Device and process for continuous preparation of glucosamine sulfate or phosphate compound

Abstract

The continuous preparation apparatus and process for glucosamine sulfate or phosphate compounds described in this invention comprises at least three chromatographic separation units connected in a specific manner to form a continuously operable closed-loop system. Each separation unit is connected via pipelines to a chromatographic column, a delivery pump, a switching valve, and a feed tank. The switching valve controls the flow direction of the feed liquid, solution, water, and waste liquid, creating a dual-function system capable of operating independently or in conjunction with other separation units. This invention utilizes a real-time dynamic axial compression column, significantly reducing the dead volume at the column head, thereby improving both separation efficiency and the concentration of glucosamine sulfate or glucosamine phosphate solutions. The alternating use of alkali and acid, along with a matching preparation process, activates weak base exchange groups to achieve exchange capacity similar to strong base exchange groups, while also promptly removing impurities adsorbed on the packing material, thus improving product quality. The entire process is a closed-loop, continuous operation via pipelines, facilitating automated control.

Description

Technical Field

[0001] The invention relates to a device and process for continuously preparing glucosamine sulfate or phosphate compounds. Background Art

[0002] Glucosamine is a natural amino monosaccharide and a specific substrate for the production of amino polysaccharides and proteoglycans in the human body. It is widely present in human soft tissues, body fluids, mucous membranes, and cartilage tissues. Exogenous supplementation of glucosamine compounds has pharmacological effects such as stimulating chondrocytes to synthesize proteoglycans, anti-inflammatory and analgesic, and protecting cartilage. It is a specific drug for the prevention and treatment of bone and joint diseases. Common varieties of glucosamine compounds include: glucosamine sulfate, glucosamine hydrochloride, glucosamine sulfate sodium salt, glucosamine sulfate potassium salt, glucosamine calcium salt, and N-glucosamine. Among the applications of glucosamine compounds, glucosamine sulfate containing sulfate groups has a more lasting and significant effect in the treatment of osteoarthritis, with fewer adverse reactions, and has a broader market application prospect in the treatment of osteoarthritis.

[0003] The preparation methods of glucosamine sulfate include organic strong base method, ion exchange method, direct sulfuric acid degradation method, ionic liquid medium synthesis method and dialysis membrane exchange method. Chem.Ber.312197 first disclosed the method of preparing glucosamine sulfate by organic strong base method in 1898. Since then, US Pat.3683076, CN201010176479.6, CN201410458623.3, and CN201911098390.X have successively disclosed similar methods for preparing glucosamine sulfate, using alcohol base to capture the acid radical of glucosamine hydrochloride, quickly separating the generated sodium chloride crystals, and adding concentrated sulfuric acid to the clear liquid to pH 3 to 3.5 to generate glucosamine sulfate, and then precipitating with organic solvent and vacuum drying to obtain glucosamine sulfate solid.

[0004] IT.19186 disclosed a method for preparing glucosamine sulfate by ion exchange in 1963. GB.1056331 and CN201610908900.5 also disclosed similar methods for preparing glucosamine sulfate, wherein a strong alkaline anion exchange resin is saturated with a sodium sulfate aqueous solution to transform the resin carrier into a sulfate type, and then the transformed resin carrier is used to exchange the glucosamine hydrochloride solution into a glucosamine sulfate solution, and further vacuum concentration, solvent precipitation, freeze drying, ethanol washing and other steps are performed to obtain glucosamine sulfate solid. CN201610908900.5 and CN201710345968.1 disclose another method for preparing glucosamine sulfate by using a strong alkaline anion exchange resin, wherein the strong alkaline anion exchange resin is first treated with an alkaline solution to convert it into an alkaline type, and then the glucosamine hydrochloride solution is exchanged into a glucosamine solution with an alkaline resin carrier, and a certain amount of sulfuric acid solution is further added to neutralize it into a glucosamine sulfate solution, and the glucosamine sulfate solid is obtained by direct freeze drying, or organic solvent precipitation and vacuum drying. WO 03 / 053448 A1 and CN201711334765.9 disclose a method for preparing glucosamine sulfate by electrodialysis membrane ion exchange. The method uses electrode current to drive charged ions in a glucosamine hydrochloride aqueous solution or a sulfate aqueous solution to migrate to different poles, and performs ion exchange at different ion exchange membranes, permeates into different dialysis tanks, exchanges the glucosamine hydrochloride solution into a glucosamine sulfate solution, and obtains a glucosamine sulfate solid after further drying.

[0005] CN01128458.7, CN20081007161.7, CN201210110261.X, and CN201210200776.9 disclose methods for preparing glucosamine sulfate by directly degrading chitin with sulfuric acid. Chitosan is degraded with a high-concentration sulfuric acid solution, and the hydrolyzate is decolorized, deacidified, concentrated, and dried to obtain glucosamine sulfate. CN201610477180.1 and CN201911009257.2 disclose methods for preparing glucosamine sulfate by degrading chitin with sulfuric acid in the presence of an ionic liquid. The degradation product is modified with bile acid in an organic solvent system, bile acylated glucosamine, neutralized with a sulfuric acid solution, concentrated, dried, and other steps to obtain glucosamine sulfate.

[0006] CN201110142458.7, CN201210464663.x, and CN201811398447.3 disclose a method for preparing glucosamine sulfate by degrading chitosan with ionic liquid or sulfuric acid. The chitosan is degraded with ionic liquid or sulfuric acid, and the degradation liquid is filtered, concentrated, ethanol precipitated, and freeze-dried to obtain glucosamine sulfate.

