学和/或药学上可接受的辅料。
第四方面，本发明提供了第一方面中的结晶D-塔格糖和第三方面中的组合物在制备食品、化妆品和/或药品中的用途。
发明的效果
本发明的结晶D-塔格糖具有块状晶习，且具有矩形六面体或与之接近的结构。由于本发明的结晶结构属于正交晶系，所以结晶的均匀性和坚固性增加。通过对休止角、堆密度以及结块率的检测， 发现本发明的结晶D-塔格糖具有不易凝聚或结块和流动性好的特点。另外，从粒度分布结果来看，本发明的结晶D-塔格糖粒度分布更加均匀。因此，相比于市售D-塔格糖产品，本发明的结晶D-塔格糖具有更加优异的产品形貌、更好的流动性和不易结块的性能，有利于提升D-塔格糖产品的品质。
由于本发明的结晶D-塔格糖更均匀，结晶的强度增加，流动性能增加，一方面降低了离心分离晶体时与母液一起损失的结晶D-塔格糖的量，另一方面减少了在干燥及转移过程中结晶粒子的破裂(结晶粒子破裂后可能会被微粉化，并且可能相对容易溶解，从而对最终产品质量产生负面影响)。同时，本发明的结晶D-塔格糖比市售D-塔格糖产品具有更高的流动性，并且由于结块少且容易分散和处理，使得其更容易储存，从而降低结晶D-塔格糖的储存和运输成本。因此，本发明的结晶D-塔格糖更适用于大规模生产。
利用本发明的结晶方法可以自由调控结晶D-塔格糖产品的粒度，以获得具有更加优异的产品形貌、更好流动性和不易结块性能的结晶D-塔格糖产品；并且这些方法在工业上都能够很容易的实现，因此更有利于结晶D-塔格糖的工业化生产。
附图说明
图1：A为市售D-塔格糖产品的光学显微镜照片，标尺为200μm；B为市售D-塔格糖产品的粒度分布结果。
图2：A为实施例1所制备的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例1所制备的结晶D-塔格糖的粒度分布结果。
图3：A为实施例2所制备的一次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例2所制备的一次结晶的结晶D-塔格糖的粒度分布结果；C为实施例2所制备的二次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；D为实施例2所制备的二次结晶的结晶D-塔格糖的粒度分布结果。
图4：A为实施例3获得的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例3获得的结晶D-塔格糖的粒度分布结果。
图5：A为实施例4所制备的一次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例4所制备的一次结晶的结晶D-塔格糖的粒度分布结果；C为实施例4二次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；D为实施例4二次结晶的结晶D-塔格糖的粒度分布结果。
图6：A为实施例5所制备的一次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例5所制备的一次结晶的结晶D-塔格糖的粒度分布结果；C为实施例5所制备的重结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；D为实施例5所制备的重结晶的结晶D-塔格糖的粒度分布结果。
图7：A为实施例6所制备的一次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；B为实施例6所制备的一次结晶的结晶D-塔格糖的粒度分布结果；C为实施例6所制备的二次结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；D为实施例6所制备的二次结晶的结晶D-塔格糖的粒度分布结果；E为实施例6所制备的重结晶的结晶D-塔格糖的光学显微镜照片，标尺为200μm；F为实施例6所制备的重结晶的结晶D-塔格糖的粒度分布结果。
具体实施方式
术语定义
除非另有说明，本发明中的术语“D-塔格糖”是指一种具有还原性的、低热量含量的单糖，具有C6H12O6的分子式和如下的结构式。除了Fischer式链状结构，包括α型和β型的Haworth式六元环状结构也涵盖在D-塔格糖的范围内。
除非另有说明，本发明中的术语“结晶D-塔格糖”是指D-塔格糖溶液的结晶产物或处于晶态(或晶体)形式的D-塔格糖，其中D-塔格糖分子以有规律的重复结构排列，而非没有重复结构的无定形固体块状物。
除非另有说明，本发明对术语“含有D-塔格糖的溶液”是没有限制的，其可以为任何溶液(例如水溶液、醇水溶液、腈水溶液等)，只要D-塔格糖可以溶解或分散在其中。例如，含有D-塔格糖的溶液的溶质(D-塔格糖)含量可以达到80％(w/w)以上，85％(w/w)以上，90％(w/w)以上，91％(w/w)以上，92％(w/w)以上，93％(w/w)以上，94％(w/w)以上，95％(w/w)以上，96％(w/w)以上，97％(w/w)以上，98％(w/w)以上或99％(w/w)以上，但本发明不限于此。
除非另有说明，本发明对术语“D-塔格糖饱和溶液”是指作为溶质的D-塔格糖在一定温度下无法在一定量溶剂中继续溶解时所得的溶液。
除非另有说明，本发明中的术语“D-塔格糖晶种”是指主要由D-塔格糖组成的细小晶体，晶种的尺寸可以达到300μm以下。
除非另有说明，本发明中的术语“培养晶体”是指在一定条件下促进可结晶物质从其过饱和溶剂中析出并形成晶体的工艺或方法。
除非另有说明，本发明中的术语“纯度”是指以含量百分比表示的物质(例如本发明中的结晶D-塔格糖)的纯度情况，可以通过例如X射线粉末衍射(XRPD)分析、差示扫描量热(DSC)分析、红外光谱(IR)分析、高效液相色谱(HPLC)分析、液相色谱/质谱联用(LC/MS)分析等方法获得，具体的纯度可以通过HPLC色谱法测定。
除非另有说明，本发明中的术语“粒度”或“粒径”是指以颗粒形式存在的物质(例如本发明中的结晶塔格糖)的尺寸情况，通常球体颗粒的粒度用直径表示，立方体颗粒的粒度用边长表示，不规则颗粒的粒度可将与该颗粒有相同行为的某一球体直径作为该颗粒的等效直径，具体的粒度可以通过粒度分析仪、光学显微镜(OM)或扫描电子显微镜(SEM)测定。
除非另有说明，本发明中的术语“休止角”或“安息角”是指在重力场中，由颗粒状物质(例如本发明中的结晶塔格糖)形成的粉料堆积体的自由表面处于平衡的极限状态时自由表面与水平面之间的 角度。休止角越小，表示粉料流动性越好。测定休止角的方法有两种：注入法及排出法。
除非另有说明，本发明中的术语“纵横比”是指颗粒状物质(例如本发明中的结晶D-塔格糖)的长直径与短直径之间的长度比，纵横比可以大致反映颗粒状物质的外部形态。纵横比的测定可以利用光学显微镜测量D-塔格糖晶体的长直径与短直径，再计算其比值。
除非另有说明，本发明中的术语“堆密度”是指将由颗粒状物质(例如本发明中的结晶D-塔格糖)形成的粉料装入容器中所测得的粉料质量与其所占容器容积(例如经过振实后的实际体积)的比值。堆密度越大，表示粉料流动性越好。具体的堆密度可以通过粉体振实密度仪测定。
结晶D-塔格糖
