CN102614119B - Method for sinomenine hydrochloride injection by using non-organic solvent - Google Patents
Method for sinomenine hydrochloride injection by using non-organic solvent Download PDFInfo
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Abstract
Provided is a method for a sinomenine hydrochloride injection by using a non-organic solvent. An absorption process by using cation exchange resin or macroporous absorption resin replaces a traditional benzene extracting and chloroform extracting (extraction) process with large toxicity, the extracting efficiency is high, operation is simple and convenient, the defect that a large dosage of organic solvent with large toxicity hurts the health of operators and pollutes the environment is overcome, the processing process of organic solvents is reduced, the environmental protection is facilitated, input on environment-protecting facilities of factories is reduced, and environment-friendly production is facilitated. Sinomenine hydrochloride extracted and separated by means of the method serves as a raw material of a pharmaceutical preparation, is high in purity and free of solvent residuals and reduces potential hazards to human body.
Description
Technical field
The present invention relates to a kind of preparation method of sinomenine hydrochloride injection, be specifically related to a kind of method that non-organic solvent extracts effective ingredient sinomenine hydrochloride injection in Caulis Sinomenii.
Background technology
Caulis Sinomenii is traditional conventional Chinese medicine, dry rattan for menispermaceous plants Sinomenium acutum and hair Sinomenium acutum, just on the books in Compendium of Material Medica, now record in Pharmacopoeia of the People's Republic of China version in 2010, have dispel the wind, the effect of the meridian dredging, diuresis, be used for the treatment of rheumatic arthralgia, arthroncus, paralysis pruritus, also have the effects such as anti-arrhythmia and blood pressure lowering.
In Caulis Sinomenii, main component is alkaloid, the composition of having found at present has sinomenine (Sinomenine), isosinomenine (Igoginomenine), China's sinomenine (SinoAcutine), short Sinomenium acutum time alkali (Acutumidine), point sinomenine (Sinaetine) and disinomenine (Diginomenine), ethyl sinomenine (ethylsinomenine), tetrahydrochysene epiberberine (sinactine), tetrahydrochysene epiberberine, Caulis menispermi ripple phenol alkali, bianfugenine, Tetrahydropalmatine etc.
Sinomenine (Sinomenine) is a kind of alkaloid monomer that extracts in Caulis Sinomenii, is the main effective ingredient of Caulis Sinomenii performance analgesia, antiinflammatory action, is separated the earliest obtaining from Japanese Caulis Sinomenii by Ishiwari etc.The sixties in 20th century, Chinese scholar Zhu Renhong also found sinomenine from domestic Caulis Sinomenii.Its hydrochlorate preparation commonly used such as ZHENGQINGFENGTONGNING PIAN, Zhengqing Fengtongning Retard Tablets, ZHENGQINGFENGTONGNING injection, be used for the treatment of rheumatic, rheumatoid arthritis clinically, and treatment ankylosing spondylitis, arrhythmia etc. are evident in efficacy.
The commercial production sinomenine hydrochloride adopts the alkalization water extraction process more at present, and it alkalization a period of time, then adds a certain amount of technical benzene, reflux, extract,, last acidify, standing, crystallize for add entry and a certain amount of Calx in Caulis Sinomenii.Caulis Sinomenii dilute sulfuric acid percolate is transferred pH value 9 with lime water, and benzene carries out counter-current extraction at 50 ℃, and benzene extraction liquid carries out anti-phase counter-current extraction, activated carbon decolorizing, crystallization with 1% hydrochloric acid.Carry out recrystallization in hot water, get sterling.(Chen Yukun " extracting technique of Chinese medicine ", 1992), existing method all uses the very large benzene of toxicity or chloroform as extracting solvent, benzene is the one-level toxic solvent, cancer rate processed is very high, and is disabled at pharmaceutical industry, and need be by very cumbersome technique ability meet the requirement of environmental protection aspect the recycling of solvent, and chloroform is the secondary toxic reagent, thereby should avoid using benzene and chloroform solvent in Chinese medicine extraction as far as possible.
Summary of the invention
The invention provides a kind of preparation method of sinomenine hydrochloride injection.
