CN102552122B - Method for preparing sinomenine hydrochloride injection - Google Patents
Method for preparing sinomenine hydrochloride injection Download PDFInfo
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Abstract
The invention provides a preparation method of a sinomenine hydrochloride injection, which adopts the step of preparing sinomenine hydrochloride with a percolation method. The preparation method has the advantages that the method is simple in operation, cold treatment is employed and heating is obviated in an extraction process, the yield is high, mother liquor treatment is simple, and the method has good safety and reliability, low pollution and positive effect on environmental protection.
Description
Technical field
The present invention relates to a kind of preparation method of sinomenine hydrochloride injection, be specifically related to a kind of percolation and extract the method that effective ingredient sinomenine hydrochloride in the Caulis Sinomenii is made the sinomenine hydrochloride injection.
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 effects such as anti-arrhythmia and blood pressure lowering.
Main component is an alkaloid in the Caulis Sinomenii, 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 the Caulis Sinomenii, is the main effective ingredient of Caulis Sinomenii performance analgesia, antiinflammatory action, is separated obtaining the earliest from Japanese Caulis Sinomenii by Ishiwari etc.The sixties in 20th century, Chinese scholar Zhu Renhong also found sinomenine from homemade Caulis Sinomenii.Its hydrochlorate preparation commonly used clinically such as ZHENGQINGFENGTONGNING PIAN, ZHENGQINGFENGTONGNING slow releasing tablet, ZHENGQINGFENGTONGNING injection are used for the treatment of rheumatic, rheumatoid arthritis, and treatment ankylosing spondylitis, arrhythmia etc. are evident in efficacy.
At present the commercial production sinomenine hydrochloride adopts the alkalization water extraction process more, and it is for adding entry and a certain amount of Calx in Caulis Sinomenii, alkalization a period of time, add a certain amount of technical benzene then, reflux, extract, in water-bath, last acidify, leave standstill, crystallize.
Document has report to introduce the extraction and the purification process of sinomenine at present, and Caulis Sinomenii dilute sulfuric acid percolate is with lime water adjust pH 9, benzene carries out counter-current extraction at 50 ℃, and benzene extraction liquid carries out the extraction of regurgitation stream, activated carbon decolorizing with 1% hydrochloric acid, recrystallization is carried out in crystallization in hot water, get pure product.(Chen Yukun " extracting technique of Chinese medicine ", 1992)
This several method all uses the very big benzene of toxicity as extracting solvent, benzene is I class toxic solvent, the murder by poisoning of human body based on blood system and neurasthenia's disease group, is shown as blood leukocytes, platelet and erythrocytopenia, dizziness, headache, hypomnesis, insomnia etc.Aplastic anemia can take place in severe patient, even leukemia, death, and is disabled at pharmaceutical industry.And the recovery of benzene is comparatively cumbersome, and the discharging difficulty reaches environmental requirement.Thereby in Chinese medicine extraction, replace the key that the raw material that contains benzene is the prevention benzolism with the raw material that does not contain benzene.
Summary of the invention
The object of the invention is to provide a kind of preparation method of sinomenine hydrochloride injection.
The present invention seeks to be achieved through the following technical solutions, the preparation method of sinomenine hydrochloride injection of the present invention comprises the steps:
The preparation method of step 1, sinomenine hydrochloride
A, preparation sinomenine hydrochloride crude product
1, extracts: 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, adding 0.1～1mol/L HCl again makes liquid level cover medicated powder 2cm, flood after 6～48 hours, begin percolation, stop percolation after 6～24 hours by the speed of 2～6ml/min, get percolate, standby;
2, extract: above-mentioned percolate is added lime cream transfer pH to 10.5～12.0, filter, filtrate adds hydrochloric acid and transfers pH to 7.0～9.5, uses chloroform extraction 2～5 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 3%～6% times of weight
2The SO4 dehydration, concentrating under reduced pressure reclaims chloroform;
3, crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 2～4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 60 ℃～70 ℃ oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for 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 4% times of weight, insulation refluxed 10～30 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets sinomenine hydrochloride;
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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly.
