WO2022117074A1 - 一种阿洛酮糖结晶的制备方法 - Google Patents

一种阿洛酮糖结晶的制备方法 Download PDF

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WO2022117074A1
WO2022117074A1 PCT/CN2021/135345 CN2021135345W WO2022117074A1 WO 2022117074 A1 WO2022117074 A1 WO 2022117074A1 CN 2021135345 W CN2021135345 W CN 2021135345W WO 2022117074 A1 WO2022117074 A1 WO 2022117074A1
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crystallization
psicose
crystal
cooling
preparation
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PCT/CN2021/135345
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English (en)
French (fr)
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杜倩
张兴晶
刘双双
干昭波
邵先豹
李方华
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山东百龙创园生物科技股份有限公司
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Priority to CA3186770A priority Critical patent/CA3186770C/en
Priority to US18/011,614 priority patent/US11780870B2/en
Priority to EP21900098.1A priority patent/EP4257595A1/en
Publication of WO2022117074A1 publication Critical patent/WO2022117074A1/zh

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    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the application relates to a preparation method of psicose crystals, belonging to the technical field of functional sugar preparation.
  • D-psicose or D-allulose is a six-carbon sugar with very low content in nature, and is an epimer of D-fructose at the C-3 site.
  • D-psicose is difficult to be digested and absorbed, and provides little energy for life activities, so it is a very useful low-calorie sweetener.
  • D-psicose can inhibit fatty liver enzymes and intestinal ⁇ -glucosidase, thereby reducing the accumulation of body fat and inhibiting the rise of blood sugar concentration.
  • the addition of D-psicose to meals reduces postprandial glycemic responses and improves insulin sensitivity and glucose tolerance.
  • D-psicose can scavenge reactive oxygen radicals more effectively.
  • D-psicose was found to prevent bis-(2-ethylhexyl)-phthalic acid-induced damage to the testis by inhibiting the production of reactive oxygen species.
  • D-psicose has neuroprotective effect on 6-hydroxydopamine-induced apoptosis, and can also inhibit the expression of monocyte chemotactic protein MCP-1 induced by high concentration of glucose. This indicates that D-psicose has a potential function in the treatment of nerve tissue degeneration and atherosclerosis and other related diseases.
  • Chinese patent document CN109748940A discloses a method for crystallizing psicose from an ethanol solution, comprising: taking a purified psicose solution and concentrating it under reduced pressure to obtain solution I; heating the concentrated solution I, adding Water ethanol, concentrated under reduced pressure again, so that the ethanol takes away the water in the psicose solution and becomes the ethanol solution II of psicose; add the concentrated solution II with absolute ethanol, heat until the psicose is completely dissolved, slowly Cooling, after precipitating crystals, continue to cool slowly, until the crystals no longer increase, obtain mixed solution III; The mixed solution III is solid-liquid separated to obtain solid IV and clear liquid V; Solid IV is dried under reduced pressure to obtain psicose crystals; The clear liquid V continues to be concentrated, and the above steps are repeated to obtain residual psicose crystals by crystallization.
  • the inventors found that the size distribution of psicose crystals obtained by the existing psicose crystallization technology is wider.
  • the application provides a preparation method of a psicose crystal (crystalline D-psicose), the crystal size distribution of the prepared psicose crystal is narrow, and more than 80% of the crystal size is in the 40-60 mesh range.
  • the inventors of the present application studied the properties of the metastable region of psicose by constructing a psicose metastable region curve.
  • the present application adopts a specific cooling interval and a specific cooling frequency in the cooling crystallization process. Based on this, the psicose crystals prepared by the method of the present application have a narrow size distribution.
  • the present application provides a method for preparing a psicose crystal, which comprises (1) evaporative crystallization, (2) crystallization, and (3) cooling crystallization, to prepare a psicose crystal.
  • the present application provides a method for preparing a psicose crystal, comprising:
  • the evaporative crystallization is when the solid content of the psicose sugar solution is 70-75% (eg, 70%-71%, 71%-72%, 72%-73%, 73%) ⁇ 74% or 74% ⁇ 75%), add crystal seeds for evaporative crystallization.
  • the crystallization is evaporative crystallization while adding water, and the solid content is kept stable during the crystallization. For example, it is stable between 80 and 85%.
  • the cooling crystallization adopts an interval cooling method for crystallization, and the cooling frequency is slow in the early stage and fast in the later stage.
  • the cooling crystallization is carried out by means of sub-interval cooling, and the sub-interval cooling operation is: in the range of 50-41° C., the temperature is lowered by 0.1-0.3° C. per hour; in the range of 41-35° C. Within the temperature range, the temperature is lowered by 0.4-0.6°C per hour; in the cooling range of 35-30°C, the temperature is lowered by 0.9-1.1°C per hour; the crystallization is stopped when the temperature drops to 30°C.
  • the present application provides a method for preparing a psicose crystal, comprising the following steps:
  • Evaporative crystallization provide a psicose sugar solution, the solid content of the psicose sugar solution is 70-75% (for example, 70-71%, 71-72%, 72-73%, 73% -74% or 74-75%), add psicose seed crystals, evaporate and crystallize at 40-50 °C, until the solid content of the psicose sugar solution is 80-85% (80-81%, 81% -82%, 82-83%, 83-84% or 84-85%);
  • cooling crystallization the psicose sugar liquid obtained after the crystallization in step (2) is completed by cooling the crystallization in different intervals, in the interval of 50 ⁇ 41 °C, the temperature is lowered by 0.1 ⁇ 0.3 °C per hour; in the interval of 41 ⁇ 35 °C In the temperature range of 35 to 30 °C, the temperature is lowered by 0.9 to 1.1 °C per hour; the crystallization is stopped at 30 °C, centrifuged, washed and dried to obtain allulose crystals.
  • the solid content of the psicose sugar solution is 70%-75%, such as 73%-75%, and the purity is ⁇ 95%. If the solid mass content of the obtained psicose sugar solution is low, the solid content of the psicose sugar solution can be increased by vacuum concentration, wherein the vacuum degree of vacuum concentration is -0.05 ⁇ 0MPa, the temperature is 35 ⁇ 40 °C.
  • the added amount of the psicose seed crystals is 1-1.5 ⁇ of the mass of the psicose sugar solution with a solid content of 70-75%.
  • the size of the psicose seed crystals is 250-280 mesh.
  • the psicose seed crystals added in this application are not suitable for either too large or too small.
  • the crystal seeds are too large and the number of seeds is insufficient, which will easily lead to the crystallization of spontaneously formed nuclei, resulting in an excessively large final crystal size distribution range, and the crystal The size is not uniform; if the seed crystal is too small, it is easy to cause a slow crystallization process.
