CN101260097A - Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate - Google Patents
Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate Download PDFInfo
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Abstract
The invention discloses a process of preparing Dehydroandrographolide Succinate Sodium and Potassium salts with Potassium Dehydroandrograpolide Succinate. The process comprises the steps of: weighing right amount of Potassium Dehydroandrograpolide Succinate, adding absolute ethyl alcohol about 3 to 6 times to make suspension; weighting mole Sodium bicarbonate in equal weight, adding water to dissolve, dripping slowly Sodium bicarbonate solution in potassium dehydroandrograpolide succinate suspension in a water bath at a temperature of between 40 and 60 DEG C, mixing into liquid medicine and defecating, dissolving impurity and filtering, putting on a 0.22 mu m filter membrane, adding absolute ethyl alcohol about 7 to 12 times while mixing, after 10 to 30 minutes of mixing, natural crystallization seeds out after 13 to 18 hours standing in room temperature; filtering and washing 2 to 3 times with right amount of absolute ethyl alcohol; filtering and drying with less pressure. The invention provides a process route of preparing potassium sodium dehydroandroan drographolide succinate for injection with high purity, which is high in process yields, high in product purity, good in solubility, less in impurity and complete in combination of Potassium and Sodium; no obvious toxic and side effect in clinic application, the preparation is more stable compared with the similar and can be prepared into various preparations.
Description
Technical field
It is the technology of feedstock production potassium sodium dehydroandroandrograsuccinate succinate with the potassium dehydroandrographolide succinate that the present invention discloses a kind of, is the optimization improvement to existing production technique, belongs to chemical medical preparing technical field.
Background technology:
The deoxydidehydrorographolide succinic acid half-ester k-na salt that the present invention relates to is (general by name: potassium sodium dehydroandroan drographolide succinate), chemical name is: 14-deshydroxy-11,12-two dehydrogenation rographolides-3,19-disuccinic acid half ester k-na salt, primary structure is the deoxydidehydrorographolide succinic acid half-ester, has heat-clearing, antisepsis and anti-inflammation, antiviral effect; The traditional technology of using at present comprises with potassium dehydroandrographolide succinate and sodium bicarbonate and is raw material, acid-base neutralisation takes place in water react, through sterile filtration, make potassium sodium dehydroandroan drographolide succinate under lyophilisation condition, product yield is low, and content is not high, the preparation pH value of making is unstable, and Impurity removal is incomplete.
Commercially available potassium sodium dehydroandroan drographolide succinate adopts potassium dehydroandrographolide succinate to make mostly, and potassium dehydroandrographolide succinate easily precipitates in the preparation process of making, and the storage time is not long, is prone to side effect, and the patient is produced some disadvantageous effects.
Summary of the invention
The invention provides a kind of is the technology of feedstock production potassium sodium dehydroandroandrograsuccinate succinate with the potassium dehydroandrographolide succinate, and it is low to have solved existing preparation technology's product yield, and content is not high, and the preparation pH value of making is unstable, the incomplete problem of Impurity removal.
Technical solution of the present invention is as follows:
Take by weighing an amount of potassium dehydroandrographolide succinate, add the dehydrated alcohol of 3～6 times of amounts, make suspension, other such as takes by weighing at the mole sodium bicarbonate, be dissolved in water, the potassium dehydroandrographolide succinate suspension is dripped sodium hydrogen carbonate solution in 40～60 ℃ of water-baths, slowly drip, be stirred to the soup clarification, separate out impurity simultaneously, cross the film of 0.22 μ m, under agitation add the dehydrated alcohol of 7～12 times of amounts, stirred 10～30 minutes, room temperature leaves standstill more than 13～18 hours spontaneous nucleation to be separated out.Filter, with an amount of absolute ethanol washing 2～3 times, filter, drying under reduced pressure is taken a sample, and carries out packing after the assay was approved.
Chemical equation is as follows:
Potassium sodium dehydroandroan drographolide succinate preparation of the present invention comprises: 'Yanhuning ' frozen-dried powder injection, potassium sodium dehydroandroan drographolide succinate aqueous injection, potassium sodium dehydroandroan drographolide succinate infusion solution.