本发明的结晶D-塔格糖可以通过X射线单晶衍射的方式获得晶系、空间群、晶胞参数、单胞分子数等参数结果。上述方法可以采用本领域常规操作中的参数设置，并且可以根据待测物质的具体理化性质酌情调整或变化。
本发明的结晶D-塔格糖的晶体学参数如下：
晶系：正交晶系；
空间群：P212121；
晶胞参数：α＝β＝γ＝90°；
单胞分子数：Z＝4。
在一项实施方案中，本发明的结晶D-塔格糖的休止角(例如，通过漏斗排出法测得)可以达到40°以下，例如40°、38°、36°、34°或其他任一角度。
在一项优选的实施方案中，上述休止角可以达到37°以下，例如37°、36°、35°、34°或其他任一角度。
在一项更优选的实施方案中，上述休止角可以达到35°以下，例如35°、34°、33°、31°或其他任一角度。
在一项实施方案中，本发明的结晶D-塔格糖的纯度(例如，通过HPLC测得)可以达到98％以上，例如98.0％、98.5％、99.0％、99.5％或其他任一纯度。
在一项优选的实施方案中，上述纯度可以达到98.5％以上，例如98.5％、98.8％、99.0％、99.5％或其他任一纯度。
在一项更优选的实施方案中，上述纯度可以达到99％以上，例如99.0％、99.2％、99.5％、99.8％或其他任一纯度。
在一项实施方案中，本发明的结晶D-塔格糖的粒度(例如，通过SEM测得)可以达到150μm以上，例如150～1200μm中的任一粒度。
在一项优选的实施方案中，上述粒度可以达到200μm以上，例如200～1000μm中的任一粒度。
在一项更优选的实施方案中，上述粒度可以达到250μm以上，例如250～800μm(尤其是300～700μm)中的任一粒度。
在一项实施方案中，本发明的结晶D-塔格糖具有相对规则的外部形态，其纵横比可以达到1.0～4.0、1.0～3.0、1.0～2.5、1.0～2.4、1.0～2.3、1.0～2.2、1.0～2.1或1.0～2.0，例如1.0、1.2、1.3、1.4、1.5、 1.6、2.0、2.1、2.2、2.3、2.4、2.5、3.0、4.0、5.0或其他任一比值。
在一项优选的实施方案中，上述纵横比可以达到1.2～2.0、1.2～1.9、1.2～1.8、1.2～1.7、1.2～1.6、1.2～1.5、1.2～1.4或1.2～1.3，例如1.2、1.3、1.4、1.5、1.6、2.0或其他任一比值。
在一项更优选的实施方案中，上述纵横比可以达到1.3～1.6、1.3～1.5或1.3～1.4，例如1.3、1.4、1.5、1.6或其他任一比值。
在一项实施方案中，本发明的结晶D-塔格糖的堆密度(例如，通过粉体振实密度仪测得)可以达到0.7g/mL以上，例如0.70、0.71、0.72、0.73、0.74、0.75、0.76、0.80、0.85、0.90g/mL或其他任一密度。
在一项优选的实施方案中，上述堆密度可以达到0.75g/mL以上，例如0.75、0.76、0.80、0.85、0.90g/mL或其他任一密度。
在一项更优选的实施方案中，上述堆密度可以达到0.85g/mL以上，例如0.85、0.86、0.87、0.89、0.90、0.92g/mL或其他任一密度。
结晶D-塔格糖的制备方法
本发明的结晶D-塔格糖的制备方法主要通过析晶、固液分离和干燥等工艺步骤，最终得到相应产品。
在一项实施方案中，本发明的结晶D-塔格糖可以通过如下方法制得，其包括：
1)将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，析晶，得到结晶D-塔格糖的糖膏；
2)将步骤1)中所述结晶D-塔格糖的糖膏进行固液分离，得到结晶D-塔格糖粗品；
3)将步骤2)中所述结晶D-塔格糖粗品干燥，得到结晶D-塔格糖。
在一项优选的实施方案中，在上述方法的步骤1)中，含有D-塔格糖的溶液的纯度可以为80wt％以上，例如80wt％、85wt％、90wt％、91wt％、92wt％、93wt％、94wt％、95wt％、96wt％、97wt％、98wt％、99wt％或其他任一纯度。
在一项更优选的实施方案中，在上述方法的步骤1)中，含有D-塔格糖的溶液的纯度可以为85wt％以上，例如85wt％、90wt％、91wt％、92wt％、93wt％、94wt％、95wt％、96wt％、97wt％、98wt％、99wt％或其他任一纯度。
在一项进一步优选的实施方案中，在上述方法的步骤1)中，含有D-塔格糖的溶液的纯度可以为90wt％以上，例如90wt％、91wt％、92wt％、93wt％、94wt％、95wt％、96wt％、97wt％、98wt％、99wt％或其他任一纯度。
上述纯度可以通过如下分离和/或纯化方法中的至少一种来实现，例如膜分离除杂、活性炭脱色、离子交换脱盐和连续色谱纯化。而上述分离和/或纯化方法可以适用于任何含有D-塔格糖的粗制溶液，例如通过化学法催化反应体系制备得到的D-塔格糖反应料液，或者通过生物法催化反应体系制备得到的塔格糖反应料液(如乳糖酶解异构化反应的反应液、淀粉酶解反应的反应液、纤维素酶解反应的反应液、发酵生产的发酵液等)。
在一项优选的实施方案中，在上述方法的步骤1)中，D-塔格糖饱和溶液可以为40℃～70℃下的饱和溶液，例如40℃、45℃、50℃、55℃、60℃、65℃、70℃或上述范围内的其他任一温度下的饱和 溶液。
在一项更优选的实施方案中，在上述方法的步骤1)中，D-塔格糖饱和溶液可以为50℃～65℃下的饱和溶液，例如50℃、52℃、55℃、58℃、60℃、62℃、65℃或上述范围内的其他任一温度下的饱和溶液。
在一项进一步优选的实施方案中，在上述方法的步骤1)中，D-塔格糖饱和溶液可以为58℃～62℃下的饱和溶液，例如58℃、59℃、60℃、61℃、62℃或上述范围内的其他任一温度下的饱和溶液。
控制D-塔格糖饱和溶液的温度以及在可选的添加晶种和/或养晶过程中保持该温度，会减小结晶初期的过饱和度，进一步避免爆发成核的可能性。
在一项优选的实施方案中，在上述方法的步骤1)中，析晶可以通过降温(冷却)、蒸发(挥发)和/或加入反溶剂等方法来实现。在本发明的制备方法中，上述析晶方法既可以任选一种单独使用(例如，单独使用降温，单独使用蒸发等)，也可以任选两种或多种组合使用(例如，组合使用两种不同的降温程序，组合使用降温和加入反溶剂等)。
在一项更优选的实施方案中，在上述方法的步骤1)中，析晶可以通过降温析晶来实现。
在一项具体的实施方案中，降温析晶可以采用线性降温。整个线性降温过程仅包括一个降温阶段，期间以单一降温速度(例如，0.5～2.0℃/h，优选0.7～1.0℃/h，或上述范围内的其他任一速度，如0.7℃/h、0.8℃/h、0.9℃/h或1.0℃/h)由起始温度(例如，58℃～62℃，或上述范围内的其他任一温度，如58℃、59℃、60℃、61℃或62℃)降至终止温度(例如，20℃以下，如或上述范围内的其他任一温度，如20℃、18℃、15℃、12℃或10℃)。
在一项更具体的实施方案中，降温析晶可以采用线性降温，以0.5～2.0℃/h的降温速度由58℃～62℃降至20℃以下。