A, preparation sinomenine hydrochloride crude product
1, extract: Caulis Sinomenii coarse powder 500 weight portions, with the 0.5mol/L HCl moistening of 500 parts by volume 2 hours, adorn percolator, add 0.5mol/L HCl again and make liquid level cover medicated powder 3cm, flood after 24 hours, begin percolation by the speed of 3ml/min, stop percolation after 15 hours, get percolate, standby;
2, extract: above-mentioned percolate is added lime cream transfer pH to 11.6, filter, filtrate adds hydrochloric acid and transfers pH to 8, uses chloroform extraction 4 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 3% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
3, crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 3, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 65 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 7 weight portions, be that 75% alcohol heating reflux is to dissolving fully with the concentration of 60 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 20 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets sinomenine hydrochloride.
A, preparation sinomenine hydrochloride crude product
1, extract: Caulis Sinomenii coarse powder 400 weight portions, with the 0.3mol/L HCl moistening of 320 parts by volume 3.5 hours, adorn percolator, add 0.3mol/L HCl again and make liquid level cover medicated powder 4cm, flood after 6 hours, begin percolation by the speed of 6ml/min, stop percolation after 8 hours, get percolate, standby;
2, extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 8.5, uses chloroform extraction 2 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 5% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
3, crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 62 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 10 weight portions, 95% alcohol heating reflux dissolving extremely fully with 120 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 25 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets sinomenine hydrochloride.
A, preparation sinomenine hydrochloride crude product
1, extracts: Caulis Sinomenii coarse powder 200 weight portions, with the 0.2mol/L HCl moistening of 900 parts by volume 3.5 hours, the dress percolator, adding 0.8mol/L HCl again makes liquid level cover medicated powder 4cm, flood after 15 hours, begin percolation, stop percolation after 20 hours by the speed of 4ml/min, get percolate, standby;
2, extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 9, uses chloroform extraction 2 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 5% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
3, crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 62 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 8 weight portions, 50% ethanol or the dissolving extremely fully of purified water reflux with 12 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 25 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets sinomenine hydrochloride.
A, preparation sinomenine hydrochloride crude product
1, extract: Caulis Sinomenii coarse powder 800 weight portions, with the 0.8mol/L HCl moistening of 300 parts by volume 1 hour, adorn percolator, add 0.2mol/L HCl again and make liquid level cover medicated powder 5cm, flood after 36 hours, begin percolation by the speed of 5ml/min, stop percolation after 8 hours, get percolate, standby;
2, extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 7, uses chloroform extraction 5 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 6% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
3, crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 2, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 68 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 6 weight portions, 80% ethanol or the dissolving extremely fully of purified water reflux with 40 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 15 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets sinomenine hydrochloride.
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ of insulations 10 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly.
The 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 preparation method of sinomenine hydrochloride injection provided by the invention, advantage are wherein to have adopted percolation to prepare the step of sinomenine hydrochloride, and advantage is simple to operate, and leaching process need not heat, and is cold treatment; The yield height, mother solution is handled simple; Safe and reliable, pollute lowly, environmental conservation is played a positive role.
