CN101279977A - Refining method of benemicin raw material and benemicin solution prepared from the benemicin raw material - Google Patents
Refining method of benemicin raw material and benemicin solution prepared from the benemicin raw material Download PDFInfo
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- CN101279977A CN101279977A CNA2008100997096A CN200810099709A CN101279977A CN 101279977 A CN101279977 A CN 101279977A CN A2008100997096 A CNA2008100997096 A CN A2008100997096A CN 200810099709 A CN200810099709 A CN 200810099709A CN 101279977 A CN101279977 A CN 101279977A
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Abstract
The invention provides a refining method to prepare the material for rifampicin and rifampicin solution prepared with the material. In the refining process of the material for rifampicin, the ratio of water and other solvent is properly controlled, and appropriate amount of antioxidant and ph regulator, etc., are added; the material is heated into reflux state in the solvent to reduce the impurity to a reasonable amount; then the heat source in the mixture is removed through active carbon; after that, the mixture is filtrated and crystallized, and the crystal is separated out and dried at low temperature. High-purity material for rifampicin can be obtained through single or repeated operations. The rifampicin solution is prepared by adding appropriate solvent, chemical inhibitor, ph regulator into the high-purity material for rifampicin. The rifampicin solution is of the capability of enduring the condition of 115 DEG C/30min(F0 is bigger than 8)for sterilization and can be stored for more than 12 months without change.
Description
Technical field
The present invention relates to medical production field, particularly relate to the process for purification and the Rifampin solution prepared therefrom of a kind of antitubercular agent-Rifampin raw material.
Background technology
The 19-20 beginning of the century, tuberculosis has been brought huge disaster to the mankind.Afterwards, along with the progress of medical science, sickness rate lungy has dropped to lower level.Yet enter 20 th century later, the tuberculosis epidemic situation is staged a comeback, and becomes one of high chronic infectious disease of threat power.After entering 21 century, reviving of regional tuberculosis epidemic situation beaten alarm bell to people again.According to the data introduction: about 1,000 ten thousand people of global annual new discovery tuberculosis patient, China are one of countries of 22 high burdens of tuberculosis in the world, because populous, its infected occupies the 2nd in the world.
At present, tuberculosis medicine commonly used is made up of Hang Shengsu, synthetic drug and Chinese medicine three major types, it is national base therapy medication that more than 20 kind of Western medicine wherein arranged, if first-line treatment drug main vazadrine, Rifampin, Streptomycin sulphate, Tibutol, pyrazinoic acid amide, rifomycins etc.
Rifampin also claims rifampicin, is the derivative of semi-synthetic rifomycin, for the semi-synthetic broad spectrum antibiotic of rifomycins, multiple pathogenic micro-organism is had anti-microbial activity.Tubercule bacillus there is high susceptibility, mycobacterium tuberculosis and part non-tuberculous mycobacteria (comprising Mycobacterium leprae etc.) are all had the obvious sterilization effect inside and outside host cell; To the good anti-microbial effect of aerobic gram positive organism tool, comprise staphylococcus product enzyme strain and methicillin resistance strain, streptococcus pneumoniae, other streptococcuses, enterococcus spp, listeria, anthrax bacillus, Clostridium perfringens, diphtheria corynebacterium, anaerobic cocci etc.; Aerobic gram-negative bacteria such as Neisseria meningitidis, hemophilus influenzae, neisseria gonorrhoeae are also had a height anti-microbial activity.Rifampin is also good to the legionella effect, to equal tool restraining effect of pathogenic agent such as chlamydia trachomatis, lymphogranuloma venereum and psittacosis.The β subunit mortise of the RNA polymerase of Rifampin and dependence DNA suppresses the synthetic of bacteria RNA, prevents that this enzyme is connected with DNA, thereby blocking-up rna transcription process stops DNA and proteic synthesizing.
Rifampin is one of kind of present clinical consumption maximum as a control line medication lungy.The Rimactane of listing comprises Rifampin tablet, rifampicin capsules, injection Rifampin powder pin, Rifampin injection etc. at present.
In the production process of various preparations, the purity of raw material is directly connected to the quality of preparation, also obviously influence stability of formulation, especially obvious to rifampicin injection, the purity of Rifampin raw material directly has influence on the stability of preparation in sterilization process and storage process.
Summary of the invention
An object of the present invention is to provide a kind of industrialized preparing process of high purity Rifampin raw material.
Another object of the present invention provides a kind of stable Rifampin solution.
