Method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride by using berberis poiretii schneid

Abstract

The invention provides a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride by using berberis poiretii schneid. The method comprises the following steps: by taking berberis poiretii schneid as a raw material, carrying out crushing, acid extraction, heat-preservation filtration clarification and membrane separation to obtain a membrane refined solution; then, the berberine hydrochloride is produced through crystallization and recrystallization; performing decoloration and fractional crystallization through alkaline anion exchange resin to produce berbamine; and carrying out macroporous adsorption resin chromatography to produce jatrorrhizine hydrochloride. The berberine hydrochloride, the berbamine and the jateorhizine hydrochloride are continuously produced and prepared, and comprehensive utilization of the berberis poiretii schneid raw material is achieved; the problem that the salt wastewater pollutes the environment can be solved, and step-by-step separation and purification of alkaloid are achieved; the membrane separation and the resin are combined, so that repeated crystallization and activated carbon decoloration are avoided, and the yield and the quality of the berbamine can be remarkably improved; the high-content jateorhizine is prepared without using an organic solvent except ethanol, and the application prospect in industry is wide.

Description

Technical Field

[0001] The invention relates to the preparation of heterocyclic compounds, and in particular to a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride by using three needles. Background Art

[0002] Three Needles is the common name for Berberis L. of the Berberaceae family. There are about 200 species of Berberis L., and most species have three-pronged thorns on their stems, hence the name Three Needles. They are widely distributed in North China, Northwest China, and Southwest China. The Three Needles listed in the 2020 edition of the Pharmacopoeia of the People's Republic of China are the roots of several plants of the same genus, including Berberis soulieana Schneid., Berberis wilsonae Hemsl., Berberis poiretii Schneid., or Berberis vernae Schneid., and the berberine hydrochloride content is not less than 0.6%. Although Sankezhen is the main raw material for the production of berberine hydrochloride (berberine) in China, the alkaloid content of many varieties varies greatly, mainly containing berberine, berbamine, jatrorrhizine, palmatine and other alkaloids and other ingredients. There are many studies on the pharmacology and clinical application of Sankezhen, especially the alkaloids - berberine hydrochloride and berbamine, but there are few reports on the process technology for extracting and separating berberine hydrochloride, berbamine and jatrorrhizine hydrochloride from Sankezhen; traditional textbooks and literature generally use salting-out method to separate alkaloids. For many years, there have been few new purification technologies applied to the preparation of Sankezhen alkaloids, especially reports on the step-by-step preparation of multiple alkaloid monomer components.

[0003] For example, a Chinese invention patent application with publication number CN106674218A discloses a method for separating and extracting berbamine and berberine from three needles, and the process is as follows: take the three needles coarse powder, put it in a glass container, add 0.2% sulfuric acid solution with a volume of 5 to 8 times the volume of the crude drug and soak it for more than 24 hours, then filter the filtrate with gauze, and extract the residue once with 3 to 5 times the volume of acid water in the same way, and combine the two filtrates in an enamel cylinder; add lime milk to adjust the pH to 12 under stirring, let it stand for 30 minutes, and filter under reduced pressure, add 8% sodium chloride solution to the filtrate, let it stand, and wait for complete precipitation; add concentrated hydrochloric acid to adjust the pH to 8 to 8.5, and place it in a water bath at 80°C for more than 30 minutes, wait for the precipitate to flocculate, take it out and let it cool, let it stand, and filter it under reduced pressure to take the precipitate; the obtained precipitate is below 60°C The mixture is dried, and then added into 30 times the volume of distilled water, heated to boiling, and filtered while hot. The filtrate obtained is berberine, and the precipitate is the crude product of berberamine. Concentrated hydrochloric acid is added dropwise to the hot solution containing berberine obtained above, and the pH is adjusted to 2. The berberine chloride is allowed to precipitate, filtered, dried at above 60°C, and weighed. The yield is generally not less than 0.2%. The precipitate containing berberamine is dried below 60°C, weighed, placed in a glass container, 20 times the volume of ethanol is added and heated to dissolve, 2% activated carbon is added, and then heated and boiled for 5 minutes, filtered hot, the filtrate is evaporated to remove ethanol until a quarter of the remaining amount, cooled, and distilled water is added dropwise until no more precipitate is precipitated. The pH is adjusted to 8~8.5 with 5% sodium hydroxide, and heated in a water bath at 80°C for about 5 minutes, allowed to stand, filtered, and dried to obtain white berberamine.

[0004] Although the patent application separates and extracts berbamine and berberine, the patent application uses dilute sulfuric acid for extraction at room temperature, which takes a long time, up to more than 24 hours. The patent application uses lime milk to adjust the pH to 12, and keeps the temperature at 80°C for more than 30 minutes when the pH is 8-8.5. The alkalization produces browning, which deepens the color of the alkaloids and has a great impact on the color of the purified product. The patent application adds 8% sodium chloride for salting out, which uses a large amount of salt and pollutes the environment. The berberine in the patent application is mainly refined by hot water and hydrochloric acid crystallization, which makes it difficult to meet the purity and color standards, and requires several repeated crystallizations and purifications. The berberamine in the patent application is only refined and decolorized by hot alcohol and activated carbon, and the purity and color are difficult to meet the standards, and it requires several repeated crystallizations and purifications. In addition, the patent application only prepares berberine hydrochloride and berberamine, and does not involve jatrorrhizine, resulting in a partial waste of resources.

[0005] In view of this, it is necessary to provide a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, so as to solve or at least alleviate the technical problems of how to simultaneously and efficiently produce berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, and how to ensure product quality and omit salting out. Summary of the invention

[0006] The main purpose of the present invention is to provide a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, aiming to solve the technical problems of how to simultaneously and efficiently produce berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, and how to ensure product quality and omit salting out.

[0007] To achieve the above object, the present invention provides a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, comprising the steps of: S1, obtaining three needle powders containing berberine, berbamine and jatrorrhizine; S2, extracting the three needle powders to obtain an extract; S3, the extract is filtered and microfiltered to obtain a clear liquid; the clear liquid is passed through a high-temperature ultrafiltration membrane to collect the liquid downstream of the membrane; the liquid downstream of the membrane is passed through a high-temperature nanofiltration membrane to collect the liquid upstream of the membrane as a membrane refined liquid; S4, adjusting the pH of the membrane refined liquid to 6-7, adjusting the pH to 2-3 with a hydrochloric acid solution after filtering; filtering after standing, collecting the first wet precipitate and the first mother liquor; adding an ethanol solution with a concentration of 60-65% to the first wet precipitate, heating and dissolving, filtering after standing, collecting the second wet precipitate and the second mother liquor; concentrating the second mother liquor so that the ethanol concentration in the second mother liquor reaches 60-65%, filtering after standing, collecting the third wet precipitate and the third mother liquor; combining the first mother liquor and the third mother liquor to obtain a berberine crystallization mother liquor; combining the second wet precipitate and the third wet precipitate to obtain a wet precipitate containing berberine hydrochloride; S5, concentrating the berberine crystallization mother liquor to obtain a first concentrated solution; passing the first concentrated solution into an alkaline anion exchange resin column, collecting the ion exchange resin decolorization solution containing the feed effluent; adjusting the pH of the ion exchange resin decolorization solution to 6-7, and concentrating to obtain a second concentrated solution; after the second concentrated solution is allowed to stand for at least 4 hours, the pH is adjusted to 8-9 to obtain a third concentrated solution; after the third concentrated solution is allowed to stand, filtering is performed to obtain a berberine crystallization mother liquor and a wet precipitate containing berberine; S6, the berbamine crystallization mother liquor is introduced into a macroporous adsorption resin column, and then desorbed, and the desorbed liquid is collected; the desorbed liquid is concentrated, and the pH is adjusted to 4-6 with a hydrochloric acid solution to obtain a refined liquid containing jatrorrhizine hydrochloride.

[0008] Furthermore, the three-needle powder is made from three needles; in terms of weight percentage, the content of berbamine in the three-needle powder is 0.5-2.0%; in terms of weight percentage and in the form of hydrochloride, the content of berberine hydrochloride in the three-needle powder is 1.0-2.5%, and the content of jatrorrhizine hydrochloride is 0.4-0.9%.