Description of drawings
Accompanying drawing 1:0.1mol/L hydrochloric acid extraction 2,4,6,10,12,24,28,30, the Ultraluminescence thin layer collection of illustrative plates after 48 hours and colour developing thin layer collection of illustrative plates
Accompanying drawing 2:0.3mol/L hydrochloric acid extraction 2,4,6,10,12,24,28,30, the Ultraluminescence thin layer collection of illustrative plates after 48 hours and colour developing thin layer collection of illustrative plates
Accompanying drawing 3:0.7mol/L hydrochloric acid extraction 2,4,6,10,12,24,28,30, the colour developing thin layer collection of illustrative plates after 48 hours
Accompanying drawing 4:1.0mol/L hydrochloric acid extraction 2,4,6,10,12,24,28,30, the colour developing thin layer collection of illustrative plates after 48 hours
Accompanying drawing 5:0.1,0.3,0.7, the 1.0mol/L concentration hydrochloric acid extraction colour developing thin layer collection of illustrative plates after 12 hours
Accompanying drawing 6: the percolation time is 2,4,6,10,12,14 hours colour developing thin layer collection of illustrative plates
Accompanying drawing 7: it is 7,8,9,10 that aqueous alkali is transferred pH, 11 fluorescence and colour developing thin layer collection of illustrative plates
Accompanying drawing 8: extract fluorescence that the usefulness chloroform extraction is 1 time, 2 times, 3 times, 4 times and colour developing thin layer chromatography
Accompanying drawing 9: percolate, aqueous alkali, weak lye, extract, elaboration, mother solution, elaboration fluorescence and colour developing thin layer chromatography
Accompanying drawing 10: sinomenine hydrochloride reference substance high-efficient liquid phase chromatogram
Accompanying drawing 11: the liquid chromatogram of sinomenine hydrochloride
Accompanying drawing 12: the thin-layer chromatogram of sinomenine hydrochloride, the 1st speckle are reference substance, and the 2nd, 3,4,5 speckles are respectively 4 samples of the present invention.
Following experimental example and embodiment are used to further specify but are not limited to the present invention.
Experimental example one: Caulis Sinomenii Study on extraction
1, test objective
By this test, determine the technological parameter of this extraction process, as dip time, percolation time, extraction times, pH regulator scope etc., optimize technology.
2, test material
2.1 raw material: the Caulis Sinomenii that the Baoji provides
2.2 instrument:
Percolator;
PHS-2F PH meter: go up Electronic Instruments Plant of Nereid section
ZF-2 type three is used ultraviolet device: go up Hai'an booth Electronic Instruments Plant
RE-52A Rotary Evaporators: Shanghai Yarong Biochemical Instrument Plant
SHB-3 recirculated water is used vacuum pump more: Zhengzhou Tu Fu instrument plant
2.3 reagent: the quartzy chemical company limited in hydrochloric acid Zhuzhou
The safe and sound fine chemistry industry of ammonia Changsha Industrial Co., Ltd.
Chloroform Chemical Reagent Co., Ltd., Sinopharm Group
Silica gel G: Qingdao Marine Chemical Co., Ltd.
Ca (OH)
2, Na
2SO4, bismuth potassium iodide weak solution, ethanol etc.
2.4 detection method: colour developing 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, method
3.1 concentration of hydrochloric acid and dip time are investigated
Take by weighing 4 parts of mistakes, 20 purpose Caulis Sinomenii coarse powder, every part of 50g is respectively charged in 4 100ml beakers; Prepare 0.1mol/L, 0.3mol/L, 0.7mol/L, 1.0mol/L hydrochloric acid, added in 4 beakers moistening respectively 0.5 hour with the hydrochloric acid of the above-mentioned concentration of 40ml, add hydrochloric acid 50ml again in each beaker with concentration, dipping, sampling in per 2 hours is taken a sample respectively 1 time.
Judgment basis:
1, by same concentration, different dip time sample is put in chronological order on same lamellae respectively, compared with the reference substance speckle, the time point of principal spot maximum is a dip time;
2, the sample of same time period, variable concentrations being put on same lamellae by the concentration order, is optium concentration with the concentration point of principal spot maximum;
When 3, representing concentration result not have significant difference, show that then the hydrochloric acid of 0.1～1.0mol/L all is fit to this extraction as if 4.
3.2 the percolation time is investigated
The hydrochloric acid of getting 3.1 described definite concentration is as solvent, cross 20 purpose sinomenine coarse powder 0.5 hour with 160ml moistening 200g, after flooding by above-mentioned definite dip time, beginning is carried out percolation with the speed of 2～3ml/min, carried out primary sample in per 2 hours, sample spot on same lamellae, when no sinomenine principal spot, is stopped percolation.Be defined as the terminal time of percolation.
