CN102219683B - Degradation product of potassium sodium dehydroandroan drographolide succinate - Google Patents
Degradation product of potassium sodium dehydroandroan drographolide succinate Download PDFInfo
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- CN102219683B CN102219683B CN201010148557.1A CN201010148557A CN102219683B CN 102219683 B CN102219683 B CN 102219683B CN 201010148557 A CN201010148557 A CN 201010148557A CN 102219683 B CN102219683 B CN 102219683B
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- potassium sodium
- dehydroandroan drographolide
- sodium dehydroandroan
- drographolide succinate
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Abstract
The invention provides a degradation product A of potassium sodium dehydroandroan drographolide succinate and a preparation method thereof and as well as an application of the potassium sodium dehydroandroan drographolide succinate serving as an impurity reference substance in the detection of related substance of the potassium sodium dehydroandroan drographolide succinate. The method comprises the steps of taking the potassium sodium dehydroandroan drographolide succinate; adding water to obtain a solution containing 24 mg of potassium sodium dehydroandroan drographolide succinate per milliliter; heating to 80 DEG C; preserving the heat and stirring for 72 hours; cooling to the room temperature; acidizing until a pH value is 1; filtering to remove precipitates; extracting the obtained filter liquor for three times by using ethyl acetate; combining organic phases and steaming the filter liquor in a rotary way until a dry product is obtained; adding methanol and a 0.1% methanoic acid-methanol solution to a residue to dissolve the residue so that a solution of about 50 mg/ml is prepared; and with C18 as a stationary phase and a 0.1% methanoic acid-methanol solution (the volume ratio is 3:7) as a mobile phase, preparing and purifying so that the degradation product A of the potassium sodium dehydroandroan drographolide succinate can be obtained.
Description
Technical field
The present invention relates to a kind of degradation product of potassium sodium dehydroandroan drographolide succinate A and preparation method thereof, and the purposes that is used as impurity reference substance in the detection of potassium sodium dehydroandroan drographolide succinate related substance.
Background technology
Potassium sodium dehydroandroan drographolide succinate is PSDS (potassium sodium dehydro-andrographohide succinatePSDS), chemistry 14-by name deshydroxy-11,12-bis-dehydrogenation rographolide-3,19-disuccinic acid half ester k-na salt, its structural formula is:
Potassium sodium dehydroandroan drographolide succinate be with traditional Chinese medicine Herba Andrographis extract rographolide with succinyl oxide esterification, dehydration, become salt refining to form; Be the new derivatives of rographolide, have the Chinese medicine west product processed of clear and definite chemical monomer.Potassium sodium dehydroandroan drographolide succinate can suppress early stage capillary permeability and increase and inflammatory exudation and oedema, and excited Pituitary Adrenal cortex hormone function, promotes ACTH to discharge specifically, increases the biosynthesizing of ACTH in prepituitary gland; The external effect with multiple viruses such as deactivation adenovirus, influenza virus, Respiroviruses.Be widely used in clinically virus pneumonia and viral upper respiratory tract infection.
Potassium sodium dehydroandroan drographolide succinate has determined curative effect, feature that toxicity is lower, but in recent years, and increasingly extensive along with clinical use has finding during the report of relevant adverse drug reaction.In September, 2009, national drug untoward reaction inspection center has issued the circular about potassium sodium dehydroandroan drographolide succinate injection security, remind the medical personnel of medical institutions and pharmaceutical production distributors, should watch out for the serious adverse reaction of potassium dehydroandrographolide succinate and potassium sodium dehydroandroan drographolide succinate injection, to pay close attention to the risk of children especially, guarantee drug safety.Advise that drug manufacturing enterprise carries out safety research simultaneously, probe into the research of its untoward reaction mechanism, interaction etc.
