Preparation of tetrandrine

Abstract

The present application relates to the medical technology, specifically relates to tetrandrine preparation method. The present application utilizes the ultrafiltration membrane to extract tetrandrine A and B from the tetrandrine powder first, then through the solvent purification and refining processes, high quality tetrandrine B with the purity of 99.5% or more and the maximum single impurity of 0.05% or less is obtained.

Description

Technical Field

[0001] This invention relates to pharmaceutical technology, specifically to a method for preparing tetrandrine. Background Technology

[0002] Pharmaceuticals are special commodities, and their market entry requires submitting a drug registration application in accordance with the "Drug Registration Management Measures." Only after approval by the National Medical Products Administration and the issuance of a drug approval number can they be marketed. To ensure the safety, efficacy, and quality control of pharmaceuticals, the state has formulated a series of laws and regulations (pharmacographies, guidelines, etc.) to guide and standardize drug research and development.

[0003] For example, Appendix 9102 of the 2020 edition of the Chinese Pharmacopoeia, "Guiding Principles for Drug Impurity Analysis," contains the following description:

[0004] Impurities are a critical quality attribute of pharmaceutical products, affecting their safety and efficacy. Pharmaceutical impurities are generally classified into: organic impurities, inorganic impurities, and residual solvents. Organic impurities with chemical structures similar to or related to the active ingredient are typically referred to as related substances. For individual impurities with an apparent content of 0.05% or higher (for active pharmaceutical ingredients: 0.1% or 0.05%, with the stricter 0.05% chosen), their structure is qualitatively determined or confirmed.

[0005] Decision tree for drug impurity identification and quality control (see) Figure 1 .

[0006] Therefore, if the amount of a single impurity exceeds the identification threshold of 0.05%, the structure of the impurity needs to be identified. If the structure poses a risk to humans, the impurity must be reduced to a safe level. If there is no risk, it should be reduced to the quality control threshold. If it cannot be reduced to the quality control threshold, the following must be conducted: ① genotoxicity studies; ② routine toxicity studies; ③ other specific toxicity endpoints. If clinical side effects are determined, the amount of the impurity must be reduced to a safe level.

[0007] The literature (Xie Mufeng's views on the research ideas of related substances in generic drug development [J]. China Pharmaceutical Industry Magazine. 2013, 44(11). 1174-1182) reports that related substance research has become the "top priority" in generic drug development. Since the revision of the "Drug Registration Management Measures" in 2007, my country's National Center for Drug Evaluation has issued a large number of guidelines, guidelines, and electronic publications on related substance research. Moreover, this research has become one of the most significantly improved indicators and technical thresholds for the center's review compared to the past.

[0008] It can be said that whether the amount of a single impurity in a substance exceeds the identification threshold is the watershed for research and development work. If it exceeds the identification threshold, the amount of research and development work and the regulatory risks of registration will increase significantly. Conversely, not only will the amount of research and development work decrease and the threshold be lowered, but the registration success rate will also be high.

[0009] *Stephania tetrandra* is a plant belonging to the genus *Stephania* in the family Menispermaceae. Its active ingredients are alkaloids, mainly tetrandrine and fangchinoline. Tetrandrine (also known as tetrandrine or tetrandrine powder) is a colorless needle crystal, insoluble in water and petroleum ether, readily soluble in organic solvents such as ethanol, acetone, ethyl acetate, diethyl ether, and chloroform, as well as dilute acid water. It is soluble in benzene, with a melting point of 216℃. It exhibits a dual melting point phenomenon; crystals formed from acetone melt at around 150℃ and solidify upon heating, remelting at 213℃. Fangchinoline (also known as tetrandrine or tetrandrine powder) has similar solubility to tetrandrine, but due to the presence of a phenolic hydroxyl group, its polarity is slightly higher than that of tetrandrine. Its solubility in benzene is lower than that of tetrandrine, but higher in ethanol.

