Continuous crystallization preparation method of high-purity berberine hydrochloride

Abstract

The present invention relates to a continuous crystallization preparation method for high-purity berberine hydrochloride, and belongs to the technical field of drug preparation. After the Phellodendron chinense extract is crushed, it is added to a sulfuric acid solution for soaking and extraction, and filtered to obtain an extract; the extract is passed through a macroporous adsorption resin column for adsorption, eluted with an ethanol solution, the eluate is collected, and concentrated under reduced pressure to obtain a preliminarily purified berberine solution; the preliminarily purified berberine solution is sent to a crystallization device, hydrochloric acid solution and seed crystals are added, and a continuous crystallization reaction is carried out; after the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor; the berberine hydrochloride crude crystals are washed with an ethanol solution and dried to obtain high-purity berberine hydrochloride; the berberine hydrochloride product prepared by the present invention has a high purity of more than 99.5%, meeting the requirements of the pharmaceutical field for high-purity products.

Description

Technical Field

[0001] The present invention relates to the technical field of drug preparation, in particular to a continuous crystallization preparation method of high-purity berberine hydrochloride. Background Art

[0002] Berberine hydrochloride, also known as berberine, is an important alkaloid with a wide range of pharmacological activities, such as antibacterial, anti-inflammatory, and antidiarrheal, and has important applications in the pharmaceutical field. Currently, there are many methods for preparing berberine hydrochloride, but traditional methods often have some problems during the crystallization process. For example, some methods use intermittent crystallization, which has low production efficiency and cannot meet the needs of large-scale industrial production; some processes produce products with low purity and high impurity content, which affects the quality and efficacy of the drug; and some methods use large amounts of chemical reagents during the crystallization process, which not only increases costs but also may cause environmental pollution.

[0003] Chinese invention patent application with publication number CN119954798A discloses a method for chemically synthesizing berberine hydrochloride, which includes first synthesizing a methyl compound, then synthesizing a condensate, and finally synthesizing berberine hydrochloride.

[0004] Chinese invention patent application publication number CN118005628A discloses a method for preparing 95% berberine hydrochloride from Phellodendron chinense. The method comprises ultrafinely grinding the Phellodendron chinense, adding 10-15 times the amount of acid solution and stirring evenly, and extracting at a constant temperature of 15-20°C for 1-2 hours, and extracting twice; combining the extracts, adjusting the pH to 7-7.5, stirring evenly, standing for 30-60 minutes, and centrifuging to obtain a centrifuge; and purifying the centrifuge through a two-stage OSN organic membrane to obtain a decolorized retained membrane liquid, which is concentrated into an extract, stirred evenly with an organic solvent, and then dissolved in hydrochloric acid. The extract is crystallized, filtered, and dried to obtain berberine hydrochloride.

[0005] In order to overcome the above problems, it is of great practical significance to develop a berberine hydrochloride crystal preparation method that can achieve continuous production, improve product purity and is green and environmentally friendly. Summary of the Invention

[0006] In order to solve the above problems, the present invention provides a continuous crystallization preparation method of high-purity berberine hydrochloride, the operating steps are:

[0007] S1. Raw material pretreatment: 80-100 parts of Phellodendron amurense extract are crushed, added to 700-1000 parts of 0.1-0.5% by mass sulfuric acid solution for immersion extraction, and filtered to obtain an extract; the extract is adsorbed by a modified macroporous adsorption resin, eluted with 30-40% by mass ethanol solution, the eluate is collected, and concentrated under reduced pressure to 1 / 3-1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0008] S2 continuous crystallization: 80-100 parts of the preliminarily purified berberine solution are fed into a crystallization device, and 60-80 parts of a 10-20% by mass hydrochloric acid solution and 0.1-0.5 parts of seed crystals are added to the crystallization device to carry out a continuous crystallization reaction;

[0009] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0010] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:(1-2);

[0011] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0012] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 5-1 / 3 of the original volume, the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base, and the crude berberine is obtained by filtration. The crude berberine is redissolved in a 0.1-0.5% by mass sulfuric acid solution, and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0013] In some embodiments, the soaking extraction temperature of S1 is 50-70°C and the time is 2-4 hours.

[0014] In some embodiments, the modified macroporous adsorption resin is prepared by the following steps:

[0015] H1: Place 100-140 parts of D101 resin, 5-10 parts of 1-vinyl-3-aminoimidazole bromide, 0.05-0.5 parts of ethylene boron anhydride pyridine complex, and 0.5-2.4 parts of azobisisobutyronitrile in 500-1000 parts of solvent, and carry out free radical graft polymerization at 80-90°C under nitrogen protection for 6-10 hours to obtain an intermediate resin with a double electrical layer structure;

[0016] H2: Continue to add 120-150 parts of perfluorobutylsulfonyl fluoride and 10-18 parts of acid-binding agent triethylamine, and react at 25-40°C for 4-6 hours. The product after the reaction is filtered, washed, dried and activated in sequence to obtain a modified macroporous adsorption resin.