[0009] Furthermore, in the step S2, the three-needle powder is extracted with a sulfuric acid solution containing an antioxidant protective agent; the concentration of the sulfuric acid solution is 0.2-0.7%, the extraction temperature is 50-65°C, and the total extraction time is not more than 8 hours.

[0010] Furthermore, in step S3, the temperature of the extract is controlled to be 60-65°C, the temperature of the clear liquid is controlled to be 60-65°C, and the temperature of the liquid downstream of the membrane is controlled to be 60-65°C; before the clear liquid passes through the high-temperature ultrafiltration membrane, the pH of the clear liquid is adjusted to 1-4; the membrane pore size used in the microfiltration is 200-800nm; the maximum temperature that the high-temperature ultrafiltration membrane can withstand is not less than 70°C; the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3-8KD; the maximum temperature that the high-temperature nanofiltration membrane can withstand is not less than 70°C; and the molecular weight cutoff of the high-temperature nanofiltration membrane is 150-300D.

[0011] Furthermore, in the step S4, an ethanol solution with a concentration of 60-65% is added to the first wet precipitate at a ratio of 1 g: 12-15 mL; and the process of concentrating the second mother liquor includes: concentrating the second mother liquor to 1 / 5-1 / 4 of the original volume.

[0012] Furthermore, in step S5, the process of concentrating the berberine crystallization mother liquor comprises: concentrating the berberine crystallization mother liquor until it has no alcohol taste, and controlling the Brix of the berberine crystallization mother liquor to be 1-3 Brix.

[0013] Furthermore, in step S5, the Brix of the second concentrated liquid is 3-8 Brix.

[0014] Furthermore, the step S5 also includes: after the first concentrated solution enters the alkaline anion exchange resin column, the column is washed with purified water, the washing column liquid is collected, and the feed effluent and the washing column liquid are combined as the ion exchange resin decolorizing liquid.

[0015] Furthermore, in the step S6, desorption is performed using an ethanol solution with a concentration of 40-45%; and the process of concentrating the desorption solution comprises: concentrating the desorption solution to 17-25 degrees Baume; The step S6 further comprises: after the berbamine crystallization mother liquor is introduced into the macroporous adsorption resin column, before the desorption is performed, washing the column with purified water.

[0016] Furthermore, the wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing berbamine is dried to obtain a berbamine product; the refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product; the berberine hydrochloride product is bright yellow, the berbamine product is white, and the jatrorrhizine hydrochloride product is reddish yellow.

[0017] Compared with the prior art, the present invention has at least the following advantages: 1. The present invention can utilize three needles to simultaneously and efficiently produce berberine hydrochloride, berberamine and jatrorrhizine hydrochloride, forming an industrially applicable three needles extraction, separation and deep processing production technology system, solving the technical problem that traditional technology does not focus on berberine hydrochloride, berberamine and jatrorrhizine hydrochloride; the present invention is the first to combine high temperature resistant membrane separation + alkaline anion exchange resin + macroporous adsorption resin, combined with step-by-step separation and step-by-step crystallization, to simultaneously prepare three alkaloid monomer components from three needles medicinal materials, realizing the comprehensive utilization of resources and creating good economic and social benefits.

[0018] 2. The present invention can improve production efficiency, significantly shorten extraction time, and reduce equipment occupancy; by extracting with dilute sulfuric acid at 50-65°C, the extraction time of more than 24 hours in the traditional process can be shortened to less than 8 hours.

[0019] 3. The present invention solves the problem of salt wastewater polluting the environment by performing high temperature resistant ultrafiltration membrane separation and nanofiltration membrane concentration and refining at 60-65°C and omitting salting out; at the same time, the present invention combines temperature control with concentration degree, standing time, resin combination and step-by-step crystallization to produce berberine hydrochloride, berbamine and jatrorrhizine hydrochloride in sequence, solving the problem of difficult separation and purification of monomer alkaloids caused by salting out all alkaloids.

[0020] 4. The present invention can reduce the process steps that deepen the color of alkaloids during the production and processing, reduce the browning reaction under alkaline conditions, and simplify the decolorization steps; the present invention avoids the adsorption loss of alkaloids caused by the use of activated carbon decolorization by adding antioxidants, step-by-step crystallization, and resin in the extraction stage, while improving the product yield, preparing yellow berberine hydrochloride, white berbamine and reddish-yellow jatrorrhizine, solving the problem of poor product color on the market.

[0021] 5. The present invention does not use high-cost separation technology processes such as silica gel and alumina chromatography, and does not use solvents other than water and ethanol, thereby improving the operability and safety of production. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] Furthermore, the technical solutions between the various embodiments of the present invention may be combined with each other, but this must be based on the fact that they can be implemented by ordinary technicians in the field. When the combination of technical solutions is mutually contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0024] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention are familiar to those skilled in the art and the description of the present invention, and any methods, equipment and materials of the prior art similar or equivalent to the methods, equipment and materials described in the embodiments of the present invention can also be used to implement the present invention.

[0025] The three needles used in the embodiments of the present invention were purchased in Sichuan and harvested in late December; the purified water used was homemade by a pure water machine, and the sulfuric acid, ethanol, ion exchange resin, and macroporous adsorption resin used were obtained through conventional commercial channels unless otherwise specified; in the present invention, the concentration of the sulfuric acid solution is the volume concentration, the concentration of the hydrochloric acid solution is the volume concentration, the concentration of the sodium hydroxide solution is the mass concentration, and the concentration of ethanol is the volume concentration, all of which are prepared with water.

[0026] In the embodiment of the present invention, the content of berberine hydrochloride is determined by high performance liquid chromatography (HPLC) according to the "berberine hydrochloride" or "three needles" item in the 2020 edition of the Pharmacopoeia of the People's Republic of China; the content of berbamine is determined by high performance liquid chromatography (HPLC); the contents of berberine hydrochloride and jatrorrhizine hydrochloride are simultaneously determined by high performance liquid chromatography (HPLC) under the "Mahonlaomu" item in the 2020 edition of the Pharmacopoeia of the People's Republic of China; the contents of berberine hydrochloride, berbamine and jatrorrhizine hydrochloride are simultaneously determined by high performance liquid chromatography (HPLC). It should be clarified that although the three needles in the present invention contain berberine, berberamine and jatrorrhizine, the unified standard for determining the content of berberine and jatrorrhizine in the 2020 edition of the "Pharmacopoeia of the People's Republic of China" is hydrochloride. Therefore, when expressing the material content of berberine and jatrorrhizine in the three needles, the present invention is calculated in the form of hydrochloride; and after completing the production in the present invention, the substances obtained are berberine hydrochloride, berberamine and jatrorrhizine hydrochloride.

[0027] The descriptions of berberine hydrochloride, berbamine and jatrorrhizine hydrochloride are as follows: Berberine hydrochloride: Also known as berberine hydrochloride, it is a yellow crystalline powder with a very bitter taste. It is easily soluble in boiling water, dissolves in hot water, slightly soluble in cold water, and is almost insoluble in cold ethanol, chloroform and ether. It is mainly used as an antibacterial drug, and is mainly used clinically for intestinal infections and bacillary dysentery, etc. It has an anti-arrhythmic effect; Chinese name: berberine hydrochloride; English name: Berberine; CAS Number: 633-65-8; Molecular formula: C 20 H 18 ClNO4; Molecular weight: 372.82.

[0028] Berbamine: a dibenzylisoquinoline alkaloid. The free form is poorly soluble in water, insoluble in alkaline water, and easily soluble in inorganic acid water and ethanol. Its hydrochloride is a white powder, easily soluble in water, and slightly bitter. It has the effects of promoting hematopoiesis, inhibiting tumors, treating anemia, and relaxing muscles. It is used to prevent and treat leukopenia caused by chemotherapy or radiotherapy, benzene poisoning, radioactive substances, and drugs in patients with tumors. Chinese name: Berbamine; English name: Berbamine; CAS Number: 6078-17-7; Molecular formula: C 37 H 40 N2O6; Molecular weight: 681.65.

