A method and crystallization system for vitamin D3

Abstract

This invention relates to a method and system for crystallizing vitamin D3. The method involves passing a solution containing dissolved vitamin D3 into a crystallization system to obtain vitamin D3 crystals. The crystallization system includes a crystallizer, which comprises a main body containing a chamber, a stirring unit disposed within the chamber, a first feed channel for introducing the solution, and an outlet. The outlet includes a first outlet and a second outlet. The distance from the first outlet to the centerline of the chamber is smaller than the distance from the second outlet to the centerline of the chamber. The crystallization method controls the stirring conditions of the stirring unit to ensure that large-diameter vitamin D3 crystals are discharged from the first outlet and small-diameter vitamin D3 crystals are discharged from the second outlet. This method can produce vitamin D3 crystals with large particle size, melting points conforming to pharmacopoeia requirements, high bioavailability, and very low solvent residue.

Description

Technical Field

[0001] This invention specifically relates to a method and system for crystallizing vitamin D3. Background Technology

[0002] Vitamin D3, also known as cholecalciferol, is a type of vitamin D. Vitamin D3 crystals specifically refer to pure vitamin D3 with a content of 100% or a biological efficacy of 40 million IU / g or higher. Current techniques for preparing vitamin D3 crystals typically involve chemically or physically purifying crude vitamin D3 oil obtained from a photochemical reaction to obtain a higher-content vitamin D3 oil. This vitamin D3 oil is then crystallized or recrystallized multiple times to obtain vitamin D3 crystals with a biological efficacy of 40 million IU / g or higher. The quality of vitamin D3 crystals is closely related to their particle size, the amount of impurities they contain (and their biological efficacy), whether their melting point meets the pharmacopoeia requirements (84-88℃), and the amount of residual solvent.

[0003] Existing technologies include methods for purifying vitamin D3 directly using freeze crystallization. For example, US Patent 3334118A discloses a method for preparing vitamin D3 crystals, which involves first saponifying vitamin D3 resin in benzene to obtain vitamin D3 butyrate, then adding acetonitrile and filtration for purification, followed by cooling and crystallization of the filtrate to obtain vitamin D3 crystals. This freeze crystallization method typically struggles to produce needle-like crystals with large particle sizes, and the crystallization process is slow and inefficient. Furthermore, the crystallization process generates colloids or flocculent substances, which to some extent inhibits the formation of vitamin D3 crystals and reduces the yield.

[0004] Existing technologies also involve first purifying the vitamin D3 using column chromatography, followed by crystallization to obtain vitamin D3 crystals. For example, Chinese patent CN100347156C discloses dissolving crude vitamin D3 photochemical oil with a bioavailability of 23.86 million IU / g in petroleum ether, eluting with ethyl acetate in an alumina chromatography column, concentrating the collected vitamin D3 fraction, and freezing and crystallizing to obtain vitamin D3 crystals that meet the pharmacopoeia requirements. Although this method can ultimately obtain crystals that meet the pharmacopoeia requirements, it requires prior separation and purification using column chromatography, necessitates the use of large amounts of solvent for elution, results in significant solvent recovery, high energy consumption, and generates substantial solid waste from the chromatography column. Furthermore, the separation yield is low, the processing capacity is small, and it is difficult to industrialize. Summary of the Invention

[0005] The purpose of this invention is to provide a method for crystallizing vitamin D3, which can prepare vitamin D3 crystals with large particle size, melting point conforming to pharmacopoeia requirements, high bioavailability, and very low solvent residue, and the yield of vitamin D3 crystals is high. The crystallization method is also easy to industrialize.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for crystallizing vitamin D3 involves passing a solution containing dissolved vitamin D3 into a crystallization system to obtain vitamin D3 crystals. The crystallization system includes a crystallizer, which comprises a main body containing a chamber, a stirring unit disposed inside the chamber, a first feed channel for introducing the solution, and a discharge port. The discharge port includes a first discharge port and a second discharge port. The distance from the first discharge port to the center line of the chamber is smaller than the distance from the second discharge port to the center line of the chamber. The crystallization method controls the stirring conditions of the stirring unit to ensure that large-diameter vitamin D3 crystals are discharged from the first discharge port and small-diameter vitamin D3 crystals are discharged from the second discharge port.

[0008] The crystallizer needs to be equipped with a feed channel to transport the solution to be crystallized into the crystallizer. The first feed channel is the interface where the vitamin solution enters the crystallizer, forming the channel through which the vitamin solution enters the internal cavity of the crystallizer.

[0009] In some embodiments, the crystallizer also includes a gas channel for introducing an inert gas. This gas channel can fill the crystallizer with an inert gas, such as nitrogen, to prevent vitamin D3 from being oxidized and destroyed.

