CN104744412A - Dehydroandrographolide succinate compound - Google Patents
Dehydroandrographolide succinate compound Download PDFInfo
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- CN104744412A CN104744412A CN201510159574.8A CN201510159574A CN104744412A CN 104744412 A CN104744412 A CN 104744412A CN 201510159574 A CN201510159574 A CN 201510159574A CN 104744412 A CN104744412 A CN 104744412A
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- dehydroandroan drographolide
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
The invention relates to a dehydroandrographolide succinate compound, particularly relates to a dehydroandrographolide succinate crystal compound, and also relates to a preparation method of the crystal. Dehydroandrographolide succinate is stable in a crystal form prepared by using the crystallizing process, uniform in grain diameter distribution, high in mobility, and particularly suitable for preparing dehydroandrographolide succinate powder-injection; moreover, the sub-packaging is facilitated.
Description
Technical field
The present invention relates to medical compounds, relate to a kind of potassium sodium dehydroandroan drographolide succinate crystalline compounds particularly.
Background technology
Potassium sodium dehydroandroan drographolide succinate, chemical name is PSDS monohydrate, shown in I.The Typical Representative medicine of this inbred plants Herba Andrographis extract-rographolide (Andrographolide) and derivative thereof, has the functions such as clearing heat and detoxicating, cool blood detumescence.
Potassium sodium dehydroandroan drographolide succinate can suppress early stage capillary vessel permeability to increase and inflammatory exudation oedema, can excited Pituitary Adrenalcortical function specifically, promotes ACTH release, increases the biosynthesizing of ACTH in prepituitary gland; The external effect with multiple viruses such as inactivated adenovirus, influenza virus, Respiroviruses.Due to the structures shape potassium sodium dehydroandroan drographolide succinate less stable of potassium sodium dehydroandroan drographolide succinate molecule itself, especially in aqueous its stability is poorer, therefore, in each stage of the preparation process of its preparation, storage and use, potassium sodium dehydroandroan drographolide succinate is easily oxidized, open loop, hydrolysis, and then affect curative effect of medication, but also the generation of untoward reaction can be caused in Clinical practice process, thus had a strong impact on the security of medication.
At present, the potassium sodium dehydroandroan drographolide succinate formulation used clinically is injection, mainly Yanhuning freeze dried powder for injection injection.Andrographolide bulk pharmaceutical is dissolved in a large amount of water for injection by the preparation method of Yanhuning freeze dried powder for injection injection, add the auxiliary material such as N.F,USP MANNITOL, phosphoric acid salt, through sterile filtration or ultrafiltration, filling after, namely lyophilize, tamponade, Zha Gai obtain 'Yanhuning ' frozen-dried powder injection.But due to potassium sodium dehydroandroan drographolide succinate unstable in aqueous, particularly in a heated condition, be more easily hydrolyzed, be oxidized, open loop.CN101057841A discloses a kind of 'Yanhuning ' frozen-dried powder injection and preparation method thereof, the process employs ion buffering to carrying out stable pH, slowing down oxidation simultaneously, improve stability with L-cysteine hydrochloride as antioxidant.At present, the Andrographolide in Andrographolide for Injection of listing normally adopts and freezes dry technology to prepare, but freeze drying technology needs to adopt expensive freeze-drier, and in preparation process, energy consumption is high, the cycle is long, and then causes cost higher.
People have started to be studied potassium sodium dehydroandroan drographolide succinate crystallization processes in recent years, prior art discloses following several method:
CN102382082A discloses a kind of new Andrographolide compound and pharmaceutical composition, wherein, the preparation method of this invention potassium sodium dehydroandroan drographolide succinate is: potassium dehydroandrographolide succinate carries out salt-forming reaction with sodium bicarbonate and obtains potassium sodium dehydroandroan drographolide succinate solution in Diluted Alcohol, and after obtain the potassium sodium dehydroandroan drographolide succinate crystal with specific X diffraction peak through dehydrated alcohol crystallization.The potassium sodium dehydroandroan drographolide succinate of gained in this invention, has low, the stay-in-grade advantage of its related substances, improves security and the validity of drug use; But the reference examples 9 as CN103193738A patent mentions the sodium potassium of gained potassium sodium dehydroandroan drographolide succinate product in this invention than on the low side, causes product solubility poor, thus affects the security of medication.