3.3 the pH value scope is investigated
After above-mentioned 3.2 percolates that obtain are regulated the above filtration of pH value to 11 with lime water, divide and get 5 parts of 50ml percolates, every part extracts respectively with the 16ml chloroform after transferring to different pH value with hydrochloric acid is counter, get extract, point is on same lamellae, minimum with impure speckle, the pH value point of principal spot maximum is the optimal pH range of accommodation.
3.4 extractant consumption and number of times are investigated
Get above-mentioned 3.3 percolates after filtering, the optimal pH of transferring pH to 3.3 to determine, adopt chloroform to extract, press 1/2 percolate volume first, the consumption of each 1/3 percolation liquid extracts later on, gets extract after each extraction, sample spot is on same lamellae, when no sinomenine speckle, end extraction, determine that this consumption and number of times are this technological parameter.
3.5 finger printing is investigated
Extract Caulis Sinomenii coarse powder 200g by above-mentioned 3.1,3.2,3.3,3.4 definite good parameters, respectively at percolation, alkalization filter, sour water is instead transferred, extraction, acidify crystallize, operation stage such as refining are got percolate, aqueous alkali, weak lye, extract, crude product, mother solution, elaboration, sample spot is analyzed on same lamellae.
3.6 thin layer chromatography point plate: get the sample 5ul of above-mentioned test respectively with 5ul point sample capillary tube, put on silica gel g thin-layer plate in order.
4, result
4.1 determining of the selection of concentration of hydrochloric acid and dip time, see Table one and accompanying drawing one to accompanying drawing five.
Table one: the solvent extraction of variable concentrations is in the thin layer situation of different time
Brief summary: the hydrochloric acid with above 4 groups of concentration floods, and can obtain 8-9 material (observing after ultraviolet light and the bismuth potassium iodide colour developing).And the hydrochloric acid extraction that adopts 0.1mol/L to obvious low than other three groups of concentration of main constituent, all be rational so choose the above concentration of 0.3mol/L (containing 0.3mol/L).0.3mol/L the dip time of hydrochloric acid tentatively is defined as reaching in 12 hours Cmax; 0.7mol/L the dip time of hydrochloric acid tentatively is defined as reaching in 10 hours maximum concentration; 1.0mol/L the dip time of hydrochloric acid tentatively is defined as reaching in 8 hours maximum concentration.
4.2 determining of percolation time sees Table two and accompanying drawing six.
Table two: the thin layer situation of different time sections during percolation
Brief summary: 6 hours is that percolation is complete.Determine to end percolation in 6-8 hour.
4.3 determining of pH value scope sees Table three and accompanying drawing seven.
Table three: different PH chromatogram situation
Brief summary: determining the 3rd point, is best pH during pH=8 promptly, is that pH=7-9 regulates allowed band between the 2nd and 4.
4.4 determining of extractant consumption and number of times sees Table four and accompanying drawing eight.
Table four: the thin layer situation of different extraction times
Brief summary: accompanying drawing eight is followed successively by the sample that extracts 1,2,3,4 times from left to right, and under the ultraviolet, speck point is strengthened successively, and the non-main constituent amount of extraction increases.Though because of all also containing micro-main constituent in the extract of third and fourth time, by-product volume increases, and can consider to extract 2 times, the method for each 1/2 consumption extracts.
5, the research of finger printing sees Table five and accompanying drawing nine.
Table five: different process stage chromatogram situation
Annotate: this extract is the sample that extracts first.
Brief summary: this adopts the hydrochloric acid percolation, can extract hydrochloric sinomenine at interior totally 9 kinds of material compositions, 7 kinds of materials are wherein arranged under ultraviolet, the bismuth potassium iodide following 2 kinds of materials that develop the color, filter again weak baseization, extraction by alkalization, effectively a kind of non-main constituent alkaloid under observed 6 kinds of materials and the colour developing under the removal ultraviolet obtains single sinomenine hydrochloride by making with extra care again.Proof this method is scientific and reasonable, simple and feasible.