[0010] In recent years, tetrandrine has been found to have good anti-cancer effects against various malignant tumors, including breast cancer, liver cancer, gastric cancer, prostate cancer, leukemia, and lung cancer. Its mechanisms of action include inducing cell cycle arrest, promoting apoptosis, and inhibiting cell migration and invasion. Studies by Yang et al. have reported that tetrandrine can induce cell cycle arrest and inhibit tumor cell proliferation by inhibiting the PI3K / AKT / MAPK pathway; studies by Lee et al. have shown that tetrandrine can promote apoptosis in pancreatic cancer cells by regulating the NR4A1 pathway, thereby exerting an anti-tumor effect; and studies by Sun et al. have found that tetrandrine can reverse multidrug resistance in tumor cells by inhibiting P-glycoprotein activity.

[0011] However, there are currently no commercially available products of tetrandrine raw materials and preparations in China.

[0012] The literature (Tao Shuhong, Yu Rong, Application of macroporous adsorption resin in the extraction of tetrandrine A and tetrandrine B from Stephania tetrandra powder [J]. Shizhen Guoyi Guoyao. 2005, 16(5). 394) reported that tetrandrine A and tetrandrine B were separated by D101 macroporous adsorption resin and silica gel column chromatography. The purity of both was greater than 98% as detected by high performance liquid chromatography. The separation method of silica gel column chromatography is not suitable for large-scale industrial production due to the limitations of silica gel activation treatment before use, the need to pay attention to the silica gel packing method, sample loading method, elution flow rate, large amount of silica gel and eluent, non-reusability, and high cost. Although the liquid chromatography conditions for content detection are provided, the specific method for content determination is not disclosed, such as whether it is the external standard method or the area normalization method. Furthermore, the method for determining impurities, the amount of the largest single impurity, and the amount of each impurity are not mentioned.

[0013] CN102649794A discloses a method for purifying tetrandrine, as follows:

[0014] (1) Extract the powdered Stephania tetrandra medicinal material by reflux or cold soaking in alcohol solution. Recover the solvent from the extract until there is no alcohol odor, and adjust the pH to acidic by adding acid. (2) Adjust the acid solution to alkali, extract with chloroform, dry-load the extract onto an ODS silica gel column, and elute with a methanol-water or acetonitrile-water mixed solvent. Recover the solvent from the eluent and dry to obtain tetrandrine. The highest content in Example 2 is 99.3%, but the specific method for content determination is not disclosed, nor are the methods for determining impurities, the amount of the largest single impurity, or the amount of each impurity mentioned.

[0015] To meet the market demand for high-purity tetrandrine, a tetrandrine with a maximum single impurity mass below the identification threshold and meeting drug registration requirements is provided. By improving the production process using conventional solvents, high-quality tetrandrine can be produced, reducing the side effects of drug use. Summary of the Invention

[0016] This invention provides a method for preparing tetrandrine, which involves three steps: extraction, separation, purification, and refining of *Stephania tetrandra* raw materials to obtain tetrandrine with a purity of over 99.5% and a maximum single impurity content below 0.05% (identification threshold). Tetrandrine has anti-inflammatory, analgesic, antihypertensive, and antitumor effects. The tetrandrine prepared by this invention, with a maximum single impurity content below the identification threshold, has fewer side effects when used in pharmaceuticals.

[0017] A method for preparing tetrandrine, comprising:

[0018] 1) Take the powder of Stephania tetrandra and extract it with methanol; filter the extract; ultrafilter the filtrate with a hollow fiber ultrafiltration membrane, and then concentrate the liquid obtained by ultrafiltration with a nanofiltration membrane under reduced pressure to obtain a concentrate; pass the concentrate through a D101 macroporous resin column, elute with methanol, collect the feed liquid and the eluent, evaporate the collected liquid to near dryness, dissolve it in acetone, filter it, and then concentrate and crystallize to obtain the extract of Stephania tetrandra extract;

[0019] 2) Dissolve the sample in acetone, filter, then concentrate, cool to crystallize, and vacuum filter to obtain the purified tetrandrine.