The main adverse reaction of potassium sodium dehydroandroan drographolide succinate shows as: general infringement main manifestations is anaphylactic shock, anaphylactoid reaction, high hot, weak etc., and wherein anaphylactic shock accounts for 27% of serious case report sum; Respiratory system damage main manifestations for having difficulty in breathing, suffocate, respiratory insufficiency etc.; Skin and annex infringement thereof show as exfoliative dermatitis, severe drug rash etc.; Other infringements comprise ypotension, tetraplegia, stupor, drug induced hepatitis etc.
At present, Chuanxinlian injection causes that the mechanism of untoward reaction is still not clear, infer factor relevant (pharmacovigilance, 2005,2 (4): 197-200) such as purity, production technique, preparation of dripping speed and medicine itself with patient's allergic constitution, dosage, liquid.Herba Andrographis series injection mainly comprises that potassium dehydroandrographolide succinate, potassium sodium dehydroandroan drographolide succinate, lotus must control three kinds.Potassium sodium dehydroandroan drographolide succinate is vinegar succinic acid half-ester k-na salt in the dehydration Herba Andrographis that forms through esterification, dehydration, one-tenth salt refining of the rographolide that extracts from traditional Chinese medicine Herba Andrographis.Production link and technique that different enterprises produce traditional Chinese medicine of the same race there are differences, and extract drugs purity is not high, and containing impurity etc. all can affect the security of its use, are one of Chinese medicine reasons of producing untoward reaction.In order to reduce and avoid the generation of untoward reaction, drug manufacturing enterprise will improve preparation technique of traditional Chinese medicine, improves Chinese medicine preparation purity, reduces the latency that untoward reaction occurs.In the rographolide process of extracting, may bring impurity into from traditional Chinese medicine Herba Andrographis; And in the preparation process of the semi-synthetic and preparation of potassium sodium dehydroandroan drographolide succinate raw material, also may produce other degraded products.Therefore using potassium sodium dehydroandroan drographolide succinate before drug use, must detect the impurity (any material that affects pharmaceutical purity is referred to as impurity) of potassium sodium dehydroandroan drographolide succinate, to guarantee the safety of clinical application.Therefore, be necessary the impurity of potassium sodium dehydroandroan drographolide succinate to carry out deep research.
The medicine impurity research governing principle of announcing according to State Food and Drug Administration's drug evaluation center (CDE), and ICH is to the regulation of medicine impurity and requirement, the limit of identification of medicine organic impurity is activeconstituents 0.1%; To being greater than the impurity of activeconstituents 0.1%, need study, and the determination method in medicine of definite impurity, to show the analytical data of impurity situation, effectively control drug quality and security.
Impurity in medicine is generally divided three classes by chemical classes and character: organic impurity, inorganic impurity and residual solvent.Organic impurity comprises impurity and the degraded product of introducing in technique, may be known or unknown, volatile or non-volatility, the chemical structure of this class impurity and the molecular formula of activeconstituents is similar or tool origin relation, therefore conventionally can be referred to as related substance again.The detection method of organic impurity comprises chemical method, spectrography, chromatography etc., because the difference of medicines structure and degraded product adopts different detection methods.By suitable analytical technology, the impurity of different structure and main ingredient are carried out to separated, detection, thereby reach the effective control to impurity.Along with development and renewal separated, detection technique, efficiently, isolation technique is combined with sensitive, stable, accurate, applicable detection means and can be made nearly all organic impurity all can obtain good separation detection under suitable condition fast.The method for detecting impurities generally adopting in quality standard is mainly high performance liquid chromatography (High Performance Liquid Chromatography; HPLC), tlc (Thin Layer Chromatography; TLC), vapor-phase chromatography (GasChromatography; GC) and capillary electrophoresis (Capillary Electrophoresis; CE).Can be according to definite detection methods such as control requirement of the physico-chemical property of determinand and impurity, chemical structure, impurity.