  • the vacuum degree of the evaporative crystallization is -0.05 to -0.1 MPa; preferably -0.01 MPa.
  • the definition of vacuum degree takes 1 standard atmospheric pressure as the reference zero point, and -0.05MPa means 0.05MPa lower than 1 standard atmospheric pressure.
  • the evaporative crystallization of step (1) is performed until the solid content of the psicose sugar solution is 81-83%.
  • step (2) the solid content of the psicose sugar solution is always between 82-83%.
  • step (2) of the present application is to reshape the crystal, so that the crystal size tends to be uniform, and at the same time, the crystal surface is grown to be smooth, and the crystal morphology is improved; wherein, the conditions of evaporative crystallization during crystal rectification are the same as those in step (1). same. After the complete crystallization, the crystallization yield can reach more than 10%, and more than 80% of the crystal size is located in 80-100 mesh.
  • the stirring speed is controlled to be 100-150 rpm; preferably 100 rpm.
  • the sub-interval cooling is in the range of 50-41°C, the temperature is lowered by 0.2°C per hour; in the range of 41-35°C, the temperature is lowered by 0.5°C per hour; Within the cooling range of ⁇ 30°C, the temperature is lowered by 1°C per hour.
  • the present application creatively studies the metastable region curve of psicose (as shown in FIG. 12 ). It can be seen from the figure that with the increase of temperature, the width of the metastable region of allulose gradually narrowed from wide. Therefore, at a higher temperature (such as 35-50 °C), the cooling frequency is too fast during cooling and crystallization, which will lead to the spontaneous nucleation of allulose and the uneven crystal size.
  • the method of constant cooling rate is not adopted, but the cooling frequency of a specific cooling interval is designed according to the metastable region curve of psicose.
  • the psicose metastable zone curve is characterized by a narrow metastable zone when the temperature is high and a wide metastable zone when the temperature is low. Therefore, the cooling frequency of cooling crystallization is slow in the early stage and fast in the later stage, which can avoid the premature cooling caused by too fast. Spontaneous nucleation, uneven crystal size, and slow crystal growth and low yield caused by slow cooling in the later stage.
  • the detection yield of psicose crystals can reach more than 55%, and more than 80% of the crystals have a size of 40-60 meshes.
  • % refers to weight percent unless otherwise specified.
  • D-psicose crystal is used interchangeably with crystalline D-psicose, and both have the same meaning.
  • the psicose sugar solution is an aqueous solution of psicose.
  • the method for preparing psicose crystals in the present application adopts a combination of evaporative crystallization method and cooling crystallization method.
  • the method is simple in preparation process, easy to operate, and has short crystallization cycle (for example, there is no need to perform multiple repeated heating and cooling processes); the method has reduced production cost and simplified preparation process (for example, no organic solvent needs to be added).
  • the application chooses to add crystal seeds when the solid content is relatively low (70-75%).
  • the viscosity of the psicose sugar solution is low, and the mass transfer performance of the material is good, which is conducive to molecular movement and molecular orientation.
  • the resistance of the crystal nuclei to approach is small, which is conducive to the crystallization process, and the growth rate of the crystal in all directions is more uniform, and the addition of seed crystals at this time can shorten the entire crystallization cycle and save energy consumption; because the crystallization starts from a low solid content , the obtained crystal yield is higher.
  • the application also optimizes the size of the seed crystal, and the size of the seed crystal is 250-280 mesh. If the seed crystal is too large and the number of seed crystals is insufficient, it will easily lead to the crystallization of spontaneously formed nuclei, resulting in an excessively large final crystal size distribution range and uneven crystal size; if the seed crystal is too small, it is easy to cause a slow crystallization process.
  • the application did not directly conduct cooling and crystallization after the evaporative crystallization, but carried out crystallization.
  • the crystallization made the crystal size tend to be uniform, and at the same time, the crystal surface was grown to be smooth, and the crystal morphology was improved; after the crystallization was completed, the crystallization
  • the yield can reach more than 10%, and more than 80% of the crystal size is located in 80-100 mesh.
  • a specific cooling interval and cooling frequency are designed according to the metastable zone curve of allulose in the cooling process.
  • the cooling crystallization helps to obtain a psicose crystal with a narrow crystal size distribution. Avoid the phenomenon of spontaneous nucleation and uneven crystal size caused by too fast cooling in the early stage, and slow crystal growth, low yield, long cycle and high energy consumption caused by too slow cooling in the later stage.
  • the obtained crystal yield is high, the yield of psicose crystals can reach more than 55%, the crystal size distribution is narrow, and the size of more than 80% crystals is located in 40-60 mesh, And the crystal surface is smooth, mirror surface, good reflectivity, regular crystal shape.
  • the technical effect exceeds the expectations of those skilled in the art, and is an unexpected technical effect.
  • Fig. 1 is the microscope photograph of the obtained crystal after the whole crystal of embodiment 1 finishes;
  • Fig. 2 is the micrograph of the obtained crystal after the crystallization of embodiment 1 finishes
  • Fig. 3 is the microscope photograph of the obtained crystal after the whole crystal of embodiment 2 finishes;
  • Fig. 4 is the microscope photograph of the obtained crystal after the crystallization of embodiment 2;
  • Fig. 5 is the microscope photograph of the obtained crystal after the whole crystal of embodiment 3 finishes;
  • Fig. 6 is the micrograph of the obtained crystal after the crystallization of embodiment 3 finishes
  • Fig. 7 is the microscope photograph of the obtained crystal after the crystallization of comparative example 1 finishes
  • Fig. 8 is the microscope photograph of the obtained crystal after the crystallization of comparative example 2 finishes
  • Fig. 9 is the microscope photograph of the obtained crystal after the crystallization of comparative example 3 finishes.
  • Fig. 10 is the microscope photograph of the obtained crystal after the crystallization of comparative example 4 finishes
  • Fig. 11 is the microscope photograph of the obtained crystal after the crystallization of comparative example 5 finishes;
  • Fig. 12 is a graph of the metastable region of psicose, in the figure, the upper curve is the supersaturation curve, and the lower curve is the saturation curve.
  • the psicose sugar solution used in the examples can be one or a combination of chemical synthesis or biocatalytic conversion.
  • the test method of crystal size distribution is obtained by step-by-step sieving using 20 mesh, 40 mesh, 60 mesh, 80 mesh and 100 mesh screen.
  • the size of the mesh has a meaning known in the art, for example, GB or ISO standards in the art may be referred to, for example, GB6005-85, ISO565-1983 standards may be referred to.
  • a preparation method of psicose crystal comprising the steps of:
  • Evaporative crystallization provide a psicose sugar solution (aqueous solution of psicose), the solid content of the psicose sugar solution is 73%, and the purity is ⁇ 95%.