[0020] 3) Mix the purified tetrandrine with water, adjust the pH to 3-4 with hydrochloric acid to obtain a mixed solution; add activated carbon; stir (e.g., 20-60 min), and vacuum filter; adjust the pH of the filtrate to 10-11 with liquid alkali, extract with chloroform, separate the extract into layers, evaporate the chloroform layer to dryness, add 95% ethanol, heat to dissolve (e.g., 68-72℃), stir (e.g., 20-60 min), vacuum filter, concentrate the filtrate, cool to crystallize, and vacuum filter again to obtain the primary purified tetrandrine; add 95% ethanol again, heat to dissolve (e.g., 68-72℃), stir (e.g., 20-60 min), vacuum filter, concentrate the filtrate, cool to crystallize, and vacuum filter again to obtain the secondary purified tetrandrine.

[0021] According to an embodiment of the present invention, the weight-volume ratio of Stephania tetrandra powder to methanol is 5:(45-55) in kg:L.

[0022] According to an embodiment of the present invention, the extraction temperature of Stephania tetrandra powder with methanol is 55-65°C, for example, 60°C. Typically, extraction can be performed three times, and the extracts are combined.

[0023] According to an embodiment of the present invention, the hollow fiber ultrafiltration membrane has a molecular weight cutoff of 1800-2200, for example 2000.

[0024] According to an embodiment of the present invention, the nanofiltration membrane has a molecular weight cutoff of 280-330, for example 300.

[0025] According to an embodiment of the present invention, based on chromatographic detection, the fraction with the highest purity of tetrandrine is taken from the collected injection solution and eluent for subsequent steps.

[0026] The chromatographic detection method is described below.

[0027] According to an embodiment of the present invention, the weight-to-volume ratio of tetrandrine extract to acetone is 1:(10-15), for example, 1:13, based on g:mL.

[0028] According to an embodiment of the present invention, step 2) is concentrated to 30-40% of the original volume.

[0029] According to an embodiment of the present invention, the temperature for cooling and crystallization in step 2) is 8-10°C.

[0030] According to an embodiment of the present invention, in step 3), the weight-volume ratio of the mixture to activated carbon is (25-35):1, for example, 30:1, in g:mL.

[0031] According to an embodiment of the present invention, in step 3), the amount of chloroform used is 3-8 times the volume of the filtrate.

[0032] According to an embodiment of the present invention, in step 3), the amount of 95% ethanol used is 15-25 times the volume of the filtrate.

[0033] According to an embodiment of the present invention, step 3) is concentrated to 30-40% of the original volume.

[0034] According to an embodiment of the present invention, the temperature for cooling crystallization in step 3) is 3°C or below.

[0035] According to an embodiment of the present invention, the method for preparing tetrandrine includes:

[0036] 1) Take the powder of Stephania tetrandra and extract it with methanol; filter the extract; ultrafilter the filtrate with a hollow fiber ultrafiltration membrane with a molecular weight cutoff of 2000, and then concentrate the liquid obtained by ultrafiltration with a nanofiltration membrane with a molecular weight cutoff of 300 under reduced pressure to obtain a concentrate; pass the concentrate through a D101 macroporous resin column, elute with methanol, collect the effluent and eluent, collect the liquid in fractions, and take the fraction with the highest purity of tetrandrine according to chromatographic detection. Evaporate the collected liquid to near dryness, dissolve it in acetone, filter it, and then concentrate and crystallize to obtain the tetrandrine extract;

[0037] 2) Dissolve the above in acetone, filter; then concentrate to 30-40% of the original volume, cool to 8-10℃ to crystallize, vacuum filter to obtain the purified tetrandrine; wherein, based on g:mL, the weight-volume ratio of tetrandrine extract to acetone is 1:(10-15).

[0038] 3) Mix the purified tetrandrine with water, adjust the pH to 3-4 with hydrochloric acid to obtain a mixture; add activated carbon; the weight-volume ratio of the mixture to activated carbon is (25-35):1 (g:mL); stir (e.g., 20-60 min), and vacuum filter; adjust the pH of the filtrate to 10-11 with liquid alkali, extract with 3-8 times the volume of chloroform, separate the extract into layers, evaporate the chloroform layer to dryness, add 15-25 times the volume of 95% ethanol, and heat to 68-72℃. Dissolve and stir (e.g., 20-60 min), vacuum filter, concentrate the filtrate to 30-40% of the original volume, cool to below 3℃ to crystallize, and vacuum filter again to obtain the primary refined product of tetrandrine; then add 15-25 times the volume of 95% ethanol, heat to 68-72℃ to dissolve, stir (e.g., 20-60 min), vacuum filter, concentrate the filtrate to 30-40% of the original volume, cool to below 3℃ to crystallize, and vacuum filter again to obtain the secondary refined product of tetrandrine.