[0010] In some embodiments, the stirring unit includes a stirring shaft and blades disposed on the stirring shaft. The blades are planar, and the plane on which the blades are located is substantially horizontal. Using this stirring unit ensures that the crystallization solution rotates only around the axis of the crystallizer along with the blades, avoiding the up-and-down turbulence of the crystallization solution by the blades. Therefore, it can be guaranteed that the crystallization solution is completely in a laminar flow state rotating around the axis of the crystallizer.

[0011] In some embodiments, the number of blades is four or more; preferably, the number of blades is four.

[0012] In some embodiments, the distance between the blade and the bottom of the main body is 1 / 3 to 1 / 2 of the height of the main body. This height setting can reduce the disturbance effect of the blade on large-diameter crystals concentrated near the center of the bottom of the main body, facilitating material discharge.

[0013] In some embodiments, the crystallization method involves controlling the solution level above the blades. The solution level needs to cover the blades; otherwise, severe turbulence will occur in the upper layer of the solution, forming a large number of crystal nuclei, resulting in the formation of fine crystals and affecting the quality of the crystals.

[0014] In some embodiments, the crystallization method controls the rotation speed of the stirring unit to be 5-50 rpm.

[0015] In some embodiments, the large particle size refers to a D50 particle size of 250-300 micrometers, preferably 280-300 micrometers.

[0016] In some embodiments, the small particle size refers to a D50 particle size of less than 250 micrometers.

[0017] Furthermore, the small particle size refers to a D50 particle size of less than 230 micrometers.

[0018] In some embodiments, the lower part of the main body is cylindrical, and the first discharge port is located at the center of the bottom of the main body; the second discharge port is close to the edge of the bottom of the main body. In this invention, "close to" means that the distance between the second discharge port and the edge of the bottom of the main body is smaller than the distance between the second discharge port and the center of the bottom of the main body.

[0019] In some embodiments, the second discharge port is connected to a crystal collecting device located inside the chamber. The crystal collecting device is provided with multiple through holes through which the small-diameter vitamin D3 crystals can enter the crystal collecting device. The upper end of the crystal collecting device is at the same horizontal height as the blade.

[0020] In some embodiments, the crystallizer further includes a second feed channel extending horizontally on the upper part of the main body; the crystallization system further includes a first circulation pipeline, a first circulation pump, and a first filter, wherein the first circulation pipeline is sequentially connected to the first discharge port, the first circulation pump, the first filter, and the second feed channel.

[0021] Preferably, the first filter is equipped with a solvent inlet pipe and a gas inlet pipe. The solvent inlet pipe facilitates rinsing of the large-diameter crystals obtained in the first filter, cleaning the mother liquor off the crystal surfaces. The large-diameter vitamin D3 crystals obtained in the first filter can be directly sold after drying, testing, and packaging.

[0022] In some embodiments, the crystallization system further includes a second circulation pipeline, a second circulation pump, and a second filter, wherein the second circulation pipeline is sequentially connected to the second discharge port, the second circulation pump, the second filter, and the second feed channel.

[0023] Preferably, the second filter is equipped with a solvent inlet pipe and a gas inlet pipe. The solvent inlet pipe facilitates rinsing of the small-diameter crystals obtained in the second filter, cleaning the mother liquor from the crystal surface. The vitamin D3 crystals obtained in the second filter are small-diameter crystals, which can be dried, tested, packaged, and sold according to customer needs; alternatively, several batches can be collected and recrystallized to obtain larger-diameter crystals; or, before the next batch of crystals cools down, they can be dissolved in the crystallization solution by opening the second circulation pipe for reuse crystallization.

[0024] In some embodiments, the main body includes a cover located at the upper part of the main body and a cylinder located at the lower part of the main body, the cover and the cylinder being sealably connected, and the first feed channel being disposed on the cover.

[0025] In some embodiments, a heat exchange medium channel is provided on the outer surface of the main body, a heat exchange medium inlet pipe is provided at the lower part of the heat exchange medium channel, and a heat exchange medium outlet pipe is provided at the upper part of the heat exchange medium channel.

[0026] Vitamin D3 oil is typically a viscous substance after solvent removal. To introduce it into the crystallizer, it needs to be dissolved by heating with a crystallization solvent. After dissolution, it is fed into the crystallizer through the first feed channel. For cooling and crystallization, preferably, a heat exchange medium channel is provided on the outer surface of the main body. The heat exchange medium in the channel exchanges heat with the outer surface of the main body and the organic solution to be crystallized inside the main body's chamber. The external heat exchange surface does not adversely affect the laminar flow state of the liquid inside the crystallizer compared to the internal heat exchange surface. A heat exchange medium inlet pipe is provided at the lower part of the heat exchange medium channel, through which the heat exchange medium enters the channel. A heat exchange medium outlet pipe is provided at the upper part of the channel, through which the heat exchange medium exits. The heat exchange medium is typically selected from brine, ethylene glycol aqueous solution, propylene glycol aqueous solution, etc. The temperature of the heat exchange medium is generally 5–10°C lower than the crystallization temperature.