  • Add psicose crystals The amount of psicose seed crystals added is 1 ⁇ of the mass of psicose sugar solution, the size of psicose seed crystals is between 250 and 280 mesh, and the conditions of 41°C and vacuum degree of -0.01MPa Evaporate and crystallize down to the solid content of the psicose sugar liquid being 81%;
  • step (3) cooling crystallization the psicose sugar liquid obtained after the crystallization of step (2) is completed by cooling the crystallization in different intervals, in the interval of 41 ⁇ 35 °C, the temperature is lowered by 0.5 °C per hour; in the cooling interval of 35 ⁇ 30 °C , the temperature is lowered by 1 °C per hour; the stirring speed is controlled to be 100 rpm during the cooling and crystallization process; the crystallization is stopped when the temperature is lowered to 30 °C, centrifugation, washing and drying are performed to obtain psicose crystals.
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 2
  • the crystal size distribution is narrow, the crystal surface is smooth, mirror surface, good light reflection, regular crystal form
  • the yield of detected psicose crystal is 58.31 %
  • the purity is 99.62%
  • the size distribution of the obtained crystals is shown in the table below, and the size of 82.31% of the crystals is located in the 40-60 mesh:
  • a preparation method of psicose crystal comprising the steps of:
  • Evaporative crystallization provide a psicose sugar solution with a solid content of 74% and a purity of ⁇ 95%, add psicose crystal seeds, and psicose crystal seeds
  • the added amount of psicose sugar solution is 1.2 ⁇ of the mass of the psicose sugar solution, the size of psicose seed crystals is between 250 and 280 meshes, and the psicose crystals are evaporated and crystallized under the conditions of
  • the solid content of the sugar liquid is 82%;
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 3, the crystal size tends to be uniform, the crystal surface grows smoothly, and the crystallization yield of psicose is 11.60%.
  • the size distribution of the obtained crystal is as follows As shown in the table, 81.56% of the crystal sizes are located at 80-100 mesh:
  • cooling crystallization the psicose sugar liquid obtained after the crystallization in step (2) is completed by dividing the temperature and crystallization in different intervals, in the interval of 45 ⁇ 41 °C, the temperature is lowered by 0.2 °C per hour; in the interval of 41 ⁇ 35 °C, Cool down by 0.5 °C per hour; in the cooling range of 35 to 30 °C, cool down by 1 °C per hour; control the stirring speed to 100 rpm during the cooling crystallization process; stop crystallization at 30 °C, centrifuge, wash, and dry to obtain psicose crystal.
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 4, the crystal size distribution is narrow, the crystal surface is smooth, mirror surface, good reflectivity, regular crystal form, the yield of detected psicose crystal is 57.89 %, the purity is 99.58%, the size distribution of the obtained crystals is shown in the table below, and the size of 82.11% of the crystals is located in the 40-60 mesh:
  • a preparation method of psicose crystal comprising the steps of:
  • Evaporative crystallization provide a psicose sugar solution with a solid content of 75% and a purity of ⁇ 95%, add psicose crystal seeds, and psicose crystal seeds
  • the added amount of psicose sugar solution is 1.5 ⁇ of the mass of the psicose sugar solution, the size of the psicose seed crystal is between 250 and 280 mesh, and the crystallization is evaporated under the conditions of 50 ° C and a vacuum degree of -0.01 MPa, until the psicose crystal
  • the solid content of the sugar syrup is 83%;
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 5, the crystal size tends to be uniform, the crystal surface grows smoothly, and the psicose crystallization yield is 10.92%.
  • the size distribution of the obtained crystal is as follows As shown in the table, 80.69% of the crystal size is located in 80-100 mesh:
  • cooling crystallization the psicose sugar liquid obtained after the crystallization in step (2) is completed by dividing the temperature and crystallization by interval, in the interval of 50 ⁇ 41 °C, the temperature is lowered by 0.2 °C per hour; in the interval of 41 ⁇ 35 °C, Cool down by 0.5 °C per hour; in the cooling range of 35 to 30 °C, cool down by 1 °C per hour; control the stirring speed to 100 rpm during the cooling crystallization process; stop crystallization at 30 °C, centrifuge, wash, and dry to obtain psicose crystal.
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 6, the crystal size distribution is narrow, the crystal surface is smooth, mirror surface, good reflectivity, regular crystal form, the yield of detected psicose crystal is 56.45 %, the purity is 99.64%, the size distribution of the obtained crystals is shown in the table below, and the size of 80.79% of the crystals is located in 40-60 mesh:
  • the crystallization of psicose was carried out according to the preparation method of Example 2, except that the psicose sugar solution in step (1) was concentrated to a solid state at 35-40° C. and a vacuum degree of -0.01MPa.
  • the substance content is 80%, psicose seed crystals are added, and other steps and operations are the same as those in Example 2.
  • the microscope photo (100 times) of the obtained crystal is shown in Figure 7.
  • the yield of the detected psicose crystal is 47.62%, and the purity is 98.97%.
  • the size distribution of the obtained crystal is shown in the following table, and the crystal size Mainly distributed in 40-60 mesh and 60-80 mesh, also distributed in other size ranges, the crystal size distribution is not concentrated:
  • the crystallization of psicose is carried out according to the preparation method of Example 2, the difference is that the size of the psicose seed crystals added in step (1) is between 180 and 200 meshes, and other steps and operations are the same as those in the embodiment. 2 are the same.
  • the microscope photo (100 times) of the obtained crystals is shown in Figure 8.
  • the yield of the detected psicose crystals is 41.54%, and the purity is 98.83%.
  • the size distribution of the obtained crystals is shown in the following table, and the crystal size Mainly distributed in 40-60 mesh, 60-80 mesh and 80-100 mesh, also distributed in other size ranges, the crystal size distribution is not concentrated, and the yield is low:
  • the crystallization of psicose was carried out according to the preparation method of Example 2, the difference was that the size of the psicose seed crystals added in step (1) was between 300 and 320 meshes, and other steps and operations were the same as those of the embodiment 2 are the same.
  • the microscope photo (100 times) of the obtained crystals is shown in Figure 9.
  • the yield of the detected psicose crystals is 41.6% and the purity is 98.91%.
  • the size distribution of the obtained crystals is shown in the following table, and the crystal size Mainly distributed in 40-60 mesh, 60-80 mesh, 80-100 mesh and below 100 mesh, and also distributed in other size ranges, the crystal size distribution is not concentrated, the crystal form is small, and the yield is low:
  • step (2) was omitted, that is, the crystallization process was not performed, and other steps and operations were the same as those of Example 2.
  • the microscope photo (100 times) of the obtained crystals is shown in Figure 10.
  • the yield of the detected psicose crystals is 45.38%, and the purity is 99.03%.