[0017] In some embodiments, the solvent is ethanol or DMF.

[0018] In some embodiments, the crystallization temperature of S2 is 30-40° C., the stirring speed is 100-200 rpm, and the crystallization reaction time is 2-4 hours.

[0019] In some embodiments, the washing number of S4 is 2-3 times, and each washing time is 5-10 minutes.

[0020] In some embodiments, the vacuum drying temperature of S5 is 50-60° C., and the drying time is 2-4 hours.

[0021] In some embodiments, the pH value of S6 is adjusted to 8-9 using sodium hydroxide solution.

[0022] The continuous crystallization preparation method of high-purity berberine hydrochloride of the present invention has the following significant effects compared with the prior art:

[0023] 1. Continuous production: The present invention adopts a continuous crystallization process, which greatly improves production efficiency compared to traditional intermittent crystallization and can meet the needs of large-scale industrial production.

[0024] 2. High-purity product: By optimizing crystallization conditions and subsequent crystal washing and mother liquor treatment steps, impurities are effectively removed. The resulting berberine hydrochloride product has a high purity of over 99.5%, meeting the pharmaceutical industry's requirements for high-purity products.

[0025] 3. Environmental protection and energy saving: During the preparation process, the use of chemical reagents is reduced, and the mother liquor can be recycled, which reduces production costs and reduces pollution to the environment, in line with the concept of green chemistry.

[0026] 4. The modified macroporous adsorption resin prepared by the present invention has an ultra-high adsorption capacity; it adsorbs by ion exchange at a pH of 2-4 and automatically desorbs when the pH is greater than 8; the fluorine chain structure can block the adsorption of flavonoid impurities and has good anti-pollution properties. DETAILED DESCRIPTION

[0027] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined invention object, the following is a detailed description in conjunction with examples and comparative examples:

[0028] Example 1: A continuous crystallization method for preparing high-purity berberine hydrochloride, the operating steps are:

[0029] S1. Raw material pretreatment: 80 g of Phellodendron amurense extract was crushed and added to 700 g of 0.1% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 30% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0030] S2 continuous crystallization: 80 g of the preliminarily purified berberine solution was fed into a crystallization device, and 60 g of a 10% by mass hydrochloric acid solution and 0.1 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0031] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0032] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:1;

[0033] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0034] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 3 of the original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.1% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0035] The soaking extraction temperature of S1 is 50° C. and the soaking extraction time is 2 hours.

[0036] The modified macroporous adsorption resin is prepared by the following steps:

[0037] H1: 100 g of D101 resin, 5 g of 1-vinyl-3-aminoimidazole bromide, 0.05 g of ethylene boron anhydride pyridine complex, and 0.5 g of azobisisobutyronitrile were placed in 500 g of solvent and subjected to free radical graft polymerization at 80°C under nitrogen protection for 6 hours to obtain an intermediate resin with a double-layer structure;

[0038] H2: 120 g of perfluorobutylsulfonyl fluoride and 10 g of acid-binding agent triethylamine were added, and the mixture was reacted at 25° C. for 4 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0039] The solvent is ethanol.

[0040] The crystallization temperature of S2 is 30° C., the stirring speed is 100 rpm, and the crystallization reaction time is 2 hours.

[0041] The washing times of S4 are 2 times, and each washing time is 5 minutes.

[0042] The vacuum drying temperature of S5 is 50° C. and the drying time is 2 hours.

[0043] The pH value of S6 was adjusted to 8 with sodium hydroxide solution.

[0044] Example 2: A continuous crystallization method for preparing high-purity berberine hydrochloride, the operating steps are as follows:

[0045] S1. Raw material pretreatment: 85 g of Phellodendron amurense extract was crushed and added to 800 g of 0.2% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 35% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0046] S2 continuous crystallization: 85 g of the preliminarily purified berberine solution was fed into a crystallization device, and 65 g of a 15% by mass hydrochloric acid solution and 0.2 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0047] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0048] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:1;

[0049] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0050] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 4 of its original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.2% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0051] The soaking extraction temperature of S1 is 55° C. and the soaking extraction time is 3 hours.