The applicant is through discovering in a large number, though the Rifampin raw material is less stable in water and other solution, but in the treating process of Rifampin raw material, suitably control the ratio of water and other solvent, suitably add suitable oxidation inhibitor, acidity-basicity regulator etc., reflux in solvent makes the total impurities reduction and is tending towards distribution rationally, remove thermal source with gac, filter, separate out crystallization, cryodrying.The single or multiple operation can obtain needed highly purified raw material.
As required, adopt suitable solvent, add suitable oxidation inhibitor, acidity-basicity regulator, dissolve highly purified Rifampin raw material, can make stable Rifampin solution.
The process for purification of Rifampin raw material provided by the invention comprises:
(a) get Rifampin raw material crude product and add in the organic solvent, add antioxidant again, and add water for injection, mix;
(b) heating is the Rifampin dissolving, adds gac, and reflux is filtered, and collects filtrate, crystallization, and drying gets purified Rifampin raw material.
Wherein, in the above-mentioned steps (a), the water for injection usage quantity is the 1-50% of organic solvent usage quantity.
In addition, in the above-mentioned steps (a), after adding antioxidant and water for injection mix, can also add acidity-basicity regulator; The acidity-basicity regulator that uses comprises one or more kinds in glacial acetic acid, meglumine, Trometamol, the diethanolamine; The usage quantity of acidity-basicity regulator is the 0-2% weight of Rifampin raw material usage quantity.
The organic solvent of above-mentioned use comprises a kind of or wherein any multiple mixture in C1～C5 alcohols, C3～C8 organic acid ester, C1～C4 organic acid, C2～C8 ethers, the C3～C8 ketone, wherein, and preferred alcohol, acetone or the mixture of the two.
In the above-mentioned steps (a), the antioxidant that uses is vitamins C, and the usage quantity of antioxidant is the 0.2-2% of Rifampin raw material operating weight.
The present invention also provides a kind of Rifampin solution, and it comprises Rifampin raw material, organic solvent, antioxidant and acidity-basicity regulator by method for preparing.Wherein, the organic solvent of use comprises one or both in propylene glycol, the poly(oxyethylene glycol) 400; The antioxidant that uses comprises one or both in vitamins C, the Sulfothiorine; The acidity-basicity regulator that uses comprises one or more kinds in sodium hydroxide, meglumine, the Trometamol.
The content of Rifampin is 10mg/ml-125mg/ml in the Rifampin solution made from aforesaid method.
According to the process for purification of Rifampin raw material provided by the invention, can obtain highly purified Rifampin raw material, the content of its total impurities can reach below 1%, and this highly purified Rifampin raw material provides favourable guarantee for the various stabilization formulations of producing Rifampin.
According to Rifampin solution provided by the invention, be characterized in that this solution can tolerate 115 ℃/30 minutes (F
0＞8) sterilising conditions, and, in 30 ℃ of thermostat containers, place after 3 months, still can meet the requirement of related substance in the national drug standards rifampicin injection quality standard (YBH08592005), that is to say can stably stored more than 12 months.
Embodiment
For more clearly the present invention will be described, below the specific embodiment of the present invention is illustrated in more detail by specific embodiment.But should be appreciated that the following stated specific embodiment only is used for the present invention is carried out exemplary illustration, but not be used for the present invention is carried out the qualification of any character, wherein material therefor, reagent etc. only are representational, and it is not limited to cited situation.The person of ordinary skill in the field can make change and the improvement that does not break away from the protection domain that claim of the present invention limits to the present invention by reading following explanation, and these changes and improving also are in the present invention's scope required for protection.
Embodiment one
Get 50 kilograms of Rifampin raw material crude products, add in 1000 liters of retort, stir 0.5 kilogram of vitamins C of adding down with 500 liters of ethanol, add 100 liters of waters for injection, stir, reflux to Rifampin dissolves fully, add 1 kilogram of gac, refluxed 45 minutes, filtered while hot is collected filtrate, filtrate is stirred cool overnight down, centrifugal collection crystallization, 40 ℃ of drying under reduced pressure 8 hours, the good fortune of getting profit Plain material; Total impurities is 0.79% (check of Rifampin raw material total impurities among the present invention, according to " method of inspection of related substance item check under two Rifampin items of Chinese pharmacopoeia version in 2005).
Embodiment two
Get 50 kilograms of Rifampin raw material crude products, add in 1000 liters of retort, stir 0.5 kilogram of vitamins C of adding down with 500 liters of acetone, add 1 kilogram of glacial acetic acid, stir, add 50 liters of waters for injection, reflux to Rifampin dissolves fully, adds 1 kilogram of gac, refluxes 45 minutes, filtered while hot, collect filtrate, filtrate is stirred cool overnight down, centrifugal collection crystallization, 40 ℃ of drying under reduced pressure 8 hours, the good fortune of getting profit Plain material; Total impurities is 0.80%.