Positively effect of the present invention has been to provide the operational path that can produce the high purity potassium sodium dehydroandroan drographolide succinate, is starting raw material with the potassium dehydroandrographolide succinate, directly adds sodium bicarbonate, and one-step synthesis goes out scorching amber.This process recovery ratio height, the product purity height, solvability is good, and impurity is few, and potassium sodium is in conjunction with complete.Do not find obvious toxic-side effects in clinical application, the preparation of making is more similar stable, can be made into various preparations.
The freeze-dry process of original potassium sodium dehydroandroan drographolide succinate is improved, produce potassium sodium dehydroandroan drographolide succinate by crystalline mode in the dehydrated alcohol solvent, purity is higher, and the yields have increased considerably, reduced energy consumption.The product purity of the present invention's preparation is higher, the preparation more stable of making, and curative effect is more definite.
Structural identification is analyzed as follows:
Nomenclature of drug
Chinese name: potassium sodium dehydroandroan drographolide succinate; English name: Potassium Sodium Dehydroandroandrographolide Succinate
Structural formula
Molecular formula: C
28H
34KNaO
10H
2O; Molecular weight: 610.68
Chinese name: 14-deshydroxy-11,12-two dehydrogenation rographolides-3,19-disuccinic acid half ester k-na salt-water thing
English name: 14-deoxy-11,12-didehydroandropholide-3,19-disuccinate potassium sodiumsalt monohydrate
Specimen
1. for the process for purification of conclusive evidence chemical structure with sample
Promptly can be used for spectrometry by above-mentioned technology purified sample, utilizing the HPLC method to record purity is 98.5%
2. method for detecting purity (HPLC)
Instrument: SPD-10AVP, detector: SPD-10ATVP
Chromatographic column: C
18The ODS post
Moving phase: 0.1mol/L potassium primary phosphate (transferring pH to 3.0)-acetonitrile (53: 47) with phosphoric acid
Flow velocity: 1.0ml/min
Detect wavelength: 251nm
Physico-chemical property
1. appearance character:
Buff powder, odorless, bitter, have draw moist.
2. solvability:
This product is easily molten in water, and slightly soluble in ethanol is insoluble in acetone and ether.
Infrared absorption spectrum
Instrument model: FTS-135FTIR
Instrumental correction: with the infrared spectra of polyphenyl second film as calibration graph
Condition determination: pressing potassium bromide troche
Table 1 potassium sodium dehydroandroan drographolide succinate infrared spectrum absorpting peak data and ownership
| Absorption peak (cm -1) | Intensity | Oscillatory type | Group |
| 3414.9 | S | v(OH) | Water |
| 3080.6 | W | v s(C-H) | Thiazolinyl hydrogen |
| 2936.2 | m | v as(C-H) | Methylene radical |
| 2851.5 | w | v s(C-H) | Methylene radical |
| 1747.1 | vs | v(C＝O) | Lactone |
| 1722.8 | s | v(C＝O) | Ester |
| 1643.1 | w | v(OH) | Crystal water |
| 1571.8 | vs | v as(COO) | Carboxylate salt |
| 1420.9 | s | v s(COO) | Carboxylate salt |
| 1352.3 | m | v as(C-O-C) | Lactone |
| 1262.8 | m | v as(C-O-C) | Ester |
| 1166.1 | m | v s(C-O-C) | Lactone |
| 1089.4 | m | v s(C-O-C) | Ester |
| 1005.6 | m | δ(＝C-H) | Ethylene linkage |
| 892.7 | w | δ(＝C-H) | Ethylene linkage |
| 810.8 | w | δ(＝C-H) | Ethylene linkage |
Resolve:
1.3414.9cm
-1The absorption peak at place is in X-H (X represents elements such as N, O) the stretching vibration absorption peak district of reactive hydrogen, shows and contains reactive hydrogen in the structure.
2.3080.6cm
-1The absorption peak at place is the stretching vibration of unsaturated C-H, shows to have undersaturated carbon-carbon bond in the molecule.
3.2936.2cm
-1, 2851.5cm
-1The absorption peak at place belongs to the asymmetric of methylene radical c h bond and symmetrical stretching vibration absorption region respectively; And these two peaks are stronger relatively, illustrate to have cycloaliphatic ring or chain alkyl in the molecule.