Goal of the invention is achieved by the following technical solution, and the preparation method of sinomenine hydrochloride injection of the present invention comprises the steps:
The preparation of step 1, sinomenine hydrochloride:
A, extraction: Caulis Sinomenii coarse powder 100～1000 weight portions, with 0.1～1mol/L HCl moistening of 60～1000 parts by volume 0.5～8 hour, the dress percolator, add again 0.1～1mol/L HCl to make liquid level cover medicated powder 2cm, flood after 6～48 hours, begin percolation by the speed of 2～5ml/min, stop percolation after 6～24 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 8-12, loading speed be 2-5 times of column volume/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soaked resin 12 hours with 8-15% ammonia solution immersion resin or 152 type resins with the 3-10% hydrochloric acid solution, be 8～11 ammonia-alcoholic solution eluting or 152 type resins with 3-10% hydrochloric acid solution eluting with pH value again, elution speed is 2-5BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid or ammonia neutralization to pH=6-8, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 5～10 weight portions, 10～95% ethanol or the dissolving extremely fully of purified water reflux with 30～120 parts by volume, the active carbon that adds the 3-6% times of weight, insulation refluxed 10～30 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, colourless to filtrate with the ethanol cleaning filter cake of 75-95%, get sinomenine hydrochloride;
Step 2, get raw material
Sinomenine hydrochloride 15～35 weight portions, sodium sulfite 0.1～3 weight portion, disodium edetate 0.1～3 weight portion;
The preparation of step 3, injection
Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.01～0.20% active carbon, carbon removal is filtered in 35～45 ℃ of insulations 5～15 minutes, supplementary injection water to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes, and get final product for 100～120 ℃.
Step 1 in the preparation method of sinomenine hydrochloride injection of the present invention can in parameter be preferably as follows:
B step: the preferred 001*2.5 of strong cation-exchanging resin, 001*4, preferred 152 types of macroporous adsorbent resin; Preferred 1: 10 of resin blade diameter length ratio; The preferred 3 times of column volumes of loading speed/hour; Soak preferred 10% ammonia solution of resin (or 5% hydrochloric acid solution); Ammonia-alcoholic solution take pH value as 8～11 is as the elute soln of cation exchange resin, and eluent is neutralized to pH=6～8 with hydrochloric acid; 5%HCl solution is as the elute soln of 152 type macroporous adsorbent resins;
C step: the active carbon that adds 4% times of weight; Preferred 40%, 55%, 60%, 75% during reflux, 80% ethanol.
In sinomenine hydrochloride injection preparation method of the present invention, step 2 can be preferably:
Sinomenine hydrochloride 25 weight portions, sodium sulfite 1 weight portion, disodium edetate 0.3 weight portion.
In sinomenine hydrochloride injection preparation method of the present invention, step 3 can be preferably:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add sodium sulfite, disodium edetate to be stirred to dissolve again, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, supplementary injection water to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃.
Weight portion in the preparation method of above-mentioned sinomenine hydrochloride injection and the pass of parts by volume are the relation of g/ml.
The inventive method adopts by cation exchange resin or absorption with macroporous adsorbent resin and replaces traditional larger benzene extraction and chloroform extraction (extraction) technique of toxicity; extract yield is high; operate easier; the harm and the pollution that overcome that consumption of organic solvent is large, toxicity cause to operator ' s health and environment greatly; reduced the processing procedure of organic solvent; more be conducive to environmental conservation, reduced the input of the environmental protection facility of factory, be conducive to environmental friendliness production.This method is extracted the sinomenine hydrochloride that separates, and as the raw material of pharmaceutical preparation, purity is higher, and no solvent residue has reduced the potential hazard to human body.
Following experimental example and embodiment are used for further illustrating but being not limited to the present invention.
Experimental example one: the Study on extraction of Caulis Sinomenii non-organic solvent
1, experimental technique
1.1 material and instrument
Caulis Sinomenii medicinal material coarse powder, macroporous adsorbent resin, sinomenine hydrochloride reference substance, hydrochloric acid, ammonia, sodium hydroxide, ethanol, sodium chloride etc.
Glass column (diameter 3cm, high by 30～40cm), HPLC high performance liquid chromatogram detector, rotary evaporimeter.