Embodiment three
Get 50 kilograms of rifampicin oral raw materials, add in 1000 liters of retort, stir 0.5 kilogram of vitamins C of adding down with 250 liters of ethanol, 250 liters of acetone, add 1 kilogram of diethanolamine, stir, reflux to Rifampin dissolves fully, add 1 kilogram of gac, refluxed 45 minutes, filtered while hot is collected filtrate, filtrate is stirred cool overnight down, centrifugal collection crystallization, 40 ℃ of drying under reduced pressure 8 hours, the good fortune of getting profit Plain material; Total impurities is 0.82%.
Embodiment four
Get 50 kilograms of rifampicin oral raw materials, add in 1000 liters of retort, stir 0.5 kilogram of vitamins C of adding down with 500 liters of ethanol, add 0.5 kilogram of 0.5 kilogram of meglumine, Trometamol, add 50 liters of waters for injection, stir, reflux to Rifampin dissolves fully, add 1 kilogram of gac, refluxed 45 minutes, filtered while hot is collected filtrate, filtrate is stirred cool overnight down, centrifugal collection crystallization.40 ℃ of drying under reduced pressure 8 hours, the good fortune of getting profit Plain material; Total impurities is 0.82%
Embodiment five
Get the total impurities that makes according to the foregoing description less than 20.4 kilograms of 1% Rifampin raw materials, add in the Agitation Tank of 300 liters of propylene glycol that are dissolved with 0.9 kilogram of sodium hydroxide, add the propylene glycol solution that is dissolved with 0.6 kilogram of ascorbic propylene glycol solution, is dissolved with 0.6 kilogram of Sulfothiorine respectively, stirring is dissolved Rifampin fully; Use the membrane filtration of 0.8 μ m and 0.22 μ m respectively, be sub-packed in the colourless or brown ampoule of 2ml or 5ml, inflated with nitrogen seals; With 115 ℃ of saturation steam sterilizations 30 minutes; Cooling, packing.The finished product total impurities is 1.4%, and single impurity of planting is no more than 0.5%.(the test basis national drug standards rifampicin injection quality standard (YBH08592005) of a Rifampin solution total impurities method of inspection check of related substance item down among the present invention).
Embodiment six
Get the total impurities that makes according to the foregoing description less than 2.04 kilograms of 1% Rifampin raw materials, add in the Agitation Tank of 30 liters of poly(oxyethylene glycol) 400 that are dissolved with 0.36 kilogram of Trometamol, add the poly(oxyethylene glycol) 400 solution that is dissolved with 0.06 kilogram of ascorbic poly(oxyethylene glycol) 400 solution, is dissolved with 0.06 kilogram of Sulfothiorine respectively, stirring is dissolved Rifampin fully; Use the membrane filtration of 0.8 μ m and 0.22 μ m respectively, be sub-packed in the colourless or brown ampoule of 2ml or 5ml, inflated with nitrogen seals; With 115 ℃ of saturation steam sterilizations 30 minutes; Cooling, packing.The finished product total impurities is 0.91%, and single impurity of planting is no more than 0.5%.
Embodiment seven
Get the total impurities that makes according to the foregoing description less than 2.04 kilograms of 1% Rifampin raw materials, add in the Agitation Tank of 24 liters of propylene glycol that are dissolved with 0.3 kilogram of Trometamol and 0.15 kilogram of meglumine, add 6 liters and add the poly(oxyethylene glycol) 400 solution that is dissolved with 0.06 kilogram of ascorbic poly(oxyethylene glycol) 400 solution, is dissolved with 0.06 kilogram of Sulfothiorine respectively, stirring is dissolved Rifampin fully; Use the membrane filtration of 0.8 μ m and 0.22 μ m respectively, in the colourless or brown ampoule of packing 2ml or 5ml, inflated with nitrogen seals; With 115 ℃ of saturation steam sterilizations 30 minutes; Cooling, packing.The finished product total impurities is 0.97%, and single impurity of planting is no more than 0.5%.
Embodiment eight
Get the total impurities that makes according to the foregoing description less than 2.04 kilograms of 1% Rifampin raw materials, add in the Agitation Tank of 30 liters of propylene glycol that are dissolved with 0.3 kilogram of diethanolamine, add the propylene glycol solution that is dissolved with 0.12 kilogram of ascorbic propylene glycol solution, is dissolved with 0.06 kilogram of Sulfothiorine respectively, stirring is dissolved Rifampin fully; Use the membrane filtration of 0.8 μ m and 0.22 μ m respectively, be sub-packed in the 5ml ampoule, inflated with nitrogen seals; With 115 ℃ of saturation steam sterilizations 30 minutes; Cooling, packing.The finished product total impurities is 0.86%, and single impurity of planting is no more than 0.5%.