在另一项具体的实施方案中，降温析晶可以采用分段降温。整个分段降温过程可以包括两个以上(例如，两个、三个、四个、五个或上述范围内的其他任一个数，优选三个)降温阶段。以包括三个降温阶段的分段降温过程为例，每个降温阶段的降温速度既可以彼此相同，也可以不尽相同，还可以各不相同，上述降温速度可以为0.35～0.70℃/h(例如，0.35℃/h、0.40℃/h、0.46℃/h、0.50℃/h、0.60℃/h、0.70℃/h或上述范围内的其他任一速度)，优选0.42～0.65℃/h(例如，0.42℃/h、0.46℃/h、0.50℃/h、0.60℃/h、0.65℃/h或上述范围内的其他任一速度)，更优选0.55～0.60℃/h(例如，0.55℃/h、0.40℃/h、0.46℃/h、0.50℃/h、0.60℃/h、0.70℃/h或上述范围内的其他任一速度)；第一降温阶段可以由起始温度(例如，58℃～62℃，或上述范围内的其他任一温度，如58℃、59℃、60℃、61℃或62℃)降至第一中间温度(例如，54℃～58℃，或上述范围内的其他任一温度，如54℃、55℃、56℃、57℃或58℃)，第二降温阶段可以由第一中间温度降至第二中间温度(例如，48℃～52℃，如48℃、49℃、50℃、51℃或52℃)，第三降温阶段可以由第二中间温度降至终止温度(例如，25℃～35℃，或上述范围内的其他任一温度，如25℃、28℃、30℃、32℃或35℃)。优选地，每个降温阶段还可以各自独立地包括在各自降温终点处的恒温处理步骤，其中，每个恒温处理步骤的时间可以各自独立地为90～150min(例如90、100、110、120、130、140、150min或上述范围内的其他任一时间)，优选90～120min(例如90、100、110或120min或上述范围内的其他任一时间)。
在另一项更具体的实施方案中，降温析晶可以采用三段降温；在第一降温阶段中，以0.35～0.70℃/h的降温速度由58℃～62℃降至54℃～58℃，随后恒温处理90-150min；在第二降温阶段中，以0.42～0.60℃/h的降温速度由54℃～58℃降至48℃～52℃，随后恒温处理90～150min；在第三降温阶段中，以0.55～0.65℃/h的降温速度由48℃～52℃降至25℃～35℃，随后恒温处理90～150min。
在另一项更优选的实施方案中，在上述方法的步骤1)中，析晶可以通过蒸发析晶来实现。
在一项具体的实施方案中，蒸发析晶可以采用真空蒸发。整个蒸发过程处于一定的真空条件下，适宜的真空度能够调整待蒸发体系中水分的蒸发速度，进而避免产品出现细晶、聚晶，而适宜的蒸发时间能够调整体系内水分的含量高低，进而在保证收率的前提下，避免体系过于粘稠，出现粘晶、聚晶。适宜的真空度可以为0.02～0.1MPa(例如，0.02、0.03、0.05、0.08、0.1MPa或上述范围内的其他任一真空度)，优选0.03～0.05MPa(例如，0.03、0.035、0.04、0.045、0.05MPa或上述范围内的其他任一真空度)。适宜的时间可以为9～35h(例如，9、10、15、20、25、30、35h或上述范围内的其他任一时间)，优选15～30h(例如，15、18、20、22、25、28、30h或上述范围内的其他任一时间)。
在又一项更优选的实施方案中，在上述方法的步骤1)中，析晶可以通过反溶剂析晶来实现。
在一项具体的实施方案中，反溶剂析晶可以采用有机溶剂(例如，醇类、腈类等)作为反溶剂。
在一项更具体的实施方案中，反溶剂析晶可以采用醇类溶剂(例如，脂肪醇、芳香醇等)作为反溶剂。
在一项进一步具体的实施方案中，反溶剂析晶可以采用C1-C4脂肪醇类溶剂(例如，甲醇、乙醇、异丙醇、叔丁醇等)作为反溶剂，优选采用甲醇和/或乙醇作为反溶剂，更优选采用乙醇作为反溶剂。
在一项优选的实施方案中，以体积计，反溶剂的添加量可以占加入后总量的80％以上(例如，80％、85％、90％、95％或上述范围内的其他任一比例)。
在一项优选的实施方案中，反溶剂的添加(例如滴加)速度可以为0.1～0.3mL/min(例如，0.1、0.15、0.2、0.25、0.3mL/min或上述范围内的其他任一速度)。
本发明的制备方法在析晶之前还可以向D-塔格糖饱和溶液中加入D-塔格糖晶种，该晶种可以通过研磨、筛分、润洗(润洗会使晶种表面变得光滑平整，降低粘晶的可能性)、再筛分等步骤制得。
在一项具体的实施方案中，步骤1)可以包括如下步骤：将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，再向D-塔格糖饱和溶液中加入D-塔格糖晶种，然后降温(例如，线性降温、分段降温)析晶，得到结晶D-塔格糖的糖膏。
在另一项具体的实施方案中，步骤1)可以包括如下步骤：将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，再向D-塔格糖饱和溶液中加入D-塔格糖晶种，然后蒸发(例如，真空蒸发)析晶，得到结晶D-塔格糖的糖膏。
在另一项具体的实施方案中，步骤1)可以包括如下步骤：将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，再向D-塔格糖饱和溶液中加入D-塔格糖晶种，然后反溶剂(例如，乙醇)析晶，得到结晶D-塔格糖的糖膏。
足量的晶种能够为析晶体系提供充足的生长面，进而降低出现伪晶和聚晶的可能性。此外，当采用降温方式进行析晶时，加入足量的晶种能够及时消耗降温过程中产生的过饱和度，降低爆发成核 的可能性。在一项优选的实施方案中，D-塔格糖晶种的添加量为D-塔格糖饱和溶液中D-塔格糖质量的5％～15％(例如，5％、8％、10％、12％、14％、15％或上述范围内的其他任一比例)，优选8％～15％(例如，8％、9％、10％、12％、14％、15％或上述范围内的其他任一比例)，更优选10％～15％(例如，10％、11％、12％、13％、14％、15％或上述范围内的其他任一比例)。
在一项优选的实施方案中，D-塔格糖晶种的尺寸可以为100～300μm(例如，100～120μm、100～150μm、120～180μm、150～200μm、200～250μm、250～300μm或上述范围内的其他任一尺寸)。
在一项更优选的实施方案中，D-塔格糖晶种的尺寸可以为100～200μm(例如，100～120μm、100～150μm、120～180μm、150～200μm或上述范围内的其他任一尺寸)。
在一项进一步优选的实施方案中，D-塔格糖晶种的尺寸可以为150～200μm(例如，150～160μm、160～180μm、180～200μm、150～200μm或上述范围内的其他任一尺寸)。
本发明的制备方法在加入D-塔格糖晶种之后、析晶之前还可以养晶。
在一项优选的实施方案中，养晶的时间可以为1～5h(例如，1、1.5、2、2.5、3、3.5、4、4.5、5h或上述范围内的其他任一时间)。
在一项更优选的实施方案中，养晶的时间可以为1～4h(例如，1、1.5、2、2.5、3、3.5、4h或上述范围内的其他任一时间)。
在一项进一步优选的实施方案中，养晶的时间可以为2～3h(例如，2、2.5、3h或上述范围内的其他任一时间)。
在一项优选的实施方案中，步骤1)中的每个步骤可以各自独立地任选在搅拌条件下进行；若在搅拌条件下进行，则搅拌速度可以为100～500rpm(例如，100、200、300、400、500rpm或上述范围内的其他任一速度)，优选200～300rpm(例如，200、220、250、280、300rpm或上述范围内的其他任一速度)。