  • the size distribution of the obtained crystals is shown in the following table, and the crystal size Mainly distributed in 40-60 mesh, 60-80 mesh, 80-100 mesh and below 100 mesh, and also distributed in other size ranges, the crystal size distribution is not concentrated, and the crystal form is small:
  • the crystallization of psicose is carried out, the difference is that in step (3), the mode of cooling in different intervals is not adopted, but the cooling crystallization is carried out in a uniformly decreasing mode, and the temperature is uniformly reduced from 45 °C. The temperature was lowered to 30° C., and the temperature was lowered by 1° C. every hour. Other steps and operations were the same as those in Example 2.
  • the microscope photo (100 times) of the obtained crystals is shown in Figure 11.
  • the yield of the detected psicose crystals is 38.94%, and the purity is 98.77%.
  • the size distribution of the obtained crystals is shown in the following table, and the crystal size Mainly distributed in 40-60 mesh, 60-80 mesh, 80-100 mesh and below 100 mesh, and also distributed in other size ranges, the crystal size distribution is not concentrated, the crystal form is small, and the yield is low:
  • the lower limit of the metastable region is the saturation concentration curve.
  • the content is the saturation concentration at the temperature. Taking the temperature as the abscissa and the saturation concentration as the ordinate, the lower limit of the metastable zone is obtained.
  • the saturated solution at a certain temperature is cooled at a cooling rate of 0.2 °C/h at a stirring speed of 50 rpm.
  • the centrifugal detection The solid content of the supernatant liquid, and the temperature at this time is recorded at the same time, which is the upper limit of the supersaturation concentration at this temperature. Taking the temperature as the abscissa and the upper limit of the supersaturation concentration as the ordinate, the upper limit of the metastable zone is obtained.
  • the curve of the metastable region of psicose measured according to the above detection method is shown in Figure 12. It can be seen from the figure that with the increase of temperature, the width of the metastable region of psicose gradually narrows from wide to wide. Therefore, at a higher temperature, such as 35-50 °C, the cooling frequency is too fast during cooling and crystallization, which will lead to the spontaneous nucleation of allulose and uneven crystal size.
  • the cooling interval and cooling frequency are important parameters.
  • the inventors of the present application have studied the properties of the metastable region of psicose by constructing a psicose metastable region curve. It can be seen from the curve of the metastable zone that as the temperature increases, the width of the metastable zone of psicose gradually narrows from wide to wide. Therefore, at higher temperatures, such as 35 to 50 °C, the frequency of cooling during cooling and crystallization Too fast will lead to the spontaneous nucleation of allulose, and the crystal size will not be uniform. Therefore, the present application adopts a specific cooling interval and a specific cooling frequency in the cooling crystallization process for the unique metastable zone curve of psicose.