Experimental example two: contrast experiment
Chloroform reflux, extract, technology in the table six: press 622 pages of attached sinomenine hydrochloride standards of Chinese Pharmacopoeia version in 2010.
Benzene reflux, extract, technology in the table six: raw material pulverizing, oven dry add the alkalization of Calx mix homogeneously, insert and add in the extraction pot that the close reflux, extract, of the full envelope of benzene concentrates, filters, cooling, separate, obtain free sinomenine, in free sinomenine, add HCl and transform generation sinomenine hydrochloride solution, carry out recrystallization with water again and obtain the product sinomenine hydrochloride.
The results are shown in Table six.
Table six: contrast and experiment
Following embodiment all can realize the effect of above-mentioned experimental example.
Embodiment one:
The oven dry of 200g Caulis Sinomenii, pulverized 20 orders, adding 0.3mol/L HCl 160ml stirs in beaker, after the moistening 6 hours, put in the percolator, add the hydrochloric acid of 0.3mol/L, make it cover liquid level 10cm, flood after 24 hours, beginning is carried out percolation with the speed of 2～3ml/min, collect percolate after 24 hours, add lime cream and regulate pH value to 11.3, filter, filtrate reuse HCl regulates pH value to 8.8, with chloroform extraction 4 times, lower floor's chloroform solution is through dehydration, concentrating under reduced pressure reclaims solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the sinomenine hydrochloride crude product;
Get sinomenine hydrochloride crude product 5.8g, be heated to backflow with 95% ethanol 90ml, add the 0.24g active carbon after the stirring and dissolving, insulation refluxed 30 minutes, filter while hot, filtrate is concentrated into 1/5, and cooling, crystallize filter, it is colourless to filtrate to clean filter cake with ethanol, sinomenine hydrochloride elaboration 2.22g, relative medical material yield more than 1.11%, content 97.9%.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment two:
The oven dry of 400g Caulis Sinomenii, pulverized 20 orders, adding 1.0mol/L HCl 300ml stirs in beaker, after the moistening 0.5 hour, put in the percolator, add the hydrochloric acid of 1N, make it cover liquid level 5cm, dipping, beginning is carried out percolation with the speed of 5ml/min after 48 hours, collects percolate after 8 hours, adds lime cream and regulates pH value to 10.8, filter, filtrate reuse HCl regulates pH value to 9.2, uses chloroform extraction 3 times, and lower floor's chloroform solution is through dehydration, concentrating under reduced pressure, reclaim solvent, concentrated solution is regulated pH value to 3.5 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the hydrochlorate of sinomenine, and recrystallization gets the sinomenine hydrochloride crude product in ethanol;
Get sinomenine hydrochloride crude product 11.2g, be heated to backflow with 95% ethanol 110ml, add the 0.5g active carbon after the stirring and dissolving, insulation refluxed 30 minutes, filter while hot, filtrate is concentrated into 1/4, and cooling, crystallize filter, it is colourless to filtrate to clean filter cake with ethanol, get sinomenine hydrochloride elaboration 4.61g, relative medical material yield 1.15%, content 96.4%.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment three:
The oven dry of 300g Caulis Sinomenii, pulverized 10 orders, adding 0.1mol/L HCl 240ml stirs in beaker, after the moistening 2 hours, put in the percolator, add the hydrochloric acid of 0.1mol/L, make it cover liquid level 8cm, flood after 36 hours, beginning is carried out percolation with the speed of 3ml/min, collects percolate after 12 hours, adds lime cream and regulates pH value to 11.5, filter, filtrate reuse HCl regulates pH value to 9.5, uses chloroform extraction 5 times, and lower floor's chloroform solution is washed to neutral through concentrating under reduced pressure, reclaim solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the hydrochlorate of sinomenine, and recrystallization gets the sinomenine hydrochloride crude product in ethanol;
Get sinomenine hydrochloride crude product 7.5g, be heated to backflow with 95% ethanol 60ml, add the 0.3g active carbon after the stirring and dissolving, insulation refluxed 30 minutes, filter while hot, filtrate is concentrated into 1/3, and cooling, crystallize filter, it is colourless to filtrate to clean filter cake with ethanol, get sinomenine hydrochloride elaboration 3.3g, relative medical material yield 1.1%, content 96.5%.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment four:
The oven dry of 1000g Caulis Sinomenii, pulverized 20 orders, adding 0.3mol/LHCl 800ml stirs in beaker, after the moistening 5 hours, put in the percolator, add the hydrochloric acid of 0.3mol/L, make it cover liquid level 2cm, flood after 6 hours, beginning is carried out percolation with the speed of 2～3ml/min, collect percolate after 24 hours, add lime cream and regulate pH value to 11.3, filter, filtrate reuse HCl regulates pH value to 8.8, with chloroform extraction 3 times, lower floor's chloroform solution is through dehydration, concentrating under reduced pressure reclaims solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the sinomenine hydrochloride crude product;
Get sinomenine hydrochloride crude product 4g, to dissolving fully, add the 0.16g active carbon with 75% ethanol 40ml reflux, insulation refluxed 20 minutes, filter while hot, filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate to clean filter cake with ethanol, gets sinomenine hydrochloride elaboration 1.62g.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment five:
The oven dry of 1000g Caulis Sinomenii, pulverized 20 orders, adding 0.3mol/L HCl 900ml stirs in beaker, after the moistening 8 hours, put in the percolator, add the hydrochloric acid of 0.3mol/L, make it cover liquid level 3cm, flood after 12 hours, beginning is carried out percolation with the speed of 2～3ml/min, collect percolate after 6 hours, add lime cream and regulate pH value to 11.4, filter, filtrate reuse HCl regulates pH value to 8.8, with chloroform extraction 2 times, lower floor's chloroform solution is through dehydration, concentrating under reduced pressure reclaims solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the sinomenine hydrochloride crude product;
Get sinomenine hydrochloride crude product 5g, to dissolving fully, add the 0.2g active carbon with 50% ethanol 37ml reflux, insulation refluxed 10 minutes, filter while hot, filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate to clean filter cake with ethanol, gets sinomenine hydrochloride elaboration 1.71g.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment six:
The oven dry of 1000g Caulis Sinomenii, pulverized 20 orders, adding 0.3mol/L HCl 700ml stirs in beaker, after the moistening 3 hours, put in the percolator, add the hydrochloric acid of 0.3mol/L, make it cover liquid level 5cm, flood after 16 hours, beginning is carried out percolation with the speed of 2～3ml/min, collect percolate after 10 hours, add lime cream and regulate pH value to 11.1, filter, filtrate reuse HCl regulates pH value to 8.8, with chloroform extraction 3 times, lower floor's chloroform solution is through dehydration, concentrating under reduced pressure reclaims solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the sinomenine hydrochloride crude product; Get sinomenine hydrochloride crude product 6g, to dissolving fully, add the 0.16g active carbon with 10% ethanol 30ml reflux, insulation refluxed 16 minutes, filter while hot, filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate to clean filter cake with ethanol, gets sinomenine hydrochloride elaboration 1.87g.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Embodiment seven:
The oven dry of 1000g Caulis Sinomenii, pulverized 20 orders, adding 0.3mol/L HCl 700ml stirs in beaker, after the moistening 1 hour, put in the percolator, add the hydrochloric acid of 0.3mol/L, make it cover liquid level 10cm, flood after 12 hours, beginning is carried out percolation with the speed of 2～3ml/min, collect percolate after 10 hours, add lime cream and regulate pH value to 11.3, filter, filtrate reuse HCl regulates pH value to 8.8, with chloroform extraction 4 times, lower floor's chloroform solution is through dehydration, concentrating under reduced pressure reclaims solvent, concentrated solution is regulated pH value to 2 with the hydrochloric acid of 6mol/L, stirs, cold filtration gets the sinomenine hydrochloride crude product; Get sinomenine hydrochloride crude product 7.8g, be heated to 80 ℃ of insulations with the 30ml purified water, the dissolving back adds the active carbon of 0.32g fully, is incubated 30 minutes, filter while hot, filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate to clean filter cake with ethanol, gets sinomenine hydrochloride elaboration 2.55g.