在一项优选的实施方案中，在上述方法的步骤2)中，固液分离可以通过离心和/或过滤等方法来实现。在本发明的制备方法中，上述固液分离方法既可以单独使用(例如，单独离心、单独过滤等)，也可以组合使用(例如，离心后过滤等)。
在一项更优选的实施方案中，在上述方法的步骤2)中，固液分离可以通过离心来实现。
在一项具体的实施方案中，离心的转速可以为2000～4000rpm(例如，2000、2500、3000、3500、4000rpm或上述范围内的其他任一转速)，时间可以为10～30min(例如，10、15、20、25、30min或上述范围内的其他任一时间)。
在另一项更优选的实施方案中，在上述方法的步骤2)中，固液分离可以通过过滤来实现。
在另一项具体的实施方案中，过滤可以为抽滤。
在一项优选的实施方案中，在上述方法的步骤3)中，干燥可以通过流化床干燥、鼓风干燥或真空干燥等方法来实现。
在一项具体的实施方案中，干燥可以为鼓风干燥。
在另一项具体的实施方案中，干燥可以为真空干燥。
在一项优选的实施方案中，干燥的温度可以为40℃～55℃(例如，40℃、45℃、50℃、55℃或上 述范围内的其他任一温度)，时间为12～24h(例如，12、15、18、24h或上述范围内的其他任一时间)。
本发明还提供了一种基于上述包括步骤1)至3)的基础方法的改进方法。该改进方法可以包括如下步骤：按照基础方法中的步骤1)和2)重复至少一次，每次将前次步骤2)中固液分离得到的液体进行二次结晶。换言之，若以基础方法中的步骤1)和2)记作一个单元，则改进方法可以包括至少两个单元。不同单元的步骤1)中的浓缩、析晶以及任选的加入晶种、养晶等步骤既可以彼此相同，也可以不尽相同，还可以各不相同。类似地，不同单元的步骤2)中的固液分离步骤既可以彼此相同，也可以不尽相同，还可以各不相同。另外，通过不同单元得到的结晶D-塔格糖粗品既可以单独干燥(每次的干燥步骤既可以彼此相同，也可以不尽相同，还可以各不相同)，也可以合并后统一干燥。
在一项具体的实施方案中，改进方案可以包括如下步骤：按照基础方法中的步骤1)和2)重复一次，将前次步骤2)中固液分离得到的液体进行二次结晶，其中：前后两次步骤1)中的析晶步骤相同(例如降温析晶)，前后两次步骤2)中的固液分离步骤相同(例如过滤，尤其是抽滤)，前后两次得到的结晶D-塔格糖粗品单独干燥(例如统一采用真空干燥)。
在另一项具体的实施方案中，改进方案可以包括如下步骤：按照基础方法中的步骤1)和2)重复一次，将前次步骤2)中固液分离得到的液体进行二次结晶，其中：前后两次步骤1)中的析晶步骤不同(例如降温析晶和反溶剂析晶)，前后两次步骤2)中的固液分离步骤相同(例如过滤，尤其是抽滤)，前后两次得到的结晶D-塔格糖粗品单独干燥(例如分别采用鼓风干燥和真空干燥)。
本发明还提供了另一种基于上述包括步骤1)至3)的基础方法的改进方法。该改进方法可以包括如下步骤：4)将步骤3)中结晶D-塔格糖进行重结晶、固液分离和干燥。
在一项优选的实施方案中，步骤4)中的重结晶可以通过降温(例如线性降温)和/或加入反溶剂(例如有机溶剂，优选醇类溶剂，更优选C1-C4脂肪醇类溶剂，进一步优选乙醇)等方法来实现。在本发明的改进方法中，上述重结晶方法既可以单独使用(例如，单独加入反溶剂)，也可以组合使用(例如，降温后加入反溶剂)。上述降温和加入反溶剂的具体工艺参数与基础方法相同或类似。
在一项优选的实施方案中，步骤4)中的固液分离可以通过过滤(例如抽滤)等方法来实现。上述过滤的具体工艺参数与基础方法相同或类似。
在一项优选的实施方案中，步骤4)中的干燥可以通过真空干燥等方法来实现。上述真空干燥的具体工艺参数与基础方法相同或类似。
在一项更优选的实施方案中，步骤4)还可以包括在重结晶之前加入D-塔格糖晶种。上述加入晶种的具体工艺参数与基础方法相同或类似。
在本发明中，至于采用基础方法还是改进方法来制备结晶D-塔格糖，通常取决于作为原料的含有D-塔格糖的溶液以及最终得到的结晶D-塔格糖是否满足相应的要求，并且可以根据实际情况进行选择和调整。
组合物
本发明的结晶D-塔格糖可以存在于食品组合物、化妆品组合物和/或药物组合物中加以施用。除非另有说明，本发明中的术语“组合物”是指由两种或两种以上组分(或成分)组成的混合物，其中包含主要成分(例如本发明的结晶D-塔格糖)以及一种或多种辅料(或次要成分)，这些辅料可以是食 品学、化妆品学和/或药学上可接受的品类。例如，术语“药学上可接受的辅料”是指与药物活性成分相容并且对受试者无害的药用辅料，包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。
在一项实施方案中，本发明的组合物可以包含本发明的结晶D-塔格糖。
在一项优选的实施方案中，除了本发明的结晶D-塔格糖以外，本发明的组合物还可以包含至少一种食品学、化妆品学和/或药学上可接受的辅料。
在一项更优选的实施方案中，本发明的组合物可以是一种食品组合物，其可以包含本发明的结晶D-塔格糖，优选还可以包含至少一种食品学上可接受的辅料。
在另一项更优选的实施方案中，本发明的组合物可以是一种化妆品组合物，其可以包含本发明的结晶D-塔格糖，优选还可以包含至少一种化妆品学上可接受的辅料。
在又一项更优选的实施方案中，本发明的组合物可以是一种药物组合物，其可以包含本发明的结晶D-塔格糖，优选还可以包含至少一种药学上可接受的辅料。
用途
无论是本发明的结晶D-塔格糖，还是本发明的组合物，都能够用于制备适于特定场景使用的产品，例如食品、化妆品、药品等。因此，本发明还提供了本发明的结晶D-塔格糖和组合物在制备食品、化妆品和/或药品中的用途。
为了进一步阐述本发明所采取的技术手段及其效果，以下通过具体实施例来说明本发明的技术方案。但应理解，所述实施例仅是范例性的，并不对本发明的范围构成任何限制。还应理解，在不偏离本发明的精神和范围下，可以对本发明技术方案的细节和形式进行修改或替换，但这些修改或替换均落入本发明的保护范围。除非另有限定，下列实施例中使用的药品、试剂、材料、仪器等均可通过常规商业手段获得。
对比例：
按照中国专利申请CN112592378A中实施例1的方法进行结晶D-塔格糖的制备，得到结晶D-塔格糖对比产品。对比例制备的结晶D-塔格糖对比产品的相关品质参数测定详见表1。
实施例1：结晶D-塔格糖的制备
S1：将淀粉酶解反应的反应液进行脱色、脱盐等分离步骤，获得纯度为90％的D-塔格糖溶液，再浓缩成60℃下的D-塔格糖饱和溶液，以200rpm的搅拌速度搅拌，然后向其中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的15％，晶种尺寸为150-200μm)，养晶2h；随后以0.46℃/h的降温速度降温至56℃，并保持120min；再以0.46℃/h的降温速度降温至50℃，并保持120min；随后再以0.6℃/h的降温速度降温至30℃，并保持120min，得到结晶D-塔格糖的糖膏。
S2：将S1中得到的结晶D-塔格糖的糖膏在3000rpm转速下离心15min进行固液分离，即得结晶D-塔格糖粗品。