  • the psicose crystals obtained by the cooling crystallization protocol of the present application have a narrow size distribution. And the crystallization efficiency, yield and purity are also high.
  • the cooling crystallization scheme of the present application avoids the phenomenon of spontaneous nucleation and uneven crystal size caused by too fast cooling in the early stage, and avoids the phenomenon of slow crystal growth, low yield, long cycle and high energy consumption caused by too slow cooling in the later stage .
  • a uniform decreasing method is adopted to conduct cooling and crystallization, the temperature is evenly lowered from 45°C to 30°C, and the temperature is lowered by 1°C per hour.
  • the crystallinity rate is 38.94% and the purity is 98.77%.
  • the size of the obtained crystals is mainly distributed in 40-60 mesh, 60-80 mesh, 80-100 mesh and below 100 mesh, and also distributed in other size ranges. The crystal size distribution is not concentrated. Small size and low yield.
  • the solids content of the initial sugar liquor is an important parameter.
  • the crystal seed is added at a lower solid content (70-75%), at this time, the viscosity of the psicose sugar solution is low, and the material mass transfer performance is good, which is conducive to molecular movement,
  • the resistance of the molecule to the crystal nucleus is small, which is conducive to the crystallization process, and the growth rate of the crystal in all directions is more uniform, and the addition of seed crystals at this time can shorten the entire crystallization cycle and save energy consumption; Crystallization started and the resulting crystals were in higher yields.
  • the size of the psicose seed crystals is an important parameter when crystallizing.
  • the size of the seed crystal is preferably 250 to 280 mesh. Crystallization is carried out by adopting crystal seeds located in this size range, and the obtained product has a narrow crystal size distribution range, uniform crystal size, fast crystallization speed and high production efficiency.

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Abstract

本申请涉及一种阿洛酮糖结晶的制备方法。本申请采用蒸发结晶法和降温结晶法相结合的方式制备阿洛酮糖晶体，制备工艺简单，易操作，结晶周期短。本申请在蒸发结晶过程中选择在较低固形物含量（70～75％）时加入晶种，利于结晶过程的进行，晶体在各方向上的生长速度更加均匀，可缩短整个结晶周期，节约能源消耗；在蒸发结晶结束后进行整晶，整晶使得晶体尺寸趋向于均一，同时使晶体表面生长至光滑，完善晶体形态；整晶后进行降温结晶，降温过程根据阿洛酮糖的介稳区曲线，设计特定的降温区间的降温频率。按照本申请的制备方法结晶结束后，得到的晶体收率高，晶体尺寸分布窄，且晶体表面光滑，呈镜面，反光性好，晶型规则。

Description

一种阿洛酮糖结晶的制备方法 技术领域
本申请涉及一种阿洛酮糖结晶的制备方法，属于功能糖制备技术领域。
背景技术
阿洛酮糖(D-psicose or D-allulose)是自然界中含量非常低的六碳糖，是D-果糖C-3位点的差向异构体。D-阿洛酮糖很难被消化吸收，几乎不为生命活动提供能量，因此是一种非常有用的低卡路里的甜味剂。在医药健康领域，D-阿洛酮糖可以抑制脂肪肝酶和肠道α-糖苷酶，从而降低体内脂肪的积累和抑制血糖浓度的上升。在膳食中添加D-阿洛酮糖可以降低餐后血糖反应，提高胰岛素的敏感性和葡萄糖耐受性。另外，相对其他稀有糖，D-阿洛酮糖能更加有效地清除活性氧自由基。在小鼠试验中，发现D-阿洛酮糖可以通过抑制活性氧的产生来阻止双-(2-乙基己基)-邻苯二甲酸诱发的对睾丸的伤害。此外D-阿洛酮糖对6-羟基多巴胺诱导的细胞凋亡有神经保护的作用，同时还能抑制高浓度葡萄糖诱导下的单核细胞趋化蛋白MCP-1的表达。这就预示着D-阿洛酮糖具有治疗神经组织退化和动脉粥样硬化等相关疾病的潜在功能。
中国专利文献CN109748940A(申请号201811470319.5)公开了一种从乙醇溶液中结晶阿洛酮糖的方法，包括：取纯化的阿洛酮糖溶液减压浓缩得到溶液I；将浓缩溶液I加热，加入无水乙醇，再次减压浓缩，使乙醇带走阿洛酮糖溶液中的水分，成为阿洛酮糖的乙醇溶液II；将浓缩液II加无水乙醇，加热至阿洛酮糖完全溶解，缓慢降温，析出晶体后继续缓慢降温，至晶体不再增多为止，得到混合液III；将混合液III固液分离，得到固体IV和清液体V；将固体IV减压干燥得到阿洛酮糖晶体；清液体V继续浓缩，重复上述步骤，结晶得到剩余阿洛酮糖晶体。
发明内容
发明人发现，在现有的阿洛酮糖结晶技术获得的阿洛酮糖晶体尺寸分布较宽。
针对现有技术的不足，本申请提供了一种阿洛酮糖结晶(crystalline D-psicose)的制备方法，制备得到的阿洛酮糖结晶的晶体尺寸分布窄，其中80％以上的晶体尺寸在40-60目的范围内。