[0029] Jatrorrhizine hydrochloride: Also known as jatrorrhizine, it is a red-yellow needle-shaped crystal with a very bitter taste. It is soluble in water and ethanol. It has the effects of detoxification, sterilization, lowering blood sugar and positive inotropic effects. Chinese name: Jatrorrhizine hydrochloride; English name: Jatrorrhizine; CAS Number: 3621-38-3; Molecular formula: C 20 H 20 ClNO4; Molecular weight: 465.28.

[0030] As a further illustration of the existing research, the currently disclosed technical contents on extracting berberine hydrochloride, berbamine and jatrorrhizine from three needles are mainly as follows: The Chinese invention patent application with publication number CN111297930A discloses a three needle extract and a preparation method thereof, wherein the preparation method comprises the following steps: (1) raw material processing: take the raw material three needles, select and wash them; (2) extraction: add dilute acid alcohol to reflux extraction; (3) filtration: solid-liquid separation to obtain filtrate a; (4) concentration: concentrate the filtrate a to be free of alcohol taste, let it stand, filter, and obtain a concentrated solution; (5) salting out: add sodium chloride to the concentrated solution, let it stand, and precipitate crystals; (6) alkalization: dissolve the crystals with hot water, alkalize with quicklime, filter, and obtain filtrate b; (7) acidification: add dilute hydrochloric acid to the filtrate b for acidification, let it stand, precipitate crystals, filter out the crystals, and rinse with water; (8) drying: dry the crystals after rinsing with water to obtain the product three needle extract. This patent application uses dilute acid and alcohol to extract the three-needle alkaloids. The use of alcohol makes the production cost relatively high; the three-needle extract is prepared by salting out with an acidic solution, alkalizing to remove impurities and acidifying to crystallize, which is actually the preparation of berberine hydrochloride, but in the preparation process, a large amount of salt is added to pollute the environment; alkalization produces browning, which deepens the color of the alkaloids and has a great influence on the color of the product obtained by crystallization and purification; a simple single crystallization is difficult to prepare high-purity, good-color berberine hydrochloride, and repeated crystallization is required; only a single berberine hydrochloride is prepared as a whole, and the valuable berbamine and jatrorrhizine are discarded, resulting in a waste of resources.

[0031] The Chinese invention patent application with publication number CN105440031A discloses a method for purifying berberine hydrochloride from three needles, which comprises the following steps: (1) taking 100-120 parts by weight of root coarse powder, passing it through a 20-mesh sieve, adding 300-400 parts by weight of a 0.5% sulfuric acid aqueous solution to immerse the drug surface, soaking for 6-10 hours, and filtering with absorbent cotton; (2) adding lime milk to the filtrate to neutralize excess sulfuric acid, adjusting the pH to 7, and standing 10-20min; (3) filter out the precipitate, add 200-300 parts by weight of ethanol to the filtrate, stir, heat to 80-90°C and reflux for 20-30min; (4) add ethanol to the filtrate and concentrate under reduced pressure until the filtrate is a brown-red slurry; (5) add 2-4% acetic acid to the brown-red slurry and heat; (6) add hydrochloric acid and acetone until the solution becomes turbid, cool with ice water until berberine hydrochloride precipitates, and dry to obtain fine berberine hydrochloride. This patent application uses dilute sulfuric acid to extract berberine hydrochloride by immersion at room temperature, which is time-consuming; acetic acid, hydrochloric acid and acetone are used for dissolution and purification under acidic conditions, and acetone has certain toxicity; it is miscible with water and a large amount is used until berberine hydrochloride is precipitated, which directly leads to high costs; the low boiling point results in large losses in recovery, making it difficult to use in production; only a single berberine hydrochloride is prepared as a whole, and the valuable berbamine and jatrorrhizine are discarded, resulting in a waste of resources.

[0032] The Chinese invention patent application with the publication number CN103059017A discloses a comprehensive extraction process design of the three needle plant resources. This design route mainly extracts berberine hydrochloride, jatrorrhizine hydrochloride, bamipine hydrochloride, and muscle relaxants simultaneously and efficiently, and also uses berbamine as a raw material to synthesize analgesics. The patent application claims that berberine hydrochloride, berberine, jatrorrhizine and bamipine are comprehensively extracted, but its technical essence lies in repeated salting out, pH adjustment, repeated crystallization of acid water or alcohol water, and activated carbon decolorization; in fact, due to the low content of bamipine in the three needles, there is no extraction value; simple pH adjustment and crystallization are difficult to prepare the three main alkaloids with high purity and good color, and repeated crystallization is required, resulting in unsatisfactory yield and quality, and it is difficult to use in production, and salting out under different pH conditions alone cannot prepare jatrorrhizine with a purity of more than 40%.

[0033] The Chinese invention patent application with publication number CN103044417A discloses a method for extracting and purifying berberine from wild three needles in Daxinganling, and in particular, relates to a new method for purifying berberine by using biological enzymatic hydrolysis, ultrasonic extraction and column chromatography purification technology; its advantages are: (1) the application of biological enzymatic hydrolysis technology allows the berberine in the cells to be fully dissolved; (2) the use of ultrasonic extraction technology reduces the heating time of the active ingredient, reduces the activity loss, and the product has high biological activity; (3) silica gel column chromatography and recrystallization purification technology further improve the purity of the active ingredient berberine, which is simple and easy to operate, greatly reduces the production cost, and can be used industrially. However, this patent application only extracts berberine hydrochloride, and does not involve berbamine and jatrorrhizine, resulting in a waste of resources. Silica gel column chromatography requires a large amount of toxic organic solvents, and there are safety risks. The preparation cost is high and cannot be applied to production.

[0034] The Chinese invention patent application with publication number CN104031057A discloses a method for producing berbamine, comprising the following steps: S1, taking 250g of three needle root powder, adding 1750mL of 2% hydrochloric acid, and leaving it for 22h; S2, filtering through double gauze, adding lime powder to the filtrate to adjust the pH value to 12, and leaving it for 30min; S3, siphoning and extracting, filtering out the residue, discarding the filter residue, taking the filtrate, adding 8% sodium chloride by volume of the filtrate for salting out, and after the precipitate is precipitated, adding hydrochloric acid to adjust the pH value to 8, heating to 80°C, maintaining for 30min, leaving it for 24h, siphoning and extracting; S4, washing and removing impurities, taking 1g and adding 20mL of ether, reflux in a water bath for 30min; S5, adding 4mL of petroleum ether, leaving it for 12h, filtering, washing the filter with a small amount of petroleum ether, and drying at 80°C to obtain berbamine. This patent application only prepares berbamine, ignoring berberine hydrochloride and jatrorrhizine, which have higher value, resulting in serious waste of resources. A large amount of sodium chloride is added for salting out, causing environmental pollution. This patent application uses ether and petroleum ether for decolorization, which are toxic, highly volatile, flammable and explosive, and have high preparation costs, and cannot be applied to production.

[0035] In summary, existing research rarely prepares berberine hydrochloride, berbamine, and jatrorrhizine hydrochloride at the same time; the extraction solvents are mainly dilute sulfuric acid and dilute acid alcohol. In comparison, the production cost of dilute sulfuric acid extraction is lower, but it takes a long time at room temperature; traditional salting out is generally used, and the amount of sodium chloride used is large, which is easy to pollute the environment; alkalization produces browning, which deepens the color of the alkaloids and has a great influence on the color of the product obtained by crystallization and purification; the use of organic solvents such as acetone, ether, and petroleum ether for decolorization and refining is not only toxic, but also highly volatile, flammable and explosive, with high preparation costs, and cannot be used in production; silica gel chromatography is used, the preparation cost is high, and it is difficult to achieve in production; simple pH adjustment, crystallization and activated carbon decolorization, the purity and color of the alkaloids are difficult to meet the standards, and several repeated crystallization purifications are required, which greatly reduces the product yield. Existing research as a whole focuses on experimental technology, which is still a certain distance from industrial production; therefore, with the upgrading and improvement of technology, it is necessary to establish a set of comprehensive industrial production and utilization technology systems for the extraction, separation and deep processing of three needles.