S3：将S2中得到的结晶D-塔格糖粗品在50℃的鼓风干燥箱中干燥12h，得到结晶D-塔格糖产品(收率为80.98％)。
对所得结晶D-塔格糖的纯度进行HPLC分析，条件如下：
色谱柱：Waters SugarPak1；
流动相：纯水；
流速：0.5mL/min；
柱温：80℃；
检测器：示差折光检测器。
HPLC分析结果为，实施例1所制备的结晶D-塔格糖的纯度为99.2％。
实施例1所制备的结晶D-塔格糖的显微镜图片和粒度分布如图2所示。结果显示，实施例1所制备的结晶D-塔格糖的粒度范围为250-859μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.3(如表1所示)。
对所得结晶D-塔格糖的晶体学参数进行测定：D-塔格糖的单晶体结构是在190K(依靠液氮维持低温)在Rigaku Saturn 70 CCD衍射仪上使用Mo-Kα辐射和石墨单色器进行分析的。强度数据的整合和缩放是通过SAINT程序实现的。这些结构用SHELXS-97直接求解，并用SHELXL-2014的全矩阵最小二乘法进行了精炼。非氢原子采用各向异性的方法进行精炼。氢原子被放置在计算出的位置上，并通过各向同性进行精炼。实施例1所制备的结晶D-塔格糖的晶体学参数如下：晶系：正交晶系；空间群：P212121；晶胞参数：α＝90.000°，β＝90.000°，γ＝90.000°；单胞分子数：Z＝4。另经测定，实施例2-6所制备的结晶D-塔格糖的晶型与实施例1相同。
实施例2：结晶D-塔格糖的制备
S1’：将乳糖酶解异构化反应的反应液进行脱色、脱盐、色谱分离等分离步骤，获得纯度为98％的D-塔格糖溶液，再浓缩成58℃下的D-塔格糖饱和溶液，以200rpm的搅拌速度，向饱和溶液中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的5％，晶种尺寸为100-120μm)，养晶3h，随后以0.7℃/h的降温速度冷却至20℃，得到结晶D-塔格糖的糖膏。
S2’：将S1’中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖一次结晶粗品和一次结晶后的母液，并对母液进行回收。
S3’：将S2’中得到的结晶D-塔格糖一次结晶粗品在40℃的真空干燥器中干燥24h，得到一次结晶的结晶D-塔格糖产品(收率为50.4％)。
S4’：将S2’中回收的母液浓缩成60℃下的D-塔格糖饱和溶液，然后向其中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的7％，晶种尺寸为100-150μm)，用一次结晶相同的方法学参数对回收的母液进行结晶，并经过分离和干燥，得到二次结晶的结晶D-塔格糖产品(收率为44.5％)。
采用与实施例1相同的HPLC分析条件，对所制备的一次结晶的结晶D-塔格糖和二次结晶的结晶D-塔格糖的纯度进行测定，结果显示，实施例2所制备的一次结晶的结晶D-塔格糖的纯度为99.8％；二次结晶的结晶D-塔格糖的纯度为99.1％。
实施例2所制备的结晶D-塔格糖的显微镜图片和粒度分布如图3所示。结果显示，实施例2所制备的一次结晶的结晶D-塔格糖的粒度范围为200-760μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.6；二次结晶的结晶D-塔格糖的粒度范围为170-700μm，通过利用光 学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.5(如表1所示)。
实施例3：结晶D-塔格糖的制备
S1：将纤维素酶解反应的反应液进行脱色、脱盐、色谱分离等分离步骤，获得纯度为96％的D-塔格糖溶液，再浓缩成65℃下的D-塔格糖饱和溶液，搅拌转速稳定在100rpm；将上述饱和溶液缓慢降温至58℃，稳定1h后，加入D-塔格糖晶种(添加量为体系中D-塔格糖质量的10％，晶种尺寸为100-150μm)，养晶3.0h；养晶结束后，开始蒸发操作，这一过程保持真空度为0.03MPa，持续蒸发30h，得到结晶D-塔格糖的糖膏。
S2：将S1中得到的结晶D-塔格糖的糖膏在3000rpm转速下离心15min进行固液分离，即得结晶D-塔格糖粗品。
S3：将S2中得到的结晶D-塔格糖粗品在50℃的鼓风干燥箱中干燥12h，得到结晶D-塔格糖产品(收率为83.99％)。
采用与实施例1相同的分析方法，对所制备的结晶D-塔格糖的纯度进行测定，结果显示，实施例3所制备的结晶D-塔格糖的纯度为99.4％。
实施例3所制备的结晶D-塔格糖的显微镜图片和粒度分布如图4所示。结果显示，实施例3所制备的结晶D-塔格糖的粒度范围为180-770μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.5(如表1所示)。
实施例4结晶D-塔格糖的制备
S1”：将发酵生产获得发酵液进行脱色、脱盐、色谱分离等分离步骤，获得纯度为92％的D-塔格糖溶液，再浓缩成60℃下的D-塔格糖饱和溶液，向其中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的8％，晶种尺寸为120-180μm)，养晶2h；随后以0.6℃/h的降温速度降温至56℃，并保持90min；再以0.5℃/h的降温速度降温至50℃，并保持120min；随后再以0.46℃/h的降温速度降温至30℃，并保持120min，得到结晶D-塔格糖的糖膏。
S2”：将S1”中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖一次结晶粗品和一次结晶后的母液，并对母液进行回收。
S3”：将S2”中得到的结晶D-塔格糖一次结晶粗品在50℃的鼓风干燥箱中干燥12h，得到一次结晶的结晶D-塔格糖产品(收率为52.3％)。
S4”：将S2”中回收的母液在60℃下蒸发浓缩成糖度为63.5％的溶液；将上述溶液缓慢降温至25℃，稳定30min后，以0.2mL/min的滴加速度滴加乙醇(乙醇与原母液的体积比为4:1)，在体系开始溶析的同时加入D-塔格糖晶种(添加量为体系中D-塔格糖质量的10％，晶种尺寸为150-200μm)，设置搅拌转速为300rpm；乙醇滴加完毕后，得到结晶D-塔格糖的糖膏。
S5”：将S4”中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖二次结晶粗品和二次结晶后的母液，并利用旋转蒸发仪将母液中的乙醇回收。
S6”：将S5”中得到的结晶D-塔格糖二次结晶粗品在40℃的真空干燥器中干燥24h，得到二次结晶的结晶D-塔格糖产品(收率为76.5％)。
采用与实施例1相同的HPLC分析条件，对所制备的一次结晶的结晶D-塔格糖和二次结晶的结晶 D-塔格糖的纯度进行测定，结果显示，实施例4所制备的一次结晶的结晶D-塔格糖的纯度为99.8％，二次结晶的结晶D-塔格糖的纯度为99.3％。
实施例4所制备的结晶D-塔格糖的显微镜图片和粒度分布如图5所示。结果显示，实施例4所制备的一次结晶的结晶D-塔格糖的粒度范围为200-790μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.4；二次结晶的结晶D-塔格糖的粒度范围为250-750μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.5(如表1所示)。