[0027] In some embodiments, the solution is obtained by dissolving vitamin D3 oil in an organic solution.

[0028] In some embodiments, the vitamin D3 oil contains 32-40 million IU / g of vitamin D3. This range is more conducive to increasing the yield of vitamin D3 crystals, while also improving crystal quality, such as increasing crystal size and bioavailability.

[0029] In some embodiments, the organic solvent is acetone or methyl formate. That is, acetone or methyl formate is used as the crystallization solvent. Acetone and methyl formate are both commonly used solvents, characterized by low boiling points, low toxicity, and large temperature-dependent solubility of vitamin D3. Their main advantage is that they more easily form needle-like crystals rather than powdery crystals.

[0030] In some embodiments, the mass ratio of the organic solvent to the vitamin D3 oil is 4–10:1. If the proportion of organic solvent is too small, the organic solution of vitamin D3 will be highly supersaturated, easily forming small crystals. If the proportion of organic solvent is too large, the organic solution of vitamin D3 will be less supersaturated, easily forming large crystals, but the amount of vitamin D3 in the crystallization mother liquor will be large, resulting in a lower crystallization yield. Using the aforementioned mass ratio can achieve the best overall crystallization effect.

[0031] In some embodiments, the cooling rate of the crystallization is 0.1 to 0.5 °C / min.

[0032] In some embodiments, the cooling crystallization temperature is -20 to 10°C. Using this temperature range is beneficial for improving crystallization yield and crystal quality.

[0033] In some embodiments, the crystallization method specifically includes the following steps: 1) adding the solution into the crystallizer through the first feed channel; 2) turning on the stirring unit to cool the crystallizer, turning on the first circulation pump and the first filter, filtering the suspension of vitamin D3 crystals discharged from the first outlet in the first filter, and returning the filtrate to the crystallizer through the second feed channel; 3) when the temperature inside the crystallizer drops to the crystallization temperature, turning on the second circulation pump and the second filter, filtering the suspension of vitamin D3 crystals discharged from the second outlet in the second filter, and returning the filtrate to the crystallizer through the second feed channel; 4) continuing steps 2) and 3) at the crystallization temperature until crystallization is complete.

[0034] Preferably, in step 1), an inert gas is also introduced into the crystallizer through the gas channel.

[0035] The present invention also provides a method for producing vitamin D3, the method comprising the steps of obtaining crude vitamin D3 oil by photochemical reaction using 7-dehydrocholesterol as raw material, purifying the crude vitamin D3 oil to obtain vitamin D3 oil, and crystallizing the vitamin D3 oil to obtain vitamin D3, wherein the crystallization adopts the aforementioned vitamin D3 crystallization method.

[0036] The present invention also provides a crystallization system for vitamin D3 crystallization, the crystallization system comprising a crystallizer, the crystallizer comprising a main body containing a chamber, a stirring unit disposed inside the chamber, a first feed channel for introducing the solution, and a discharge port, the discharge port comprising a first discharge port and a second discharge port, the first discharge port being less than the second discharge port being less than the center line of the chamber, the stirring unit comprising a stirring shaft and blades disposed on the stirring shaft, the blades being planar, and the plane on which the blades are located being substantially horizontal.

[0037] In some embodiments, the number of blades is four or more, preferably four.

[0038] In some embodiments, the distance between the blade and the bottom of the main body is 1 / 3 to 1 / 2 of the height of the main body.

[0039] In some embodiments, the lower part of the main body is cylindrical, the first discharge port is located at the center of the bottom of the main body, and the second discharge port is close to the edge of the bottom of the main body.

[0040] In some embodiments, the second discharge port is connected to a crystal collecting device located inside the chamber. The crystal collecting device is provided with multiple through holes with a diameter of 5-10 mm. The upper end of the crystal collecting device is at the same horizontal height as the blade.

[0041] In some embodiments, the crystallizer further includes a second feed channel extending horizontally on the upper part of the main body; the crystallization system further includes a first circulation pipeline, a first circulation pump, and a first filter, wherein the first circulation pipeline is sequentially connected to the first discharge port, the first circulation pump, the first filter, and the second feed channel.

[0042] Preferably, the first filter is provided with a solvent inlet pipe and a gas inlet pipe.

[0043] In some embodiments, the crystallization system further includes a second circulation pipeline, a second circulation pump, and a second filter, wherein the second circulation pipeline is sequentially connected to the second discharge port, the second circulation pump, the second filter, and the second feed channel.

[0044] Preferably, the second filter is provided with a solvent inlet pipe and a gas inlet pipe.