CN102643255A discloses a kind of Andrographolide compound.This invention mainly adopts the mixed solvent of ether and ethanol to carry out the potassium sodium dehydroandroan drographolide succinate crystal that crystallization obtains stable in properties under the effect of sound field, and this crystal has specific X-diffraction peak, is used for making ' Tanhuning ' injection and 'Yanhuning ' frozen-dried powder injection by this compound.But on the one hand, in this invention, the preparation of potassium sodium dehydroandroan drographolide succinate needs under the effect of sound field, is unfavorable for the suitability for industrialized production of product; On the other hand, the reference examples 10 as CN103193738A patent mentions the sodium potassium of gained potassium sodium dehydroandroan drographolide succinate product in this invention than on the low side, causes product solubility poor, thus affects the security of medication; In addition, owing to needing to use extremely inflammable and explosive ether solvent in this technique, be a kind of test seriously for safety in production.
CN103193738A discloses potassium sodium dehydroandroan drographolide succinate crystallization and uses thereof, wherein, the preparation method of this invention potassium sodium dehydroandroan drographolide succinate crystal is: potassium dehydroandrographolide succinate carries out salt-forming reaction with sodium bicarbonate and obtains potassium sodium dehydroandroan drographolide succinate solution in Diluted Alcohol, then spray-driedly obtains the potassium sodium dehydroandroan drographolide succinate crystal with specific X diffraction peak.On the one hand, due to the singularity of drying process with atomizing, it is limited in one's ability in raising product purity; On the other hand, because potassium sodium dehydroandroan drographolide succinate product is to temperature sensitive, and in spray-drying process, the temperature of 70 ~ 90 DEG C can cause the reduction of quality product, thus affects the security of medication.
CN103755670A discloses a kind of Andrographolide compound and pharmaceutical composition thereof, wherein, the Andrographolide compound that this invention obtains contains 2 crystal water, and its preparation method is: potassium sodium dehydroandroan drographolide succinate raw material is dissolved in the mixed solvent of second alcohol and water by a., obtains potassium sodium dehydroandroan drographolide succinate solution; B. add the mixing solutions of acetone and ether to stream in above-mentioned potassium sodium dehydroandroan drographolide succinate solution, crystallization of at the uniform velocity lowering the temperature, leave standstill growing the grain, filter, filter cake adopts washing with acetone, and namely drying under reduced pressure obtains Andrographolide compound.This invention gained Andrographolide compound has that purity is high, the advantage of good stability.But, owing to needing to use extremely inflammable and explosive ether solvent in this technique, be a kind of test seriously for safety in production.
In sum, a kind of even particle size distribution, good fluidity are provided, are beneficial to and directly carry out aseptic subpackaged potassium sodium dehydroandroan drographolide succinate crystal formation and preparation method thereof, the development of potassium sodium dehydroandroan drographolide succinate technology of preparing and the treatment of relative disease are had great importance.The present inventor is in the process studied potassium sodium dehydroandroan drographolide succinate crystallization processes, and by a large amount of tests, obtain a kind of new Andrographolide compound crystal, this compound even particle size distribution, good fluidity, is particularly useful for making potassium sodium dehydroandroan drographolide succinate powder ampoule agent for injection.
Summary of the invention
The object of the invention is to propose a kind of new Andrographolide compound crystal formation, this crystal formation even particle size distribution, good fluidity, is beneficial to packing, is specially adapted to potassium sodium dehydroandroan drographolide succinate powder ampoule agent for injection.
A kind of Andrographolide compound crystal formation provided by the invention, use Cu-K α diffraction, its X-ray powder diffraction pattern in diffraction angle 2 θ=5.4 ± 0.2 °, there is characteristic diffraction peak at 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 °, 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places.