实施例5：结晶D-塔格糖的制备
S1”：将淀粉酶解反应的反应液进行脱色、脱盐等分离步骤，获得纯度为85％的D-塔格糖溶液，再浓缩成58℃下的D-塔格糖饱和溶液，以100rpm的搅拌速度，向饱和溶液中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的8％，晶种尺寸为100-150μm)，养晶3h，随后以1℃/h的降温速度冷却至20℃，得到结晶D-塔格糖的糖膏。
S2”：将S1”中得到的结晶D-塔格糖的糖膏在3000rpm转速下离心15min进行固液分离，即得结晶D-塔格糖一次结晶粗品。
S3”：将S2”中得到的结晶D-塔格糖一次结晶粗品在55℃的真空干燥器中干燥12h，得到一次结晶的结晶D-塔格糖产品(收率为38.45％)。
采用与实施例1相同的HPLC分析条件，对所制备的一次结晶的结晶D-塔格糖的纯度进行测定，结果显示，实施例5所制备的一次结晶的结晶D-塔格糖的纯度为98.2％。
实施例5所制备的一次结晶的结晶D-塔格糖的显微镜图片和粒度分布如图6A和6B所示。结果显示，实施例5所制备的一次结晶的结晶D-塔格糖的粒度范围为20-860μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为2.1。实验结果表明，实施例5所制备的一次结晶的晶体易聚集，粒度分布不均匀，会有许多碎晶出现。这表明除了D-塔格糖之外的其他成分作为杂质干扰了结晶D-塔格糖的生长，当使用的D-塔格糖结晶的原料纯度比较低时，会影响结晶D-塔格糖的形貌，粒度分布等，从而影响D-塔格糖产品的品质。
为了进一步改善一次结晶的结晶D-塔格糖的品质，采用乙醇对结晶D-塔格糖进行重结晶。
S4”：将S3”中得到的一次结晶的结晶D-塔格糖在60℃下溶解，并且浓缩成糖度为62％的溶液；接着将上述溶液缓慢降温至20℃，稳定30min后，以0.25mL/min的滴加速度滴加乙醇(乙醇与原母液体积比为6:1)，在体系开始溶析的同时加入D-塔格糖晶种(添加量为体系中D-塔格糖质量的10％，晶种尺寸为100-150μm)，设置搅拌转速为300rpm；乙醇滴加完毕后，得到结晶D-塔格糖的糖膏。
S5”：将S4”中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖重结晶粗品和重结晶后的母液，并利用旋转蒸发仪将母液中的乙醇回收。
S6”：将S5”中得到的结晶D-塔格糖重结晶粗品在40℃的真空干燥器中干燥24h，得到重结晶的结晶D-塔格糖产品(收率为80.95％)。
采用与实施例1相同的HPLC分析条件，对所制备的重结晶的结晶D-塔格糖的纯度进行测定，结果显示，实施例5所制备的重结晶的结晶D-塔格糖纯度为99.5％。
实施例5所制备的重结晶的结晶D-塔格糖的显微镜图片和粒度分布如图6C和6D所示。结果显示， 实施例5所制备的重结晶的D-塔格糖的粒度范围为200-850μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.4(如表1所示)。
实施例6：结晶D-塔格糖的制备
S1’：将淀粉酶解反应的反应液进行脱色、脱盐、色谱分离等分离步骤，获得纯度为97％的D-塔格糖溶液，再浓缩成60℃下的D-塔格糖饱和溶液，以200rpm的搅拌速度，向饱和溶液中加入D-塔格糖晶种(添加量为饱和溶液中D-塔格糖质量的8％，晶种尺寸为100-120μm)，养晶3h，随后以1.0℃/h的降温速度冷却至20℃，得到结晶D-塔格糖的糖膏。
S2’：将S1’中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖一次结晶品和一次结晶后的母液，并对母液进行回收。
S3’：将S2’中得到的结晶D-塔格糖一次结晶品在40℃的真空干燥器中干燥24h，得到一次结晶的结晶D-塔格糖产品(收率为42.5％)。
为了提高结晶的总收率，将一次结晶后的母液进行二次结晶。
S4’：将一次结晶后的母液浓缩成60℃下的D-塔格糖饱和溶液，搅拌转速稳定在100rpm；将上述饱和溶液缓慢降温至58℃，稳定1h后，加入D-塔格糖晶种(添加量为体系中D-塔格糖质量的9％，晶种尺寸为100-150μm)，养晶3.0h；养晶结束后，开始蒸发操作，这一过程保持真空度为0.05MPa，持续蒸发30h，得到结晶D-塔格糖的糖膏。
S5’：将S4’中得到的结晶D-塔格糖的糖膏在3000rpm转速下离心15min进行固液分离，即得二次结晶的结晶D-塔格糖产品(收率为85.21％)。
采用与实施例1相同的HPLC分析条件，对所制备的一次结晶和二次结晶的D-塔格糖的纯度进行测定，结果显示，实施例6所制备的一次结晶的结晶D-塔格糖纯度为99.6％；二次结晶的结晶D-塔格糖纯度为98.0％。
实施例6所制备的一次结晶和二次结晶的结晶D-塔格糖的显微镜图片和粒度分布如图7A、7B、7C和7D所示。结果显示，实施例6所制备的一次结晶的结晶D-塔格糖的粒度范围为130-586μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.7；二次结晶的结晶D-塔格糖的粒度范围为8-290μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为2.3(如表1所示)。实验结果表明，实施例6所制备的二次结晶的晶体细小且易聚集，并且纯度受到了一定程度的影响。这表明除了D-塔格糖之外的其他成分作为杂质干扰了结晶D-塔格糖的生长，当使用的D-塔格糖结晶的原料纯度比较低时，会影响结晶D-塔格糖的形貌、粒度等，从而影响D-塔格糖产品的品质。
为了进一步改善二次结晶的结晶D-塔格糖的品质，采用乙醇对结晶D-塔格糖进行重结晶。
S6’：将S5’中得到的一次结晶的结晶D-塔格糖在60℃下溶解，并且浓缩成糖度为60％的溶液；接着将上述溶液缓慢降温至30℃，稳定30min后，以0.2mL/min的滴加速度滴加乙醇(乙醇与原母液体积比为5:1)，在体系开始溶析的同时加入D-塔格糖晶种(添加量为体系中D-塔格糖质量的11％，晶种尺寸为100-150μm)，设置搅拌转速为200rpm；乙醇滴加完毕后，得到结晶D-塔格糖的糖膏。
S7’：将S5’中得到的结晶D-塔格糖的糖膏以抽滤的方式进行固液分离，得到结晶D-塔格糖重结 晶粗品和重结晶后的母液，并利用旋转蒸发仪将母液中的乙醇回收。
S8’：将S8’中得到的结晶D-塔格糖重结晶粗品在40℃的真空干燥器中干燥24h，得到重结晶的结晶D-塔格糖产品(收率为75.65％)。
采用与实施例1相同的HPLC分析条件，对所制备的重结晶的结晶D-塔格糖的纯度进行测定，结果显示，实施例6所制备的重结晶的结晶D-塔格糖纯度为99.6％。
实施例6所制备的重结晶的结晶D-塔格糖的显微镜图片和粒度分布如图7E和7F所示。结果显示，实施例6所制备的重结晶的D-塔格糖的粒度范围为300-1110μm，通过利用光学显微镜测量D-塔格糖晶体的长直径与短直径，最后计算纵横比为1.4(如表1所示)。