[0036] The present invention mainly realizes the production of berberine hydrochloride, berberamine and jatrorrhizine hydrochloride through the following aspects: (1) comprehensively utilizing the resources of three needle medicinal materials, continuously producing and preparing three high value-added products of berberine hydrochloride, berberamine and jatrorrhizine, and reducing the production cost; (2) improving production efficiency, reducing equipment occupation, and changing the traditional process of long-term immersion extraction; (3) adding no or less salt as much as possible to reduce the pollution of salt wastewater to the environment; (4) improving the color of the product, reducing the process steps that deepen the color during the production and processing, or simplifying the decolorization step; (5) improving the yield of alkaloid products, using innovative technologies such as membrane separation and resin combination for separation and purification, and avoiding repeated crystallization and activated carbon decolorization and other process steps that reduce the product yield; (6) not using silica gel, alumina chromatography process and organic solvents other than ethanol, thereby improving the operability and safety of production.

[0037] The present invention provides a method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, the steps of which are: S1, broken: Obtain three needles powder; the three needles powder is made from three needles, and the three needles powder contains berberine, berbamine and jatrorrhizine; the process of obtaining the three needles powder includes: crushing the raw materials into coarse powder that is basically the size of grains.

[0038] In the present invention, the content of berbamine in the three-needle powder is 0.5-2.0% by weight; the content of berberine hydrochloride in the three-needle powder is 1.0-2.5% by weight and in the form of hydrochloride, and the content of jatrorrhizine hydrochloride is 0.4-0.9%.

[0039] For Tripterygium wilfordii, in addition to the root, the stem bark also contains relatively high content of berberine, berbamine and jatrorrhizine. In order to expand the increasingly reduced medicinal parts of the medicinal materials that can be used to extract alkaloids and improve the comprehensive utilization of resources, the content of the main alkaloids of Tripterygium wilfordii is comprehensively considered, and the root and stem bark of Tripterygium wilfordii are used as extraction raw materials in the present invention.

[0040] S2, acid leaching: The three-needle powder is extracted with a sulfuric acid solution containing an antioxidant to obtain an extract; the concentration of the sulfuric acid solution is 0.2-0.7%, the extraction temperature is 50-65°C, and the total extraction time is not more than 8 hours, and can further be 5-8 hours.

[0041] In the present invention, the antioxidant protective agent includes vitamin C and ferrous sulfate, the mass ratio of the vitamin C to the ferrous sulfate is 1 to 3:1; the mass percentage of the antioxidant protective agent and the three needle powder is 1.0 to 4.0%. The present invention stirs during the extraction process, and specifically can stir intermittently, such as: stirring is started at intervals of 10 minutes or air pressure recoil is performed for 2 minutes.

[0042] In the present invention, the number of leaching is three times; when performing the first leaching, the ratio of the sulfuric acid solution to the three needle powder is controlled to be 5-7 mL: 1 g, the three needle powder is leached in the sulfuric acid solution for 2-4 hours, and the first filtrate and the first filter residue are collected after filtering; when performing the second leaching, the ratio of the sulfuric acid solution to the three needle powder is controlled to be 4-6 mL: 1 g, the first filter residue is leached in the sulfuric acid solution for 1-3 hours, and the second filtrate and the second filter residue are collected after filtering; when performing the third leaching, the ratio of the sulfuric acid solution to the three needle powder is controlled to be 5-7 mL: 1 g, the second filter residue is leached in the sulfuric acid solution for 0.5-1.5 hours, and the third filtrate is collected after filtering; the first filtrate and the second filtrate are combined as the extract, and the third filtrate is used for the leaching of the next batch of the three needle powder. Of course, without considering the third leaching, the number of leaching can also be two, and the first leaching and the second leaching are performed, and then the first filtrate and the second filtrate are combined as the extract.

[0043] In the present invention, during the first extraction, the mass percentage of the antioxidant protective agent and the three needle powder is 1.0~2.0%; during the second extraction, the mass percentage of the antioxidant protective agent and the three needle powder is 0.3~0.8%; during the third extraction, the mass percentage of the antioxidant protective agent and the three needle powder is 0.1~0.3%.

[0044] S3, heat preservation, filtration, clarification and membrane separation: S31, controlling the temperature of the extract to be 60-65°C; performing primary filtration and microfiltration on the extract in sequence to obtain a clear liquid; the pore size of the membrane used for the microfiltration is 200-800nm.

[0045] In the present invention, the primary filtration includes tripod bag centrifugal filtration or plate and frame filtration, and the microfiltration uses a ceramic membrane with a pore size of 200-800nm; the material of the ceramic membrane is alumina or zirconia.

[0046] In the present invention, when the liquid after the primary filtration is subjected to the microfiltration, when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract, hot water is added to the upstream liquid (the volume of the hot water is 1.5 to 2.5 times the volume of the upstream liquid, and the temperature is 60 to 65°C) to dilute it, and continue to pass through the membrane; when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract again, hot water is added to the upstream liquid again (the volume of the hot water is 1.5 to 2.5 times the volume of the upstream liquid, and the temperature is 60 to 65°C) to dilute it, and continue to pass through the membrane.

[0047] S32, controlling the temperature of the clear liquid to be 60-65°C; adjusting the pH of the clear liquid to be 1-4 with an alkali solution, and then passing the clear liquid through a high temperature ultrafiltration membrane to collect the liquid downstream of the membrane.

[0048] The maximum temperature that the high-temperature ultrafiltration membrane can withstand is not less than 70°C, and the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3~8KD; specifically, the high-temperature ultrafiltration membrane can withstand a maximum temperature of 70°C, and is prepared using a unique high-temperature resistant membrane yarn and paper membrane process. The membrane material is PES (polyethersulfone) or PVDF (polyvinylidene fluoride), and the model is UE series (such as UE005-8040H); that is, the membrane material of the high-temperature ultrafiltration membrane includes one or more of polyethersulfone and polyvinylidene fluoride.

[0049] In the present invention, when the clear liquid passes through the high-temperature ultrafiltration membrane, when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract, hot water is added to the upstream liquid (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65° C.) to dilute it, and continue to pass through the membrane; when the volume of the upstream liquid is only 1 / 30 to 1 / 40 of the extract again, hot water is added to the upstream liquid again (the volume of the hot water is 1.5 to 2.5 times the volume of the residual liquid of the upstream liquid, and the temperature is 60 to 65° C.) to dilute it, and continue to pass through the membrane.

[0050] S33, controlling the temperature of the liquid downstream of the membrane to 60-65°C; passing the liquid downstream of the membrane through a high-temperature nanofiltration membrane, collecting the liquid upstream of the membrane, and using the liquid upstream of the membrane as a membrane refined liquid.

[0051] The maximum temperature that the high-temperature nanofiltration membrane can withstand is not less than 70°C, and the molecular weight cutoff of the high-temperature nanofiltration membrane is 150~300D; specifically, the maximum temperature that the high-temperature nanofiltration membrane can withstand is 70°C, and the membrane material is PES (polyethersulfone), UF series (such as UF8040); that is, the membrane material of the high-temperature nanofiltration membrane includes polyethersulfone.

[0052] S4, Production of berberine hydrochloride: S41, using alkaline solution to adjust the pH of the membrane refined liquid to 6-7, and then filtering; using hydrochloric acid solution to adjust the pH of the filtered liquid to 2-3, and standing at 5-25°C for at least 48h or 48-72h to allow the precipitate to fully precipitate; after standing, filtering (suction filtration or plate and frame filtration) to collect the first wet precipitate and the first mother liquor.

[0053] S42, adding 60-65% ethanol solution to the first wet precipitate at a ratio of 1 g: 12-15 mL, and heating to 80-90° C. to completely dissolve the precipitate; when the first wet precipitate is completely dissolved, standing at 5-25° C. for at least 20 h or 22-26 h; after standing, filtering (suction filtration or plate and frame filtration) to collect the second wet precipitate and the second mother liquor.