The X-ray powder diffraction of described Andrographolide compound also comprises diffraction angle 2 θ=16.4 ± 0.2 °, there is characteristic diffraction peak at 18.3 ± 0.2 °, 27.6 ± 0.2 ° places.
The X diffraction powder diffractogram of described Andrographolide compound is shown in Fig. 1.
The infared spectrum of described Andrographolide compound is shown in Fig. 2.
The size distribution of described Andrographolide compound is D10≤30 μm, D50=90 μm ~ 150 μm, D90≤300 μm.
The slope of repose of described Andrographolide compound crystal is 25 ~ 30 °.
Present invention also offers a kind of method preparing above-mentioned Andrographolide compound crystal formation, this simple process, good stability, with low cost, be beneficial to Product industrialization and produce.
Andrographolide compound preparation method of the present invention comprises the steps:
1) by potassium sodium dehydroandroan drographolide succinate, ethanol, water with after certain proportion mixing under 35 ~ 45 DEG C of temperature condition stirring and dissolving, add Medicinal Charcoal and stir 15 ~ 30min, filter carbon removal, obtain potassium sodium dehydroandroan drographolide succinate solution;
2) potassium sodium dehydroandroan drographolide succinate solution is directly added dropwise in methyl tertiary butyl ether with the speed of 5 ~ 20ml/min, stirring and crystallizing, obtains crystal solution;
3) crystal solution is filtered, adopt a small amount of methyl tertiary butyl ether to wash, namely obtain Andrographolide compound crystal in 40 ~ 45 DEG C of drying under reduced pressure.
In described step 1), the mass volume ratio of potassium sodium dehydroandroan drographolide succinate and water, ethanol is 1:0.5 ~ 2:1 ~ 5g/ml/ml, and wherein ethanol is 95% ethanol or dehydrated alcohol.
Described step 2) in the mass volume ratio of potassium sodium dehydroandroan drographolide succinate and methyl tertiary butyl ether be 1:10 ~ 15 g/ml.
The preparation method of Andrographolide compound of the present invention can obtain aseptic Andrographolide compound crystal under rigorous aseptic working condition.
Present invention also offers one and prepare powder ampoule agent for injection by above-mentioned Andrographolide compound crystal formation.
Compared with the existing technology, advantage of the present invention is as follows:
1, the potassium sodium dehydroandroan drographolide succinate crystal that obtains of the present invention, has the X-ray powder diffractogram spectrum signature being obviously different from existing potassium sodium dehydroandroan drographolide succinate crystal formation, belongs to a kind of brand-new crystal formation.
2, the potassium sodium dehydroandroan drographolide succinate even particle size distribution that obtains of the present invention, slope of repose≤30 °, good fluidity, are beneficial to packing, and content uniformity is little, are specially adapted to aseptic subpackagedly prepare potassium sodium dehydroandroan drographolide succinate powder injection.
3, the potassium sodium dehydroandroan drographolide succinate crystal purity that obtains of the present invention is high, and sodium potassium ratio is 1.00 ± 0.05, good stability, and 6 months accelerated test results show that its crystal formation is substantially constant.
4, the potassium sodium dehydroandroan drographolide succinate crystal that obtains of the present invention, directly aseptic subpackagedly can obtain Andrographolide in Andrographolide for Injection powder injection, thus farthest avoid the reduction of potassium sodium dehydroandroan drographolide succinate product purity in formulation process, thus meet the demand of clinical application, improve security and the validity of drug use; This preparation technology is easy simultaneously, process costs is cheap, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1: the X-powder diagram of Andrographolide compound crystal formation prepared by the embodiment of the present invention 1;
Fig. 2: the infrared spectrogram of Andrographolide compound crystal formation prepared by the embodiment of the present invention 1.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Should be understood that following examples only for illustration of the present invention but not for limiting the scope of the invention.