1.2 method and result
1.2.1 decision method
(1) the alkaloid indicator is selected
Press method preparation bismuth potassium iodide weak solution of Chinese Pharmacopoeia version in 2010, basic iron potassium cyanide, three kinds of alkaloid indicators of silico-tungstic acid test solution, getting respectively 1～2 drips in checking liquid, precipitate, chromogenic reaction, experiment contrast premenstruum shows that the indication of silico-tungstic acid test solution is the most directly perceived, sensitive.This experimental design adopts the silico-tungstic acid test solution as the indicator of endpoint.
(2) thin layer chromatography: immobile phase: silica gel thin-layer plate; Developing solvent: methanol: water: ammonia=8: 1: 1; Developer: rare bismuth potassium iodide solution.
(3) high performance liquid chromatography
Be filler with octadecylsilane chemically bonded silica; Take acetonitrile-0.78% sodium dihydrogen phosphate (12: 88) as mobile phase; The detection wavelength is 265nm.30 ℃ of column temperatures, flow velocity 1.0ml/min.
1.2.2. the type selecting of resin
(1) resin model
The D-101 type, nonpolar macroporous adsorption resin, manufacturer: Tianjin sea light chemical industry;
The LSD001 type, polar macroporous adsorption resin, manufacturer: Xi'an Lanxiao Sci-Tech Co., Ltd.;
The D-312 type, macroporous adsorbent resin, manufacturer: Shandong Lukang Record Pharmaceuticals Co., Ltd.;
The DM21 type, macroporous adsorbent resin, manufacturer: Shandong Lukang Record Pharmaceuticals Co., Ltd.;
The HPD722 type, low pole macroporous adsorbent resin, manufacturer: Cangzhou Bon Adsorption Material Science and Technology Co., Ltd.
152 types, cation exchange resin, manufacturer: Shandong Lukang Record Pharmaceuticals Co., Ltd.;
732 types, sodium type cation exchange resin, manufacturer: Cangzhou Bon Adsorption Material Science and Technology Co., Ltd.
001 * 2.5 type, H type cation exchange resin, manufacturer: Shandong Lukang Record Pharmaceuticals Co., Ltd.;
001 * 4 type, H type cation exchange resin, manufacturer: Shandong Lukang Record Pharmaceuticals Co., Ltd.;
(2) method
Choose macroporous resin or the ion exchange resin 10g～20g of above-mentioned different manufacturers, different model, upper 30mm*300mm glass exchange column after pretreatment, get the percolate (pH is transferred to 3) of 1000g medical material, be divided into 7 equal portions, flow through resin by certain speed, general loading speed is 2～3BV/h, the special resin reference velocity of pressing, have to precipitate with the inspection of silico-tungstic acid test solution to effluent to stop loading, wash with water to eluent substantially without till color.Applied sample amount and the absorbability of contrast different resins, the resin model of selected good best producer is chosen 2～3 kinds of resins as the adsorbing material of this product.
The absorption situation of table 1 different model resin upper prop
Only investigate the absorption situation from indicator, thin layer and observe phenomena because of above experiment, can't accurately judge the absorption situation of resin, the later stage uses liquid chromatograph instead associated resin is investigated.
1, sinomenine hydrochloride raw material absorption: the sinomenine hydrochloride solution of preparation 2% (2g → 100ml), get respectively D101,001*4, three kinds of each 2g of resin of DM21 in conical flask, add the above-mentioned obtain solution of 10ml, vibrations are 12 hours on repeatedly Turning motion device, Liquid Detection the results are shown in following table
Table 2: the absorption HPLC result of different resins static adsorption sinomenine hydrochloride material liquid
2, extract stock solution absorption, get respectively 001*2.5,001*4,152 types, AB-8 type, HPD600 type, 732 types, DM21 type, the treated good resin 2g of D101 type puts in the 100ml conical flask, add the percolation stock solution 25ml of extraction, Liquid Detection the results are shown in following table:
Table 3: the absorption HPLC result of the percolate that different resins static adsorption Caulis Sinomenii extracts
Above result shows, above-mentioned several resin absorption abilities comparisons: 001*2.5＞001*4＞152 types.AB-8, HPD600 type, DM21 type, D101 type, 732 types etc. because of absorbability in percolate too a little less than.