[0007] CN201410740474.X (2014) discloses a method for preparing glucosamine sulfate using N-acetylglucosamine as a raw material. The method uses a strong alkaline ion exchange resin to catalyze the deacetylation of an N-acetylglucosamine solution, and the N-acetylglucosamine solution is continuously circulated through a strong alkaline ion exchange resin bed until it is completely deacetylated, and then concentrated and dried to obtain glucosamine sulfate.

[0008] Different inventions demonstrate the diversity of glucosamine sulfate preparation methods and product characteristics. The organic strong base method, chitin and chitosan degradation method have high test solution concentrations in the overall process and are easy to prepare on a large scale, but the product purity is relatively low. The ion exchange method includes the electrodialysis method, which has a low test solution concentration in the process, but can produce a product of higher purity. These inventions provide suitable preparation methods for glucosamine sulfate for different application levels.

[0009] The ion exchange method is the preferred method for preparing high-purity glucosamine sulfate. It has a simple device, is easy to operate, and has no heavy pollution sources. However, this method uses strong base anion resin fillers, and the exchange capacity often drops sharply after multiple cycles. First, some quaternary ammonium groups will dissociate and lose the ability to split neutral salts; second, the contamination of the resin fillers by strong impurities in the raw materials causes the resin fillers to lose their exchange effect. Strong base anion resin fillers all have weak base anion groups. The differences in the adsorption and analytical exchange mechanisms of different ions will cause the adsorption and chelation accumulation of strong impurities on the resin carrier. If not handled in time, they will be continuously released during operation and contaminate the product. If a simple ion exchange device is used, the dead volume at the column head not only seriously affects the separation efficiency, but also greatly increases the elution exchange time. These problems have not yet received attention and resolution in the disclosed patents or literature on the preparation of glucosamine sulfate by ion exchange. Summary of the invention

[0010] The purpose of the present invention is to provide a continuous preparation device and process for glucosamine sulfate or phosphate compounds, which can not only ensure that the weak base exchange group and the strong base exchange group have similar exchange capacity, but also can timely remove strongly acting adsorbed and chelated impurities, improve the quality of the produced glucosamine sulfate products, and realize pipelined fully enclosed continuous operation, which is efficient and safe.

[0011] The present invention is implemented as follows: a continuous preparation device for glucosamine sulfate or phosphate compound, wherein the continuous preparation device comprises at least three chromatographic separation units, namely, a first separation unit, a second separation unit, and a third separation unit are connected in a certain manner to form a continuously operable closed-loop system, and each separation unit comprises a chromatographic column, an infusion pump, a switching valve, and a liquid storage tank;

[0012] The first separation unit comprises a first chromatography column, a first pre-column switching valve, and a first post-column switching valve; the first chromatography column is connected to the Q1 channel of the first pre-column switching valve in front of the column, and the first post-column switching valve is connected to the H1 channel of the first post-column switching valve in the back of the column;

[0013] The second separation unit comprises a second chromatography column, a second pre-column switching valve, and a second post-column switching valve; the pre-column of the second chromatography column is connected to the Q2 channel of the second pre-column switching valve, and the post-column is connected to the H2 channel of the second post-column switching valve;

[0014] The third separation unit comprises a third chromatography column, a third pre-column switching valve, and a third post-column switching valve; the pre-column of the third chromatography column is connected to the Q3 channel of the pre-column switching valve, and the post-column is connected to the H3 channel of the post-column switching valve;

[0015] The three pre-column switching valves are respectively provided with five switching channels, namely, QA, QB, QC, QD and QE. The A1 channel of the first pre-column switching valve, the A2 channel of the second pre-column switching valve and the A3 channel of the third pre-column switching valve are respectively connected to the first liquid collection tank through pipelines; the B1 channel of the first pre-column switching valve, the B2 channel of the second pre-column switching valve and the B3 channel of the third pre-column switching valve are respectively connected to the second liquid collection tank through pipelines; the C1 channel of the first pre-column switching valve, the C2 channel of the second pre-column switching valve and the C3 channel of the third pre-column switching valve are respectively connected to the second liquid collection tank through pipelines. The outlet end of the first infusion pump is connected through a pipeline, and the inlet end of the first infusion pump is connected to the first liquid supply storage tank; the D1 channel of the first pre-column switching valve, the D2 channel of the second pre-column switching valve, and the D3 channel of the third pre-column switching valve are respectively connected to the outlet end of the second infusion pump through pipelines, and the inlet end of the second infusion pump is connected to the second liquid supply storage tank; the E1 channel of the first pre-column switching valve, the E2 channel of the second pre-column switching valve, and the E3 channel of the third pre-column switching valve are respectively connected to the outlet end of the third infusion pump through pipelines, and the inlet end of the third infusion pump is connected to the third liquid supply storage tank;

[0016] The three post-column switching valves are respectively provided with five switching channels, HV, HW, HX, HY and HZ; the V1 channel of the first post-column switching valve, the V2 channel of the second post-column switching valve and the V3 channel of the third post-column switching valve are respectively connected to the third liquid collection tank through pipelines; the W1 channel of the first post-column switching valve, the W2 channel of the second post-column switching valve and the W3 channel of the third post-column switching valve are respectively connected to the outlet end of the fifth infusion pump through pipelines, and the inlet end of the fifth infusion pump is connected to the fourth liquid supply tank; the first post-column switching valve The X1 channel of the second post-column switching valve, the X2 channel of the second post-column switching valve, and the X3 channel of the third post-column switching valve are respectively connected to the outlet end of the fourth infusion pump through pipelines, and the inlet end of the fourth infusion pump is connected to the third liquid supply tank; the Y1 channel of the first post-column switching valve, the Y2 channel of the second post-column switching valve, and the Y3 channel of the third post-column switching valve are respectively connected to the fifth liquid collection tank; the Z1 channel of the first post-column switching valve, the Z2 channel of the second post-column switching valve, and the Z3 channel of the third post-column switching valve are respectively connected to the fourth liquid collection tank through pipelines.