[0054] S43, concentrating the second mother liquor to 1 / 5~1 / 4 of the original volume (vacuum decompression concentration), and then adding high-grade ethanol to the second mother liquor to make the ethanol concentration in the second mother liquor reach 60~65%; letting the second mother liquor stand at 5~25°C for at least 20h or 22~26h, filtering (suction filtration or plate and frame filtration) after completion of standing, and collecting the third wet precipitate and the third mother liquor.

[0055] S44, combining the first mother liquor and the third mother liquor to obtain a berberine crystallization mother liquor; combining the second wet precipitate and the third wet precipitate to obtain a wet precipitate containing berberine hydrochloride.

[0056] S5, Production of Berbamine: S51, ion exchange resin decolorization: the berberine crystallization mother liquor is concentrated until there is no alcohol taste (the ethanol is recovered by vacuum decompression until there is no alcohol taste), and the berberine crystallization mother liquor is further concentrated until the Brix of the berberine crystallization mother liquor is 1-3 Brix, to obtain a first concentrated solution.

[0057] The first concentrated solution is passed through an alkaline anion exchange resin column at room temperature (e.g., 5-25°C), the feed effluent is collected, and the feed effluent is used as an ion exchange resin decolorizing solution; further, after the first concentrated solution is passed through the alkaline anion exchange resin column, it is passed through a 3-5BV purification water washing column, 0-3BV of the water washing column liquid is collected, and the feed effluent and the water washing column liquid are combined as the ion exchange resin decolorizing solution.

[0058] In the present invention, the basic anion exchange resin column includes one of gel-type acrylic acid strong base anion resin, gel-type acrylic acid weak base anion resin, gel-type styrene strong base anion resin, gel-type styrene weak base anion resin, macroporous acrylic acid strong base anion resin, macroporous acrylic acid weak base anion resin, macroporous styrene strong base anion resin, and macroporous styrene weak base anion resin. Preferred models: D900, D941, D316, D296, D280.

[0059] S52, fractional crystallization: adjusting the pH of the ion exchange resin decolorant to 6-7, and then vacuum decompression concentrating to 3-8 Brix to obtain a second concentrated solution; the second concentrated solution is allowed to stand at 5-25°C (preferably 5-20°C) for at least 4h or 4-6h to allow partial precipitation, and then the pH of the second concentrated solution is adjusted to 8-9 to obtain a third concentrated solution; the third concentrated solution is allowed to stand at 5-25°C (preferably 5-20°C) for at least 10h or 10-15h to allow complete precipitation, and then filtered (suction filtration or plate-frame filtration) to obtain a berbamine crystallization mother liquor and a wet precipitate containing berbamine. Further, the present invention uses alkali solution to adjust the pH of the ion exchange resin decolorant to 6-7, and uses alkali solution to adjust the pH of the second concentrated solution to 8-9.

[0060] S6, production of jatrorrhizine hydrochloride: The berbamine crystallization mother liquor is fed into a macroporous adsorption resin column, and then desorbed with an ethanol solution having a concentration of 40-45%, and the desorbed liquid is collected; the desorbed liquid is concentrated (vacuum reduced pressure concentration) to 17-25 degrees Baume, and the pH is adjusted to 4-6 with a hydrochloric acid solution to obtain a refined liquid containing jatrorrhizine hydrochloride; further, after the berbamine crystallization mother liquor is fed into the macroporous adsorption resin column, before the desorption is performed, it is fed into a 2-4 BV purification water washing column.

[0061] In the present invention, the resin in the macroporous adsorption resin column includes one of a non-polar macroporous adsorption resin and a weakly polar macroporous adsorption resin; specifically, the resin in the macroporous adsorption resin includes one of non-polar D101, LX-100B, LX-T28, or includes weakly polar AB-8; In the present invention, the purification of jatrorrhizine hydrochloride is a combination of separation of berberine hydrochloride and berbamine, membrane separation in step S3 and purification by macroporous adsorption resin after ion exchange resin decolorization in step S5.

[0062] S7, Drying: The wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing berbamine is dried to obtain a berbamine product; the refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product; the berberine hydrochloride product is bright yellow, the berbamine product is white, and the jatrorrhizine hydrochloride product is reddish yellow.

[0063] Specifically, the wet precipitate containing berberine hydrochloride, the wet precipitate containing berbamine, and the refined liquid containing jatrorrhizine are vacuum dried or microwave vacuum dried at a temperature of 60-65° C. and a vacuum degree of ≧-0.085 MPa to obtain bright yellow berberine hydrochloride, white berbamine, and red-yellow jatrorrhizine hydrochloride, respectively.

[0064] The present invention continuously produces and prepares three kinds of high value-added products, realizing the comprehensive utilization of raw materials; through the special high-temperature resistant membrane insulation separation and crystallization, it replaces the traditional salting out, solves the problem of salt wastewater polluting the environment, and realizes the step-by-step separation and purification of alkaloids; through the combination of membrane separation and resin, it avoids repeated crystallization and activated carbon decolorization, significantly improves the yield and quality of berbamine, and does not use organic solvents other than silica gel and ethanol to prepare high-content jatrorrhizine; forms an advanced and practical three-needle extraction, separation and deep processing production technology system.

[0065] As a supplementary explanation, in the present invention, the alkali solution in step S3, step S4 and step S5 is a sodium hydroxide solution with a concentration of 1-3%; in step S4 and step S6, the concentration of the hydrochloric acid solution is 1-3%.

[0066] In the step S2 of the present invention, the concentration of the sulfuric acid solution is 0.2-0.7%. If the concentration is too low, the amount used will be too large, and if the concentration is too high, waste will be caused and production costs will be increased, and there will be obvious acid corrosion to the pipeline system.

[0067] In the step S2 of the present invention, the leaching temperature is 50-65°C; the conventional process uses room temperature dilute acid leaching, which takes more than 24 hours, has a long production cycle, seriously occupies equipment, and has low efficiency; when the temperature exceeds 75°C, the color of the acid extract is significantly deepened, which is not conducive to product decolorization and purification, and damages the alkaloids, reducing the content of the extract, and the higher the temperature, the more obvious it is; the leaching temperature of the present invention can extract the three alkaloid components faster, with stable content, short time, and high extraction efficiency.

[0068] In the step S2 of the present invention, the antioxidant protective agent is a substance compounded with vitamin C and ferrous sulfate in a certain proportion; by adding a specific antioxidant protective agent, especially a compound substance, not only can the color deepening of the extract be slowed down, but the alkaloid components can also be kept stable and not easily destroyed in a heating environment of 50-65°C, which is beneficial to decolorization and refining.

[0069] In the step S3 of the present invention, the temperature is maintained at 60-65°C; at this temperature, the three-needle alkaloids, especially the sulfates of berberine, berbamine and jatrorrhizine, have a large solubility and are not easy to precipitate, which is conducive to membrane separation and purification; when the temperature is room temperature, the extract will become turbid and precipitate, and in severe cases, the membrane pores will be blocked and the equipment will be damaged; when the temperature is too high, it is not conducive to the stability of the content of the alkaloid components, and it also exceeds the maximum temperature that the special membrane can withstand, and the alkaloids cannot be purified by membrane separation.

[0070] In the step S3 of the present invention, the liquid obtained after the primary filtration is clarified by microfiltration through a ceramic membrane made of aluminum oxide or zirconium oxide with a pore size of 200-800 nm; at 60-65° C., the precipitate in the extract can be removed by microfiltration through the ceramic membrane with the pore size to obtain a clear and transparent liquid without post-precipitation, which is beneficial to membrane separation and purification.

[0071] In the step S3 of the present invention, the high temperature ultrafiltration membrane can withstand a maximum temperature of 70°C, has a molecular weight cutoff of 3~8KD, is prepared by a unique high temperature resistant membrane silk and paper membrane process, and is made of PES or PVDF, and is a UE series (such as UE005-8040H). This special specification of ultrafiltration membrane can be used for preliminary purification of three needle alkaloids, because the maximum temperature that ordinary ultrafiltration membranes can withstand is 45°C, and under 45°C conditions, due to the difference in solubility of different alkaloid sulfates, especially berberine sulfate, when the ultrafiltration membrane runs to a smaller volume, it will precipitate with other impurities and block the membrane pores, which will not only damage the equipment and make the process impossible, but also reduce the product yield; the molecular weight cutoff of 3~8KD can remove most impurities and pigments, while the three needle alkaloid sulfate can be completely passed through, thereby obtaining a higher purity of three needle total alkaloids.