[0052] The modified macroporous adsorption resin is prepared by the following steps:

[0053] H1: 110 g of D101 resin, 6 g of 1-vinyl-3-aminoimidazole bromide, 0.2 g of ethylene boron anhydride pyridine complex, and 1 g of azobisisobutyronitrile were placed in 600 g of solvent and subjected to free radical graft polymerization at 85°C under nitrogen protection for 7 hours to obtain an intermediate resin with a double-layer structure;

[0054] H2: 130 g of perfluorobutylsulfonyl fluoride and 12 g of acid-binding agent triethylamine were added, and the mixture was reacted at 30° C. for 5 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0055] The solvent is ethanol.

[0056] The crystallization temperature of S2 is 35° C., the stirring speed is 150 rpm, and the crystallization reaction time is 3 hours.

[0057] The washing times of S4 are 2 times, and each washing time is 5 minutes.

[0058] The vacuum drying temperature of S5 is 55° C. and the drying time is 3 hours.

[0059] The pH value of S6 was adjusted to 8.5 with sodium hydroxide solution.

[0060] Example 3: A continuous crystallization method for preparing high-purity berberine hydrochloride, the operating steps are:

[0061] S1. Raw material pretreatment: 95 g of Phellodendron amurense extract was crushed and added to 900 g of 0.4% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 35% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 3 of the original volume to obtain a preliminarily purified berberine solution;

[0062] S2 continuous crystallization: 95 g of the preliminarily purified berberine solution was fed into a crystallization device, and 75 g of a 15% by mass hydrochloric acid solution and 0.4 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0063] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0064] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:2;

[0065] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0066] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 4 of its original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.4% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0067] The soaking extraction temperature of S1 is 65° C. and the soaking extraction time is 3 hours.

[0068] The modified macroporous adsorption resin is prepared by the following steps:

[0069] H1: 130 g of D101 resin, 8 g of 1-vinyl-3-aminoimidazole bromide, 0.4 g of ethylene boron anhydride pyridine complex, and 2 g of azobisisobutyronitrile were placed in 800 g of solvent and subjected to free radical graft polymerization at 85°C under nitrogen protection for 9 hours to obtain an intermediate resin with a double-layer structure;

[0070] H2: 140 g of perfluorobutylsulfonyl fluoride and 16 g of acid-binding agent triethylamine were added, and the mixture was reacted at 35° C. for 5 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0071] The solvent is DMF.

[0072] The crystallization temperature of S2 is 35° C., the stirring speed is 150 rpm, and the crystallization reaction time is 3 hours.

[0073] The washing times of S4 are 3 times, and each washing time is 10 minutes.

[0074] The vacuum drying temperature of S5 is 55° C. and the drying time is 3 hours.

[0075] The pH value of S6 was adjusted to 8.5 with sodium hydroxide solution.

[0076] Example 4: A continuous crystallization method for preparing high-purity berberine hydrochloride, the operating steps are:

[0077] S1. Raw material pretreatment: 100 g of Phellodendron chinense extract was crushed and added to 1000 g of 0.5% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 40% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 3 of the original volume to obtain a preliminarily purified berberine solution;

[0078] S2 continuous crystallization: 100 g of the preliminarily purified berberine solution was fed into a crystallization device, and 80 g of a 20% by mass hydrochloric acid solution and 0.5 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0079] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0080] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:2;

[0081] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0082] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 5 of its original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.5% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0083] The soaking extraction temperature of S1 is 70° C. and the soaking extraction time is 4 hours.

[0084] The modified macroporous adsorption resin is prepared by the following steps:

[0085] H1: 140 g of D101 resin, 10 g of 1-vinyl-3-aminoimidazole bromide, 0.5 g of ethylene boron anhydride pyridine complex, and 2.4 g of azobisisobutyronitrile were placed in 1000 g of solvent and subjected to free radical graft polymerization at 90°C under nitrogen protection for 10 hours to obtain an intermediate resin with a double-layer structure;

[0086] H2: 150 g of perfluorobutylsulfonyl fluoride and 18 g of acid-binding agent triethylamine were added, and the mixture was reacted at 40° C. for 6 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0087] The solvent is DMF.

[0088] The crystallization temperature of S2 is 40° C., the stirring speed is 200 rpm, and the crystallization reaction time is 4 hours.

[0089] The washing times of S4 are 3 times, and each washing time is 10 minutes.

[0090] The vacuum drying temperature of S5 is 60° C. and the drying time is 4 hours.

[0091] The pH value of S6 was adjusted to 9 with sodium hydroxide solution.