1.2.3 desorbing or eluting
According to above experimental result, selected 001*2.5,001*4,152 3 kinds of resins.Each resin is tested by following design.
(1) cation-adsorption resin (001*4,001*2.5)
1. 5% ammonia liquid.
2. 10% ammonia liquid.
3. 95% alcoholic solution.
4. transfer the alcoholic solution of PH to 8-11 with ammonia.
5. salt, diluted acid.(the 5%HCl solution of NH4Cl)
6. salt, rare alcohol.(20%NaCl+ alcoholic solution)
Get sour water percolate 500ml, by resin column, be washed till neutrality with purified water with the flow velocity of 2-3BV/h, more respectively with the speed eluting of different eluents with 2-3BV/h, till the inanimate object alkali reaction.Measure the sinomenine hydrochloride content in each duplicate samples, calculate eluting rate.The contrast elute effect.
The impact of the different eluents of table 4 on the sinomenine hydrochloride elute effect
Above experimental result shows: after cationic resin absorption, the employing pH value is ammonia-alcoholic solution of 8～11, can obtain elute effect preferably.
(2) macroporous adsorbent resin (152 type)
1. 50% alcoholic solution.
2. 75% alcoholic solution.
3. 95% alcoholic solution.
4. 5%HCl solution.
Get sour water percolate 500ml, by resin column, be washed till neutrality with purified water with the flow velocity of 2～3BV/h, more respectively with the speed eluting of different eluents with 2～3BV/h, till the inanimate object alkali reaction.Measure the sinomenine hydrochloride content in each duplicate samples, calculate eluting rate.The contrast elute effect.
Table 5 152 types adopt different eluents on the impact of sinomenine hydrochloride elute effect
Experimental result shows: adopt different eluents to carry out desorbing to the adsorption liquid of 152 type resins, only HCl has desorption effect, therefore this resin adopts 5%HCl to carry out eluting.
1.2.3 static adsorption is determined desorption condition
By the selected good eluent of above-mentioned experiment, adopt the mode of static adsorption, after absorption 12 hours, resin during inanimate object alkali, is added the 12ml stripping liquid with the purified water rinsing to the water, shook Liquid Detection 12 hours.Result is as follows:
The percolate adsorption and desorption HPLC result that table 6 static adsorption Caulis Sinomenii extracts
Above result shows, adopts the stripping liquid of determining to carry out desorbing, all can separate the sinomenine hydrochloride of sucking-off resin absorption.
1.3 conclusion
Adopt macroporous adsorbent resin and cation exchange resin, sinomenine hydrochloride there is larger adsorption, by experiment, selected 001*2.5, two kinds of cation exchange resiies of 001*4,152 type macroporous adsorbent resins are as the optimum resin of this sinomenine hydrochloride purification, adopt ammonia-alcoholic solution (pH8～11) as the elute soln of cation exchange resin, 5%HCl is as the elute soln of 152 type macroporous adsorbent resins.
Following embodiment all can realize the effect of above-mentioned experimental example.
Embodiment 1: a kind of preparation method of sinomenine hydrochloride injection of non-organic solvent, the method comprises the steps:
A, extraction: Caulis Sinomenii coarse powder 500kg, the 0.5mol/L HCl moistening of use 500L 3 hours, dress percolator, add again 0.5mol/L HCl to make liquid level cover medicated powder 2cm, flood after 12 hours, begin percolation by the speed of 3ml/min, stop percolation after 12 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 10, loading speed be 3 times of column volumes/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soak resin 12h with 10% ammonia solution immersion resin or 152 type resins with 5% hydrochloric acid solution, transfer the alcoholic solution eluting of PH to 9 or 152 type resins with 5% hydrochloric acid solution eluting with 10% ammonia again, elution speed is 3BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid or with ammonia neutralization to pH=6～8, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 8kg, 75% ethanol or the dissolving extremely fully of purified water reflux with 100L, add 5% bulking value active carbon doubly, insulation refluxed 20 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 80% cleans filter cake, gets sinomenine hydrochloride;
Take sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, the supplementary injection water is checked to full dose, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃, make 1000ml, specification: 2ml:50mg.