[0039] This invention utilizes an ultrafiltration membrane to first extract tetrandrine A and B from Stephania tetrandra powder, and then obtains high-quality tetrandrine B with a purity of over 99.5% and a single impurity content of less than 0.05% through solvent purification and refining processes.

[0040] The present invention also includes tetrandrine prepared by the above method, with a maximum single impurity of less than 0.05%, for example 0.04%.

[0041] This invention utilizes ultrafiltration membranes for alkaloid extraction, which, compared to traditional organic solvent extraction, saves raw materials, reduces environmental pollution, lowers costs, provides excellent impurity and pyrogen removal, and requires less space. Further purification and refining yields high-quality tetrandrine with a purity exceeding 99.5% and single impurities controlled below 0.05%. According to the "Technical Guidelines for Impurity Research in Chemical Drugs," single impurities not exceeding 0.05% are within the identification limit and do not require determination of their chemical structure. This reduces the workload and cost of impurity structure confirmation while meeting the requirements for active pharmaceutical ingredient registration. Furthermore, high-purity tetrandrine results in fewer side effects when used in pharmaceuticals. Attached Figure Description

[0042] Figure 1 A decision tree for drug impurity identification and quality control.

[0043] Figure 2 The liquid chromatogram is for the applicability of the tetrandrine system.

[0044] Figure 3 The image shows the liquid chromatogram of tetrandrine reference standard-1.

[0045] Figure 4 The image shows the liquid chromatogram of tetrandrine reference standard-2.

[0046] Figure 5 This is the liquid chromatogram of the tetrandrine sample. Detailed Implementation

[0047] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the invention.

[0048] Example 1

[0049] Extraction process

[0050] Method ①: Take 5 kg of Stephania tetrandra powder, extract it three times with 50 L of methanol at 60 °C, filter the extract, recover the methanol solvent, let the concentrated liquid crystallize, and filter to obtain 421 g of precipitate. The purity of Stephania tetrandra A is 42.3%, and the purity of Stephania tetrandra B is 15.6%.

[0051] Method ②: Take 5 kg of Stephania tetrandra powder, extract it three times with 50 L of methanol at 60 °C, filter the extract, recover the methanol solvent, filter the concentrated liquid with acid water, adjust the alkali and extract with chloroform, concentrate the chloroform layer to dryness, dissolve it with acetone, filter, concentrate and crystallize to obtain 152 g of Stephania tetrandra extract, with Stephania tetrandra A purity of 60.1% and Stephania tetrandra B purity of 30.3%.

[0052] Method ③: Take 5 kg of Stephania tetrandra powder and extract it three times with 50 L of methanol at 60 °C. Filter the extract and ultrafilter the filtrate using a hollow fiber ultrafiltration membrane with a molecular weight cutoff of 2000. The ultrafiltered liquid is then concentrated under reduced pressure using a nanofiltration membrane with a molecular weight cutoff of 300 to obtain a concentrated solution. Pass the concentrated solution through a D101 macroporous resin column and elute with an appropriate amount of methanol. Collect the effluent and eluent, and collect the liquid in fractions. Based on chromatographic detection, take the fraction with the highest purity of tetrandrine. Evaporate the collected liquid to near dryness, dissolve it in acetone, filter, and then concentrate and crystallize to obtain 67.5 g of tetrandrine extract, with a tetrandrine A purity of 17.8% and a tetrandrine B purity of 80.2%.

[0053] Summary of extraction process: The purity of the tetrandrine extract obtained by experimental method ③ is higher than that obtained by experimental methods ① and ②.