Embodiment 1: the preparation of new potassium sodium dehydroandroan drographolide succinate crystalline compounds
The dehydrated alcohol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 1 part of volume and 2.5 parts of volumes is added successively in material-compound tank, stirring and dissolving under 40 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 15min, filter carbon removal, through the filter of 0.22 μm of filter membrane essence, obtain potassium sodium dehydroandroan drographolide succinate sterile solution;
Directly be added dropwise to the speed of 10ml/min in the methyl tertiary butyl ether of 15 parts of volumes after 0.22 μm of membrane filtration by potassium sodium dehydroandroan drographolide succinate solution in aseptic district, stirring and crystallizing, obtains crystal solution;
Filtering for crystallizing liquid, adopts the methyl tertiary butyl ether washing of 1 part of volume, namely obtains the aseptic new Andrographolide compound crystal of about 0.92 part of weight in 40 DEG C of drying under reduced pressure.
After measured, the Na/K ratio of this potassium sodium dehydroandroan drographolide succinate crystal is 1.03, and the size distribution of this Andrographolide compound is D10=22 μm, D50=120 μm, D90=200 μm, and the slope of repose of crystal powder is 28 °, and it is 99.9% that sample detects sample purity through HPLC.Axonometry X-ray powder diffraction prepared by embodiment 1, detecting instrument model is PANalytical X-PRO, with Cu – K α for source of radiation.Concrete outcome in table 1, Fig. 1.
The PXRD characteristic peak of the potassium sodium dehydroandroan drographolide succinate crystal form A that table 1 embodiment 1 is obtained
Those skilled in the art are to be understood that, each crystal formation data listed by the present invention, owing to being subject to the impact of many factors, X-ray powder diffraction measured by same crystal formation go out that peak position or intensity can there is some difference, therefore, the experimental error value of the diffraction peak 2 θ value in its X-ray powder diffraction of crystal formation of the present invention can be ± and 0.2 °.
Embodiment 2: the preparation of new Andrographolide compound
95% ethanol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 0.5 part of volume and 2.5 parts of volumes is added successively in material-compound tank, stirring and dissolving under 35 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 30min, filters carbon removal, obtains potassium sodium dehydroandroan drographolide succinate solution;
Directly be added dropwise to the speed of 10ml/min in the methyl tertiary butyl ether of 10 parts of volumes by potassium sodium dehydroandroan drographolide succinate solution, stirring and crystallizing, obtains crystal solution;
Crystal solution is filtered, and adopts the methyl tertiary butyl ether washing of 0.5 part of volume, namely obtains the new Andrographolide compound crystal of about 0.86 part of weight in 40 DEG C of drying under reduced pressure.The X-ray powder diffraction obtained by the measurement of Cu-K alpha-ray is that 5.4 ± 0.2 °, 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 °, 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places show characteristic peak at 2 θ, and its X-ray powder diffraction is consistent with embodiment 1.The Na/K ratio of this crystal is 0.95, and the size distribution of this Andrographolide compound is D10=18 μm, D50=90 μm, D90=180 μm, and the slope of repose of crystal powder is 30 °, and it is 99.9% that sample detects sample purity through HPLC.
Embodiment 3: the preparation of new Andrographolide compound
The dehydrated alcohol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 0.5 part of volume and 5 parts of volumes is added successively in material-compound tank, stirring and dissolving under 45 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 20min, filters carbon removal, obtains potassium sodium dehydroandroan drographolide succinate solution;
Directly be added dropwise to the speed of 20ml/min in the methyl tertiary butyl ether of 15 parts of volumes by potassium sodium dehydroandroan drographolide succinate solution, stirring and crystallizing, obtains crystal solution;
Crystal solution is filtered, and adopts the methyl tertiary butyl ether washing of 1 part of volume, namely obtains the new Andrographolide compound crystal of about 0.85 part of weight in 45 DEG C of drying under reduced pressure.The X-ray powder diffraction obtained by the measurement of Cu-K alpha-ray is 5.4 ± 0.2 °, 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 at 2 θ
., 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places show characteristic peak, its X-ray powder diffraction is consistent with embodiment 1.The Na/K ratio of this crystal is 0.95, and the size distribution of this Andrographolide compound is D10=20 μm, D50=100 μm, D90=220 μm, and the slope of repose of crystal powder is 29 °, and it is 99.9% that sample detects sample purity through HPLC.