4.1747.1cm
-1And 1722.8cm
-1The strong absorption peak and the 1350～1050cm at place
-1Strong absorption peak in the scope shows and contains two types ester carbonyl group in the molecule.1571.8cm
-1And 1420.9cm
-1There is carboxylate salt in the strong absorption peak at place in the prompting molecule.
5.1640cm
-1The absorption peak at place is in conjunction with 3414.9cm
-1There is crystal water in the absorption peak prompting molecule at place.
6.1000～670cm
-1Scope is represented the out-of-plane deformation vibration of alkene=C-H, and can judge the replacement situation of alkene.1005.6cm
-1Represent trans disubstituted olefin=the C-H out-of-plane deformation vibration; 892.7cm
-1The disubstituted olefin of expression substituting group on same carbon atom=the C-H out-of-plane deformation vibration; 810.8cm
-1Represent three substituted olefines=the C-H out-of-plane deformation vibration.
Ultra-violet absorption spectrum (UV)
Instrument: Lambda900 ultraviolet spectrophotometer
Method: sample ligand is made certain concentration solution, and with used solvent as blank, adopt the 1cm cuvette, in 200～400nm scope, measure.Instrumental correction is carried out for 22 pages by 2005 editions two appendix of Chinese Pharmacopoeia with calibrating.
Solvent: water, the 0.1mol/L HCl aqueous solution, the 0.1mol/LNaOH aqueous solution
Test liquid: all be made into the solution that concentration is 20.0 μ g/mL
The ultraviolet spectrum data and the ownership of table 2 potassium sodium dehydroandroan drographolide succinate sample
Resolve: this product absorbs similar substantially in water, acidic solution medium ultraviolet, occur the last one absorption peak near 250nm, can be defined as the K absorption band, illustrates to have α, β-unsaturated double-bond in the molecule.In basic solution, decompose, produce big red shift.Therefore, can think and contain the alpha, beta-unsaturated esters structure in the molecule.
Nuclear magnetic resonance spectrum
Proton nmr spectra (
1H-NMR) and
1H-
1H COSY spectrum
Instrument: INOVA-400 type nuclear magnetic resonance analyser
Condition determination: solvent D
2O
Measurement result:
Table 3 potassium sodium dehydroandroan drographolide succinate sample
1H-NMR spectrum data and ownership
| The proton sequence number | Chemical shift δ (ppm) | Proton number | Multiplicity | Coupling constant J (Hz) |
| 17 | 0.73 | 3 | s | |
| 18 | 0.92 | 3 | |
|
| 1 | 1.16 | 1 | m | |
| 5 | 1.30 | 1 | d | 12.1 |
| 1、6 | 1.41 | 2 | |
|
| 2 | 1.56 | 2 | m | |
| 6 | 1.79 | 1 | d | 12.1 |
| 7 | 1.95 | 1 | m |
| 7、9 23、27 | 2.37 | 6 | m | |
| 22、26 | 2.49 | 4 | |
|
| 19 | 4.13 | 1 | d | 11.6 |
| 19 | 4.28 | 1 | d | 11.6 |
| 20 | 4.43 | 1 | s | |
| 3 | 4.49 | 1 | dd | 4.9、11.4 |
| 20 | 4.72 | 1 | s | |
| 15 | 4.84 | 2 | s | |
| 12 | 6.05 | 1 | d | 15.8 |
| 11 | 6.62 | 1 | dd | 15.8、10.0 |
| 14 | 7.46 | 1 | s |
Resolve:
1The HNMR spectrum provides 34 hydrogen atoms, and is identical with H atom number in the potassium sodium dehydroandroan drographolide succinate molecule, according to their chemical shift, that their ownership is as follows:
1.1 it is unimodal that δ 0.73,0.92ppm are, and contains 3 protons, showing to be on methyl absorption peak and the carbon adjacent with them does not have hydrogen, infers that therefore they are 17 and 18 s' methyl.
1.2 8 hydrogen are arranged in δ 1.16～1.95ppm scope, and they are hexa-atomic fat ring hydrogens.
1.3 10 hydrogen are arranged in δ 2.37～2.49ppm scope, and wherein 8 is the methylene peak that links to each other with carbonyl in the succsinic acid, all the other 2 may be hexa-atomic fat ring hydrogen;
1.4 7 hydrogen are arranged in δ 4.13～4.84ppm scope, wherein 5 be with carbon that oxygen links to each other on hydrogen, all the other 2 may be the hydrogen on the ethylene linkage;
1.5 3 hydrogen are arranged in δ 6.05～7.46ppm scope, are the hydrogen on the ethylene linkage.