[0045] In some embodiments, the main body includes a cover located at the upper part of the main body and a cylinder located at the lower part of the main body, the cover and the cylinder being sealably connected, and the first feed channel being disposed on the cover.

[0046] In some embodiments, a heat exchange medium channel is provided on the outer surface of the main body, a heat exchange medium inlet pipe is provided at the lower part of the heat exchange medium channel, and a heat exchange medium outlet pipe is provided at the upper part of the heat exchange medium channel.

[0047] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0048] 1) The crystallizer used in the crystallization method of the present invention can maintain the vitamin D3 crystallization solution in a laminar flow state rotating around the axis of the crystallizer. During the crystallization process, the vitamin D3 crystallization solution can be in a state of minimal supersaturation and complete stillness. This can effectively control the formation and growth of vitamin D3 crystal nuclei, making it easy to form large-diameter vitamin D3 crystals. These crystals have a large particle size, a high melting point (meeting the pharmacopoeia's requirement of 84-88℃), a short melting range, fewer entrained impurities, high bioavailability, and very low solvent residue.

[0049] 2) Based on the different distribution of vitamin D3 crystals of different particle sizes in the crystallizer, the present invention sets a first discharge port and a second discharge port in the crystallizer. The first discharge port is used to discharge large-particle-size vitamin D3 crystals, and the second discharge port is used to discharge small-particle-size vitamin D3 crystals. This can conveniently and effectively separate large-particle-size and small-particle-size vitamin D3 crystals. Large-particle-size vitamin D3 crystals have large particle size, high melting point (conforming to the pharmacopoeia's 84-88℃), and short melting range. They also carry fewer impurities, have high bioavailability, and very low solvent residue. Small-particle-size vitamin D3 crystals can be used directly or recrystallized to improve particle size or crystal quality. Attached Figure Description

[0050] Figure 1 This is a schematic diagram of a crystallization system for vitamin D3 crystallization used in an embodiment of the present invention;

[0051] Figure 2 This is a top view of the stirring unit used in an embodiment of the present invention.

[0052] Wherein, 1-crystallizer; 11-cover; 111-first feed channel; 112-gas channel; 12-cylinder; 121-second feed channel; 131-first discharge port; 132-second discharge port; 133-crystal collecting device; 141-stirring shaft; 142-blade; 15-heat exchange medium channel; 151-heat exchange medium inlet pipe; 152-heat exchange medium outlet pipe; 2-second circulation pump; 3-second filter; 31-gas inlet pipe; 32-solvent inlet pipe; 4-first circulation pump; 5-first filter. Detailed Implementation

[0053] Existing technologies for preparing vitamin D3 crystals suffer from problems such as small crystal size, numerous impurities, low melting point, large solvent handling volume, high solvent residue, complex process steps, and insufficient yield. The innovation of this invention lies in the use of a specific crystallizer to crystallize vitamin D3 solutions, such as organic solutions of vitamin D3 oil. This crystallizer is equipped with a stirring unit, including a stirring shaft and blades mounted on the shaft. The blades are planar, and the plane on which the blades are located is essentially horizontal. During stirring, this unit maintains the aforementioned solution in a laminar flow state rotating around the crystallizer's axis. The inventors discovered in their research on the crystallization behavior of vitamin D3 that when a saturated vitamin D3 solution is under conditions of minimal supersaturation and complete stillness, vitamin D3 crystals with large particle sizes and melting points conforming to pharmacopoeia specifications can be obtained. The aforementioned crystallizer maintains a laminar flow state in the vitamin D3 solution, ensuring complete stillness. During slow cooling and crystallization, the solution achieves minimal supersaturation and complete stillness, resulting in large-diameter vitamin D3 crystals with melting points above 84°C, conforming to the pharmacopoeia's melting point range. The crystallizer maintains a layered state within the vitamin D3 solution, effectively controlling the formation and growth of crystal nuclei. It provides a favorable crystallization environment, promoting the formation of large-diameter vitamin D3 crystals.

[0054] During crystallization, vitamin D3 crystals of different sizes are suspended in the crystallization solvent. Driven by the blades of the stirring unit, the vitamin D3 crystals rotate around the crystallizer's axis, maintaining a laminar flow. Smaller crystal particles have relatively large surface drag and relatively small shape drag; larger crystal particles have relatively large shape drag and relatively small surface drag. That is, for smaller crystal particles, solution viscosity has a greater impact on particle motion, while the effect of gravity can be ignored. For larger crystal particles, gravity has a greater impact on particle motion, while the effect of solution viscosity can be ignored. When the stirring unit rotates, the blades directly act on the liquid solution, causing the liquid to rotate around the crystallizer's axis. Whether crystal particles rotate with the liquid depends on the magnitude of the viscous force acting on them, and is not significantly related to gravity. Smaller crystal particles experience a greater viscous force relative to gravity, making them more likely to rotate with the liquid. As they rotate, they experience a greater centrifugal force, resulting in smaller crystals accumulating near the inner wall of the crystallizer. Larger crystals, however, are more affected by gravity than viscous force and will accumulate near the bottom of the crystallizer. Meanwhile, large-diameter crystals are much less affected by viscous forces than by gravity, so unlike small-diameter crystals, they do not easily rotate with the solution and do not tend to move towards the inner wall of the crystallizer. Instead, they tend to slowly accumulate towards the center of the bottom of the crystallizer. Thus, a state is formed where large-diameter crystals accumulate at the center of the bottom and spin, while small-diameter crystals accumulate near the bottom of the inner wall of the crystallizer and rotate with the liquid.