Embodiment 4: the preparation of new Andrographolide compound
The dehydrated alcohol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 2 parts of volumes and 1 part of volume is added successively in material-compound tank, stirring and dissolving under 35 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 30min, filters carbon removal, obtains potassium sodium dehydroandroan drographolide succinate solution;
Directly be added dropwise to the speed of 5ml/min in the methyl tertiary butyl ether of 15 parts of volumes by potassium sodium dehydroandroan drographolide succinate solution, stirring and crystallizing, obtains crystal solution;
Crystal solution is filtered, and adopts the methyl tertiary butyl ether washing of 0.8 part of volume, namely obtains the new Andrographolide compound crystal of about 0.89 part of weight in 45 DEG C of drying under reduced pressure.The X-ray powder diffraction obtained by the measurement of Cu-K alpha-ray is 5.4 ± 0.2 °, 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 at 2 θ
., 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places show characteristic peak, its X-ray powder diffraction is consistent with embodiment 1.The Na/K ratio of this crystal is 1.05, and the size distribution of this Andrographolide compound is D10=30 μm, D50=145 μm, D90=280 μm, and the slope of repose of crystal powder is 25 °, and it is 99.8% that sample detects sample purity through HPLC.
Embodiment 5: the preparation of new Andrographolide compound
The dehydrated alcohol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 1 part of volume and 5 parts of volumes is added successively in material-compound tank, stirring and dissolving under 35 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 30min, filters carbon removal, obtains potassium sodium dehydroandroan drographolide succinate solution;
Directly be added dropwise to the speed of 20ml/min in the methyl tertiary butyl ether of 12.5 parts of volumes by potassium sodium dehydroandroan drographolide succinate solution, stirring and crystallizing, obtains crystal solution;
Crystal solution is filtered, and adopts the methyl tertiary butyl ether washing of 1.5 parts of volumes, namely obtains the new Andrographolide compound crystal of about 0.90 part of weight in 40 DEG C of drying under reduced pressure.The X-ray powder diffraction obtained by the measurement of Cu-K alpha-ray is 5.4 ± 0.2 ° at 2 θ, 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 °, 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places show characteristic peak, its X-ray powder diffraction is consistent with embodiment 1, the Na/K ratio of this crystal is 0.99, the size distribution of this Andrographolide compound is D10=25 μm, D50=130 μm, D90=250 μm, the slope of repose of crystal powder is 26 °, it is 99.9% that sample detects sample purity through HPLC.
Embodiment 6: the preparation of new Andrographolide compound
95% ethanol of the potassium sodium dehydroandroan drographolide succinate raw material of 1 part of weight, the water for injection of 1 part of volume and 3 parts of volumes is added successively in material-compound tank, stirring and dissolving under 40 DEG C of temperature condition, the Medicinal Charcoal adding 0.1 part of weight in molten clear feed liquid stirs 20min, filters carbon removal, obtains potassium sodium dehydroandroan drographolide succinate solution;
Directly be added dropwise to the speed of 10ml/min in the methyl tertiary butyl ether of 15 parts of volumes by potassium sodium dehydroandroan drographolide succinate solution, stirring and crystallizing, obtains crystal solution;
Crystal solution is filtered, and adopts the methyl tertiary butyl ether washing of 1 part of volume, namely obtains the new Andrographolide compound crystal of about 0.94 part of weight in 40 DEG C of drying under reduced pressure.The X-ray powder diffraction obtained by the measurement of Cu-K alpha-ray is 5.4 ± 0.2 ° at 2 θ, 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 °, 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places show characteristic peak, its X-ray powder diffraction is consistent with embodiment 1, the Na/K ratio of this crystal is 0.93, the size distribution of this Andrographolide compound is D10=28 μm, D50=150 μm, D90=300 μm, the slope of repose of crystal powder is 25 °, it is 99.8% that sample detects sample purity through HPLC.
Embodiment 7: the medicinal preparations preparing potassium sodium dehydroandroan drographolide succinate: Andrographolide in Andrographolide for Injection powder injection
Specification: 200mg
Prescription:
Potassium sodium dehydroandroan drographolide succinate 200g
Make 1000 bottles altogether
Preparation technology:
Andrographolide sterile powder end embodiment 1 obtained aseptically is divided and is filled in aseptic cillin bottle, every bottled amount 200mg.