实施例7：休止角的测定
为了分析结晶D-塔格糖的流动性，测定了市售D-塔格糖产品(来源于林路生物科技(黄石)有限公司)、对比例所制备的结晶D-塔格糖和实施例1-6所制备的结晶D-塔格糖的休止角。
具体测定方法如下：将D-塔格糖从一定高度的漏斗中自然下落到水平板上，直到漏斗中不再有晶体流出，随后测量晶体斜面与水平板组成的夹角的角度，即为休止角。
市售D-塔格糖产品、对比例所制备的结晶D-塔格糖和实施例1-6所制备的结晶D-塔格糖的休止角情况如表1所示。实验结果表明，与市售产品和对比例所制备的结晶D-塔格糖相比，实施例1-6所制备的结晶D-塔格糖均具有更小的休止角，因此具有更加优异的流动性。
实施例8：堆密度的测定
对市售D-塔格糖产品(来源于林路生物科技(黄石)有限公司)、对比例所制备的结晶D-塔格糖和实施例1-6所制备的结晶D-塔格糖的堆密度进行测定。
具体测定方法如下：在分析天平中准确称取D-塔格糖样品2g，随后加入到5mL量筒中，将量筒固定到振实密度仪上震动10min，随后读取震动后的体积，样品质量与体积的比值即为堆密度。
市售D-塔格糖产品、对比例所制备的结晶D-塔格糖和实施例1-5所制备的结晶D-塔格糖的堆密度如表1所示。实验结果表明，实施例1-6所制备的结晶D-塔格糖均比市售产品和对比例所制备的结晶D-塔格糖具有更高的堆密度(如实施例1所制备的结晶D-塔格糖的堆密度是市售D-塔格糖产品堆密度的1.5倍)，表明实施例1-6所制备的结晶D-塔格糖比市售产品的流动性更好。较高的堆密度使得实施例1-6所制备的结晶D-塔格糖在干燥及转移过程中结晶粒子的破裂减少，这有利于改善结晶D-塔格糖制备过程中的操作环境。
实施例9：结块率的测定
对市售D-塔格糖产品(来源于林路生物科技(黄石)有限公司)、对比例所制备的结晶D-塔格糖和实施例1-6所制备的结晶D-塔格糖的结块率进行测定。
具体测定方法如下：用分析天平准确称量样品5g，平铺于玻璃皿中。将样品和玻璃皿在电子天平上整体称重。轻轻晃动玻璃皿，使样品分布均匀，呈连续接触无叠层状态。然后放入恒温恒湿箱中，温度设定为25℃，湿度在60％-30％左右，每6h循环一次，反复循环5次，循环完成后，将结块的样品挑出，称重，结块样品与初始样品的质量比即为结块率。
市售D-塔格糖产品、对比例所制备的结晶D-塔格糖和实施例1-6所制备的结晶D-塔格糖的结块 率如表1所示。实验结果表明，实施例1-6所制备的结晶D-塔格糖均比市售产品和对比例所制备的结晶D-塔格糖具有显著降低的结块率(如实施例1所制备的结晶D-塔格糖的结块率仅是市售D-塔格糖产品结块率的0.14倍)，因此实施例1-6所制备的结晶D-塔格糖更不易结块，更便于储存。
表1.不同来源结晶D-塔格糖产品的性质比较
通过以上实验，得出如下结论：
从光学显微镜照片可以发现，市售D-塔格糖产品聚结严重，而实施例1-5所制备的结晶D-塔格糖的产品在外观形貌上具有块状晶习，且具有矩形六面体或与之接近的结构。由于本发明的结晶结构接近于立方晶系，所以结晶的均匀性和坚固性增加。
从粒度分布结果来看，本发明的结晶D-塔格糖粒度分布更加均匀。
通过对休止角、堆密度以及结块率的检测，表明本发明的结晶D-塔格糖具有不易凝聚或结块和流动性好的特点。
因此，相比于市售的塔格糖产品，本发明的塔格糖产品具有更加优异的产品形貌、更好的流动性和不易结块的性能，有利于提升D-塔格糖产品的品质。

Claims (17)

  1. 一种结晶D-塔格糖，其休止角在40°以下，优选在37°以下，更优选在35°以下。
  2. 根据权利要求1所述的结晶D-塔格糖，其特征在于，其纯度在98％以上，优选在98.5％以上，更优选在99％以上。
  3. 根据权利要求1或2所述的结晶D-塔格糖，其特征在于，其粒度在150μm以上，优选在200μm以上，更优选在250μm以上。
  4. 根据权利要求1至3中任一项所述的结晶D-塔格糖，其特征在于，其纵横比为1.0～4.0，优选1.2～2.0，更优选1.3～1.6。
  5. 根据权利要求1至4中任一项所述的结晶D-塔格糖，其特征在于，其堆密度在0.7g/mL以上，优选在0.75g/mL以上，更优选在0.85g/mL以上。
  6. 根据权利要求1至5中任一项所述的结晶D-塔格糖的制备方法，其包括如下步骤：
    1)将含有D-塔格糖的溶液浓缩成D-塔格糖饱和溶液，析晶，得到结晶D-塔格糖的糖膏；
    2)将步骤1)中所述结晶D-塔格糖的糖膏进行固液分离，得到结晶D-塔格糖粗品；
    3)将步骤2)中所述结晶D-塔格糖粗品干燥，得到结晶D-塔格糖。
  7. 根据权利要求6所述的制备方法，其特征在于，
    步骤1)中所述含有D-塔格糖的溶液的纯度为80wt％以上，优选85wt％以上，更优选90wt％以上。
  8. 根据权利要求6或7所述的制备方法，其特征在于，
    步骤1)中所述D-塔格糖饱和溶液为40℃～70℃下的饱和溶液，优选为50℃～65℃下的饱和溶液，更优选为58℃～62℃下的饱和溶液。
  9. 根据权利要求6至8中任一项所述的制备方法，其特征在于，
    步骤1)中所述析晶选自如下方法中的至少一种：降温析晶、蒸发析晶和反溶剂析晶；
    ●当所述析晶包括降温析晶时，所述降温为线性降温或分段降温；
    优选地，所述线性降温包括一个降温阶段，其中：起始温度为58℃～62℃，终止温度为20℃以下，降温速度为0.5～2.0℃/h，优选0.7～1.0℃/h；或者，
    优选地，所述分段降温包括三个降温阶段，其中：第一降温阶段的起始温度为58℃～62℃，终止温度为54℃～58℃；第二降温阶段的起始温度为54℃～58℃，终止温度为48℃～52℃；第三降温阶段的起始温度为48℃～52℃，终止温度为25℃～35℃；每个所述降温阶段的降温速度各自独立地为0.35～0.70℃/h，优选0.42～0.65℃/h，更优选0.55～0.60℃/h；更优选地，每个所述降温阶段还各自独立地包括在各 自终止温度下的恒温处理，其中，每个所述恒温处理的时间各自独立地为90～150min，优选90～120min；
    ●当所述析晶包括蒸发析晶时，所述蒸发为真空蒸发；
    优选地，所述真空蒸发的真空度为0.02～0.1MPa，优选0.03～0.05MPa，时间为9～35h，优选15～30h；
    ●当所述析晶包括反溶剂析晶时，所述反溶剂为有机溶剂，优选醇类溶剂，更优选C1-C4脂肪醇类溶剂；
    优选地，所述反溶剂的体积占将其加入后体系总体积的80％以上；
    优选地，所述反溶剂的添加速度为0.1～0.3mL/min。
  10. 根据权利要求6至9中任一项所述的制备方法，其特征在于，
    在步骤1)中析晶之前还包括如下步骤：向所述D-塔格糖饱和溶液中加入D-塔格糖晶种；
    优选地，所述D-塔格糖晶种的添加量为所述D-塔格糖饱和溶液中D-塔格糖质量的5％～15％，优选8％～15％，更优选10％～15％；
    优选地，所述D-塔格糖晶种的尺寸为100～300μm，优选100～200μm，更优选150～200μm。
  11. 根据权利要求10所述的制备方法，其特征在于，
    在步骤1)中加入D-塔格糖晶种之后还包括养晶步骤；