本申请发明人通过构建阿洛酮糖介稳区曲线，研究了阿洛酮糖的介稳区性质。针对阿洛酮糖的独特介稳区曲线，本申请在降温结晶过程中采用了特定的降温区间和特定的降温频率。基于此，本申请方法制备的阿洛酮糖晶体具有窄的尺寸分布。
本申请的技术方案如下：
在一些实施方案中，本申请提供一种阿洛酮糖结晶的制备方法，依次经过(1)蒸发结晶、(2)整晶、(3)降温结晶，制备得到阿洛酮糖结晶。
在一些实施方案中，本申请提供一种阿洛酮糖结晶的制备方法，包括：
(1)对阿洛酮糖糖液(D-psicose syrup)实施蒸发结晶(evaporative crystallization)；
(2)对上一步产物实施整晶(crystallization regulation)；
(3)对上一步产物实施降温结晶(cooling crystallization)，得到阿洛酮糖结晶(crystalline D-psicose)。
在一些实施方案中，所述蒸发结晶是在阿洛酮糖糖液的固形物质量含量为70～75％(例如70％～71％，71％～72％，72％～73％，73％～74％或74％～75％)时加入晶种(crystal seeds)进行蒸发结晶。
在一些实施方案中，所述整晶是边补加水边蒸发结晶，并使得整晶过程中固形物质量含量维持稳定。例如稳定在80～85％之间。
在一些实施方案中，所述降温结晶采用分区间降温的方式进行结晶，降温频率前期慢、后期快。
在一些实施方案中，所述降温结晶采用分区间降温的方式进行结晶，所述分区间降温的操作为：在50～41℃区间内，每小时降温0.1～0.3℃；在41～35℃区间内，每小时降温0.4～0.6℃；在35～30℃降温区间内，每小时降温0.9～1.1℃；降至30℃停止结晶。
在一些实施方案中，本申请提供一种阿洛酮糖结晶的制备方法，包括以下步骤：
(1)蒸发结晶：提供阿洛酮糖糖液，所述阿洛酮糖糖液的固形物质量含量为70～75％(例如70-71％、71-72％、72-73％、73-74％或74-75％)，加入阿洛酮糖晶种，40～50℃下蒸发结晶，至阿洛酮糖糖液的固形物质量含量为80～85％(80-81％、81-82％、82-83％、83-84％或84-85％)；
(2)整晶：向步骤(1)得到的阿洛酮糖糖液体系中补加水，同时继续进行蒸发结晶，使得阿洛酮糖糖液的固形物质量含量始终在80～85％(80-81％、81-82％、82-83％、83-84％或84-85％)之间，整晶时间为4～8h(4-5h、5-6h、6-7h或7-8h)；
(3)降温结晶：将步骤(2)整晶结束后得到的阿洛酮糖糖液分区间降温结晶，在50～41℃区间内，每小时降温0.1～0.3℃；在41～35℃区间内，每小时降温0.4～0.6℃；在35～30℃降温区间内，每小时降温0.9～1.1℃；降至30℃停止结晶，离心、洗涤、干燥，即得阿洛酮糖晶体。
在一些实施方案中，步骤(1)蒸发结晶中，所述阿洛酮糖糖液的固形物质量含量为70％～75％，如73％-75％，纯度≥95％。若取得的阿洛酮糖糖液的固形物含量(solid mass content)较低，可采用真空浓缩的方式将阿洛酮糖糖液的固形物含量提高，其中真空浓缩的真空度为-0.05～0MPa，温度为35～40℃。
在一些实施方案中，步骤(1)蒸发结晶中，所述阿洛酮糖晶种的加量为固形物质量含量为70～75％的阿洛酮糖糖液质量的1～1.5‰。
在一些实施方案中，步骤(1)蒸发结晶中，所述阿洛酮糖晶种的尺寸为250～280目。本申请中加入的阿洛酮糖晶种过大或过小均不适合，晶种过大，晶种个数不足，容易导致结晶出自发形成的核，导致最终晶体尺寸分布区间过大，晶体大小不均匀；晶种过小，容易导致结晶进程缓慢。
在一些实施方案中，步骤(1)蒸发结晶中，所述蒸发结晶的真空度为-0.05～-0.1MPa；优选为-0.01MPa。真空度的定义以1个标准大气压为基准零点，-0.05MPa表示比1个标准大气压低0.05MPa。
在一些实施方案中，步骤(1)蒸发结晶中，蒸发结晶至阿洛酮糖糖液的固形物质量含量为81～83％。
在一些实施方案中，步骤(2)整晶中，阿洛酮糖糖液的固形物质量含量始终在82～83％之间。
本申请步骤(2)的目的为整晶，使晶体尺寸趋向于均一，同时使晶体表面生长至光滑，完善晶体形态；其中，整晶时蒸发结晶的条件与步骤(1)中蒸发结晶的条件相同。整晶结束后，结晶收率可到10％以上，80％以上的晶体尺寸位于80-100目。
在一些实施方案中，步骤(3)降温结晶过程中，控制搅拌转速为100～150rpm；优选为100rpm。
在一些实施方案中，步骤(3)降温结晶中，所述分区间降温是在50～41℃区间内，每小时降温0.2℃；在41～35℃区间内，每小时降温0.5℃；在35～30℃降温区间内，每小时降温1℃。
本申请创造性地研究了阿洛酮糖的介稳区曲线(如图12所示)。从图中可以看出，随着温度的升高，阿洛酮糖介稳区的宽度由宽逐渐变窄。因此在较高的温度(如35～50℃)下，降温结晶时降温频率过快，会导致阿洛酮糖自发成核，晶体尺寸不均匀。
本申请步骤(3)降温结晶中，未采用恒定降温速率的方式，而是依据阿洛酮糖的介稳区曲线，设计特定的降温区间的降温频率。阿洛酮糖介稳区曲线呈现温度高时介稳区宽度窄，温度低时介稳区宽度宽的特点，因此降温结晶的降温频率前期慢，后期快，这样可以避免前期降温过快导致的自发成核、晶体尺寸不均匀现象，以及后期降温过慢导致的晶体生长缓慢、收率低的现象。结晶结束后，检测阿洛酮糖晶体的收率可达到55％以上，80％以上晶体的尺寸位于40～60目。
在一些实施方案中，除非特别说明，％是指重量百分含量。
在一些实施方案中，阿洛酮糖晶体(D-psicose crystal)与结晶阿洛酮糖(crystalline D-psicose)互换使用，二者具有相同的含义。
在一些实施方案中，阿洛酮糖糖液是阿洛酮糖的水溶液。
有益效果
本申请一个或多个实施方案具有以下一项或多项有益效果：
1、本申请制备阿洛酮糖晶体的方法采用蒸发结晶法和降温结晶法相结合的方式。该方法制备工艺简单，易操作，结晶周期短(例如无需实施多次反复加热和冷却的过程)；该方法具有降低的生产成本，简化的制备工艺(例如无需添加有机溶剂)。
2、本申请在蒸发结晶过程中选择在较低固形物含量(70～75％)时加入晶种，此时阿洛酮糖糖液粘度低，物料传质性能好，利于分子运动，分子向晶核靠拢的阻力小，利于结晶过程的进行，晶体在各方向上的生长速度更加均匀，且此时加入晶种，可缩短整个结晶周期，节约能源消耗；由于从低固形物含量时开始结晶，所得晶体收率更高。
3、本申请还对晶种的大小进行了优化，晶种尺寸为250～280目。晶种过大，晶种个数不足，容易导致结晶出自发形成的核，导致最终晶体尺寸分布区间过大，晶体大小不均匀；晶种过小，容易导致结晶进程缓慢。
4、本申请在蒸发结晶结束后并没有直接进行降温结晶，而是进行了整晶，整晶使得晶体尺寸趋向于均一，同时使晶体表面生长至光滑，完善晶体形态；整晶结束后，结晶收率可到10％以上，80％以上的晶体尺寸位于80-100目。
5、本申请在降温过程中根据阿洛酮糖的介稳区曲线，设计特定的降温区间和降温频率。该降温结晶有助于获得晶体尺寸分布窄的阿洛酮糖结晶。避免前期降温过快导致的自发成核、晶体尺寸不均匀现象，以及后期降温过慢导致的晶体生长缓慢、收率低、周期长、能耗高的现象。
5、按照本申请的制备方法结晶结束后，得到的晶体收率高，阿洛酮糖晶体的收率可达到55％以上，晶体尺寸分布窄，80％以上晶体的尺寸位于40～60目，且晶体表面光滑，呈镜面，反光性好，晶型规则。该技术效果超出了本领域技术人员的预期，属于预料不到的技术效果。
附图说明
图1为实施例1整晶结束后所得晶体的显微镜照片；
图2为实施例1结晶结束后所得晶体的显微镜照片；
图3为实施例2整晶结束后所得晶体的显微镜照片；
图4为实施例2结晶结束后所得晶体的显微镜照片；