[0017] The pre-column switching valve and post-column switching valve of the present invention both have good sealing performance. When each switching valve switches to a certain channel, the channel is connected, and the remaining channels are in a disconnected state. The chromatography column is a real-time dynamic axial compression chromatography column, which has the functions of automatically adjusting the column bed height and compacting the column bed in real time; the chromatography column can perform bidirectional chromatography operations. The infusion pump is a corrosion-resistant diaphragm pump or a plunger pump.

[0018] The continuous preparation process of glucosamine sulfate or phosphate compound of the present invention performs corresponding procedures, program combinations, and post-treatment steps in the order of alkali treatment, acid treatment, and glucosamine hydrochloride exchange treatment in three chromatographic separation units to activate the resin filler and prepare glucosamine sulfate compound or glucosamine phosphate compound; the corresponding procedures are respectively procedure 1, procedure 2, procedure 3, procedure 4, procedure 5, procedure 6, procedure 7, procedure 8, and procedure 9;

[0019] The alkali used in the alkali treatment is: 1-10% sodium hydroxide or potassium hydroxide aqueous solution;

[0020] The acid used in the acid treatment is: 1-10% sulfuric acid or phosphoric acid or sodium hydrogen sulfate or potassium hydrogen sulfate or sodium dihydrogen phosphate or potassium dihydrogen phosphate aqueous solution;

[0021] The glucosamine hydrochloride exchange treatment uses a glucosamine hydrochloride aqueous solution with a concentration of 15% to saturation; the resin filler is an alkaline ion exchange resin; and the water used in the aqueous solution is sterilized deionized water;

[0022] The procedure 1 is: switching the first column front switching valve to the Q1-D1 channel mode, switching the first column back switching valve to the H1-Z1 channel mode, starting the second infusion pump to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then closing the second infusion pump; then, switching the first column front switching valve to the Q1-E1 channel mode, switching the first column back switching valve to the H1-Y1 channel mode, starting the third infusion pump to pass deionized water until the pH value of the effluent is ≤8.5, and closing the third infusion pump;

[0023] The procedure 2 is: switch the first column front switching valve to the Q1-C1 channel mode, switch the first column back switching valve to the H1-V1 channel mode, start the first infusion pump, and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, close the first infusion pump; then, switch the first column front switching valve to the Q1-E1 channel mode, switch the first column back switching valve to the H1-Y1 channel mode, start the third infusion pump, add deionized water until the pH value of the effluent is greater than 5.5, and close the third infusion pump;

[0024] The procedure 3 is: switch the second column front switching valve to the Q2-D2 channel mode, switch the second column back switching valve to the H2-Z2 channel mode, start the second infusion pump to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then turn off the second infusion pump; then, switch the second column front switching valve to the Q2-E2 channel mode, switch the second column back switching valve to the H2-Y2 channel mode, start the third infusion pump to pass deionized water until the pH value of the effluent is ≤8.5, and turn off the third infusion pump;

[0025] The procedure 4 is: switch the switching valve before the first column to the Q1-A1 channel mode, switch the switching valve after the first column to the H1-W1 channel mode, start the fifth infusion pump, supersaturate the glucosamine hydrochloride aqueous solution, until the effluent just detects Cl - , turn off the fifth infusion pump; then, switch the switching valve before the first column to the Q1-B1 channel mode, switch the switching valve after the first column to the H1-X1 channel mode, start the fourth infusion pump, pass 1 to 3 times the volume of resin deionized water, and turn off the fourth infusion pump;

[0026] The procedure 5 is: switch the second column front switching valve to the Q2-C2 channel mode, switch the second column back switching valve to the H2-V2 channel mode, start the first infusion pump, and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, close the first infusion pump; then, switch the second column front switching valve to the Q2-E2 channel mode, switch the second column back switching valve to the H2-Y2 channel mode, start the third infusion pump, add deionized water until the pH value of the effluent is greater than 5.5, and close the third infusion pump;

[0027] The procedure 6 is: switch the switching valve before the third column to the Q3-D3 channel mode, switch the switching valve after the third column to the H3-Z3 channel mode, start the second infusion pump to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then turn off the second infusion pump; then, switch the switching valve before the third column to the Q3-E3 channel mode, switch the switching valve after the third column to the H3-Y3 channel mode, start the third infusion pump to pass deionized water until the pH value of the effluent is ≤8.5, and turn off the third infusion pump;

[0028] The procedure 7 is: switch the second column front switching valve to the Q2-A2 channel mode, switch the second column back switching valve to the H2-W2 channel mode, start the fifth infusion pump, supersaturate the glucosamine hydrochloride aqueous solution until the effluent just detects Cl - , turn off the fifth infusion pump; then, switch the second column front switching valve to the Q2-B2 channel mode, switch the second column rear switching valve to the H2-X2 channel mode, start the fourth infusion pump, pass 1 to 3 times the volume of resin deionized water, and turn off the fourth infusion pump;