Embodiment 8: the medicinal preparations preparing potassium sodium dehydroandroan drographolide succinate: Andrographolide in Andrographolide for Injection powder injection
Specification: 80mg
Prescription:
Potassium sodium dehydroandroan drographolide succinate 80g
Make 1000 bottles altogether
Preparation technology:
Andrographolide sterile powder end embodiment 1 obtained aseptically is divided and is filled in aseptic cillin bottle, every bottled amount 80mg.
Embodiment 9: the medicinal preparations preparing potassium sodium dehydroandroan drographolide succinate: Andrographolide in Andrographolide for Injection powder injection
Specification: 40mg
Prescription:
Potassium sodium dehydroandroan drographolide succinate 40g
Make 1000 bottles altogether
Preparation technology:
Andrographolide sterile powder end embodiment 1 obtained aseptically is divided and is filled in aseptic cillin bottle, every bottled amount 40mg.
Test example 1
This test is the stability test of the potassium sodium dehydroandroan drographolide succinate medicine that the present invention obtains.
1, accelerated test: the powder injection that embodiment 7 is obtained, simulation listing packaging, within 6 months, investigate through accelerated test (in temperature 40 DEG C, relative humidity 75%), respectively at the 1st, 2,3, sampling in June, investigate according to project in quality standard and method, and compare with 0 day result, test-results is in table 2:
Table 2 Andrographolide in Andrographolide for Injection powder pin accelerated test result
Result shows: the acidity of the potassium sodium dehydroandroan drographolide succinate powder injection product under 6 months accelerated test conditions adopting new Andrographolide compound crystal provided by the invention to obtain, clarity, moisture, related substance, content and sodium potassium ratio have no significant change; In addition, the potassium sodium dehydroandroan drographolide succinate crystal that the embodiment of the present invention 1 is obtained 1,3, June all do not find crystal conversion in accelerated stability test result.Show the good stability of the potassium sodium dehydroandroan drographolide succinate powder injection of potassium sodium dehydroandroan drographolide succinate crystal preparation of the present invention.
Identical test is carried out to the potassium sodium dehydroandroan drographolide succinate powder injection of other embodiments of the present invention, there is similar result.
2, test of long duration: the powder injection that embodiment 7 is obtained, simulation listing packaging, within 24 months, investigate through test of long duration (room temperature keeps sample), respectively at sampling in the 3rd, 6,9,12,18,24 month, investigate according to project in quality standard and method, and compare with 0 day result, test-results is in table 3:
Table 3 Andrographolide in Andrographolide for Injection powder pin long-term test results
Result shows: adopt new Andrographolide compound crystal provided by the invention obtained potassium sodium dehydroandroan drographolide succinate powder injection product related substance and content under 24 months test of long duration conditions slightly to change, all the other indices have no significant change; In addition, the potassium sodium dehydroandroan drographolide succinate crystal that the embodiment of the present invention 1 is obtained does not all find crystal conversion in long-term stable experiment result.Show the good stability of the potassium sodium dehydroandroan drographolide succinate powder injection of potassium sodium dehydroandroan drographolide succinate crystal preparation of the present invention.
Identical test is carried out to the potassium sodium dehydroandroan drographolide succinate powder injection of other embodiments of the present invention, there is similar result.
Claims (8)
1. one kind such as formula the Andrographolide compound shown in I
It is characterized in that, described Andrographolide compound is crystal, the X-ray powder diffraction pattern using the measurement of Cu-K alpha-ray to obtain in diffraction angle 2 θ=5.4 ± 0.2 °, there is characteristic diffraction peak at 8.0 ± 0.2 °, 10.7 ± 0.2 °, 13.0 ± 0.2 °, 15.3 ± 0.2 °, 15.8 ± 0.2 °, 17.0 ± 0.2 °, 20.1 ± 0.2 °, 20.7 ± 0.2 ° and 23.4 ± 0.2 ° of places.