[0054] Purification process

[0055] Method ①: Take 10g of each of the extracts from methods ①, ②, and ③, add methanol at a weight-to-volume ratio (g:mL) of 13, heat to dissolve and filter, concentrate to 30% of the original volume, cool to 8℃ to crystallize, and vacuum filter to obtain the purified tetrandrine. The results are shown in the table below:

[0056]

[0057] Method ②: Take 10g of each of the extracts from methods ①, ②, and ③, add 13 times their weight-volume (g:mL) of ethanol, heat to dissolve and filter, concentrate to 30% of the original volume, cool to 8℃ to crystallize, and vacuum filter to obtain the purified tetrandrine. The results are shown in the table below:

[0058]

[0059] Method ③: Take 10g of each of the extracts from methods ①, ②, and ③, add acetone at a weight-to-volume ratio (g:mL) of 13, heat to dissolve, filter, concentrate to 30% of the original volume, cool to 8℃ for crystallization, and vacuum filter to obtain the purified tetrandrine. The results are shown in the table below:

[0060]

[0061] Method ④: Take 10g of each of the extracts from methods ①, ②, and ③, add ethyl acetate at a weight-to-volume ratio of 13 times (g:mL), heat to dissolve and filter, concentrate to 30% of the original volume, cool to 8℃ to crystallize, and vacuum filter to obtain the purified tetrandrine. The results are shown in the table below:

[0062]

[0063] Summary of purification process: The purity of the tebufenozide purified by extraction method ③ + purification method ③ is higher than that obtained by other methods.

[0064] Refining process:

[0065] The 12 purified products obtained in the above experiment were added to drinking water at a weight-to-volume ratio of 5, the pH was adjusted to 3 with hydrochloric acid, activated carbon at a weight-to-volume ratio of 1 / 30 (g:mL) was added, the mixture was stirred for half an hour, vacuum filtered, the filtrate was adjusted to pH 10 with liquid alkali, and extracted with chloroform at a volume of 5. The extract was separated into layers, the chloroform layer was evaporated to dryness, 20 volumes of 95% ethanol were added, the mixture was heated to 70℃ to dissolve, stirred for half an hour, vacuum filtered, the filtrate was concentrated to 30% of its original volume, cooled to below 3℃ to crystallize, and vacuum filtered again to obtain the primary purified tetrandrine. This was then dissolved again with 20 volumes of 95% ethanol at 70℃, stirred for half an hour, vacuum filtered, the filtrate was concentrated to 30% of its original volume, cooled to below 3℃ to crystallize, and vacuum filtered again to obtain the secondary purified tetrandrine. Specific test results are shown in the table below:

[0066]

[0067] In summary, based on the above experiments, the optimal process is extraction method ③ + purification method ③ + refining, yielding the highest purity tetrandrine product, reaching 99.8%, with a maximum single impurity of 0.04%. According to the "Technical Guidelines for Impurity Research in Chemical Drugs," a single impurity of no more than 0.05% falls within the identification limit, eliminating the need to determine its chemical structure. This reduces the workload and cost of impurity structure confirmation while meeting the requirements for active pharmaceutical ingredient registration. Furthermore, high-purity tetrandrine results in fewer side effects when used in pharmaceuticals.

[0068] Figure 2 The liquid chromatogram is for the applicability of the tetrandrine system. Figure 3 The image shows the liquid chromatogram of tetrandrine reference standard-1. Figure 4 The image shows the liquid chromatogram of tetrandrine reference standard-2. Figure 5 This is the liquid chromatogram of the tetrandrine sample. The detection method is described below.

[0069] The purity of the product obtained under optimal conditions in each step is shown in the table below:

[0070]

[0071] In summary, based on the above experiments, using extraction method ③, purification method ③, and refining procedures yields a tetrandrine product with a purity of 99.8% and a maximum single impurity of 0.04% (see liquid chromatogram). Figure 5 ).

[0072] The detection methods used in this article are as follows:

[0073] 1. Appearance: Take 2.0g of this product and observe it with the naked eye on white paper. It should be an off-white or pale yellow crystalline powder.

[0074] 2. Identification by HPLC: Under the related substances section, the retention time of the main peak of this product should be consistent with the retention time of the main peak of the working reference.