[0029] The procedure 8 is: switch the switching valve before the third column to the Q3-C3 channel mode, switch the switching valve after the first column to the H3-V3 channel mode, start the first infusion pump, and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, close the first infusion pump; then, switch the switching valve before the third column to the Q3-E3 channel mode, switch the switching valve after the third column to the H3-Y3 channel mode, start the third infusion pump, add deionized water until the pH value of the effluent is greater than 5.5, and close the third infusion pump;

[0030] The procedure 9 is: switch the switching valve before the third column to the Q3-A3 channel mode, switch the switching valve after the third column to the H3-W3 channel mode, start the fifth infusion pump, supersaturate the glucosamine hydrochloride aqueous solution, until the effluent just detects Cl - , turn off the fifth infusion pump; then, switch the switching valve before the third column to the Q3-B3 channel mode, switch the switching valve after the third column to the H3-X3 channel mode, start the fourth infusion pump, pass 1 to 3 times the volume of resin deionized water, and turn off the fourth infusion pump;

[0031] The program combination is: 1. Execute program 4, program 5 and program 6 in the first, second and third separation units respectively; 2. Execute program 1, program 7 and program 8 in the first, second and third separation units respectively; 3. Execute program 2, program 3 and program 9 in the first, second and third separation units respectively; 4. Then, repeat steps 1 to 3 continuously, so that glucosamine sulfate solution or glucosamine phosphate solution can be continuously prepared;

[0032] The post-treatment process is to spray-dry the glucosamine sulfate solution or glucosamine phosphate solution obtained by the circular preparation to obtain a glucosamine sulfate compound solid powder or a glucosamine phosphate compound solid powder; or to obtain a glucosamine sulfate compound solid or a glucosamine phosphate compound solid by freeze-drying.

[0033] The beneficial effects of the present invention are that the real-time dynamic axial compression chromatography column is used to greatly reduce the dead volume of the column head, improve the separation efficiency, save reagents and water, and improve the concentration of the prepared glucosamine sulfate solution or glucosamine phosphate solution; the use of alkali and acid alternation and a matching reverse preparation process can not only activate the weak base exchange group to have an exchange capacity similar to that of the strong base exchange group, but also timely remove the adsorbed and chelated impurities on the filler carrier, thereby improving the quality of the produced glucosamine sulfate product or glucosamine phosphate product; the use of a pipelined closed and continuous operation mode is convenient for automatic control and operation; independent acid, alkali, water, raw material liquid supply and waste liquid receiving systems can avoid cross contamination, and are efficient, hygienic, safe, energy-saving and consumption-saving. Independent wastewater treatment or reuse can also be performed. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 It is a structural schematic diagram of the present invention.

[0035] In the figure: 11. the first chromatography column; 12. the switching valve before the first column; 13. the switching valve after the first column; 21. the second chromatography column; 22. the switching valve before the second column; 23. the switching valve after the second column; 31. the third chromatography column; 32. the switching valve before the third column; 33. the switching valve after the third column; 41. the first infusion pump; 42. the second infusion pump; 43. the third infusion pump; 44. the fourth infusion pump; 45. the fifth infusion pump; 51. the first liquid supply tank; 52. the second liquid supply tank; 53. the third liquid supply tank; 54. the fourth liquid supply tank; 61. the first liquid collection tank; 62. the second liquid collection tank; 63. the third liquid collection tank; 64. the fourth liquid collection tank; 65. the fifth liquid collection tank. DETAILED DESCRIPTION

[0036] The present invention provides a device and process for continuously preparing glucosamine sulfate or phosphate compounds, such as Figure 1As shown, in the continuous preparation device: the front ends of three axially compressed first chromatography columns 11, second chromatography columns 21, and third chromatography columns 31 of the same model are respectively connected to the Q1 channel of the first column front switching valve 12, the Q2 channel of the second column front switching valve 22, and the Q3 channel of the third column front switching valve 32 through pipelines; the rear ends of the columns are respectively connected to the H1 channel of the first column rear switching valve 13, the H2 channel of the second column rear switching valve 23, and the H3 channel of the third column rear switching valve 33 through pipelines; the A1 channel of the first column front switching valve 12, the A2 channel of the second column front switching valve 22, and the A3 channel of the third column front switching valve 32 They are respectively connected to the first liquid collection tank 61; the B1 channel of the first column front switching valve 12, the B2 channel of the second column front switching valve 22, and the B3 channel of the third column front switching valve 32 are respectively connected to the second liquid collection tank 62; the C1 channel of the first column front switching valve 12, the C2 channel of the second column front switching valve 22, and the C3 channel of the third column front switching valve 32 are respectively connected to the outlet end of the first infusion pump 41, and then connected to the first liquid supply tank 51; the D1 channel of the first column front switching valve 12, the D2 channel of the second column front switching valve 22, and the D3 channel of the third column front switching valve 32 are respectively connected to the outlet end of the second infusion pump 42 , and then connected to the second liquid supply storage tank 52; the E1 channel of the first column front switching valve 12, the E2 channel of the second column front switching valve 22, and the E3 channel of the third column front switching valve 32 are respectively connected to the outlet end of the third infusion pump 43, and then connected to the third liquid supply storage tank 53; the W1 channel of the first column rear switching valve 13, the W2 channel of the second column rear switching valve 23, and the W3 channel of the third column rear switching valve 33 are respectively connected to the outlet end of the fifth infusion pump 45, and then connected to the fifth liquid supply storage tank 54; the V1 channel of the first column rear switching valve 13, the V2 channel of the second column rear switching valve 23, and the V3 channel of the third column rear switching valve 33 The channels are respectively connected to the third liquid collecting tank 63; the X1 channel of the first post-column switching valve 13, the X2 channel of the second post-column switching valve 23, and the X3 channel of the third post-column switching valve 33 are respectively connected to the outlet end of the fourth infusion pump 44, and then connected to the third liquid supply tank 53; the Y1 channel of the first post-column switching valve 13, the Y2 channel of the second post-column switching valve 23, and the Y3 channel of the third post-column switching valve 33 are respectively connected to the fifth liquid collecting tank 65; the Z1 channel of the first post-column switching valve 13, the Z2 channel of the second post-column switching valve 23, and the Z3 channel of the third post-column switching valve 33 are respectively connected to the fourth liquid collecting tank 64.