[0092] Comparative Example 1: Continuous crystallization preparation method of high-purity berberine hydrochloride, the operating steps are:

[0093] S1. Raw material pretreatment: 80 g of Phellodendron chinense extract was crushed and added to 700 g of 0.1% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed on D101 macroporous adsorption resin, eluted with 30% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0094] S2 continuous crystallization: 80 g of the preliminarily purified berberine solution was fed into a crystallization device, and 60 g of a 10% by mass hydrochloric acid solution and 0.1 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0095] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0096] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:1;

[0097] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0098] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 3 of the original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.1% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0099] The soaking extraction temperature of S1 is 50° C. and the soaking extraction time is 2 hours.

[0100] The crystallization temperature of S2 is 30° C., the stirring speed is 100 rpm, and the crystallization reaction time is 2 hours.

[0101] The washing times of S4 are 2 times, and each washing time is 5 minutes.

[0102] The vacuum drying temperature of S5 is 50° C. and the drying time is 2 hours.

[0103] The pH value of S6 was adjusted to 8 with sodium hydroxide solution.

[0104] Comparative Example 2: Continuous crystallization preparation method of high-purity berberine hydrochloride, the operating steps are:

[0105] S1. Raw material pretreatment: 80 g of Phellodendron amurense extract was crushed and added to 700 g of 0.1% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 30% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0106] S2 continuous crystallization: 80 g of the preliminarily purified berberine solution was fed into a crystallization device, and 60 g of a 10% by mass hydrochloric acid solution and 0.1 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0107] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0108] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:1;

[0109] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0110] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 3 of the original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.1% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0111] The soaking extraction temperature of S1 is 50° C. and the soaking extraction time is 2 hours.

[0112] The modified macroporous adsorption resin is prepared by the following steps:

[0113] H1: 100 g of D101 resin, 0.05 g of ethylene boric anhydride pyridine complex, and 0.5 g of azobisisobutyronitrile were placed in 500 g of solvent and subjected to free radical graft polymerization at 80°C under nitrogen protection for 6 hours;

[0114] H2: 120 g of perfluorobutylsulfonyl fluoride and 10 g of acid-binding agent triethylamine were added, and the mixture was reacted at 25° C. for 4 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0115] The solvent is ethanol.

[0116] The crystallization temperature of S2 is 30° C., the stirring speed is 100 rpm, and the crystallization reaction time is 2 hours.

[0117] The washing times of S4 are 2 times, and each washing time is 5 minutes.

[0118] The vacuum drying temperature of S5 is 50° C. and the drying time is 2 hours.

[0119] The pH value of S6 was adjusted to 8 with sodium hydroxide solution.

[0120] Comparative Example 3: Continuous crystallization preparation method of high-purity berberine hydrochloride, the operating steps are:

[0121] S1. Raw material pretreatment: 80 g of Phellodendron amurense extract was crushed and added to 700 g of 0.1% by mass sulfuric acid solution for immersion extraction, and the extract was filtered to obtain an extract; the extract was adsorbed by a modified macroporous adsorption resin, eluted with 30% by mass ethanol solution, and the eluate was collected and concentrated under reduced pressure to 1 / 2 of the original volume to obtain a preliminarily purified berberine solution;

[0122] S2 continuous crystallization: 80 g of the preliminarily purified berberine solution was fed into a crystallization device, and 60 g of a 10% by mass hydrochloric acid solution and 0.1 g of seed crystals were added to the crystallization device to carry out a continuous crystallization reaction;

[0123] S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor;

[0124] S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:1;

[0125] S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product;

[0126] S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 3 of the original volume, and the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base. The crude berberine is filtered to obtain the crude berberine. The crude berberine is redissolved in a 0.1% by mass sulfuric acid solution and pretreated according to the steps of S1 before use in subsequent continuous crystallization.

[0127] The soaking extraction temperature of S1 is 50° C. and the soaking extraction time is 2 hours.

[0128] The modified macroporous adsorption resin is prepared by the following steps:

[0129] H1: 100 g of D101 resin, 5 g of 1-vinyl-3-aminoimidazole bromide, and 0.5 g of azobisisobutyronitrile were placed in 500 g of solvent and subjected to free radical graft polymerization at 80°C under nitrogen protection for 6 hours;

[0130] H2: 120 g of perfluorobutylsulfonyl fluoride and 10 g of acid-binding agent triethylamine were added, and the mixture was reacted at 25° C. for 4 hours. The reaction product was filtered, washed, dried, and activated in sequence to obtain a modified macroporous adsorption resin.

[0131] The solvent is ethanol.

[0132] The crystallization temperature of S2 is 30° C., the stirring speed is 100 rpm, and the crystallization reaction time is 2 hours.

[0133] The washing times of S4 are 2 times, and each washing time is 5 minutes.