Quantitatively general HPLC methods that adopt of organic impurity, also adopt other methods such as TLC, GC sometimes.HPLC method is compared with TLC method, and HPLC method is highly sensitive, and detectability is low, and therefore favorable reproducibility is more and more widely used.As adopt HPLC method, its quantivative approach to have 1. impurity Standard reference; The principal constituent Self-control method of the 2. correction up factor; 3. the principal constituent Self-control method of the not correction up factor; 4. areas of peak normalization method.In aforesaid method, 1. standard measure is more accurate, can carry out accurate quantitative analysis to the impurity of required detection, but must have the reference substance (standard substance) of known accurate content.2. method reply correction factor is strictly measured, and is only applicable to the control of known impurities.3. the prerequisite of method is that supposition impurity is identical with the response factor of principal constituent, is applicable to have with principal constituent the impurity of identical or similar chromophoric group.4. method is simple and efficient, but because of each impurity response factor not necessarily identical, impurity level and principal constituent amount not necessarily in same linearity range, instrument is to the integral accuracy of trace impurity and constant principal constituent and accuracy equal factor mutually not, so adopt and have certain limitation in quality standard.
At present, in first of < < national drug standards > > pharmaceutical chemicals provincial standard rising national standard, in potassium sodium dehydroandroan drographolide succinate, potassium dehydroandrographolide succinate raw material and Andrographolide in Andrographolide for Injection standard, related substance is to adopt tlc (TLC), has that sensitivity is low, the problem of poor reproducibility.Therefore, in < < Pharmacopoeia of People's Republic of China > > 2005 editions, the related substance of potassium dehydroandrographolide succinate and Potassium DehydroandrograpolidSuccinate Succinate for Injection has adopted the Self-control method of HPLC.In like manner, in the standard of potassium sodium dehydroandroan drographolide succinate and Andrographolide in Andrographolide for Injection, related substance also has the Self-control method that adopts HPLC.Self-control method is that hypothesis all the components all goes out all and all impurity separated with principal constituent all under the prerequisite identical with principal constituent response factor of peak, all impurity, its result just can show the purity for this material completely truly, potassium sodium dehydroandroan drographolide succinate is derivative from Chinese medical extract, complicated component, adopt known impurities Standard reference checked for impurities content, be not subject to the impact of the conditions such as impurity and principal constituent non_uniform response, can position and energy Accurate Determining foreign matter content impurity.Therefore, obtain the impurity reference substance of potassium sodium dehydroandroan drographolide succinate, reference substance by this impurity as potassium sodium dehydroandroan drographolide succinate known impurities, can detect the content of this impurity in potassium sodium dehydroandroan drographolide succinate accurately and effectively, and the security of the quality of strict control potassium sodium dehydroandroan drographolide succinate raw material and injection liquid, raising medicine is had great importance.
Summary of the invention
First, the invention provides the degradation product of potassium sodium dehydroandroan drographolide succinate A with following structure:
Secondly, the invention provides the preparation method of degradation product of potassium sodium dehydroandroan drographolide succinate A.
Finally, the invention provides degradation product of potassium sodium dehydroandroan drographolide succinate A and in potassium sodium dehydroandroan drographolide succinate related substance detects, be used as the purposes of reference substance.
Potassium sodium dehydroandroan drographolide succinate be with traditional Chinese medicine Herba Andrographis extract rographolide with succinyl oxide esterification, dehydration, become salt refining to form, the general impurity of product that derives from Chinese medical extract is more.In carrying out the process of potassium sodium dehydroandroan drographolide succinate impurity research, the relative content that we find that there is an impurity is the highest, and we are called impurity A.In study on the stability, find, under the conditions such as high temperature, high humidity and illumination, the increase of this impurity is also obvious.Potassium sodium dehydroandroan drographolide succinate is diterpene ginkgolide, and in molecule, has conjugated double bond, is easy to occur hydrolysis and oxidizing reaction.Therefore, we infer that impurity A is the degraded product of potassium sodium dehydroandroan drographolide succinate.For controlling better the quality of potassium sodium dehydroandroan drographolide succinate, obtain the reference substance of this impurity, we have prepared degraded product A, and finish structure confirmation.Degraded product A is a new compound, has not yet to see bibliographical information.