1H-
1In the H COSY spectrum, the H of δ 6.62ppm and high field region H have coherent signal, thereby determine that it is C
11-H, and definite C
9-H is positioned at δ 2.37ppm place.C
11-H and C
12-H is correlated with, so δ 6.05ppm is C
12-H.Because the H of δ 7.46ppm is relevant with two H at δ 4.84ppm place, thereby concludes that δ 7.46ppm is C
14-H, and δ 4.84ppm is two C
15-H.
Remaining hydrogen only by hydrogen spectrum and
1H-
1H COSY spectrum can't accurately belong to hydrogen, and palpus combined carbon spectrum, HMQC spectrum, HMBC spectrum are resolved, and it resolves a part of as follows.
Carbon-13 nmr spectra (
13C-NMR)
Instrument model: INOVA-400 type nuclear magnetic resonance analyser
Solvent: D
2O
Measurement result:
Table 4 potassium sodium dehydroandroan drographolide succinate sample
13C-NMR data and ownership
Resolve: have 26 peaks on the carbon spectrum, compare few 2 with molecular formula, show the carbon that has chemical environment identical in the molecule.By carbon spectrum, DEPT spectrum and hydrocarbon relevant spectrum, can belong to as follows:
2.1 saturated carbon
There are 16 peaks in the saturated carbon district, and by the DEPT spectrum as can be known, δ 13.4,20.6ppm are two primary carbons, illustrate that they are C
17And C
18δ 22.4, δ 22.4, δ 29.6, δ 29.8, δ 30.7, δ 30.8, δ 35.0, δ 36.4, δ 64.2, δ 70.3 are 10 secondary carbon; δ 37.1, δ 40.1ppm are 2 quaternary carbon peaks; δ 52.7, δ 59.6, δ 79.6ppm are 3 tertiary carbon peaks.
2.2 unsaturated carbon
By the DEPT spectrum as can be known, there is 1 secondary carbon in the unsaturated carbon district, and δ=107.0ppm can be defined as C
20δ 119.8, δ 133.7, δ 146.0ppm are 3 tertiary carbons, should represent C
11, C
12, C
14δ 126.6, δ 148.7ppm are 2 quaternary carbons, should represent C
8, C
13δ 174.3, δ 174.7, δ 179.4ppm represent 3 carbonyls, but 5 carbonyls are arranged in the molecule, and this is because the carbonylation environment of two one-tenth carboxylate salts is identical, shows as a peak; Similar two become the carbonyl of ester also to show as a peak.
In HMQC, δ 146.0ppm and C
14-H is relevant, should be C
14δ 133.7ppm and C
11-H is relevant, should be C
11δ 119.8ppm and C
12-H is relevant, should be C
12δ 70.3ppm and C
15-H is relevant, should be C
15With C
20Relevant two hydrogen of δ 4.43, δ 4.72ppm should be two C
20-H.Two hydrogen of δ 4.13, δ 4.28ppm of low are relevant with the C at δ 64.2ppm place, thereby determine that it is two C
19-H, the C at δ 64.2ppm place is C
19The hydrogen δ 4.49ppm of low place should be C
3-H, the carbon signal at associated δ 79.9ppm place must be C
3
In HMBC, the carbon and the C at δ 174.3ppm place
12-H, C
14-H, C
15-H is all long-range relevant, and is carbonyl carbon, should be C
16δ 126.6ppm and C
14-H, C
11-H, C
12-H, C
15-H is all long-range relevant, should be C
13Another unsaturated carbon δ 148.7ppm should be C
8δ 59.6ppm and C
11-H, C
12-H, C
20-H is all long-range relevant, should be C
9With C
19The long-range relevant tertiary carbon of-H removes C
3Should be C5 outward, δ 52.7ppm; The carbon at δ 40.1ppm place is quaternary carbon, and and C
3-H, C
19-H is all long-range relevant, should be C
4The carbon at δ 37.1ppm place is quaternary carbon, and and C
11-H, C
12-H is all long-range relevant, should be C
10The carbon at δ 35.0ppm place is secondary carbon, and and C
20-H is long-range relevant, should be C
7The carbon at δ 22.4ppm place is secondary carbon, and and C
3-H is long-range relevant, should be C
2The hydrogen and the C at δ 0.92ppm place
3, C
19, C
5, C
4Long-range being correlated with arranged, show that it is 18 methyl hydrogen; The hydrogen and the C at δ 0.73ppm place
9, C
5, C
10Long-range being correlated with arranged, show that it is 17 methyl hydrogen.The hydrogen and the C at δ 1.95ppm place
8, C
20Long-range relevant, should be C
7-H; The hydrogen and the C at δ 1.30ppm place
17, C
18, C
4, C
10, C
19Long-range relevant, should be C
5-H; The hydrogen and the C at δ 1.16ppm place
17, C
10, C
9, C
3Long-range relevant, should be C
1-H.