[0072] In the step S3 of the present invention, the high-temperature nanofiltration membrane can withstand a maximum temperature of 70°C, a molecular weight cutoff of about 200D, and the membrane material is PES, UF series (such as UF8040). This specification of nanofiltration membrane can concentrate the ultrafiltration membrane separation liquid of three needle alkaloids, because the maximum temperature that ordinary nanofiltration membranes can withstand is 45°C, and under 45°C conditions, due to the difference in solubility of different alkaloid sulfates, especially berberine sulfate, during the nanofiltration membrane concentration process, it will precipitate with other impurities and block the membrane pores, which will not only damage the equipment and make the process impossible to proceed, but also reduce the product yield; the molecular weight cutoff of about 200D can completely intercept the three needle alkaloids. At 60~65°C, high temperature resistant nanofiltration membrane concentration can replace traditional vacuum decompression concentration to obtain membrane refined liquid.

[0073] In the step S4 of the present invention, berberine hydrochloride needs to use dilute alkali to adjust the pH of the membrane refined liquid to 6-7 before crystallization, filter, and then use dilute hydrochloric acid to adjust the pH to 2-3. The solubility of the three needle alkaloid sulfate is greater than that of the hydrochloride, and the solubility of berberine, berbamine and jatrorrhizine sulfate is not much different, which is not conducive to the crystallization of monomer alkaloids; however, the solubility of berberine hydrochloride in cold and hot water is quite different, and the hydrochloride is conducive to separating berberine from the total alkaloids first, while berbamine and jatrorrhizine continue to remain in the solution, therefore, the sulfate needs to be converted into hydrochloride.

[0074] In the step S4 of the present invention, the pH of the berberine hydrochloride crystallization condition is 2-3, naturally cooled to room temperature, and allowed to stand for at least 48 hours or 48-72 hours; the recrystallization condition is 60-65% ethanol, heated at 80-90°C to completely dissolve the precipitate, and allowed to stand after naturally cooling to room temperature; the stepwise crystallization condition is to concentrate the recrystallization mother liquor to 1 / 5-1 / 4 of the original volume, add high ethanol to adjust the ethanol concentration to 60-65%, and let it stand after naturally cooling to room temperature.

[0075] After separation and concentration with a high temperature resistant ultrafiltration membrane and a nanofiltration membrane in the aforementioned process, when a certain volume and natural cooling to room temperature are allowed to stand for a sufficient period of precipitation, berberine hydrochloride can be completely crystallized without adding sodium chloride, while only a small amount of berberamine hydrochloride and jatrorrhizine are precipitated simultaneously with berberine hydrochloride, which is significantly different from the phenomenon that a large amount of berberamine and jatrorrhizine are precipitated simultaneously with berberine hydrochloride by traditional salting out. In the present invention, the high temperature resistant membrane separation method can not only replace the traditional salting out to completely precipitate berberine hydrochloride, but also obtain berberine hydrochloride crystals with higher purity, avoiding the defects of salting out to precipitate most other alkaloids, such as berberamine and jatrorrhizine, which increases the difficulty of later purification and the pollution of the environment caused by the traditional salting out with the addition of a large amount of salt. Recrystallization and fractional crystallization from 60-65% ethanol can obtain berberine hydrochloride with a purity of more than 97%, while solving the practical problem that high ethanol concentration is difficult to recover in industrial production due to the use of ethanol with a concentration of more than 80% in the traditional process, and completely separate it from the small amount of berberine hydrochloride and jatrorrhizine precipitated in the crystallization stage.

[0076] In the step S5 of the present invention, the crystallization conditions of berbamine are first decolorization with ion exchange resin, and then step-by-step crystallization at pH 6-7, concentration 3-8 Brix, standing for more than 4 hours and pH 8-9, standing for more than 10 hours.

[0077] In the present invention, step-by-step separation is the key to the continuous preparation of three needle alkaloids. The mother liquor after separating berberine hydrochloride first still contains a large amount of pigments. Although such pigments have substantially the same molecular weight and / or molecular structure as alkaloids, and after the aforementioned membrane separation, they still exist with alkaloids and are not easy to separate, but a certain specification and model of alkaline anion exchange resin column can exchange and adsorb with these pigments without adsorbing alkaloid components. Therefore, alkaloids mainly composed of berberine and jatrorrhizine can be separated from most of the pigments by an alkaline anion exchange resin column, thereby obtaining alkaloids with good color and high purity. Berbamine will partially crystallize when the pH is 6 to 7. Although the crystallization is slow, the color and crystal form are good. When the pH is continuously adjusted to 8 to 9, it can be completely precipitated after a certain period of time. Compared with the crystallization precipitation with the pH adjusted to 8 to 9 at one time, the step-by-step crystallization with pH adjusted has good color and crystal form, and the purity is increased to more than 98%. Therefore, after separation by a high-temperature resistant membrane and decolorization by an alkaline anion exchange resin column, combined with the step-by-step crystallization technology, the difficult problem of traditional technology for refining berbamine, which requires repeated pH adjustment, addition of activated carbon for decolorization, and repeated crystallization of alcohol and water, which affects the yield and has high production costs, is solved by simply adjusting the pH once in a step-by-step manner.

[0078] In the step S5 of the present invention, the resin in the basic anion exchange resin column can be a gel-type and macroporous acrylic acid weak base anion resin, an acrylic acid strong base and weak base anion resin, a gel-type and macroporous styrene strong base anion resin, a macroporous acrylic acid strong base anion resin, a macroporous styrene weak base anion resin, etc., preferably models: D900, D941, D316, D296, D280. The crystallization mother liquor after separation of berberine hydrochloride contains more pigments, and it is necessary to further separate the pigments from the alkaloids represented by berbamine and jatrorrhizine. There are literature reports on the use of cation exchange resins to purify alkaloids. Although the cation resin has no adsorption on the pigment, the three needle alkaloids exchange and adsorb with the cation resin and are difficult to resolve. The overall desorption rate is less than 20%, resulting in a large amount of losses and cannot be used in production. Through a large number of comparative experiments, it was found that another method is to remove the pigment first, that is, to use anion exchange resin to exchange and adsorb the pigment. This resin has no adsorption to the three-needle alkaloids, so that the alkaloids represented by berbamine and jatrorrhizine flow out from the anion resin column, thereby achieving the separation of alkaloids and pigments.

[0079] In the step S6 of the present invention, the resin in the macroporous adsorption resin column is non-polar D101, LX-100B, LX-T28, etc., weakly polar AB-8, etc.; the desorption ethanol concentration is 40~45%. In the present invention, a macroporous adsorption resin of a certain specification has a strong adsorption to jatrorrhizine, but has a small adsorption to other impurities in the mother liquor after separating berberine. After the refining and decolorization process steps such as high temperature resistant membrane separation and ion exchange resin have been carried out in the early stage, berberine hydrochloride and berberine are separated step by step, and the impurities can be separated by a macroporous adsorption resin of a specific specification. When the ethanol concentration is high, the jatrorrhizine adsorbed on the resin and the impurities will be desorbed together, and by controlling the appropriate ethanol concentration, only jatrorrhizine can be desorbed without desorbing most impurities, thereby preparing jatrorrhizine with a purity of more than 80%.

[0080] The following are specific examples of the present invention: Example 1 A method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, the steps of which are: S1, broken: A total of 800 kg of dried three-needle medicinal materials were taken and crushed into coarse powder roughly the size of grains using a hammer mill.

[0081] The content of the crude powder of the three-needle medicinal material was tested. The content of berbamine was 0.87% by mass; the content of berberine hydrochloride was 1.58% by mass and in the form of hydrochloride, and the content of jatrorrhizine hydrochloride was 0.65%.