2. Andrographolide compound as claimed in claim 1, its X-ray powder diffraction is also included in diffraction angle 2 θ=16.4 ± 0.2 °, there is characteristic diffraction peak at 18.3 ± 0.2 °, 27.6 ± 0.2 ° places.
3. Andrographolide compound as claimed in claim 1, it is characterized in that, its X-diffraction powder diffractogram as shown in Figure 1.
4. Andrographolide compound as claimed in claim 1, it is characterized in that, the size distribution of described Andrographolide compound is D10≤30 μm, D50=90 μm ~ 150 μm, D90≤300 μm.
5. Andrographolide compound as claimed in claim 1, it is characterized in that, the slope of repose of described Andrographolide compound crystal is 25 ~ 30 °.
6. the preparation method of Andrographolide compound as claimed in claim 1, is characterized in that, comprise the following steps: 1) by after potassium sodium dehydroandroan drographolide succinate, the mixing of second alcohol and water under 35 ~ 45 DEG C of conditions stirring and dissolving, add Medicinal Charcoal, insulated and stirred 15 ~ 30min, filters carbon removal, obtained potassium sodium dehydroandroan drographolide succinate solution; Wherein the mass volume ratio of potassium sodium dehydroandroan drographolide succinate, water and ethanol is 1g:0.5 ~ 2 ml:1 ~ 5ml;
2) be added dropwise in methyl tertiary butyl ether by the potassium sodium dehydroandroan drographolide succinate solution of step 1) gained with the speed of 5 ~ 20ml/min, stirring and crystallizing, obtains crystal solution, and wherein the mass volume ratio of potassium sodium dehydroandroan drographolide succinate and methyl tertiary butyl ether is 1g:10 ~ 15ml;
3) filtration step 2) crystal solution of gained, with methyl tertiary butyl ether washing, namely obtain Andrographolide compound crystal in 40 ~ 45 DEG C of drying under reduced pressure.
7. method, wherein step 1) ~ 3 as claimed in claim 6) adopt aseptic technique, the potassium sodium dehydroandroan drographolide succinate crystal obtained is aseptic powder.
8. an Andrographolide in Andrographolide for Injection, aseptic subpackaged obtained by potassium sodium dehydroandroan drographolide succinate crystal according to claim 1.
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Citations (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927854A (en) * | 2005-09-06 | 2007-03-14 | 黄金秀 | Preparation method of potassium sodium dehydroandroan drographolide succinate, potassium sodium dehydroandroan drographolide succinate preparation and preparation method thereof |
| CN101016283A (en) * | 2007-03-07 | 2007-08-15 | 福州聚英医药有限公司 | Preparation of tanhuning |
| CN101057841A (en) * | 2007-05-30 | 2007-10-24 | 黑龙江省珍宝岛制药有限公司 | 'Yanhuning' frozen-dried powder injection and its preparation method |
| 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 |
| CN101270101A (en) * | 2008-05-08 | 2008-09-24 | 海南斯达制药有限公司 | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection |
| US20110077295A1 (en) * | 2007-08-08 | 2011-03-31 | Panorama Research Inc. | Andrographolide derivatives and use thereof in manufacture of medicaments |
| 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 |
| 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 |
| CN102584752A (en) * | 2011-12-27 | 2012-07-18 | 开封制药(集团)有限公司 | Preparation method of andrographolide bulk pharmaceutical |
| CN102603684A (en) * | 2012-01-19 | 2012-07-25 | 黑龙江珍宝岛药业股份有限公司 | Sterile andrographolide and preparation method thereof |
| CN102617527A (en) * | 2012-03-01 | 2012-08-01 | 湖北荷普药业股份有限公司 | Method for preparing potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN102885775A (en) * | 2011-07-19 | 2013-01-23 | 重庆莱美药业股份有限公司 | Andrographolide sterile powder and its preparation method |
| CN103087017A (en) * | 2013-02-28 | 2013-05-08 | 成都倍特药业有限公司 | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product |