[0055] This invention, by setting a first outlet and a second outlet in the crystallizer and controlling the distance of the first outlet from the center line of the chamber to be smaller than the distance of the second outlet from the center line of the chamber, allows large-diameter crystals to be discharged from the first outlet and small-diameter crystals to be discharged from the second outlet. This results in vitamin D3 crystals with sufficiently large particle size and a sufficiently high melting point, meeting pharmacopoeia requirements. Preferably, the first outlet is located at the center of the bottom of the main body, serving as the outlet for large-diameter crystals; the second outlet is near the edge of the bottom of the main body, serving as the outlet for small-diameter crystals. More preferably, the second outlet is connected to a crystal collecting device located inside the chamber. The crystal collecting device has multiple through holes through which smaller-diameter vitamin D3 crystals can enter. The upper end of the crystal collecting device is at the same horizontal level as the blades. The second outlet, serving as the outlet for small-diameter crystals, separates the fine crystals from the crystallizer, effectively reducing the number of crystal nuclei and avoiding the formation of a large number of small crystals, thus ensuring a high yield of large-diameter crystals.

[0056] Another innovation of this invention is that the crystallizer also includes a second feed channel extending horizontally at the upper part of the main body, and the crystallization system also includes a first circulation pipeline, a first circulation pump, and a first filter. The first circulation pipeline is sequentially connected to the first outlet, the first circulation pump, the first filter, and the second feed channel. Similarly, the crystallization system also includes a second circulation pipeline, a second circulation pump, and a second filter, with the second circulation pipeline sequentially connected to the second outlet, the second circulation pump, the second filter, and the second feed channel. The liquid flow direction in the second feed channel is the same as the liquid flow direction driven by the stirring unit within the crystallizer. The second feed channel serves as the interface for the crystallization filtrate to re-enter the crystallizer, forming a channel for the filtrate to enter the internal cavity of the crystallizer. This invention controls the organic solution of vitamin D3 in a laminar flow state, avoiding turbulent flow fields that are conducive to crystal nucleus formation but unfavorable to crystal nucleus growth, thus preventing the formation of a large number of tiny crystals. The liquid flow direction entering the crystallizer from the second feed channel is consistent with the mainstream direction within the crystallizer, reducing the adverse effects of liquid mixing on the flow state.

[0057] The first circulation line primarily separates the large-diameter crystals formed in the crystallizer to obtain a qualified product, and returns the filtrate to the crystallizer to prevent changes in the total amount of solution in the crystallizer from affecting the crystallization process. The second circulation line separates the formed microcrystals from the crystallizer, thus controlling the number of crystal nuclei. Returning the filtrate to the crystallizer controls the total amount of material in the crystallizer, preventing changes in material quantity from disrupting the laminar flow pattern. To obtain the largest possible crystals, the stirring speed can be kept as low as possible, and the flow rate in the second circulation line can be appropriately increased to control the concentration of crystal nuclei or microcrystals in the crystallizer at a low level, avoiding the formation of a large number of small-diameter crystals. Conversely, to obtain small-diameter crystals, the stirring speed can be increased appropriately, and the flow rate in the second circulation line can be decreased to control the concentration of crystal nuclei or microcrystals in the crystallizer at a higher level, thus forming smaller-diameter crystals. However, it is essential to control the flow pattern of the crystallization solution in the crystallizer to a laminar state as much as possible. Otherwise, strong turbulence will form a large number of crystal nuclei, eventually resulting in powdery microcrystals. These powdery microcrystals are prone to residual solvent and impurities due to their fast crystallization speed, leading to excessive solvent residue and low crystal bioavailability.

[0058] Another innovation of this invention lies in using vitamin D3 oil with a specific vitamin D3 content as a crystallization raw material. The vitamin D3 content in the vitamin D3 oil has a decisive influence on the crystallization yield and crystal quality. Crude vitamin D3 oil obtained from 7-dehydrocholesterol via photochemical reaction typically contains around 30 million IU / g. The inventors discovered that directly using this crude vitamin D3 oil as a raw material and employing a cooling crystallization process results in low yield and high cost. Crystallization with vitamin D3 oil containing at least 32 million IU / g obtained through chemical purification or chromatographic separation is more suitable. Preferably, the vitamin D3 oil contains 32-40 million IU / g of vitamin D3. Using the aforementioned vitamin D3-content essential oil as a crystallization raw material can improve the crystallization yield and crystal quality, such as larger crystal size and higher bioavailability.