[0075] 3. For acid-insoluble substances, take 0.1g of this product, add 1ml of dilute hydrochloric acid and 10ml of water, shake well, and the solution should be clear.

[0076] 4. The color of the solution is determined by taking the solution from the section on the insoluble substances in acid and comparing it with the yellow standard colorimetric solution No. 1. The solution should not be darker than the original color.

[0077] 5 Loss on drying

[0078] Weigh two 1g portions of this product, dry them in an 80℃ drying oven for 3 hours, and determine the loss on drying according to the "Operating Procedure for Determination of Loss on Drying". The result should not exceed 2.0%.

[0079] Calculation formula:

[0080]

[0081] W0: Constant weight of empty weighing bottle, g;

[0082] W1: Sample weight, g;

[0083] W2: Empty weighing bottle after drying + constant weight of sample, g;

[0084] 6. Related Substances: High-performance liquid chromatography (HPLC)

[0085] 6.1 Reagents: Acetonitrile (chromatographic grade), methanol (chromatographic grade), triethylamine,

[0086] 6.2 Chromatographic conditions: Chromatograph: Agilent 1100 or similar;

[0087] Column: C18;

[0088] Column temperature: 25℃;

[0089] Flow rate: 1.0 ml / min;

[0090] Wavelength: 280nm;

[0091] Injection volume: 20 μl;

[0092] 6.3 Solution Preparation

[0093] Mobile phase: Acetonitrile-water-methanol-triethylamine were mixed in a volume ratio of 300:650:50:3, the pH was adjusted to 2.0 with perchloric acid, and the mixture was filtered through a 0.45 μm organic phase filter membrane.

[0094] Test solution: Weigh approximately 20 mg of the test sample accurately and place it in a 50 ml volumetric flask. Dissolve and dilute to the mark with the mobile phase and shake well.

[0095] Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, add mobile phase to dilute to the mark, and shake well.

[0096] System suitability solution: Take 1 mg each of tetrandrine A and tetrandrine B reference standards, add mobile phase to dissolve to 10 ml, and shake well.

[0097] 6.4 Procedure

[0098] 6.4.1 System Suitability: For a single solution injection, the resolution between the peaks of tetrandrine A and tetrandrine B should be greater than 2.0, and the theoretical plate number calculated based on the tetrandrine A peak should be no less than 2000.

[0099] 6.4.2 Inject the control solution twice and adjust the instrument sensitivity so that the peak height of the main component is about 15% of full scale.

[0100] 6.4.3 The test solution is injected once, and the running time is up to three times the retention time of the main peak.

[0101] 6.5 Calculation: Calculated using the external standard method

[0102] Calculation formula:

[0103]

[0104] A 杂质 Peak area of ​​impurities (single or total);

[0105] A 对照 : Peak area of ​​the control solution.

[0106] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing tetrandrine, characterized in that, include: 1) Take the powder of Stephania tetrandra and extract it with methanol; filter the extract; ultrafilter the filtrate with a hollow fiber ultrafiltration membrane, and then concentrate the liquid obtained by ultrafiltration with a nanofiltration membrane under reduced pressure to obtain a concentrate; pass the concentrate through a D101 macroporous resin column, elute with methanol, collect the feed liquid and the eluent, evaporate the collected liquid to near dryness, dissolve it with acetone, filter it, and then concentrate and crystallize to obtain the extract of Stephania tetrandra extract; 2) Dissolve the tetrandrine extract in acetone, filter, then concentrate, cool and crystallize, and vacuum filter to obtain the purified tetrandrine. 3) Mix the purified tetrandrine with water, adjust the pH to 3-4 with hydrochloric acid to obtain a mixed solution; add activated carbon; stir, and vacuum filter; adjust the pH of the filtrate to 10-11 with liquid alkali, extract with chloroform, separate the extract into layers, evaporate the chloroform layer to dryness, add 95% ethanol, heat to dissolve, stir, vacuum filter, concentrate the filtrate, cool to crystallize, and vacuum filter to obtain the primary purified tetrandrine; add 95% ethanol again, heat to dissolve, stir, vacuum filter, concentrate the filtrate, cool to crystallize, and vacuum filter to obtain the secondary purified tetrandrine. The hollow fiber ultrafiltration membrane has a molecular weight cutoff of 1800-2200; The nanofiltration membrane has a molecular weight cutoff of 280-330.