[0134] The vacuum drying temperature of S5 is 50° C. and the drying time is 2 hours.

[0135] The pH value of S6 was adjusted to 8 with sodium hydroxide solution.

[0136] Berberine hydrochloride purity test: determined by high performance liquid chromatography.

[0137] Table 1: Test results of various embodiments and comparative examples

[0138]

[0139] Through the data analysis of the above examples and comparative examples, the berberine hydrochloride product prepared by the present invention has a high purity of more than 99.5%, which meets the requirements of the pharmaceutical field for high-purity products.

[0140] The above description is merely a preferred embodiment of the present invention and does not constitute any form of limitation to the present invention. Although the present invention has been disclosed as above in terms of a preferred embodiment, it is not intended to limit the present invention. Any person skilled in the art can, without departing from the scope of the technical solution of the present invention, make some changes or modifications to equivalent embodiments using the technical contents disclosed above. However, any brief modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention are still within the scope of the technical solution of the present invention.

Claims

1. A continuous crystallization method for preparing high-purity berberine hydrochloride, characterized in that: The operation steps are as follows, calculated by mass: S1. Raw material pretreatment: crush 80-100 parts of Phellodendron amurense extract, add it to 700-1000 parts of 0.1-0.5% by mass sulfuric acid solution for immersion extraction, and filter to obtain an extract; The extract was adsorbed by a modified macroporous adsorption resin, eluted with a 30-40% by mass ethanol solution, the eluate was collected, and concentrated under reduced pressure to 1 / 3-1 / 2 of the original volume to obtain a preliminarily purified berberine solution; S2 continuous crystallization: 80-100 parts of the preliminarily purified berberine solution are fed into a crystallization device, and 60-80 parts of a 10-20% by mass hydrochloric acid solution and 0.1-0.5 parts of seed crystals are added to the crystallization device to carry out a continuous crystallization reaction; S3 solid-liquid separation: After the crystallization reaction is completed, the crystallization liquid is sent to a centrifuge for solid-liquid separation to obtain berberine hydrochloride crude crystals and mother liquor; S4 crystal washing: washing the crude berberine hydrochloride crystals with an ethanol-water mixed solution to remove impurities on the crystal surface, wherein the volume ratio of ethanol to water is 1:(1-2); S5 Drying: vacuum drying the washed berberine hydrochloride crystals to obtain a high-purity berberine hydrochloride product; S6 Mother Liquor Treatment: The mother liquor obtained by solid-liquid separation is concentrated under reduced pressure to 1 / 5-1 / 3 of the original volume, the pH value is adjusted with sodium hydroxide solution to precipitate berberine as a free base, and the crude berberine is obtained by filtration. The crude berberine is redissolved in a 0.1-0.5% by mass sulfuric acid solution, and pretreated according to the steps of S1 before use in subsequent continuous crystallization; The modified macroporous adsorption resin is prepared by reacting D101 resin, 1-vinyl-3-aminoimidazole bromide, ethylene boron anhydride pyridine complex, perfluorobutylsulfonyl fluoride and acid binding agent triethylamine.

2. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The soaking extraction temperature of S1 is 50-70° C. and the soaking extraction time is 2-4 hours.

3. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The modified macroporous adsorption resin is prepared by the following steps: H1: Place 100-140 parts of D101 resin, 5-10 parts of 1-vinyl-3-aminoimidazole bromide, 0.05-0.5 parts of ethylene boron anhydride pyridine complex, and 0.5-2.4 parts of azobisisobutyronitrile in 500-1000 parts of solvent, and carry out free radical graft polymerization at 80-90°C under nitrogen protection for 6-10 hours to obtain an intermediate resin with a double electrical layer structure; H2: Continue to add 120-150 parts of perfluorobutylsulfonyl fluoride and 10-18 parts of acid-binding agent triethylamine, and react at 25-40°C for 4-6 hours. The product after the reaction is filtered, washed, dried and activated in sequence to obtain a modified macroporous adsorption resin.

4. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 3, characterized in that: The solvent is ethanol or DMF.

5. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The crystallization temperature of the crystallization reaction of S2 is 30-40° C., the stirring speed is 100-200 rpm, and the crystallization reaction time is 2-4 hours.

6. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The washing times of S4 are 2-3 times, and each washing time is 5-10 minutes.

7. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The vacuum drying temperature of S5 is 50-60° C., and the drying time is 2-4 hours.

8. The continuous crystallization preparation method of high-purity berberine hydrochloride according to claim 1, characterized in that: The pH value of S6 is adjusted to 8-9 with sodium hydroxide solution.

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