In conjunction with H-H COSY spectrum, two hydrogen of δ 1.56ppm and C
3-H is relevant, should be C
2-H; δ 1.41ppm and C
5-H is relevant, should be C
6-H.
Mass spectrum
Instrument model: Bruker APEX II FT-ICRMS
Condition determination: SI source
Test-results:
The high resolution mass spectrum data of table 5 potassium sodium dehydroandroan drographolide succinate sample
Resolve: in the high resolution negative ion mass spectrum of sample, fragment ion peak is less, can obviously see two quasi-molecular ion peaks, and the molecular formula that calculates potassium sodium dehydroandroan drographolide succinate in view of the above is C
28H
34O
10KNa.
Integration analysis
1. the sample that is used for structural identification is to get through making with extra care, and the purity of its HPLC is 98.5%.
2. the molecular formula that can calculate potassium sodium dehydroandroan drographolide succinate from high resolution mass spectrum is C
28H
34KNaO
10, its degree of unsaturation is 11.Three two keys (3), five carbonyls (5) are arranged in the molecule, and three rings (3) are totally 11 degrees of unsaturation, conform to the structural formula of potassium sodium dehydroandroan drographolide succinate.
3. from infrared spectra, there are two ester carbonyl groups in the molecule as can be seen, have carboxylate structure simultaneously; There is crystal water in the infrared spectra prompting in the molecule.
4. UV spectrum shows and has the alpha, beta-unsaturated esters structure in the molecule.
5. determine to exist in the molecule one five yuan α, β-unsaturated lactone, and this lactonic ring and an exocyclic double bond conjugation in conjunction with hydrogen spectrum, carbon spectrum and COSY spectrum, HMQC and HMBC.Unimodal the showing at δ 0.73 and δ 0.92ppm place exists two isolated methyl that link to each other with quaternary carbon in the molecule, show in conjunction with DEPT spectrum, HMQC and HMBC to have two six-rings that adjoin in the molecule again.Its structure is as follows:
The quality approach analysis of potassium sodium dehydroandroan drographolide succinate
Appearance character
This product is a micro-yellow powder, odorless, bitter.
Draw moist
It is an amount of to get this product, accurate claims surely, under 25 ℃, the condition of RH75% ± 5% sample is tiled in the plate, places 10 days, weighs respectively at the 5th day and the 10th day, and the calculating moisture absorption is increased weight.
This product moisture absorption weightening finish is all greater than 5%, illustrate this product have draw moist.
Differentiate
Chemical colour reaction is differentiated
Get the about 2mg of this product, add Diluted Alcohol 1ml, after the dissolving, add 3, each 2 of 5-dinitrobenzoic acid ethanolic soln (1.5 → 100) and sodium hydroxide solutions (0.8 → 100), mixing, i.e. displaing amaranth.
Spectrophotometry
Get the solution under the assay item, measure, in 200～400nm scope, scan according to spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A).The sample maximum absorption wavelength is 251nm.
Natrium potassium salt is differentiated
According to two appendix III of Chinese Pharmacopoeia version in 2005 (20 pages of appendix) natrium potassium salt identification.
This product that takes a morsel, soluble in water, get platinum filament and dip in after moistening with hydrochloric acid and get trial-product, in colourless flame, burn, flame promptly shows aureus.