[0059] Another innovation of this invention lies in controlling a specific cooling rate. The supersaturation of the organic solution of vitamin D3 is affected by both the concentration of vitamin D3 in the organic solution and the cooling rate. The inventors discovered that controlling the cooling rate to 0.1-0.5℃ / min allows for a relatively stable supersaturation of the organic solution, thereby improving the stability of the entire crystallization process. This reduces the impact of concentration fluctuations, temperature fluctuations, and vitamin D3 oil quality fluctuations on the final vitamin D3 crystallization yield and crystal quality.

[0060] The crystallization system of the present invention can be specifically implemented as follows:

[0061] like Figure 1 As shown, the crystallization system includes a crystallizer 1, a first circulation pipeline, a first circulation pump 4, a first filter 5, a second circulation pipeline, a second circulation pump 2, and a second filter 3. The crystallizer 1 includes a main body containing a chamber, a stirring unit disposed within the chamber, a first feed channel 111 for introducing a solution, a discharge port, and a gas channel 112 for introducing inert gas. The discharge port includes a first discharge port 131 and a second discharge port 132, with the first discharge port 131 being less than the second discharge port 132. The crystallizer 1 also includes a second feed channel 121 extending horizontally from the upper part of the main body. The first circulation pipeline is sequentially connected to the first discharge port, the first circulation pump 4, the first filter 5, and the second feed channel 121. The second circulation pipeline is sequentially connected to the second discharge port, the second circulation pump 2, the second filter 3, and the second feed channel 121. Both the first filter 5 and the second filter 3 are equipped with a solvent inlet pipe 32 and a gas inlet pipe 31.

[0062] like Figure 2As shown, the stirring unit includes a stirring shaft 141 and blades 142 disposed on the stirring shaft 141. The blades 142 are planar, and the plane on which the blades 142 are located is essentially horizontal. The number of blades 142 is not particularly limited, but preferably four or more, such as... Figure 2 As shown, four blades are more preferred. The height of the blades 142 is not particularly limited, but preferably, the distance between the blades 142 and the bottom of the main body is 1 / 3 to 1 / 2 of the height of the main body.

[0063] like Figure 1 As shown, the main body includes a cover 11 at the top and a cylinder 12 at the bottom. The cover 11 and cylinder 12 are sealed together. A first feed channel 111 is provided on the cover 11. The lower part of the main body is cylindrical. A first discharge port 131 is located at the center of the bottom of the main body; a second discharge port 132 is located near the edge of the bottom of the main body. The second discharge port 132 is connected to a crystal collecting device 133 located inside the chamber. The crystal collecting device 133 has multiple through holes with a diameter of 5-10 mm. The upper end of the crystal collecting device 133 is at the same horizontal height as the blade 142. A heat exchange medium channel 15 is provided on the outer surface of the main body. A heat exchange medium inlet pipe 151 is provided at the lower part of the heat exchange medium channel 15, and a heat exchange medium outlet pipe 152 is provided at the upper part of the heat exchange medium channel 15.

[0064] The technical solutions of the present invention will be described in detail below with reference to specific embodiments, so that those skilled in the art can better understand and implement the technical solutions of the present invention, but the present invention is not limited to the scope of the examples described.

[0065] Example 1

[0066] This embodiment provides a method for crystallizing vitamin D3, using... Figure 1 The crystallization system shown undergoes crystallization. The diameter of the lower cylinder is 1.0 m, the cylinder height is 0.85 m, the distance from the agitator to the bottom of the main body is 0.3 m, and the agitator diameter is 0.6 m. The specific steps of the crystallization method are as follows:

[0067] 1) Cooling crystallization

[0068] A methyl formate solution containing dissolved vitamin D3 oil is added to the crystallizer through the first feed channel. The temperature of the methyl formate solution is 28.5℃, the mass of vitamin D3 oil is 50.0 kg (vitamin D3 content is 34.59 million IU / g), and the mass of methyl formate is 320 kg. Nitrogen gas is used to displace oxygen in the crystallizer. The agitator in the crystallizer is turned on, and its rotation speed is set to 20 r / min, with a blade edge linear velocity of 0.6 m / s. The valve on the heat exchange medium inlet pipe outside the crystallizer is opened to introduce a -5℃ ethylene glycol aqueous solution into the heat exchange medium channel for cooling. The flow rate of the ethylene glycol aqueous solution is controlled, and the cooling rate is maintained at 0.3℃ / min. The first circulation pump and the first filter are turned on, and the flow rate of the first circulation pipeline is controlled at 1.20 m³ / min. 3 / h. The large-particle-size crystal suspension enriched near the first discharge port is pressurized by the first circulation pump and then filtered by the first filter. The filtered filtrate is returned to the crystallizer through the second feed channel.