[0037] Fill the first chromatography column 11, the second chromatography column 21, and the third chromatography column 31 with equal amounts and appropriate volumes of alkaline ion exchange resins, respectively, debug the device as required, make sure that the pathways are connected normally, that the infusion pumps and switching valves can work normally, and clean the entire system with sterile deionized water.

[0038] The following is the process flow of the present invention.

[0039] In such Figure 1 In the continuous preparation device shown, the acid solution, alkaline solution and glucosamine hydrochloride solution of the selected concentration are respectively injected into the first liquid supply storage tank 51, the second liquid supply storage tank 52 and the fourth liquid supply storage tank 54, and sterilized deionized water is injected into the third liquid supply storage tank 53.

[0040] First, execute procedure 1, switch the first column pre-switching valve 12 to the Q1-D1 channel mode, switch the first column post-switching valve 13 to the H1-Z1 channel mode, start the second infusion pump 42, and after passing 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of the alkaline solution, turn off the second infusion pump 42. Next, switch the first column pre-switching valve 12 to the Q1-E1 channel mode, switch the first column post-switching valve 13 to the H1-Y1 channel mode, start the third infusion pump 43 to pass deionized water until the pH value of the effluent is ≤8.5, and turn off the third infusion pump 43. At this time, the first chromatography column 11 has completed the alkali treatment process. Second, execute procedure 2, switch the first column pre-switching valve 12 to the Q1-C1 channel mode, switch the first column post-switching valve 13 to the H1-V1 channel mode, start the first infusion pump 41, and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration of the acid solution, turn off the first infusion pump 41. Next, the first column pre-switching valve 12 is switched to the Q1-E1 channel mode, the first column post-switching valve 13 is switched to the H1-Y1 channel mode, the third infusion pump 43 is started, deionized water is added until the pH value of the effluent is greater than 5.5, and the third infusion pump 43 is turned off. While executing procedure 2, execute procedure 3, switch the second column pre-switching valve 22 to the Q2-D2 channel mode, switch the second column post-switching valve 23 to the H2-Z2 channel mode, start the second infusion pump 42 to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then turn off the second infusion pump 42. Next, switch the second column pre-switching valve 22 to the Q2-E2 channel mode, switch the second column post-switching valve 23 to the H2-Y2 channel mode, start the third infusion pump 43 to add deionized water until the pH value of the effluent is ≤8.5, and turn off the third infusion pump 42. At this time, the first chromatography column 11 has completed the acid treatment process, and the second chromatography column 21 has completed the alkali treatment process. Third, execute procedure 4, switch the first column front switching valve 12 to the Q1-A1 channel mode, switch the first column rear switching valve 13 to the H1-W1 channel mode, start the fifth infusion pump 45, and pass the saturated aqueous solution of glucosamine hydrochloride until Cl is just detected in the effluent. -, turn off the fifth infusion pump 45. Next, switch the first pre-column switching valve 12 to the Q1-B1 channel mode, switch the first post-column switching valve 13 to the H1-X1 channel mode, start the fourth infusion pump 44, pass 1 to 3 times the volume of resin with deionized water, and turn off the fourth infusion pump 44; at the same time, execute procedure 5, switch the second pre-column switching valve 22 to the Q2-C2 channel mode, switch the second post-column switching valve 23 to the H2-V2 channel mode, start the first infusion pump 41, pass 1.5 to 5 times the volume of resin with a 3 to 8% mass concentration acid solution, and then turn off the first infusion pump 41. Next, the second column pre-switching valve 22 is switched to the Q2-E2 channel mode, the second column post-switching valve 23 is switched to the H2-Y2 channel mode, the third infusion pump 43 is started, deionized water is added until the pH value of the effluent is greater than 5.5, and the third infusion pump 43 is closed; and program 6 is also executed simultaneously, the third column pre-switching valve 32 is switched to the Q3-D3 channel mode, the third column post-switching valve 33 is switched to the H3-Z3 channel mode, the second infusion pump 42 is started to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then the second infusion pump 42 is closed. Next, the third column pre-switching valve 32 is switched to the Q3-E3 channel mode, the third column post-switching valve 33 is switched to the H3-Y3 channel mode, the third infusion pump 43 is started to pass deionized water until the pH value of the effluent is ≤8.5, and the third infusion pump 43 is closed. At this time, the first chromatography column 