| CN103113330A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide salifying process |
| CN103113331A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide synthetic method |
| CN103193738A (en) * | 2013-04-16 | 2013-07-10 | 成都天台山制药有限公司 | Dehydroandrographolide succinate crystal and use thereof |
| 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 |
| CN104119304A (en) * | 2013-04-26 | 2014-10-29 | 重庆莱美药业股份有限公司 | Method for aseptic production of potassium sodium dehydroandroan drographolide succinate in vertical logistics system |
| CN104151275A (en) * | 2014-09-01 | 2014-11-19 | 瑞阳制药有限公司 | Preparation method of andrographolide compound |
| CN104161729A (en) * | 2014-05-22 | 2014-11-26 | 杭州长典医药科技有限公司 | Special ultrafine potassium sodium dehydroandroandrographolide succinate powder preparation and preparation method thereof |
-
2015
- 2015-04-07 CN CN201510159574.8A patent/CN104744412A/en active Pending
Patent Citations (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927854A (en) * | 2005-09-06 | 2007-03-14 | 黄金秀 | Preparation method of potassium sodium dehydroandroan drographolide succinate, potassium sodium dehydroandroan drographolide succinate preparation and preparation method thereof |
| CN101016283A (en) * | 2007-03-07 | 2007-08-15 | 福州聚英医药有限公司 | Preparation of tanhuning |
| CN101057841A (en) * | 2007-05-30 | 2007-10-24 | 黑龙江省珍宝岛制药有限公司 | 'Yanhuning' frozen-dried powder injection and its preparation method |
| US20110077295A1 (en) * | 2007-08-08 | 2011-03-31 | Panorama Research Inc. | Andrographolide derivatives and use thereof in manufacture of medicaments |
| 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 |
| CN101270101A (en) * | 2008-05-08 | 2008-09-24 | 海南斯达制药有限公司 | Method for preparing potassium sodium dehydroandroan drographolide succinate for injection and its freeze-dried injection |
| 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 |
| CN102863408A (en) * | 2011-07-06 | 2013-01-09 | 重庆莱美药业股份有限公司 | Preparation method of andrographolide |
| CN102885775A (en) * | 2011-07-19 | 2013-01-23 | 重庆莱美药业股份有限公司 | Andrographolide sterile powder and its preparation method |
| 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 |
| CN102584752A (en) * | 2011-12-27 | 2012-07-18 | 开封制药(集团)有限公司 | Preparation method of andrographolide bulk pharmaceutical |
| CN102603684A (en) * | 2012-01-19 | 2012-07-25 | 黑龙江珍宝岛药业股份有限公司 | Sterile andrographolide and preparation method thereof |
| CN102617527A (en) * | 2012-03-01 | 2012-08-01 | 湖北荷普药业股份有限公司 | Method for preparing potassium dehydroandrographolide succinate or potassium sodium dehydroandroan drographolide succinate |
| CN102643255A (en) * | 2012-03-27 | 2012-08-22 | 黄金秀 | Andrographolide compound |
| CN103087017A (en) * | 2013-02-28 | 2013-05-08 | 成都倍特药业有限公司 | Refinement method of crude potassium sodium dehydroandroan drographolide succinate product |
| CN103113330A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide salifying process |
| CN103113331A (en) * | 2013-02-28 | 2013-05-22 | 成都倍特药业有限公司 | Andrographolide synthetic method |
| CN103193738A (en) * | 2013-04-16 | 2013-07-10 | 成都天台山制药有限公司 | Dehydroandrographolide succinate crystal and use thereof |
| CN104119304A (en) * | 2013-04-26 | 2014-10-29 | 重庆莱美药业股份有限公司 | Method for aseptic production of potassium sodium dehydroandroan drographolide succinate in vertical logistics system |
| 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 |
| CN104161729A (en) * | 2014-05-22 | 2014-11-26 | 杭州长典医药科技有限公司 | Special ultrafine potassium sodium dehydroandroandrographolide succinate powder preparation and preparation method thereof |
| CN104151275A (en) * | 2014-09-01 | 2014-11-19 | 瑞阳制药有限公司 | Preparation method of andrographolide compound |
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Application publication date: 20150701 |