[0069] When the temperature inside the crystallizer reaches 5℃, start the second circulation pump and the second filter, and control the flow rate of the second circulation pipeline to 0.25m³ / h. 3 The small-particle-size crystal suspension enriched near the second discharge port is pressurized by the second circulation pump and then filtered by the second filter. The filtered filtrate is returned to the crystallizer through the second feed channel. The temperature inside the crystallizer is controlled at 5°C, and crystallization is carried out continuously. The completion of the crystallization process is determined by a sight glass set on the inlet pipe of the first circulation pump.

[0070] 2) Washing and drying

[0071] After confirming that crystallization was complete, the first and second circulation pumps were turned off. The filter cake in the first filter was drained with nitrogen. 5L of methyl formate at 0℃ was slowly added into the first filter through the solvent inlet pipe to wash the filter cake. This washing was repeated twice, for a total of three washes. The washed filter cake was dried in a vacuum drying oven at 40℃ and a vacuum of ≥-0.085MPa for 8 hours. Finally, 35.6Kg of vitamin D3 crystals were obtained from the first filter (vitamin D3 content, i.e., bioavailability, was 40.23 million IU / g, D(50) was 278μm, melting point was 84.5~85.9℃, and the residual amount of methyl formate in the crystals was detected by gas headspace sampling and external standard method (no residual amount of methyl formate was detected). The specific rotation was +109.0°, and the crystallization yield of the first filter was calculated to be 82.8%.

[0072] The filter cake in the second filter was drained using nitrogen gas. Then, 1.5 L of methyl formate at 0°C was slowly added to the second filter through the solvent inlet pipe to wash the filter cake. This washing process was repeated twice, for a total of three washes. The washed filter cake was dried in a vacuum drying oven at 40°C and a vacuum of ≥-0.085 MPa for 8 hours. Finally, 3.4 kg of vitamin D3 crystals were obtained from the second filter (vitamin D3 content, i.e., bioavailability, was 39.98 million IU / g; D(50) was 212 μm; melting point was 82.0–83.9°C; methyl formate residue was 10.0 ppm), with a specific rotation of +107.8°. The calculated crystallization yield of the second filter was 7.9%.

[0073] Example 2

[0074] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the mass of methyl formate is adjusted to 200 kg.

[0075] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0076] Example 3

[0077] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the mass of methyl formate is adjusted to 500 kg.

[0078] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0079] Example 4

[0080] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the crystallization temperature in the crystallizer is controlled at -20°C.

[0081] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0082] Example 5

[0083] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the crystallization temperature in the crystallizer is controlled at 10°C.

[0084] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0085] Example 6

[0086] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the cooling rate in the crystallizer is controlled at 0.5℃ / min.

[0087] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0088] Example 7

[0089] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the cooling rate in the crystallizer is controlled at 0.1℃ / min.

[0090] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0091] Comparative Example 1

[0092] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the cooling rate in the crystallizer is controlled at 0.8℃ / min.

[0093] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0094] Comparative Example 2

[0095] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the flow rate of the second circulation pipeline is controlled to be 0 m³ / s. 3 / h.

[0096] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0097] Comparative Example 3

[0098] This embodiment provides a method for crystallizing vitamin D3. The crystallization system and specific crystallization steps are basically the same as in Embodiment 1, except that the mass of vitamin D3 oil added is also 50.0 kg, but the vitamin D3 content is 31.58 million IU / g.

[0099] The final results of obtaining vitamin D3 crystals from the first and second filters are shown in Table 1 below.

[0100]

[0101] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for crystallizing vitamin D3, comprising passing a solution containing dissolved vitamin D3 into a crystallization system for crystallization to obtain vitamin D3 crystals, wherein the crystallization system includes a crystallizer, the crystallizer comprising a main body containing a chamber, a stirring unit disposed inside the chamber, a first feed channel for introducing the solution, and a discharge port, characterized in that: The discharge port includes a first discharge port and a second discharge port. The distance of the first discharge port from the center line of the chamber is smaller than the distance of the second discharge port from the center line of the chamber. The crystallization method controls the stirring conditions of the stirring unit to discharge large-diameter vitamin D3 crystals from the first discharge port and small-diameter vitamin D3 crystals from the second discharge port. The term "large particle size" refers to a D50 particle size of 250-300 micrometers, and the term "small particle size" refers to a D50 particle size of less than 250 micrometers. The stirring unit includes a stirring shaft and blades disposed on the stirring shaft. The blades are planar and the plane on which the blades are located is basically horizontal. The crystallizer also includes a second feed channel extending horizontally on the upper part of the main body; the crystallization system also includes a first circulation pipeline, a first circulation pump, and a first filter, wherein the first circulation pipeline is sequentially connected to the first discharge port, the first circulation pump, the first filter, and the second feed channel; The crystallization system further includes a second circulation pipeline, a second circulation pump, and a second filter. The second circulation pipeline is connected in sequence to the second discharge port, the second circulation pump, the second filter, and the second feed channel. The solution is obtained by dissolving vitamin D3 oil in an organic solution; the vitamin D3 oil contains 32-40 million IU / g of vitamin D3. The cooling rate during crystallization is 0.1–0.5 °C / min.

2. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The distance between the blade and the bottom of the main body is 1 / 3 to 1 / 2 of the height of the main body; and / or, in the crystallization method, the rotation speed of the stirring unit is controlled to be 5-50 rpm.

3. The method for crystallizing vitamin D3 according to claim 2, characterized in that: The number of blades is four or more; and / or, in the crystallization method, the liquid level of the solution is controlled above the blades.

4. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The term "large particle size" refers to a D50 particle size of 280-300 micrometers.

5. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The lower part of the main body is cylindrical, and the first discharge port is located at the center of the bottom of the main body; the second discharge port is close to the edge of the bottom of the main body.

6. The method for crystallizing vitamin D3 according to claim 2, characterized in that: The second discharge port is connected to a crystal collecting device located inside the chamber. The crystal collecting device is provided with multiple through holes, through which the small-diameter vitamin D3 crystals can enter the crystal collecting device. The upper end of the crystal collecting device is at the same horizontal height as the blade.

7. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The first filter is equipped with a solvent inlet pipe and a gas inlet pipe.

8. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The second filter is equipped with a solvent inlet pipe and a gas inlet pipe.

9. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The organic solvent is acetone or methyl formate; and / or, the mass ratio of the organic solvent to the vitamin D3 oil is 4 to 10:1; and / or, the crystallization temperature is -20 to 10°C.

10. The method for crystallizing vitamin D3 according to claim 1, characterized in that: The crystallization method includes the following steps: 1) adding the solution into the crystallizer through the first feed channel; 2) turning on the stirring unit to cool the crystallizer, turning on the first circulation pump and the first filter, filtering the suspension of vitamin D3 crystals discharged from the first outlet in the first filter, and returning the filtrate to the crystallizer through the second feed channel; 3) when the temperature inside the crystallizer drops to the crystallization temperature, turning on the second circulation pump and the second filter, filtering the suspension of vitamin D3 crystals discharged from the second outlet in the second filter, and returning the filtrate to the crystallizer through the second feed channel; 4) continuing steps 2) and 3) at the crystallization temperature until crystallization is complete.

11. A method for producing vitamin D3, the method comprising the steps of obtaining crude vitamin D3 oil from 7-dehydrocholesterol via a photochemical reaction, purifying the crude vitamin D3 oil to obtain vitamin D3 oil, and crystallizing the vitamin D3 oil to obtain vitamin D3, characterized in that: The crystallization is performed using the vitamin D3 crystallization method according to any one of claims 1-10.

12. A crystallization system for vitamin D3 crystallization, the crystallization system comprising a crystallizer, the crystallizer comprising a main body containing a chamber, a stirring unit disposed inside the chamber, a first feed channel for introducing the solution, and a discharge port, characterized in that: The discharge port includes a first discharge port and a second discharge port. The distance of the first discharge port from the center line of the chamber is smaller than the distance of the second discharge port from the center line of the chamber. The stirring unit includes a stirring shaft and blades disposed on the stirring shaft. The blades are planar and the plane on which the blades are located is basically horizontal. The distance between the blade and the bottom of the main body is 1 / 3 to 1 / 2 of the height of the main body; The second discharge port is located near the edge of the bottom of the main body and is disposed on the bottom of the main body; The second discharge port is connected to a crystal collecting device located inside the chamber. The crystal collecting device is provided with multiple through holes with a diameter of 5-10 mm. The upper end of the crystal collecting device is at the same horizontal height as the blade. The crystallizer also includes a second feed channel extending horizontally on the upper part of the main body; the crystallization system also includes a first circulation pipeline, a first circulation pump, and a first filter, wherein the first circulation pipeline is sequentially connected to the first discharge port, the first circulation pump, the first filter, and the second feed channel; The crystallization system also includes a second circulation pipeline, a second circulation pump, and a second filter. The second circulation pipeline is sequentially connected to the second discharge port, the second circulation pump, the second filter, and the second feed channel.

13. The crystallization system for vitamin D3 crystallization according to claim 12, characterized in that: The lower part of the main body is cylindrical, and the first discharge port is located at the center of the bottom of the main body.

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