11 has completed the preparation of glucosamine sulfate, the second chromatography column 21 has completed the acid treatment process, and the third chromatography column 31 has completed the alkali treatment process. Fourth, execute procedure 1, switch the first column pre-switching valve 12 to the Q1-D1 channel mode, switch the first column post-switching valve 13 to the H1-Z1 channel mode, start the second infusion pump 42 to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then turn off the second infusion pump 42. Next, switch the first column pre-switching valve 12 to the Q1-E1 channel mode, switch the first column post-switching valve 13 to the H1-Y1 channel mode, start the third infusion pump 43 to pass deionized water until the pH value of the effluent is ≤8.5, and turn off the third infusion pump 43; at the same time, execute procedure 7, switch the second column pre-switching valve 22 to the Q2-A2 channel mode, switch the second column post-switching valve 23 to the H2-W2 channel mode, start the fifth infusion pump 45, pass the saturated aqueous solution of glucosamine hydrochloride, until the effluent just detects Cl -, turn off the fifth infusion pump 45. Then, switch the second column pre-switching valve 22 to the Q2-B2 channel mode, the second column post-switching valve 23 to the H2-X2 channel mode, start the fourth infusion pump 44, pass 1 to 3 times the volume of resin deionized water, and turn off the fourth infusion pump 44; also execute procedure 8 at the same time, switch the third column pre-switching valve 32 to the Q3-C3 channel mode, switch the first column post-switching valve 33 to the H3-V3 channel mode, start the first infusion pump 41, pass 1.5 to 5 times the volume of resin with a 3 to 8% mass concentration of acid solution, and turn off the first infusion pump 41. Then, switch the third column pre-switching valve 32 to the Q3-E3 channel mode, switch the third column post-switching valve 33 to the H3-Y3 channel mode, start the third infusion pump 43, pass deionized water until the pH value of the effluent is greater than 5.5, and turn off the third infusion pump 43. At this time, the first chromatography column 11 enters the second round of alkali treatment process; the second chromatography column 21 enters the preparation process of glucosamine sulfate; the third chromatography column 31 completes the acid treatment process. Fifth, execute procedure 2, switch the first column pre-switching valve 12 to the Q1-C1 channel mode, switch the first column post-switching valve 13 to the H1-V1 channel mode, start the first infusion pump 41, and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, turn off the first infusion pump 41. Next, the first pre-column switching valve 12 is switched to the Q1-E1 channel mode, the first post-column switching valve 13 is switched to the H1-Y1 channel mode, the third infusion pump 43 is started, deionized water is added until the pH value of the effluent is greater than 5.5, and the third infusion pump 43 is turned off; at the same time, procedure 3 is executed, the second pre-column switching valve 22 is switched to the Q2-D2 channel mode, the second post-column switching valve 23 is switched to the H2-Z2 channel mode, the second infusion pump 42 is started, and after passing 2 to 5 times the volume of the resin with a 3 to 8% mass concentration alkaline solution, the second infusion pump 42 is turned off. Next, the second column front switching valve 22 is switched to the Q2-E2 channel mode, the second column rear switching valve 23 is switched to the H2-Y2 channel mode, the third infusion pump 43 is started to add deionized water until the pH value of the effluent is ≤8.5, and the third infusion pump 43 is turned off; at the same time, procedure 9 is executed to switch the third column front switching valve 32 to the Q3-A3 channel mode, the third column rear switching valve 33 is switched to the H3-W3 channel mode, and the fifth infusion pump 45 is started to pass the saturated aqueous solution of glucosamine hydrochloride until the effluent just detects Cl - , turn off the fifth infusion pump 45. Then, switch the third column front switching valve 32 to the Q3-B3 channel mode, switch the third column rear switching valve 33 to the H3-X3 channel mode, start the fourth infusion pump 44, pass 1 to 3 times the volume of resin deionized water, and turn off the fourth infusion pump 44. At this time, the first chromatography column 11 enters the second round of acid treatment process; the second chromatography column 21 completes the second round of alkali treatment process; the third chromatography column 31 enters the preparation process of glucosamine sulfate. Sixth, by repeating the third to fifth steps continuously, the glucosamine sulfate solution can be continuously prepared.

[0041] The prepared glucosamine sulfate solution or glucosamine phosphate solution is spray-dried to obtain high-quality glucosamine sulfate compound solid powder or glucosamine phosphate compound solid powder, or is freeze-dried to obtain high-quality glucosamine sulfate compound solid or glucosamine phosphate compound solid.