2. The tetrandrine preparation method according to claim 1, characterized in that, The weight-to-volume ratio of Stephania tetrandra powder to methanol, expressed as kg:L, is 5:(45-55); and / or, The extraction temperature for Stephania tetrandra powder with methanol is 55-65℃.

3. The tetrandrine preparation method according to claim 1, characterized in that, The hollow fiber ultrafiltration membrane has a molecular weight cutoff of 2000.

4. The tetrandrine preparation method according to claim 1, characterized in that, The nanofiltration membrane has a molecular weight cutoff of 300.

5. The tetrandrine preparation method according to claim 1, characterized in that, The weight-to-volume ratio of tetrandrine extract to acetone, expressed as g:mL, is 1:(10-15).

6. The tetrandrine preparation method according to claim 5, characterized in that, The weight-to-volume ratio of the tetrandrine extract to acetone is 1:

13.

7. The tetrandrine preparation method according to claim 1, characterized in that, Step 2) Concentrate to 30-40% of the original volume; and / or, Step 2) The cooling crystallization temperature is 8-10℃.

8. The tetrandrine preparation method according to claim 1, characterized in that, In step 3), the weight-volume ratio of the mixture to activated carbon is (25-35):1, expressed in g:mL.

9. The tetrandrine preparation method according to claim 8, characterized in that, The weight-to-volume ratio of the mixture to activated carbon is 30:

1.

10. The tetrandrine preparation method according to claim 1, characterized in that, In step 3), the amount of chloroform used is 3-8 times the volume of the filtrate; and / or, In step 3), the amount of 95% ethanol used is 15-25 times the volume of the filtrate; and / or, Step 3) Concentrate to 30-40% of the original volume; and / or, Step 3) Cooling and crystallization at a temperature of 3°C or below.

11. The method for preparing tetrandrine according to claim 1, characterized in that, include: 1) Take the powder of Stephania tetrandra and extract it with methanol; filter the extract; ultrafilter the filtrate with a hollow fiber ultrafiltration membrane with a molecular weight cutoff of 2000, and then concentrate the liquid obtained by ultrafiltration with a nanofiltration membrane with a molecular weight cutoff of 300 under reduced pressure to obtain a concentrate; pass the concentrate through a D101 macroporous resin column, elute with methanol, collect the effluent and eluent, collect the liquid in fractions, and take the fraction with the highest purity of tetrandrine according to chromatographic detection, evaporate the collected liquid to near dryness, dissolve it in acetone, filter it, and then concentrate and crystallize to obtain tetrandrine extract; 2) Dissolve the above in acetone, filter; then concentrate to 30-40% of the original volume, cool to 8-10℃ to crystallize, and vacuum filter to obtain the purified tetrandrine; wherein, the weight-volume ratio of tetrandrine extract to acetone is 1:(10-15) based on g:mL. 3) Mix the purified tetrandrine with water, adjust the pH to 3-4 with hydrochloric acid to obtain a mixed solution; add activated carbon; the weight-volume ratio of the mixed solution to activated carbon is (25-35):1 (g:mL); stir and vacuum filter; adjust the pH of the filtrate to 10-11 with liquid alkali, extract with 3-8 times the volume of chloroform, separate the extract into layers, evaporate the chloroform layer to dryness, add 15-25 times the volume of 95% ethanol, heat to 68-72℃ to dissolve, stir, vacuum filter, concentrate the filtrate to 30-40% of the original volume, cool to below 3℃ to crystallize, vacuum filter to obtain the primary purified tetrandrine; add another 15-25 times the volume of 95% ethanol, heat to 68-72℃ to dissolve, stir, vacuum filter, concentrate the filtrate to 30-40% of the original volume, cool to below 3℃ to crystallize, vacuum filter to obtain the secondary purified tetrandrine.

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