    优选地，所述养晶的时间为1～5h，优选1～4h，更优选2～3h。
  12. 根据权利要求6至11中任一项所述的制备方法，其特征在于，
    步骤2)中所述固液分离选自如下方法中的至少一种：离心和过滤；
    ●当所述固液分离为离心时，所述离心的转速为2000～4000rpm，优选3000rpm，时间为10～30min，优选15min；
    ●当所述固液分离为过滤时，所述过滤为抽滤。
  13. 根据权利要求6至12中任一项所述的制备方法，其特征在于，
    步骤3)中所述干燥选自如下方法中的任意一种：流化床干燥、鼓风干燥和真空干燥；
    优选地，所述干燥的温度为40℃～55℃，时间为12～24h。
  14. 根据权利要求6至13中任一项所述的制备方法，其特征在于，
    所述制备方法还包括如下步骤：按照步骤1)和2)重复至少一次，每次将前次步骤2)中所述固液分离得到的液体进行二次结晶；
    优选地，按照步骤1)和2)重复一次，将前次步骤2)中所述固液分离得到的液体进行二次结晶。
  15. 根据权利要求6至14中任一项所述的制备方法，其特征在于，
    所述制备方法还包括如下步骤：
    4)将步骤3)中所述结晶D-塔格糖进行重结晶、固液分离和干燥。
  16. 一种组合物，其包含根据权利要求1至5中任一项所述的结晶D-塔格糖，优选还包含至少一种食品学、化妆品学和/或药学上可接受的辅料。
  17. 根据权利要求1至5中任一项所述的结晶D-塔格糖和根据权利要求16所述的组合物在制备食品、化妆品和/或药品中的用途。
PCT/CN2023/082252 2022-03-18 2023-03-17 高纯度结晶d-塔格糖，包含其的组合物，以及制备方法和用途 WO2023174422A1 (zh)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002053588A (ja) * 2000-08-08 2002-02-19 Nippon Shokuhin Kako Co Ltd 結晶タガトースの製造方法
CN102296129A (zh) * 2011-06-16 2011-12-28 禹城绿健生物技术有限公司 一种同时生产乳果糖和塔格糖的工艺
CN102876752A (zh) * 2012-09-07 2013-01-16 山东绿健生物技术有限公司 一种结晶塔格糖的生产方法
CN112592378A (zh) * 2021-03-01 2021-04-02 中国科学院天津工业生物技术研究所 一种制备高纯度结晶塔格糖的方法
CN112708702A (zh) * 2021-02-07 2021-04-27 安徽禾庚生物技术有限公司 一种生产植物源d-塔格糖的方法
CN112778358A (zh) * 2019-11-08 2021-05-11 中国科学院天津工业生物技术研究所 一种体外多酶体系制备的小分子化合物的分离提取方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002053588A (ja) * 2000-08-08 2002-02-19 Nippon Shokuhin Kako Co Ltd 結晶タガトースの製造方法
CN102296129A (zh) * 2011-06-16 2011-12-28 禹城绿健生物技术有限公司 一种同时生产乳果糖和塔格糖的工艺
CN102876752A (zh) * 2012-09-07 2013-01-16 山东绿健生物技术有限公司 一种结晶塔格糖的生产方法
CN112778358A (zh) * 2019-11-08 2021-05-11 中国科学院天津工业生物技术研究所 一种体外多酶体系制备的小分子化合物的分离提取方法
CN112708702A (zh) * 2021-02-07 2021-04-27 安徽禾庚生物技术有限公司 一种生产植物源d-塔格糖的方法
CN112592378A (zh) * 2021-03-01 2021-04-02 中国科学院天津工业生物技术研究所 一种制备高纯度结晶塔格糖的方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
"Key technologies and typical examples of new oligosaccharide production", 30 September 2006, SCIENCE AND TECHNOLOGY LITERATURE PRESS, CN, ISBN: 7-5023-5402-6, article ZHENG, JIANXIAN: "Key Technology of Tagatose Production", pages: 239 - 240, XP009549364 *
DANG, JIANZHANG: "FERMENTATION PROCESS TUTORIAL 2ND EDITION", 31 July 2016, CHINA LIGHT INDUSTRY PRESS, CN, ISBN: 978-7-5184-0892-4, article DANG, JIANZHANG: "3. Crystal growth", pages: 238, XP009549368 *
HUANG WENXIA, MU WANMENG, JIANG BO : "Study on Separation and Purification of D-tagatose", FOOD AND FERMENTATION INDUSTRIES, vol. 34, no. 6, 1 January 2008 (2008-01-01), pages 168 - 171, XP093089913 *
WANG DONGBO, WANG YING, LI YUAN, SHI TING, HAN DANDAN, GONG JUNBO: "Uncovering the role of impurity sugars on the crystallization of d-tagatose crystal: Experiments and molecular dynamics simulations", FOOD CHEMISTRY, ELSEVIER LTD., NL, vol. 397, 1 December 2022 (2022-12-01), NL , pages 133762, XP093089934, ISSN: 0308-8146, DOI: 10.1016/j.foodchem.2022.133762 *
XIN, CHENGFU ET AL.: "The Optimization of Tagatose's Crystallization Conditions", CHINA FOOD ADDITIVES, no. 1, 15 February 2013 (2013-02-15), XP009548598 *

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