Embodiment 2: a kind of preparation method of sinomenine hydrochloride injection of non-organic solvent, the method comprises the steps:
A, extraction: Caulis Sinomenii coarse powder 800kg, the 0.9mol/L HCl moistening of use 1000L 5 hours, dress percolator, add again 0.9mol/L HCl to make liquid level cover medicated powder 2cm, flood after 20 hours, begin percolation by the speed of 5ml/min, stop percolation after 24 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin 001*4 type or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 10, loading speed be 5 times of column volumes/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soaked resin 12 hours with 10% ammonia solution immersion resin or 152 type resins with 8% hydrochloric acid solution, transfer again alcoholic solution eluting or the 152 type resin 8% hydrochloric acid solution eluting of PH to 9 with 12% ammonia, elution speed is 5BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid neutralization or with ammonia neutralization to pH=7, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 10kg, 85% ethanol or the dissolving extremely fully of purified water reflux with 120L, add 5% bulking value active carbon doubly, insulation refluxed 30 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 75% cleans filter cake, gets sinomenine hydrochloride;
Take sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, the supplementary injection water is checked to full dose, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃, make 1000ml, specification: 2ml:50mg.
Embodiment 3: a kind of preparation method of sinomenine hydrochloride injection of non-organic solvent, the method comprises the steps:
A, extraction: Caulis Sinomenii coarse powder 800kg, the 0.7mol/L HCl moistening of use 900L 6 hours, dress percolator, add again 0.8mol/L HCl to make liquid level cover medicated powder 2cm, flood after 24 hours, begin percolation by the speed of 3ml/min, stop percolation after 24 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 10, loading speed is 3 times of column volume/h, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soaked resin 12 hours with 10% ammonia solution immersion resin or 152 type resins with 7% hydrochloric acid solution, transfer again alcoholic solution eluting or the 152 type resin 5% hydrochloric acid solution eluting of PH to 9 with 12% ammonia, elution speed is 4BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid or with ammonia neutralization to pH=7, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 6kg, 55% ethanol or the dissolving extremely fully of purified water reflux with 80L, add 3% bulking value active carbon doubly, insulation refluxed 10～30 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 80% cleans filter cake, gets sinomenine hydrochloride;
Take sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, the supplementary injection water is checked to full dose, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃, make 1000ml, specification: 2ml:50mg.
Embodiment 4: a kind of preparation method of sinomenine hydrochloride injection of non-organic solvent, the method comprises the steps:
A, extraction: Caulis Sinomenii coarse powder 500kg, the 0.5mol/L HCl moistening of use 500L 3 hours, dress percolator, add again 0.5mol/L HCl to make liquid level cover medicated powder 2cm, flood after 12 hours, begin percolation by the speed of 3ml/min, stop percolation after 12 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 10, loading speed be 3 times of column volumes/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soak resin 12h with 10% ammonia solution immersion resin or 152 type resins with 5% hydrochloric acid solution, transfer the alcoholic solution eluting of PH to 9 or 152 type resins with 5% hydrochloric acid solution eluting with 10% ammonia again, elution speed is 3BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid or with ammonia neutralization to pH=6～8, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 8kg, 75% ethanol or the dissolving extremely fully of purified water reflux with 100L, add 5% bulking value active carbon doubly, insulation refluxed 20 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 80% cleans filter cake, gets sinomenine hydrochloride;
Take sinomenine hydrochloride 15g, sodium sulfite 3g, disodium edetate 0.1g; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, the supplementary injection water is checked to full dose, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃, make 1000ml, specification: 2ml:50mg.