[0082] S2, acid leaching: Throw the coarse powder into 6m 3 Extract with dilute sulfuric acid in an enamel extraction tank.

[0083] The present embodiment extracts three times, and the third extraction is a set extraction; the extraction temperature is 56°C; the stirring mode during extraction is: stirring is turned on for 2 minutes at intervals of 10 minutes; during the three extractions, the amount of antioxidant added is 10.0kg, 4.5kg, and 1.5kg, respectively, and the antioxidant is composed of vitamin C and ferrous sulfate in a mass ratio of 2:1; during the three extractions, the extraction time is 3.0h, 2.0h, and 1.0h, respectively; the concentration of dilute sulfuric acid used in the three extractions is 0.3%; during the three extractions, the amount of dilute sulfuric acid added is 4800L, 4000L, and 4800L, respectively; after each extraction, filtration is performed, and the filter residue enters the next extraction, and the filtrates from the previous two extractions are combined to obtain 7100L of extract.

[0084] S3, heat preservation, filtration, clarification and membrane separation: S31, maintaining the temperature of the extract at 62°C; firstly subjecting the extract to plate-and-frame filtration, and then clarifying the filtrate through microfiltration of a ceramic membrane made of zirconium oxide and having a pore size of 500nm; when only 200L of the upstream liquid remains, 400L of hot water at a temperature of 65°C is added to dilute the upstream liquid, and the membrane is continued to pass; when only 200L of the upstream liquid remains again, 400L of hot water at a temperature of 65°C is added again to dilute the upstream liquid, and the membrane is continued to pass; the liquid downstream of the membrane is collected to obtain a clear liquid; S32, maintain the temperature of the clear liquid at 62℃; adjust the pH value of the clear liquid to 3 with 2% sodium hydroxide solution, and pass it through a high-temperature ultrafiltration membrane (membrane material PVDF, model UE005-8040H) that can withstand a maximum temperature of 70℃ and has a molecular weight cutoff of 5KD; when only 200L of the upstream liquid is left, add 400L of hot water at a temperature of 62℃ to dilute the upstream liquid and continue to pass through the membrane; when only 200L of the upstream liquid is left again, add 400L of hot water at a temperature of 62℃ to dilute the upstream liquid and continue to pass through the membrane; collect the downstream liquid of the membrane, about 8200L; S33, maintain the temperature of the liquid downstream of the membrane (derived from step S32) at 62°C; pass the liquid downstream of the membrane through a high-temperature nanofiltration membrane (material PES, model UF8040) that can withstand a maximum temperature of 70°C and has a molecular weight cutoff of 200D, collect the liquid upstream of the membrane, and obtain a membrane refined liquid, about 450L.

[0085] S4, Production of berberine hydrochloride: S41, adjusting the pH of the membrane refined liquid to 6 with a 2% sodium hydroxide solution, plate-and-frame filtration, and then adjusting the pH to 2 with a 2% hydrochloric acid solution, naturally cooling to room temperature (in this embodiment, the liquid temperature at room temperature is about 15° C.), and standing at room temperature for 65 hours to allow the precipitate to fully precipitate, plate-and-frame filtration, collecting the wet precipitate and the mother liquor respectively, weighing and measuring the volume, and obtaining 34.96 kg of wet precipitate and 420 L of mother liquor; S42, add 450L of 64% ethanol, heat at 85°C and stir to completely dissolve the wet precipitate in step S41, cool naturally to room temperature, and stand at room temperature for 24 hours, filter by plate and frame, collect the wet precipitate and mother liquor respectively, weigh and measure the volume, and obtain 17.20kg of wet precipitate and 440L of mother liquor; S43, vacuum-concentrating the 440 L mother liquor in step S42 to 100 L, adding high-grade ethanol to adjust the ethanol concentration to 60%, naturally cooling to room temperature, and standing at room temperature for 24 h, plate-and-frame filtering, collecting the wet precipitate and the mother liquor separately, and obtaining 6.40 kg of wet precipitate and 110 L of mother liquor; S44, combining the mother liquors in step S41 and step S43 to obtain about 530 L of berberine crystallization mother liquor; combining the wet precipitates in step S42 and step S43 to obtain 23.6 kg of bright yellow berberine hydrochloride (containing the wet precipitate of berberine hydrochloride).

[0086] S5, Production of Berbamine: S51, ion exchange resin decolorization: the berberine crystal mother liquor is vacuum-reduced at a temperature of 62°C to recover ethanol until there is no alcohol taste, water is added to remove alcohol, and the mixture is concentrated to 450L (2.9Brix), and cooled to room temperature; then, a basic anion exchange resin column containing 75kg model D900 is introduced, and after the feed is completed, a 300L purified water washing column (4BV) is introduced, and the feed effluent and 200L water washing column liquid (2.7BV) are collected and combined to obtain an ion exchange resin decolorization liquid; S52, step-by-step crystallization: adjust the pH of the ion exchange resin decolorization liquid to 7 with 2% sodium hydroxide solution, concentrate it to 200L (6Brix) under vacuum pressure, and let it stand at room temperature for 5 hours to allow part of the white precipitate to precipitate; then, continue to adjust the pH to 9 with 2% sodium hydroxide solution, let it stand at room temperature for 12 hours to allow the precipitate to precipitate completely; finally, filter by plate and frame, collect the wet precipitate and mother liquor separately, and obtain 13.30kg of white berbamine (wet precipitate containing berbamine) and about 190L of berbamine crystallization mother liquor.

[0087] S6, production of jatrorrhizine hydrochloride: The berbamine crystallization mother liquor was fed into a non-polar macroporous adsorption resin column containing 200 kg of LX-T28, and then fed into a 600 L purified water washing column (3BV) after the feeding was completed. Then, it was desorbed with 800 L of 40% ethanol, and the desorbed liquid was collected and concentrated to 18 degrees Baume under vacuum pressure. The pH was adjusted to 4 with a 2% hydrochloric acid solution to obtain a refined liquid containing jatrorrhizine.

[0088] S7, Drying: The wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing berbamine is dried to obtain a berbamine product; the refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product; the drying method is: microwave vacuum drying, the temperature is 62°C, and the vacuum degree is ≧-0.085MPa.

[0089] In this embodiment, the mass of the berberine hydrochloride product is 10.62 kg, the mass of the berberine hydrochloride product is 5.95 kg, and the mass of the jatrorrhizine hydrochloride product is 4.32 kg; in this embodiment, the berberine hydrochloride product is bright yellow, the berberamine product is white, and the jatrorrhizine hydrochloride product is reddish yellow.

[0090] In the berberine hydrochloride product of this embodiment, the mass proportion of berberine hydrochloride is 97.86%; in the berbamine product of this embodiment, the mass proportion of berbamine is 98.25%; in the jatrorrhizine hydrochloride product of this embodiment, the mass proportion of jatrorrhizine hydrochloride is 82.20%.

[0091] Comparative Example 1 Compared with Example 1, the fractional crystallization in step S52 is adjusted to direct crystallization in this comparative example, and other conditions remain unchanged.

[0092] In this comparative example, the direct crystallization process is as follows: the pH of the ion exchange resin decolorizing solution is directly adjusted to 9 with 2% sodium hydroxide solution, concentrated to 200 L under vacuum decompression, and allowed to stand at room temperature for 17 hours; then, plate and frame filtration is performed to collect the wet precipitate and the mother liquor separately, and 13.46 kg of white berbamine (wet precipitate containing berbamine) and about 190 L of berbamine crystallization mother liquor are obtained.

[0093] In this comparative example, the mass of the berbamine product is 6.02 kg, and the mass proportion of berbamine in the berbamine product is 97.10%.

[0094] Comparative Example 2 Compared with Example 1, the basic anion exchange resin column in step S51 is adjusted to a granular activated carbon column in this comparative example, and other conditions remain unchanged.

[0095] In this comparative example, the mass of the berbamine product is 4.62 kg, the mass proportion of berbamine in the berbamine product is 96.30%, and the color is off-white.