The preparation method of degradation product of potassium sodium dehydroandroan drographolide succinate A is as follows: get potassium sodium dehydroandroan drographolide succinate, add water and make every 1ml approximately containing the solution of 24mg, be heated to 80 ℃, insulated and stirred 72 hours.Be cooled to room temperature, the hydrochloric acid soln that drips 1mol/L is acidified to pH=1, filters, and removes throw out, and the filtrate obtaining is used with the ethyl acetate of water equivalent and extracted three times, merges organic phase; Organic phase is revolved and is steamed to dry in 40 ℃ of water-baths; In resistates, add methyl alcohol (methyl alcohol: resistates=1ml: 1g), then add 0.1% formic acid-methyl alcohol (volume ratio is 3: 7) to dissolve, make the solution of about 50mg/ml.Take C18 as stationary phase, and 0.1% formic acid-methyl alcohol (volume ratio 3: 7) is moving phase, is prepared purifying, obtains degradation product of potassium sodium dehydroandroan drographolide succinate A.
Thinking based on above preparation method, those skilled in the art can, according to the guidance of this degraded product structure, design other synthetic routes to obtain degraded product A.
Degradation product of potassium sodium dehydroandroan drographolide succinate A of the present invention, its physical constant and spectroscopic data are as follows:
This product is pale yellow crystals; Molecular formula C
28h
36o
12, LC-ESI/TOFMS analytical results is in Table 1.
Table 1 LC-ESI/TOFMS analyzes accurate molecular weight result
The maximum absorption wavelength of ultra-violet absorption spectrum is 264nm; Infrared spectra (KBr) cm-1:3444 (vOH), 2927 (vC-H), 2854 (vC-H), 1719 (vC=O), 1614 (vC=C), 1407 (vC-O), 1165 (vC-O-C).Adopt nuclear magnetic resonance analyser (100MHz) and high resolution NMR instrument (400MHz) to determine all carbon atoms of this compound and the signal of hydrogen atom ownership.
13c and
1h nuclear magnetic resonance data is in Table 2.
Table 2
13c and
1h nuclear magnetic resonance data (DMSO-d
6)
Make after degradation product of potassium sodium dehydroandroan drographolide succinate A, when carrying out the detection of potassium sodium dehydroandroan drographolide succinate related substance, using degraded product A as impurity reference substance, adopt HPLC method to measure the content of degraded product A in potassium sodium dehydroandroan drographolide succinate.
Measuring method:
According to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010), measure.
Chromatographic condition: be weighting agent with octadecylsilane chemically bonded silica; 0.05% potassium dihydrogen phosphate (with phosphoric acid adjust pH to 2.5 ± 0.1)-methyl alcohol (4: 6) of take is moving phase; Detect wavelength 251nm.
Method: it is appropriate to get this product, adds moving phase and makes in every 1ml approximately the solution containing potassium sodium dehydroandroan drographolide succinate 1mg, as need testing solution.Separately getting precision, to take impurity A appropriate, makes the solution of approximately impure A 10 μ g in every 1ml, in contrast product solution by moving phase.According to above-mentioned chromatographic condition, get respectively each 20 μ l injection liquid chromatographies of need testing solution and reference substance solution, record color atlas, the content by external standard method with calculated by peak area impurity A.
Measuring method can be with reference to above method, and those skilled in the art also can as the case may be, adjust chromatographic condition etc.
Embodiment
Below by embodiment, come further the present invention to be explained, but be not appreciated that it is that the scope of the invention is construed as limiting.