Check
Potential of hydrogen
Get this product 0.15g, add water 15ml, make dissolving, measure (two appendix VI of Chinese Pharmacopoeia version in 2005 H) in accordance with the law.This product and potential of hydrogen are all in 6.0～8.0 scopes as a result.
The clarity of solution and color
Get this product 0.1g, add water 10ml dissolving after, measure (two appendix IX of Chinese Pharmacopoeia version in 2005 A, IXB) in accordance with the law.Clarity of solution of this product and color are qualified as a result.
Pyrogen
Get this product, add an amount of dissolving of sterilized water for injection after, add the chlorination sodium injection and make the solution that contains 2mg among every 1ml, check (two appendix XI of Chinese Pharmacopoeia version in 2005 D) in accordance with the law.Dosage is by the every 1kg injection of rabbit body weight 5ml, and the result is up to specification.
Weight loss on drying
Getting this product, is siccative with the Vanadium Pentoxide in FLAKES,, checks (two appendix VIII of Chinese Pharmacopoeia version in 2005 L) to constant weight at 60 ℃ of drying under reduced pressure in accordance with the law.This product weight loss on drying is less than 4.0% as a result.
Related substance
High performance liquid chromatography
Method
Assay method: get this product, add moving phase and make the contrast solution that contains 2.5 μ g among the need testing solution that contains 0.25mg among every 1ml and the every 1ml; According to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2005 D) test, be weighting agent with the octadecylsilane chemically bonded silica; 0.1mol/L (transferring pH to 3.0 with phosphoric acid)-acetonitrile (53: 47) is a moving phase to potassium primary phosphate; Detect wavelength 251nm.Number of theoretical plate calculates by the potassium sodium dehydroandroan drographolide succinate peak should be not less than 2500, and the resolution of potassium sodium dehydroandroan drographolide succinate peak and each impurity peaks should be up to specification.Get contrast solution 20 μ l, inject liquid chromatograph, regulate detection sensitivity, make the peak height of principal constituent be about 10% of registering instrument full range; Get each 20 μ l of above-mentioned two kinds of solution again, inject liquid chromatograph respectively, the record color atlas is to 3 times of the principal constituent retention time; Trial-product is as showing impurity peaks, and arbitrary single impurity peak area must not be greater than contrast solution main peak area (1.0%); Each impurity peaks peak area sum must not be greater than 3 times (3.0%) of contrast solution main peak area.
The result: this product related substance is less than 3.0%, and is up to specification.
Assay
Method
Get this product 28mg, the accurate title, decide.Put in the 100ml measuring bottle, add Diluted Alcohol and make dissolving in right amount, add acetic acid 0.1ml, be diluted to scale with Diluted Alcohol, shake up, precision is measured 5ml, puts in the 50ml measuring bottle, adds Diluted Alcohol and is diluted to scale, shakes up; It is that siccative is an amount of to the deoxydidehydrorographolide succinic acid half-ester reference substance of constant weight at 60 ℃ of drying under reduced pressure that other precision takes by weighing with the Vanadium Pentoxide in FLAKES, makes the solution that contains 25ug among every 1ml by the same method.Get above-mentioned two kinds of solution,, measure optical density respectively at the 251nm place according to spectrophotometry (two appendix IV of Chinese Pharmacopoeia version in 2005 A).The content and 1.1128 that deoxydidehydrorographolide succinic acid half-ester in the trial-product is tried to achieve in calculating multiplies each other, and promptly gets to contain C in the trial-product
28H
34KNaO
10Weight.
This product content is all more than 99% as a result.
Description of drawings
Fig. 1 potassium sodium dehydroandroan drographolide succinate infrared spectrogram;
Fig. 2 potassium sodium dehydroandroan drographolide succinate proton NMR spectrum figure;
Fig. 3 potassium sodium dehydroandroan drographolide succinate
13The C nmr spectrum;
Fig. 4 potassium sodium dehydroandroan drographolide succinate
13C DEPT135 nmr spectrum;
Fig. 5 potassium sodium dehydroandroan drographolide succinate x-ray diffraction pattern.
Embodiment
For the ease of understanding the present invention, especially exemplified by following examples.Its effect is understood that it is to explaination of the present invention but not to any type of restriction of the present invention.