Embodiment 5: a kind of preparation method of sinomenine hydrochloride injection of non-organic solvent, the method comprises the steps:
A, extraction: Caulis Sinomenii coarse powder 800kg, the 0.9mol/L HCl moistening of use 1000L 5 hours, dress percolator, add again 0.9mol/L HCl to make liquid level cover medicated powder 2cm, flood after 20 hours, begin percolation by the speed of 5ml/min, stop percolation after 24 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin 001*4 type or the 152 type resins of having handled well on percolate, blade diameter length ratio 1: 10, loading speed be 5 times of column volumes/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soaked resin 12 hours with 10% ammonia solution immersion resin or 152 type resins with 8% hydrochloric acid solution, transfer again alcoholic solution eluting or the 152 type resin 8% hydrochloric acid solution eluting of PH to 9 with 12% ammonia, elution speed is 5BV/h, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid neutralization or with ammonia neutralization to pH=7, desalination, concentrate drying, get the sinomenine hydrochloride crude product.
C, refining: get sinomenine hydrochloride crude product 10kg, 85% ethanol or the dissolving extremely fully of purified water reflux with 120L, add 5% bulking value active carbon doubly, insulation refluxed 30 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 75% cleans filter cake, gets sinomenine hydrochloride;
Take sinomenine hydrochloride 35g, sodium sulfite 0.1g, disodium edetate 3g; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, the supplementary injection water is checked to full dose, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃, make 1000ml, specification: 2ml:50mg.
Attached: 1, silico-tungstic acid test solution inspection method
Silico-tungstic acid test solution preparation: press appendix 109 of Chinese Pharmacopoeia version in 2010.
Get 1ml and be examined liquid in color comparison tube, add 1 to 2 silico-tungstic acid test solution, observe.
2, thin layer chromatography
Thin layer chromatography condition immobile phase: silica gel thin-layer plate
Developing solvent: methanol: water: ammonia=8: 1: 1
Developer: bismuth potassium iodide weak solution
Point sample amount: 5ul
3, pH value is that ammonia-alcoholic solution of 8～11 is namely transferred the alcoholic solution of pH to 8～11 with the ammonia of 8-15%.
Claims (12)
1. the preparation method of a sinomenine hydrochloride injection, is characterized in that the method comprises the steps:
The preparation of step 1, sinomenine hydrochloride:
A, extraction: Caulis Sinomenii coarse powder 100～1000 weight portions, with 0.1～1mol/L HCl moistening of 60～1000 parts by volume 0.5～8 hour, the dress percolator, add again 0.1～1mol/L HCl to make liquid level cover medicated powder 2cm, flood after 6～48 hours, begin percolation by the speed of 2～5ml/min, stop percolation after 6～24 hours, get percolate, standby;
B, upper prop eluting: with cation exchange resin or the 152 type macroporous adsorbent resins of having handled well on percolate, blade diameter length ratio 1:8-12, loading speed be 2-5 times of column volume/hour, with the inspection of silico-tungstic acid test solution, precipitation is arranged to effluent, and thin layer chromatography stops loading when detecting inanimate object alkaline spot point, stop when being eluted to eluent without color with purified water, soaked resin 12 hours with the 8-15% ammonia solution, or soaked 152 type macroporous adsorbent resin 12 hours with the 3-10% hydrochloric acid solution, be 8～11 ammonia-alcoholic solution eluting or 152 type macroporous adsorbent resins with 3-10% hydrochloric acid solution eluting with pH value again, elution speed be 2-5 times of column volume/hour, eluent receives when with the inspection of silico-tungstic acid test solution, precipitation being arranged, receiving eluent stops when precipitating with the inspection of silico-tungstic acid test solution, merge eluent, with hydrochloric acid or ammonia neutralization to pH=6-8, desalination, concentrate drying, get the sinomenine hydrochloride crude product,
C, refining: get sinomenine hydrochloride crude product 5～10 weight portions, 10～95% ethanol or the dissolving extremely fully of purified water reflux with 30～120 parts by volume, the active carbon that adds the 3-6% times of weight, insulation refluxed 10～30 minutes, filtered while hot, and filtrate is concentrated, cooling, crystallize, filter, colourless to filtrate with the ethanol cleaning filter cake of 75-95%, get sinomenine hydrochloride;
Step 2, get raw material
Sinomenine hydrochloride 15～35 weight portions, sodium sulfite 0.1～3 weight portion, disodium edetate 0.1～3 weight portion;
The preparation of step 3, injection
Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add again sodium sulfite, disodium edetate to be stirred to dissolve, continue to fill nitrogen, add 0.01～0.20% active carbon, carbon removal is filtered in 35～45 ℃ of insulations 5～15 minutes, supplementary injection water to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes, and get final product for 100～120 ℃.