Embodiment
Get potassium sodium dehydroandroan drographolide succinate 4g, add water and make every 1ml approximately containing the solution of 24mg, be heated to 80 ℃, insulated and stirred 72 hours.Be cooled to room temperature, the hydrochloric acid soln that drips 1mol/L is acidified to pH=1, filters, and removes throw out, and the filtrate obtaining is used with the ethyl acetate of water equivalent and extracted three times, merges organic phase; Organic phase is revolved and is steamed to dry in 40 ℃ of water-baths; In resistates, add methyl alcohol 4ml, then add 0.1% formic acid-methyl alcohol (3: 7) to dissolve, make the solution of about 50mg/ml, injection liquid chromatography is prepared purifying.Chromatographic condition: Agilent 1200 preparative liquid chromatography systems, ZORBAX SB C18 (21.2 * 250mm7 μ m); Moving phase: 0.1% formic acid-methyl alcohol (3: 7); Detect wavelength: 251nm.Obtain degradation product of potassium sodium dehydroandroan drographolide succinate A 150mg, HPLC purity: 98.4%.
Claims (3)
1. a degradation product of potassium sodium dehydroandroan drographolide succinate, its structural formula is:
2. the preparation method of degraded product described in claim 1, comprises the steps: to get potassium sodium dehydroandroan drographolide succinate, adds water and makes every 1mL containing the solution of potassium sodium dehydroandroan drographolide succinate 24mg, is heated to 80 ℃, insulated and stirred 72 hours; Be cooled to room temperature, the hydrochloric acid soln that drips 1mol/L is acidified to pH=1, filters, and removes throw out, and the filtrate obtaining is used with the ethyl acetate of water equivalent and extracted three times, merges organic phase; Organic phase is revolved and is steamed to dry in 40 ℃ of water-baths; In resistates, add methyl alcohol, wherein methyl alcohol: resistates=1mL: 1g, then add 0.1% formic acid-dissolve with methanol, make the solution of 50mg/mL; Take octadecylsilane chemically bonded silica as stationary phase, and 0.1% formic acid-methyl alcohol is moving phase, is prepared purifying; The volume ratio of wherein said 0.1% formic acid-methyl alcohol is 3: 7.
3. a measuring method for degradation product of potassium sodium dehydroandroan drographolide succinate, is characterized in that right to use requires degraded product described in 1 as impurity reference substance, adopts HPLC method to measure the content of this degraded product in potassium sodium dehydroandroan drographolide succinate.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1670528A (en) * | 2004-03-18 | 2005-09-21 | 广东奇方药业有限公司 | Application of high-performance liquid phase method in detecting related substances in potassium sodium pehydroandroandrographolide succinate raw material and preparation |
| CN101260097A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
| CN101260098A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinate |
| CN101531649A (en) * | 2008-03-12 | 2009-09-16 | 北京天恒永康医药科技有限责任公司 | Method for preparing andrographolide derivatives and preparation thereof |
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| WO2006101538A2 (en) * | 2004-11-08 | 2006-09-28 | Cornell Research Foundation, Inc. | Andrographolide derivatives to treat viral infections |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1670528A (en) * | 2004-03-18 | 2005-09-21 | 广东奇方药业有限公司 | Application of high-performance liquid phase method in detecting related substances in potassium sodium pehydroandroandrographolide succinate raw material and preparation |
| CN101531649A (en) * | 2008-03-12 | 2009-09-16 | 北京天恒永康医药科技有限责任公司 | Method for preparing andrographolide derivatives and preparation thereof |
| CN101260097A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinic by using potassium dehydroandrographolide succinate |
| CN101260098A (en) * | 2008-04-18 | 2008-09-10 | 长春迈灵生物工程有限公司 | Technique for preparing potassium sodium dehydroandroandrographolide succinate |
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Effective date of registration: 20161223 Address after: 401121 Chongqing City, Yubei District and the town of starlight avenue, No. 100 Patentee after: Yaoyou Pharmaceutical Co., Ltd., Chongqing Patentee after: Chongqing Carelife Pharmaceutical Co., Ltd. Address before: 401121 Chongqing City, Yubei District and the town of starlight avenue, No. 100 Patentee before: Yaoyou Pharmaceutical Co., Ltd., Chongqing |