Embodiment 1:
Take by weighing the 200g potassium dehydroandrographolide succinate, add the 650ml dehydrated alcohol, make suspension, other takes by weighing the 29.5g sodium bicarbonate, adds the dissolving of water heating in water bath, and the potassium dehydroandrographolide succinate suspension is dripped sodium hydrogen carbonate solution in 45 ℃ of water-baths, slowly drip, be stirred to the soup clarification, separate out impurity simultaneously, cross the film of 0.22 μ m, the dehydrated alcohol that under agitation adds 1500ml, stirred 10 minutes, room temperature left standstill 15 hours, and spontaneous nucleation is separated out.Filter, use 1000ml absolute ethanol washing 2 times, filter, 50 ℃ of drying under reduced pressure get pale yellow powder 176g.
Embodiment 2:
Take by weighing the 400g potassium dehydroandrographolide succinate, add the dehydrated alcohol of 2000ml, make suspension, other takes by weighing the 63.2g sodium bicarbonate, adds the dissolving of water heating in water bath, and the potassium dehydroandrographolide succinate suspension is dripped sodium hydrogen carbonate solution in 50 ℃ of water-baths, slowly drip, be stirred to the soup clarification, separate out impurity simultaneously, cross the film of 0.22 μ m, the dehydrated alcohol that under agitation adds 3600ml, stirred 20 minutes, room temperature left standstill 18 hours, and spontaneous nucleation is separated out.Filter, use 2300ml absolute ethanol washing 3 times, filter, 55 ℃ of drying under reduced pressure get pale yellow powder 336g.
Embodiment 3:
Take by weighing the 600g potassium dehydroandrographolide succinate, add the dehydrated alcohol of 3600ml, make suspension, other takes by weighing the 91.3g sodium bicarbonate, adds the dissolving of water heating in water bath, and the potassium dehydroandrographolide succinate suspension is dripped sodium hydrogen carbonate solution in 60 ℃ of water-baths, slowly drip, be stirred to the soup clarification, separate out impurity simultaneously, cross the film of 0.22 μ m, the dehydrated alcohol that under agitation adds 7200ml, stirred 30 minutes, room temperature left standstill 20 hours, and spontaneous nucleation is separated out.Filter, use 3600ml absolute ethanol washing 3 times, filter, 60 ℃ of drying under reduced pressure get pale yellow powder 498g.
Claims (1)
1, a kind of is the technology of feedstock production potassium sodium dehydroandroandrograsuccinate succinate with the potassium dehydroandrographolide succinate, may further comprise the steps:
Take by weighing an amount of potassium dehydroandrographolide succinate, add the dehydrated alcohol of 3～6 times of amounts, make suspension, other such as takes by weighing at the mole sodium bicarbonate, be dissolved in water, the potassium dehydroandrographolide succinate suspension is dripped sodium hydrogen carbonate solution in 40～60 ℃ of water-baths, slowly drip, be stirred to the soup clarification, separate out impurity simultaneously, cross the film of 0.22 μ m, under agitation add the dehydrated alcohol of 7～12 times of amounts, stirred 10～30 minutes, room temperature leaves standstill more than 13～18 hours spontaneous nucleation to be separated out; Filter, with an amount of absolute ethanol washing 2～3 times, filtration, drying under reduced pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100506179A CN101260097B (en) | 2008-04-18 | 2008-04-18 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100506179A CN101260097B (en) | 2008-04-18 | 2008-04-18 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
Publications (2)
| Publication Number | Publication Date |
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| CN101260097A true CN101260097A (en) | 2008-09-10 |
| CN101260097B CN101260097B (en) | 2012-05-02 |
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| CN102030731A (en) * | 2010-12-28 | 2011-04-27 | 哈药集团三精制药股份有限公司 | Technique for preparing high-purity potassium sodium dehydroandroan drographolide succinate at low temperature by solvent crystallization |
| CN102219683A (en) * | 2010-04-16 | 2011-10-19 | 重庆药友制药有限责任公司 | Degradation product of potassium sodium dehydroandroan drographolide succinate |
| CN102367243A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN102382082A (en) * | 2011-09-07 | 2012-03-21 | 周晓东 | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