[0042] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A device for continuously preparing glucosamine sulfate or phosphate compounds, characterized in that: The continuous preparation device comprises at least three chromatographic separation units, namely, a first separation unit, a second separation unit, and a third separation unit are connected in a certain manner to form a continuously operable closed-loop system, and each separation unit is composed of a chromatographic column, an infusion pump, a switching valve, and a liquid storage tank; The first separation unit comprises a first chromatography column (11), a first pre-column switching valve (12), and a first post-column switching valve (13); the pre-column of the first chromatography column (11) is connected to the Q1 channel of the first pre-column switching valve (12), and the post-column is connected to the H1 channel of the first post-column switching valve (13); The second separation unit comprises a second chromatography column (21), a second pre-column switching valve (22), and a second post-column switching valve (23); the pre-column of the second chromatography column (21) is connected to the Q2 channel of the second pre-column switching valve (22), and the post-column is connected to the H2 channel of the second post-column switching valve (23); The third separation unit comprises a third chromatography column (31), a third pre-column switching valve (32), and a third post-column switching valve (33); the pre-column of the third chromatography column (31) is connected to the Q3 channel of the third pre-column switching valve (32), and the post-column is connected to the H3 channel of the third post-column switching valve (33); The three pre-column switching valves are respectively provided with five switching channels, namely QA, QB, QC, QD and QE; the A1 channel of the first pre-column switching valve, the A2 channel of the second pre-column switching valve and the A3 channel of the third pre-column switching valve are respectively connected to the first liquid collecting storage tank (61) through pipelines; the B1 channel of the first pre-column switching valve, the B2 channel of the second pre-column switching valve and the B3 channel of the third pre-column switching valve are respectively connected to the second liquid collecting storage tank (62) through pipelines; the C1 channel of the first pre-column switching valve, the C2 channel of the second pre-column switching valve and the C3 channel of the third pre-column switching valve are respectively connected to the first infusion pump (41) through pipelines. The outlet end of the first infusion pump (41) is connected to the first liquid supply storage tank (51); the D1 channel of the first pre-column switching valve, the D2 channel of the second pre-column switching valve, and the D3 channel of the third pre-column switching valve are respectively connected to the outlet end of the second infusion pump (42) through pipelines, and the inlet end of the second infusion pump (42) is connected to the second liquid supply storage tank (52); the E1 channel of the first pre-column switching valve, the E2 channel of the second pre-column switching valve, and the E3 channel of the third pre-column switching valve are respectively connected to the outlet end of the third infusion pump (43) through pipelines, and the inlet end of the third infusion pump (43) is connected to the third liquid supply storage tank (53); The three post-column switching valves are respectively provided with five switching channels, namely HV, HW, HX, HY and HZ; the V1 channel of the first post-column switching valve, the V2 channel of the second post-column switching valve and the V3 channel of the third post-column switching valve are respectively connected to the third liquid collection tank (63) through pipelines; the W1 channel of the first post-column switching valve, the W2 channel of the second post-column switching valve and the W3 channel of the third post-column switching valve are respectively connected to the outlet end of the fifth infusion pump (45) through pipelines; the inlet end of the fifth infusion pump (45) is connected to the fourth liquid supply tank (54); the X1 channel of the first post-column switching valve is connected to the outlet end of the fifth infusion pump (45) through pipelines; ... The 1 channel of the first post-column switching valve, the X2 channel of the second post-column switching valve, and the X3 channel of the third post-column switching valve are respectively connected to the outlet end of the fourth infusion pump (44) through pipelines, and the inlet end of the fourth infusion pump (44) is connected to the third liquid supply storage tank (53); the Y1 channel of the first post-column switching valve, the Y2 channel of the second post-column switching valve, and the Y3 channel of the third post-column switching valve are respectively connected to the fifth liquid collection storage tank (65); the Z1 channel of the first post-column switching valve, the Z2 channel of the second post-column switching valve, and the Z3 channel of the third post-column switching valve are respectively connected to the fourth liquid collection storage tank (64) through pipelines.

2. The continuous preparation device for glucosamine sulfate or phosphate compound according to claim 1, characterized in that: The pre-column switching valve and the post-column switching valve both have good sealing properties. When each switching valve switches to a certain channel, the channel is connected, and the remaining channels are in a disconnected state.

3. The continuous preparation device for glucosamine sulfate or phosphate compound according to claim 1, characterized in that: The chromatography column is a real-time dynamic axial compression chromatography column, which has the functions of automatically adjusting the column bed height and compacting the column bed in real time; the chromatography column can perform bidirectional chromatography operation.

4. The continuous preparation device for glucosamine sulfate or phosphate compound according to claim 1, characterized in that: The infusion pump is a corrosion-resistant diaphragm pump or a plunger pump.