图5为实施例3整晶结束后所得晶体的显微镜照片；
图6为实施例3结晶结束后所得晶体的显微镜照片；
图7为对比例1结晶结束后所得晶体的显微镜照片；
图8为对比例2结晶结束后所得晶体的显微镜照片；
图9为对比例3结晶结束后所得晶体的显微镜照片；
图10为对比例4结晶结束后所得晶体的显微镜照片；
图11为对比例5结晶结束后所得晶体的显微镜照片；
图12为阿洛酮糖的介稳区曲线图，图中，上方曲线为过饱和度曲线，下方曲线为饱和度曲线。
具体实施方式
下面结合实施例对本申请的技术方案作进一步说明，但是本申请的保护范围并不仅限于此。实施例中涉及的材料或仪器，若无特殊说明，均为本领域普通商品；实施例中涉及的实验操作，若无特殊说明，均为本领域常规实验操作。
实施例中使用的阿洛酮糖糖液可以是化学合成或者生物催化转化中的一种或者两种的组合。
除非特别说明，以下使用的％均表示重量百分含量。
以下实施方式中，晶体尺寸分布的测试方法是采用20目、40目、60目、80目和100目的筛网逐级筛分获得。
在一些实施方案中，目数(mesh)的尺寸具有本领域公知的含义，例如可以参考本领域GB或ISO标准，例如可以参考GB6005-85、ISO565-1983标准。
实施例1
一种阿洛酮糖结晶的制备方法，包括步骤如下：
(1)蒸发结晶：提供阿洛酮糖糖液(阿洛酮糖的水溶液)，所述阿洛酮糖糖液的固形物质量含量为73％，纯度≥95％，加入阿洛酮糖晶种，阿洛酮糖晶种的加量为阿洛酮糖糖液质量的1‰，阿洛酮糖晶种的尺寸为位于250～280目之间，41℃、真空度为-0.01MPa条件下蒸发结晶，至阿洛酮糖糖液的固形物质量含量为81％；
(2)整晶：向步骤(1)得到的阿洛酮糖糖液体系中补加水，同时继续在41℃、真空度为-0.01MPa条件下进行蒸发结晶，使得阿洛酮糖糖液的固形物质量含量始终在82～83％之间，整晶时间为4h；
整晶结束后，所得晶体的显微镜照片(100倍)如图1所示，晶体尺寸趋向于均一(uniform)，晶体表面生长光滑，检测阿洛酮糖结晶收率为12.34％，所得晶体的尺寸分布情况如下表所示，81.32％的晶体尺寸位于80-100目：
表1.实施例1整晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000001
(3)降温结晶：将步骤(2)整晶结束后得到的阿洛酮糖糖液分区间降温结晶，在41～35℃区间内，每小时降温0.5℃；在35～30℃降温区间内，每小时降温1℃；降温结晶过程中控制搅拌转速为100rpm；降至30℃停止结晶，离心、洗涤、干燥，即得阿洛酮糖晶体。
结晶结束后，所得晶体的显微镜照片(100倍)如图2所示，晶体尺寸分布窄，晶体表面光滑，呈镜面，反光性好，晶型规则，检测阿洛酮糖晶体的收率为58.31％，纯度为99.62％，所得晶体的尺寸分布情况如下表所示，82.31％晶体的尺寸位于40～60目：
表2.实施例1结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000002
实施例2
一种阿洛酮糖结晶的制备方法，包括步骤如下：
(1)蒸发结晶：提供阿洛酮糖糖液，所述阿洛酮糖糖液的固形物质量含量为74％，纯度≥95％，加入阿洛酮糖晶种，阿洛酮糖晶种的加量为阿洛酮糖糖液质量的1.2‰，阿洛酮糖晶种的尺寸位于250～280目之间，45℃、真空度为-0.01MPa条件下蒸发结晶，至阿洛酮糖糖液的固形物质量含量为82％；
(2)整晶：向步骤(1)得到的阿洛酮糖糖液体系中补加水，同时继续在45℃、真空度为-0.01MPa条件下进行蒸发结晶，使得阿洛酮糖糖液的固形物质量含量始终在82～83％之间，整晶时间为6h；
整晶结束后，所得晶体的显微镜照片(100倍)如图3所示，晶体尺寸趋向于均一，晶体表面生长光滑，检测阿洛酮糖结晶收率为11.60％，所得晶体的尺寸分布情况如下表所示，81.56％的晶体尺寸位于80-100目：
表3.实施例2整晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000003
(3)降温结晶：将步骤(2)整晶结束后得到的阿洛酮糖糖液分区间降温结晶，在45～41℃区间内，每小时降温0.2℃；在41～35℃区间内，每小时降温0.5℃；在35～30℃降温区间内，每小时降温1℃；降温结晶过程中控制搅拌转速为100rpm；降至30℃停止结晶，离心、洗涤、干燥，即得阿洛酮糖晶体。
结晶结束后，所得晶体的显微镜照片(100倍)如图4所示，晶体尺寸分布窄，晶体表面光滑，呈镜面，反光性好，晶型规则，检测阿洛酮糖晶体的收率为57.89％，纯度为99.58％，所得晶体的尺寸分布情况如下表所示，82.11％晶体的尺寸位于40～60目：
表4.实施例2结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000004
实施例3
一种阿洛酮糖结晶的制备方法，包括步骤如下：
(1)蒸发结晶：提供阿洛酮糖糖液，所述阿洛酮糖糖液的固形物质量含量为75％，纯度≥95％，加入阿洛酮糖晶种，阿洛酮糖晶种的加量为阿洛酮糖糖液质量的1.5‰，阿洛酮糖晶种的尺寸为位于250～280目之间，50℃、真空度为-0.01MPa条件下蒸发结晶，至阿洛酮糖糖液的固形物质量含量为83％；
(2)整晶：向步骤(1)得到的阿洛酮糖糖液体系中补加水，同时继续在50℃、真空度为-0.01MPa条件下进行蒸发结晶，使得阿洛酮糖糖液的固形物质量含量始终在82～83％之间，整晶时间为8h；
整晶结束后，所得晶体的显微镜照片(100倍)如图5所示，晶体尺寸趋向于均一，晶体表面生长光滑，检测阿洛酮糖结晶收率为10.92％，所得晶体的尺寸分布情况如下表所示，80.69％的晶体尺寸位于80-100目：
表5.实施例3整晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000005
(3)降温结晶：将步骤(2)整晶结束后得到的阿洛酮糖糖液分区间降温结晶，在50～41℃区间内，每小时降温0.2℃；在41～35℃区间内，每小时降温0.5℃；在35～30℃降温区间内，每小时降温1℃；降温结晶过程中控制搅拌转速为100rpm；降至30℃停止结晶，离心、洗涤、干燥，即得阿洛酮糖晶体。
结晶结束后，所得晶体的显微镜照片(100倍)如图6所示，晶体尺寸分布窄，晶体表面光滑，呈镜面，反光性好，晶型规则，检测阿洛酮糖晶体的收率为56.45％，纯度为99.64％，所得晶体的尺寸分布情况如下表所示，80.79％晶体的尺寸位于40～60目：
表6.实施例3结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000006
对比例1
按照实施例2的制备方法进行阿洛酮糖的结晶，不同之处在于，将步骤(1)中的阿洛酮糖糖液在35～40℃、真空度为-0.01MPa条件下浓缩至固形物质量含量为80％时加入阿洛酮糖晶种，其他步骤与操作均与实施例2相同。
结晶结束后，所得晶体的显微镜照片(100倍)如图7所示，检测阿洛酮糖晶体的收率为47.62％，纯度为98.97％，所得晶体的尺寸分布情况如下表所示，晶体尺寸主要分布在40-60目和60-80目，其他尺寸范围内也有分布，晶体尺寸分布不集中：
表7.对比例1结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000007
对比例2
按照实施例2的制备方法进行阿洛酮糖的结晶，不同之处在于，步骤(1)加入的阿洛酮糖晶种的尺寸位于180～200目之间，其他步骤与操作均与实施例2相同。
结晶结束后，所得晶体的显微镜照片(100倍)如图8所示，检测阿洛酮糖晶体的收率为41.54％，纯度为98.83％，所得晶体的尺寸分布情况如下表所示，晶体尺寸主要分布在40-60目、60-80目和80-100目，其他尺寸范围内也有分布，晶体尺寸分布不集中，且收率低:
表8.对比例2结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000008
对比例3
按照实施例2的制备方法进行阿洛酮糖的结晶，不同之处在于，步骤(1)加入的阿洛酮糖晶种的尺寸位于300～320目之间，其他步骤与操作均与实施例2相同。
结晶结束后，所得晶体的显微镜照片(100倍)如图9所示，检测阿洛酮糖晶体的收率为41.6％，纯度为98.91％，所得晶体的尺寸分布情况如下表所示，晶体尺寸主要分布 在40-60目、60-80目、80-100目和100目以下，其他尺寸范围内也有分布，晶体尺寸分布不集中，晶型小，且收率低：
表9.对比例3结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000009
对比例4
按照实施例2的制备方法进行阿洛酮糖的结晶，不同之处在于，省略步骤(2)，即不进行整晶过程，其他步骤与操作均与实施例2相同。
结晶结束后，所得晶体的显微镜照片(100倍)如图10所示，检测阿洛酮糖晶体的收率为45.38％，纯度为99.03％，所得晶体的尺寸分布情况如下表所示，晶体尺寸主要分布在40-60目、60-80目、80-100目和100目以下，其他尺寸范围内也有分布，晶体尺寸分布不集中，晶型小：
表10.对比例4结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000010
对比例5
按照实施例2的制备方法进行阿洛酮糖的结晶，不同之处在于，步骤(3)中不采用分区间降温的方式，而是采用均匀递减的方式进行降温结晶，将温度从45℃均匀降至30℃，每小时降温1℃，其他步骤与操作均与实施例2相同。
结晶结束后，所得晶体的显微镜照片(100倍)如图11所示，检测阿洛酮糖晶体的收率为38.94％，纯度为98.77％，所得晶体的尺寸分布情况如下表所示，晶体尺寸主要分布在40-60目、60-80目、80-100目和100目以下，其他尺寸范围内也有分布，晶体尺寸分布不集中，晶型小，且收率低：
表11.对比例5结晶结束后的晶体尺寸分布情况
Figure PCTCN2021135345-appb-000011
Figure PCTCN2021135345-appb-000012
实验：阿洛酮糖的介稳区曲线(curve of metastable zone)测定
检测方法：
阿洛酮糖糖液的介稳区下限的测定：介稳区下限即为饱和浓度曲线，在一定的温度下，向水中添加阿洛酮糖粉末直至不溶解，离心后检测上清液固形物含量，即为该温度下的饱和浓度。以温度为横坐标，饱和浓度为纵坐标作图，即得到介稳区下限。
阿洛酮糖糖液的介稳区上限的测定：将一定温度下的饱和溶液，在搅拌转速50rpm下，按照0.2℃/h的降温速率进行降温，当溶液中有晶体析出时，离心检测上清液的固形物含量，同时记录此时温度，即为该温度下的过饱和浓度上限。以温度为横坐标，过饱和浓度上限为纵坐标作图，即得到介稳区上限。
按照上述检测方法测定的阿洛酮糖的介稳区曲线如图12所示，从图中可以看出，随着温度的升高，阿洛酮糖介稳区的宽度由宽逐渐变窄，因此在较高的温度下，如35～50℃，降温结晶时降温频率过快，会导致阿洛酮糖自发成核，晶体尺寸不均匀。
实验结论
由实施例1～3和对比例1～5的实验数据，能够获得以下实验结论
在结晶时，降温区间和降温频率是重要的参数，本申请发明人通过构建阿洛酮糖介稳区曲线，研究了阿洛酮糖的介稳区性质。从介稳区曲线可以看出，随着温度的升高，阿洛酮糖介稳区的宽度由宽逐渐变窄，因此在较高的温度下，如35～50℃，降温结晶时降温频率过快，会导致阿洛酮糖自发成核，晶体尺寸不均匀。所以本申请针对阿洛酮糖的独特介稳区曲线，在降温结晶过程中采用了特定的降温区间和特定的降温频率。本申请的降温结晶方案获得的阿洛酮糖晶体具有窄的尺寸分布。而且结晶效率、收率、纯度也较高。
本申请的降温结晶方案避免了前期降温过快导致的自发成核、晶体尺寸不均匀的现象，以及避免了后期降温过慢导致的晶体生长缓慢、收率低、周期长、能耗高的现象。若不采用本申请方案，比如对比例5采用了均匀递减的方式进行降温结晶，将温度从45℃均匀降至30℃，每小时降温1℃，结晶结束后，检测阿洛酮糖晶体的收率为38.94％，纯度为98.77％，所得晶体的尺寸主要分布在40-60目、60-80目、80-100目和100目以下，其他尺寸范围内也有分布，晶体尺寸分布不集中，晶型小，且收率低。
在结晶时，初始糖液中的固形物含量是重要的参数。本申请通过研究发现，在蒸发结晶过程中选择在较低固形物含量(70～75％)时加入晶种，此时阿洛酮糖糖液粘度低，物料传质性能好，利于分子运动，分子向晶核靠拢的阻力小，利于结晶过程的进行，晶 体在各方向上的生长速度更加均匀，且此时加入晶种，可缩短整个结晶周期，节约能源消耗；由于从低固形物含量时开始结晶，所得晶体收率更高。若不采用本申请方案，比如对比例1在阿洛酮糖糖液的固形物质量含量为80％时加入晶种进行结晶，检测到阿洛酮糖晶体的收率为47.62％，纯度为98.97％，所得晶体的尺寸分布不集中，无法达到本申请的发明目的。
在结晶时，阿洛酮糖晶种的尺寸是重要的参数。晶种的尺寸优选为250～280目。采用位于该尺寸范围内的晶种进行结晶，获得的产品晶体尺寸分布区间窄，晶体尺寸均匀，而且结晶速度较快，生产效率高。

Claims (8)

  1. 一种阿洛酮糖结晶的制备方法，其特征在于，依次经过蒸发结晶、整晶、降温结晶，制备得到阿洛酮糖结晶；
    所述蒸发结晶是在固形物质量含量为70～75％时加入晶种进行蒸发结晶；
    所述降温结晶采用分区间降温的方式进行结晶，降温频率前期慢、后期快；所述分区间降温的操作为：在50～41℃区间内，每小时降温0.1～0.3℃；在41～35℃区间内，每小时降温0.4～0.6℃；在35～30℃降温区间内，每小时降温0.9～1.1℃；降至30℃停止结晶。
  2. 如权利要求1所述的制备方法，其特征在于，所述整晶是边补加水边蒸发结晶，并使得整晶过程中固形物质量含量维持稳定。
  3. 如权利要求1所述的制备方法，其特征在于，具体包括步骤如下：
    (1)蒸发结晶：取阿洛酮糖糖液，所述阿洛酮糖糖液的固形物质量含量为70～75％，加入阿洛酮糖晶种，40～50℃下蒸发结晶，至阿洛酮糖糖液的固形物质量含量为80～85％；
    (2)整晶：向步骤(1)得到的阿洛酮糖糖液体系中补加水，同时继续进行蒸发结晶，使得阿洛酮糖糖液的固形物质量含量始终在80～85％之间，整晶时间为4～8h；
    (3)降温结晶：将步骤(2)整晶结束后得到的阿洛酮糖糖液分区间降温结晶，在50～41℃区间内，每小时降温0.1～0.3℃；在41～35℃区间内，每小时降温0.4～0.6℃；在35～30℃降温区间内，每小时降温0.9～1.1℃；降至30℃停止结晶，离心、洗涤、干燥，即得阿洛酮糖晶体。
  4. 如权利要求3所述的制备方法，其特征在于，步骤(1)中所述阿洛酮糖糖液的固形物质量含量为73-75％，纯度≥95％。
  5. 如权利要求3所述的制备方法，其特征在于，步骤(1)中所述阿洛酮糖晶种的加量为固形物质量含量为70～75％的阿洛酮糖糖液质量的1～1.5‰。
  6. 如权利要求3所述的制备方法，其特征在于，步骤(1)中所述阿洛酮糖晶种的尺寸为250～280目。
  7. 如权利要求3所述的制备方法，其特征在于，步骤(1)中所述蒸发结晶的真空度为-0.05～-0.1MPa。
  8. 如权利要求3所述的制备方法，其特征在于，步骤(3)中降温结晶过程中控制搅拌转速为100～150rpm。
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