[0096] Comparative Example 3 Compared with Example 1, the use of the basic anion exchange resin column in step S51 is omitted in this comparative example (the production process of berbamine is adjusted accordingly), and other conditions remain unchanged.

[0097] In this comparative example, the production process of berbamine is as follows: the berberine crystallization mother liquor is vacuum-decompressed at a temperature of 62°C to recover ethanol until there is no alcohol taste, water is added to remove alcohol, concentrated to 450L, and cooled to room temperature. Then, the pH is adjusted to 7 with a 2% sodium hydroxide solution, vacuum-decompressed and concentrated to 200L (6.5Brix), and allowed to stand at room temperature for 5 hours to allow part of the yellow-white precipitate to precipitate; thereafter, the pH is continued to be adjusted to 9 with a 2% sodium hydroxide solution, and allowed to stand at room temperature for 12 hours; finally, plate-and-frame filtration is performed to collect the wet precipitate and the mother liquor separately, and 13.56kg of white berbamine (wet precipitate containing berbamine) and about 190L of berbamine crystallization mother liquor are obtained.

[0098] In this comparative example, the mass of the berbamine product is 6.06 kg, the mass proportion of berbamine in the berbamine product is 96.50%, and the color is yellow-white.

[0099] Comparative Example 4 Compared with Example 1, the extraction temperature in step S2 was adjusted to 15° C. in this comparative example, and other conditions remained unchanged.

[0100] In this comparative example, the mass of berberine hydrochloride product is 7.65 kg, the mass of berbamine product is 4.65 kg, and the mass of jatrorrhizine hydrochloride product is 3.28 kg; the results show that when extracted at room temperature for the same time as in Example 1, the yields of the three alkaloids are all less than 70%, and they cannot be fully extracted.

[0101] Comparative Example 5 Compared with Example 1, in this comparative example, the temperature of the clear liquid in step S32 is adjusted to 42° C., and other conditions remain unchanged.

[0102] In this comparative example, after the ultrafiltration membrane ran for 1 hour, the flux dropped from 1200L / h to 350L / h, a significant drop, and could not run normally, requiring shutdown for cleaning, and the upstream liquid volume was greater than 1200L.

[0103] Comparative Example 6 Compared with Example 1, in this comparative example, the temperature of the membrane downstream liquid (derived from step S32) in step S33 is adjusted to 42° C., and other conditions remain unchanged.

[0104] In this comparative example, after the nanofiltration membrane ran for 30 minutes, the flux dropped from 1000L / h to 250L / h, a significant drop, and could not operate normally, requiring shutdown for cleaning, and the upstream liquid volume was greater than 3000L.

[0105] The above technical solutions of the present invention are only preferred embodiments of the present invention, and are not intended to limit the patent scope of the present invention. All equivalent structural changes made using the specification of the present invention under the technical concept of the present invention, or directly / indirectly applied in other related technical fields, are included in the patent protection scope of the present invention.

Claims

1. A method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles, characterized in that: Includes steps: S1, obtaining three needle powders containing berberine, berbamine and jatrorrhizine; S2, extracting the three needle powders to obtain an extract; S3, the extract is filtered and microfiltered to obtain a clear solution; Passing the clear liquid through a high temperature ultrafiltration membrane, and collecting the liquid downstream of the membrane; Passing the downstream liquid of the membrane through a high-temperature nanofiltration membrane, and collecting the upstream liquid of the membrane as a membrane refined liquid; S4, adjusting the pH of the membrane refined liquid to 6-7, and adjusting the pH to 2-3 with a hydrochloric acid solution after filtering; After standing, filtering is performed to collect the first wet precipitate and the first mother liquor; Adding 60-65% ethanol solution to the first wet precipitate, heating and dissolving, letting it stand and filtering, collecting the second wet precipitate and the second mother liquor; concentrating the second mother liquor so that the ethanol concentration in the second mother liquor reaches 60-65%, letting it stand and filtering, collecting the third wet precipitate and the third mother liquor; combining the first mother liquor and the third mother liquor to obtain the berberine crystallization mother liquor; combining the second wet precipitate and the third wet precipitate to obtain a wet precipitate containing berberine hydrochloride; S5, concentrating the berberine crystallization mother liquor to obtain a first concentrated solution; passing the first concentrated solution into a basic anion exchange resin column, and collecting the ion exchange resin decolorized solution containing the feed effluent; The pH of the ion exchange resin decolorized liquid is adjusted to 6-7, and concentrated to obtain a second concentrated liquid; after the second concentrated liquid is allowed to stand for at least 4 hours, the pH is adjusted to 8-9 to obtain a third concentrated liquid; after the third concentrated liquid is allowed to stand, it is filtered to obtain a berbamine crystal mother liquor and a wet precipitate containing berbamine; S6, the berbamine crystallization mother liquor is introduced into a macroporous adsorption resin column, and then desorbed, and the desorbed liquid is collected; the desorbed liquid is concentrated, and the pH is adjusted to 4-6 with a hydrochloric acid solution to obtain a refined liquid containing jatrorrhizine hydrochloride.

2. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: The three needle powder is made of three needles as raw materials; in terms of weight percentage, the content of berbamine in the three needle powder is 0.5-2.0%; in terms of weight percentage and in the form of hydrochloride, the content of berberine hydrochloride in the three needle powder is 1.0-2.5%, and the content of jatrorrhizine hydrochloride is 0.4-0.9%.

3. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S2, the three-needle powder is extracted with a sulfuric acid solution containing an antioxidant protective agent; the concentration of the sulfuric acid solution is 0.2-0.7%, the extraction temperature is 50-65°C, and the total extraction time is not more than 8 hours.

4. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S3, the temperature of the extract is controlled to be 60-65°C, the temperature of the clear liquid is controlled to be 60-65°C, and the temperature of the liquid downstream of the membrane is controlled to be 60-65°C; before the clear liquid passes through the high-temperature ultrafiltration membrane, the pH of the clear liquid is adjusted to 1-4; the membrane pore size used in the microfiltration is 200-800nm; the maximum temperature of the high-temperature ultrafiltration membrane is not less than 70°C; the molecular weight cutoff of the high-temperature ultrafiltration membrane is 3-8KD; the maximum temperature of the high-temperature nanofiltration membrane is not less than 70°C; the molecular weight cutoff of the high-temperature nanofiltration membrane is 150-300D.

5. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S4, an ethanol solution with a concentration of 60-65% is added to the first wet precipitate at a ratio of 1 g: 12-15 mL; The process of concentrating the second mother liquor includes: concentrating the second mother liquor to 1 / 5 to 1 / 4 of the original volume.

6. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S5, the process of concentrating the berberine crystallization mother liquor comprises: concentrating the berberine crystallization mother liquor until there is no alcohol taste, and controlling the Brix of the berberine crystallization mother liquor to be 1-3 Brix.

7. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S5, the Brix of the second concentrated liquid is 3-8 Brix.

8. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: The step S5 further comprises: after the first concentrated solution is fed into the alkaline anion exchange resin column, the column is washed with purified water, the washed column liquid is collected, and the feed effluent and the washed column liquid are combined as the ion exchange resin decolorizing liquid.

9. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to claim 1, characterized in that: In the step S6, desorption is performed using an ethanol solution with a concentration of 40-45%; The process of concentrating the desorption liquid comprises: concentrating the desorption liquid to 17 to 25 degrees Baume; The step S6 further comprises: after the berbamine crystallization mother liquor is introduced into the macroporous adsorption resin column, before the desorption is performed, washing the column with purified water.

10. The method for producing berberine hydrochloride, berbamine and jatrorrhizine hydrochloride using three needles according to any one of claims 1 to 9, characterized in that: The wet precipitate containing berberine hydrochloride is dried to obtain a berberine hydrochloride product; the wet precipitate containing berbamine is dried to obtain a berbamine product; the refined liquid containing jatrorrhizine hydrochloride is dried to obtain a jatrorrhizine hydrochloride product; the berberine hydrochloride product is bright yellow, the berbamine product is white, and the jatrorrhizine hydrochloride product is reddish yellow.