5. A continuous preparation process for glucosamine sulfate or phosphate compounds, characterized in that: The preparation process is based on the continuous preparation device for glucosamine sulfate or phosphate compound as claimed in claim 1, and in three chromatographic separation units, the corresponding procedures, program combinations, and post-treatment steps are performed in the order of alkali treatment, acid treatment, and glucosamine hydrochloride exchange treatment to activate the resin filler and prepare the glucosamine sulfate compound or glucosamine phosphate compound; the procedures are respectively procedure 1, procedure 2, procedure 3, procedure 4, procedure 5, procedure 6, procedure 7, procedure 8, and procedure 9; The alkali used in the alkali treatment is: 1-10% sodium hydroxide or potassium hydroxide aqueous solution; The acid used in the acid treatment is: 1-10% sulfuric acid or phosphoric acid or sodium hydrogen sulfate or potassium hydrogen sulfate or sodium dihydrogen phosphate or potassium dihydrogen phosphate aqueous solution; The glucosamine hydrochloride exchange treatment uses a glucosamine hydrochloride aqueous solution with a concentration of 15% to saturation; the resin filler is an alkaline ion exchange resin; and the water used in the aqueous solution is sterilized deionized water; The procedure 1 is: switching the first pre-column switching valve (12) to the Q1-D1 channel mode, switching the first post-column switching valve (13) to the H1-Z1 channel mode, starting the second infusion pump (42) to pass 2 to 5 times the volume of the resin and an alkaline solution with a mass concentration of 3 to 8%, and then closing the second infusion pump (42); then, switching the first pre-column switching valve (12) to the Q1-E1 channel mode, switching the first post-column switching valve (13) to the H1-Y1 channel mode, starting the third infusion pump (43) to pass deionized water until the pH value of the effluent is ≤8.5, and then closing the third infusion pump (43); The procedure 2 is: switching the first pre-column switching valve (12) to the Q1-C1 channel mode, switching the first post-column switching valve (13) to the H1-V1 channel mode, starting the first infusion pump (41), and after passing 1.5 to 5 times the volume of the resin with an acid solution having a mass concentration of 3 to 8%, closing the first infusion pump (41); then, switching the first pre-column switching valve (12) to the Q1-E1 channel mode, switching the first post-column switching valve (13) to the H1-Y1 channel mode, starting the third infusion pump (43), adding deionized water until the pH value of the effluent is greater than 5.5, and closing the third infusion pump (43); The procedure 3 is: switching the second pre-column switching valve (22) to the Q2-D2 channel mode, switching the second post-column switching valve (23) to the H2-Z2 channel mode, starting the second infusion pump (42) to pass 2 to 5 times the volume of the resin and an alkaline solution with a mass concentration of 3 to 8%, and then closing the second infusion pump (42); then, switching the second pre-column switching valve (22) to the Q2-E2 channel mode, switching the second post-column switching valve (23) to the H2-Y2 channel mode, starting the third infusion pump (43) to pass deionized water until the pH value of the effluent is ≤8.5, and closing the third infusion pump (43); The procedure 4 is: switching the first column front switching valve (12) to the Q1-A1 channel mode, switching the first column rear switching valve (13) to the H1-W1 channel mode, starting the fifth infusion pump (45), supersaturated glucosamine hydrochloride aqueous solution, until the effluent just detects Cl - , turn off the fifth infusion pump (45); then, switch the first column front switching valve (12) to the Q1-B1 channel mode, switch the first column rear switching valve (13) to the H1-X1 channel mode, start the fourth infusion pump (44), pass 1 to 3 times the volume of the resin with deionized water, and turn off the fourth infusion pump (44); The procedure 5 is: switching the second pre-column switching valve (22) to the Q2-C2 channel mode, switching the second post-column switching valve (23) to the H2-V2 channel mode, starting the first infusion pump (41), and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, closing the first infusion pump (41); then, switching the second pre-column switching valve (22) to the Q2-E2 channel mode, switching the second post-column switching valve (23) to the H2-Y2 channel mode, starting the third infusion pump (43), adding deionized water until the pH value of the effluent is greater than 5.5, and closing the third infusion pump (43); The procedure 6 is: switching the third column front switching valve (32) to the Q3-D3 channel mode, switching the third column back switching valve (33) to the H3-Z3 channel mode, starting the second infusion pump (42) to pass 2 to 5 times the volume of the resin with a 3 to 8% mass concentration of alkaline solution, and then closing the second infusion pump (42); then, switching the third column front switching valve (32) to the Q3-E3 channel mode, switching the third column back switching valve (33) to the H3-Y3 channel mode, starting the third infusion pump (43) to pass deionized water until the pH value of the effluent is ≤8.5, and closing the third infusion pump (43); The procedure 7 is: switching the second column front switching valve (22) to the Q2-A2 channel mode, switching the second column rear switching valve (23) to the H2-W2 channel mode, starting the fifth infusion pump (45), supersaturated glucosamine hydrochloride aqueous solution, until the effluent just detects Cl - , turn off the fifth infusion pump (45); then, switch the second column front switching valve (22) to the Q2-B2 channel mode, switch the second column rear switching valve (23) to the H2-X2 channel mode, start the fourth infusion pump (44), pass 1 to 3 times the volume of the resin with deionized water, and turn off the fourth infusion pump (44); The procedure 8 is: switching the third column front switching valve (32) to the Q3-C3 channel mode, switching the first column back switching valve (33) to the H3-V3 channel mode, starting the first infusion pump (41), and after passing 1.5 to 5 times the volume of the resin with a 3 to 8% mass concentration acid solution, closing the first infusion pump (41); then, switching the third column front switching valve (32) to the Q3-E3 channel mode, switching the first column back switching valve (33) to the H3-Y3 channel mode, starting the third infusion pump (43), adding deionized water until the pH value of the effluent is greater than 5.5, and closing the third infusion pump (43); The procedure 9 is: switching the third column front switching valve (32) to the Q3-A3 channel mode, switching the third column rear switching valve (33) to the H3-W3 channel mode, starting the fifth infusion pump (45), supersaturated glucosamine hydrochloride aqueous solution, until the effluent just detects Cl - , turn off the fifth infusion pump (45); then, switch the third column front switching valve (32) to the Q3-B3 channel mode, switch the third column rear switching valve (33) to the H3-X3 channel mode, start the fourth infusion pump (44), pass 1 to 3 times the volume of the resin with deionized water, and turn off the fourth infusion pump (44); The program combination is:

1. Execute program 4, program 5 and program 6 in the first, second and third separation units respectively; 2. Execute program 1, program 7 and program 8 in the first, second and third separation units respectively; 3. Execute program 2, program 3 and program 9 in the first, second and third separation units respectively; 4. Then, repeat steps 1 to 3 continuously, so that glucosamine sulfate solution or glucosamine phosphate solution can be continuously prepared; The post-treatment process is to spray-dry the glucosamine sulfate solution or glucosamine phosphate solution obtained by the circular preparation to obtain a glucosamine sulfate compound solid powder or a glucosamine phosphate compound solid powder; or to obtain a glucosamine sulfate compound solid or a glucosamine phosphate compound solid by freeze-drying.

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