| CN103113330A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide salifying process |
| CN103755670A (en) * | 2014-02-20 | 2014-04-30 | 湖北美林药业有限公司 | Potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN104744412A (en) * | 2015-04-07 | 2015-07-01 | 重庆药友制药有限责任公司 | Dehydroandrographolide succinate compound |
| CN106854190A (en) * | 2016-11-18 | 2017-06-16 | 珠海同源药业有限公司 | A kind of new Andrographolide compound and its pharmaceutical composition |
| CN107823182A (en) * | 2017-12-15 | 2018-03-23 | 黄山中皇制药有限公司 | The andrographolide capsulae enterosolubilis and preparation method of a kind of efficacy stability |
| CN107982241A (en) * | 2017-12-15 | 2018-05-04 | 黄山中皇制药有限公司 | A kind of andrographolide enteric coated preparations and preparation method |
| CN107982240A (en) * | 2017-12-15 | 2018-05-04 | 黄山中皇制药有限公司 | It is a kind of can accurate dissolution andrographolide enteric coated particles and preparation method |
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| CN100465171C (en) * | 2005-09-06 | 2009-03-04 | 黄金秀 | Preparation method of potassium sodium dehydroandroan drographolide succinate, potassium sodium dehydroandroan drographolide succinate preparation and preparation method thereof |
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| CN102219683A (en) * | 2010-04-16 | 2011-10-19 | 重庆药友制药有限责任公司 | Degradation product of potassium sodium dehydroandroan drographolide succinate |
| CN102219683B (en) * | 2010-04-16 | 2014-11-05 | 重庆药友制药有限责任公司 | Degradation product of potassium sodium dehydroandroan drographolide succinate |
| CN102030731B (en) * | 2010-12-28 | 2012-07-11 | 哈药集团三精制药股份有限公司 | Technique for preparing high-purity potassium sodium dehydroandroan drographolide succinate at low temperature by solvent crystallization |
| CN102030731A (en) * | 2010-12-28 | 2011-04-27 | 哈药集团三精制药股份有限公司 | Technique for preparing high-purity potassium sodium dehydroandroan drographolide succinate at low temperature by solvent crystallization |
| CN102367243B (en) * | 2011-08-26 | 2013-03-27 | 贺金凤 | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN102367243A (en) * | 2011-08-26 | 2012-03-07 | 贺金凤 | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
| CN102382082B (en) * | 2011-09-07 | 2012-07-18 | 周晓东 | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof |
| CN102382082A (en) * | 2011-09-07 | 2012-03-21 | 周晓东 | Novel potassium sodium dehydroandroan drographolide succinate compound and drug combination thereof |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
| CN103113330B (en) * | 2013-02-28 | 2016-01-20 | 成都倍特药业有限公司 | Potassium Sodium Dehydroandroan drographolide Succinate salifying process |
| CN103113330A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide salifying process |
| CN103755670A (en) * | 2014-02-20 | 2014-04-30 | 湖北美林药业有限公司 | Potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof |
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| CN104744412A (en) * | 2015-04-07 | 2015-07-01 | 重庆药友制药有限责任公司 | Dehydroandrographolide succinate compound |
| CN106854190A (en) * | 2016-11-18 | 2017-06-16 | 珠海同源药业有限公司 | A kind of new Andrographolide compound and its pharmaceutical composition |
| CN107823182A (en) * | 2017-12-15 | 2018-03-23 | 黄山中皇制药有限公司 | The andrographolide capsulae enterosolubilis and preparation method of a kind of efficacy stability |
| CN107982241A (en) * | 2017-12-15 | 2018-05-04 | 黄山中皇制药有限公司 | A kind of andrographolide enteric coated preparations and preparation method |
| CN107982240A (en) * | 2017-12-15 | 2018-05-04 | 黄山中皇制药有限公司 | It is a kind of can accurate dissolution andrographolide enteric coated particles and preparation method |
| CN108042503A (en) * | 2017-12-15 | 2018-05-18 | 黄山中皇制药有限公司 | A kind of efficient andrographolide enteric coatel tablets and preparation method |
| CN107982241B (en) * | 2017-12-15 | 2020-11-13 | 黄山中皇制药有限公司 | Potassium sodium dehydroandroan drographolide succinate enteric preparation and preparation method thereof |
| CN107982240B (en) * | 2017-12-15 | 2020-11-17 | 黄山中皇制药有限公司 | Potassium sodium dehydroandroan drographolide succinate enteric coated granules capable of being accurately dissolved out and preparation method thereof |
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