Take by weighing sinomenine hydrochloride 25g, sodium sulfite 1g, disodium edetate 0.3g; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ are incubated 10 minutes, filter carbon removal, replenish water for injection to full dose, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly, make 1000ml, specification: 2ml:50mg.
Above embodiment all no longer contains sinomenine in the raw material slag after with the hydrochloric acid percolation.The yield of sinomenine is more than 1.1% of material quantity, content 94～99%.
Claims (8)
1. the preparation method of a sinomenine hydrochloride injection is characterized in that this method comprises the steps:
The preparation method of step 1, sinomenine hydrochloride
A, preparation sinomenine hydrochloride crude product
Extract: 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, adding 0.1～1mol/L HCl again makes liquid level cover medicated powder 2cm, flood after 6～48 hours, begin percolation, stop percolation after 6～24 hours by the speed of 2～6ml/min, get percolate, standby;
Extract: above-mentioned percolate is added lime cream transfer pH to 10.5～12.0, filter, filtrate adds hydrochloric acid and transfers pH to 7.0～9.5, uses chloroform extraction 2～5 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 3%～6% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
Crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 2～4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 60 ℃～70 ℃ oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for 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 4% times of weight, insulation refluxed 10～30 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets 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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly;
The 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.
2. the preparation method of a sinomenine hydrochloride injection is characterized in that this method comprises the steps:
The preparation method of step 1, sinomenine hydrochloride
A, preparation sinomenine hydrochloride crude product
Extract: Caulis Sinomenii coarse powder 500 weight portions, with the 0.5mol/L HCl moistening of 500 parts by volume 2 hours, adorn percolator, add 0.5mol/L HCl again and make liquid level cover medicated powder 3cm, flood after 24 hours, begin percolation by the speed of 3ml/min, stop percolation after 15 hours, get percolate, standby;
Extract: above-mentioned percolate is added lime cream transfer pH to 11.6, filter, filtrate adds hydrochloric acid and transfers pH to 8, uses chloroform extraction 4 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 3% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
Crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 3, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 65 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 7 weight portions, be that 75% alcohol heating reflux is to dissolving fully with the concentration of 60 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 20 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets 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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly;
The 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.
3. the preparation method of a sinomenine hydrochloride injection is characterized in that this method comprises the steps:
The preparation method of step 1, sinomenine hydrochloride
A, preparation sinomenine hydrochloride crude product
Extract: Caulis Sinomenii coarse powder 400 weight portions, with the 0.3mol/L HCl moistening of 320 parts by volume 3.5 hours, adorn percolator, add 0.3mol/L HCl again and make liquid level cover medicated powder 4cm, flood after 6 hours, begin percolation by the speed of 6ml/min, stop percolation after 8 hours, get percolate, standby;
Extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 8.5, uses chloroform extraction 2 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 5% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
Crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 62 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 10 weight portions, with the 95% alcohol heating reflux dissolving extremely fully of 120 parts by volume, add the active carbon of 4% times of weight, insulation refluxed 25 minutes, filter while hot, filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets 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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly;
The 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.
4. the preparation method of a sinomenine hydrochloride injection is characterized in that this method comprises the steps:
The preparation method of step 1, sinomenine hydrochloride:
A, preparation sinomenine hydrochloride crude product
Extract: Caulis Sinomenii coarse powder 200 weight portions, with the 0.2mol/L HCl moistening of 900 parts by volume 3.5 hours, adorn percolator, add 0.8mol/L HCl again and make liquid level cover medicated powder 4cm, flood after 15 hours, begin percolation by the speed of 4ml/min, stop percolation after 20 hours, get percolate, standby;
Extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 9, uses chloroform extraction 2 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 5% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
Crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 4, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 62 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 8 weight portions, 50% ethanol or the dissolving extremely fully of purified water reflux with 12 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 25 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets 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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly;
The 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.