2. the preparation method of sinomenine hydrochloride injection as claimed in claim 1 is characterized in that in the method that in step 1 B step, cation exchange resin is 001*2.5,001*4 type resin, and macroporous adsorbent resin is 152 types; The resin blade diameter length ratio is 1:10.
3. the preparation method of sinomenine hydrochloride injection as claimed in claim 1 is characterized in that in the method adding the active carbon of 4% times of weight in step 1 C step; During reflux, concentration of alcohol is 40%, 55%, 60%, 75% or 80%.
4. the preparation method of sinomenine hydrochloride injection as claimed in claim 1 is characterized in that in the method in step 1 B step, loading speed be 3 times of column volumes/hour; Soak resin with 10% ammonia solution or 5% hydrochloric acid solution.
5. the preparation method of sinomenine hydrochloride injection as claimed in claim 1 is characterized in that in the method in step 1 B step, and with ammonia-alcoholic solution of pH8-11 elute soln as cation exchange resin, eluent is neutralized to pH=6～8 with hydrochloric acid; 5%HCl solution is as the elute soln of 152 type macroporous adsorbent resins.
6. as the preparation method of the arbitrary described sinomenine hydrochloride injection of claim 1-5, it is characterized in that the step 2 in the method is:
Sinomenine hydrochloride 25 weight portions, sodium sulfite 1 weight portion, disodium edetate 0.3 weight portion.
7. as the preparation method of the arbitrary described sinomenine hydrochloride injection of claim 1-5, it is characterized in that the step 2 in the method is:
Sinomenine hydrochloride 15 weight portions, sodium sulfite 3 weight portions, disodium edetate 0.1 weight portion.
8. as the preparation method of the arbitrary described sinomenine hydrochloride injection of claim 1-5, it is characterized in that the step 2 in the method is:
Sinomenine hydrochloride 35 weight portions, sodium sulfite 0.1 weight portion, disodium edetate 3 weight portions.
9. as the preparation method of the arbitrary described sinomenine hydrochloride injection of claim 1-5, it is characterized in that the step 3 in the method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add sodium sulfite, disodium edetate to be stirred to dissolve again, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, supplementary injection water to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃.
10. the preparation method of sinomenine hydrochloride injection as claimed in claim 6 is characterized in that the step 3 in the method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add sodium sulfite, disodium edetate to be stirred to dissolve again, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, supplementary injection water to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃.
11. the preparation method of sinomenine hydrochloride injection as claimed in claim 7 is characterized in that the step 3 in the method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add sodium sulfite, disodium edetate to be stirred to dissolve again, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, supplementary injection water to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃.
12. the preparation method of sinomenine hydrochloride injection as claimed in claim 8 is characterized in that the step 3 in the method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add sinomenine hydrochloride to be stirred to dissolve; Add sodium sulfite, disodium edetate to be stirred to dissolve again, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, supplementary injection water to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes, and get final product for 100 ℃.
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| CN105315210B (en) * | 2014-07-29 | 2019-05-17 | 湖南正清制药集团股份有限公司 | A method of the high efficiency extraction Sinomenine from caulis sinomenii |
| CN105439952B (en) * | 2014-09-29 | 2019-05-17 | 湖南正清制药集团股份有限公司 | A method of preparing Sinomenine pharmaceutical preparation |
| CN106632040B (en) * | 2015-11-04 | 2019-11-08 | 湖南正清制药集团股份有限公司 | A method of circulation extracts Sinomenine from caulis sinomenii |
| CN105963283B (en) * | 2016-06-15 | 2019-02-22 | 湖南正清制药集团股份有限公司 | A kind of Sinomenine imbedibility preparation and preparation method thereof |
| CN110731980A (en) * | 2019-11-19 | 2020-01-31 | 苏州永健生物医药有限公司 | Method for enriching alkaloids from Clerodendranthus spicatus leaves |
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| CN1174983C (en) * | 2002-07-05 | 2004-11-10 | 上海中医药大学 | Method for purifying diversine |
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