5. the preparation method of a sinomenine hydrochloride injection is characterized in that this method comprises the steps:
The preparation method of step 1, sinomenine hydrochloride
A, preparation sinomenine hydrochloride crude product
Extract: Caulis Sinomenii coarse powder 800 weight portions, with the 0.8mol/L HCl moistening of 300 parts by volume 1 hour, adorn percolator, add 0.2mol/L HCl again and make liquid level cover medicated powder 5cm, flood after 36 hours, begin percolation by the speed of 5ml/min, stop percolation after 8 hours, get percolate, standby;
Extract: above-mentioned percolate is added lime cream transfer pH to 11.3, filter, filtrate adds hydrochloric acid and transfers pH to 7, uses chloroform extraction 5 times; The combined chloroform layer washes with water to neutrality, adds the anhydrous Na of 6% times of weight
2SO
4Dehydration, concentrating under reduced pressure reclaims chloroform;
Crystallization: concentrated solution splashes into 6mol/L HCl and transfers pH to 2, and be stirred to the come-up solids and disperse, cold preservation, sucking filtration discards filtrate, and 68 ℃ of oven dry filter cakes get yellow sinomenine hydrochloride crude product;
B, sinomenine hydrochloride process for refining
Get sinomenine hydrochloride crude product 6 weight portions, 80% ethanol or the dissolving extremely fully of purified water reflux with 40 parts by volume, the active carbon that adds 4% times of weight, insulation refluxed 15 minutes, filtered while hot, and filtrate concentrates, cooling, crystallize, filter, it is colourless to filtrate that the ethanol with 95% cleans filter cake, gets 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 the sinomenine hydrochloride stirring and make dissolving; Adding sodium sulfite, disodium edetate again stirs and makes dissolving, continue to fill nitrogen, the active carbon of adding 0.01～0.20%, 35～45 ℃ are incubated 5～15 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining fills the nitrogen embedding to clear and bright, sterilized 20～40 minutes for 100～120 ℃, promptly;
The 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.
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 this 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 3 in this method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ of insulations 10 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly.
8. the preparation method of sinomenine hydrochloride injection as claimed in claim 6 is characterized in that the step 3 in this method is:
Get sinomenine hydrochloride, sodium sulfite, disodium edetate; Get water for injection, fill nitrogen, add the sinomenine hydrochloride stirring and make dissolving; Add sodium sulfite, disodium edetate again and stir and make dissolving, continue to fill nitrogen, add 0.1% active carbon, 35～45 ℃ of insulations 10 minutes, filter carbon removal, replenish water for injection to 1000 parts by volume, check, fine straining is to clear and bright, fill the nitrogen embedding, sterilized 30 minutes for 100 ℃, promptly.
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| CN106265516A (en) * | 2016-08-04 | 2017-01-04 | 长沙原道医药科技开发有限公司 | Sinomenine hydrochloride spray prepared by a kind of inorganic solvent and preparation method thereof |
| CN106265515A (en) * | 2016-08-04 | 2017-01-04 | 长沙原道医药科技开发有限公司 | Sinomenine hydrochloride spray prepared by a kind of organic solvent and preparation method thereof |
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| CN1125724A (en) * | 1995-11-15 | 1996-07-03 | 西安天诚医药生物工程有限公司 | Preparation method of diversine |
| CN101347408A (en) * | 2008-09-05 | 2009-01-21 | 李蕴麟 | Kukoline intravenous transfusion preparation |
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| CN1125724A (en) * | 1995-11-15 | 1996-07-03 | 西安天诚医药生物工程有限公司 | Preparation method of diversine |
| CN101347408A (en) * | 2008-09-05 | 2009-01-21 | 李蕴麟 | Kukoline intravenous transfusion preparation |
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