Embodiment nine
Get the total impurities that makes according to the foregoing description less than 2.04 kilograms of 1% Rifampin raw materials, add in the Agitation Tank of 30 liters of propylene glycol that are dissolved with 0.32 kilogram of meglumine, add the propylene glycol solution that is dissolved with 0.06 kilogram of ascorbic propylene glycol solution, is dissolved with 0.12 kilogram of Sulfothiorine respectively, stirring is dissolved Rifampin fully; Use the membrane filtration of 0.8 μ m and 0.22 μ m respectively, be sub-packed in the colourless or brown ampoule of 2ml or 5ml, inflated with nitrogen seals; With 115 ℃ of saturation steam sterilizations 30 minutes; Cooling, packing.The finished product total impurities is 0.92%, and single impurity of planting is no more than 0.5%.
Embodiment ten
Stability experiment:
Get prepared 5ml Rifampin solution example of embodiment five, embodiment six, embodiment seven and reference substance (by the commercially available prod that Shuangding Pharmaceutical Co., Ltd., Shenyang produces according to prior art, lot number: 071010, specification: 5ml:300mg.), in 30 ℃ of thermostat containers, placed 3 months, in the amount of 1,2,3 check sample total impuritieses at the end of month (related substances), compare during with 0 month.
Can find out from experimental result: the sample of three test lot numbers is in experiment periods, and total impurities has the trend of increase, in the experiment end of term, can meet the requirement of related substance in the national drug standards rifampicin injection quality standard (YBH08592005); Explanation is under corresponding condition of storage, and the sample of three test lot numbers all should be able to reach the shelf lives more than 1 year.
It can also be seen that from experimental result: gained Rifampin solution of the present invention is compared with reference substance, and rear impurity content was starkly lower than reference substance solution in three months, and gained Rifampin stability of solution promptly of the present invention is apparently higher than reference substance solution.
Claims (9)
1. the process for purification of a Rifampin raw material is characterized in that comprising the following steps:
(a) get Rifampin raw material crude product and add in the organic solvent, add antioxidant again, and add water for injection, mix;
(b) add gac, reflux is filtered, and collects filtrate, crystallization, and drying gets purified Rifampin raw material;
Wherein, in the above-mentioned steps (a), the water for injection usage quantity is the 1-50% of organic solvent usage quantity.
2. the process for purification of Rifampin raw material according to claim 1 is characterized in that step (a) also comprises, after mixing, adds acidity-basicity regulator, is heated to Rifampin and dissolves fully.
3. the process for purification of Rifampin raw material according to claim 1 and 2 is characterized in that organic solvent is ethanol, acetone or the mixture of the two.
4. the process for purification of Rifampin raw material according to claim 1 and 2 is characterized in that the antioxidant that uses is vitamins C in the step (a), and the usage quantity of antioxidant is the 0.2-2% of Rifampin raw material weight.
5. the process for purification of Rifampin raw material according to claim 2, it is characterized in that, the acidity-basicity regulator that uses comprises one or more kinds in glacial acetic acid, meglumine, Trometamol, diethanolamine, the Monoethanolamine MEA BASF, and the usage quantity of acidity-basicity regulator is the 0-2% of Rifampin raw material weight.
6. a Rifampin solution is characterized in that comprising Rifampin raw material, organic solvent, antioxidant and acidity-basicity regulator by the described method preparation of claim 1.
7. Rifampin solution according to claim 6 is characterized in that organic solvent comprises one or both in propylene glycol, the poly(oxyethylene glycol) 400.
8. Rifampin solution according to claim 6 is characterized in that antioxidant comprises one or both in vitamins C, the Sulfothiorine.
9. Rifampin solution according to claim 6 is characterized in that, acidity-basicity regulator comprises one or more kinds in sodium hydroxide, meglumine, the Trometamol.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008100997096A CN101279977A (en) | 2008-05-21 | 2008-05-21 | Refining method of benemicin raw material and benemicin solution prepared from the benemicin raw material |
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| CNA2008100997096A CN101279977A (en) | 2008-05-21 | 2008-05-21 | Refining method of benemicin raw material and benemicin solution prepared from the benemicin raw material |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079749A (en) * | 2010-11-25 | 2011-06-01 | 河北欣港药业有限公司 | Method for producing rifampicin raw material medicines with densities of less than or equal to 0.3g/ml and more than or equal to 0.8g/ml |
| CN103755723A (en) * | 2014-02-07 | 2014-04-30 | 天津大学 | Method for preparing rifampicin I crystal form |
| CN103772413A (en) * | 2014-02-07 | 2014-05-07 | 天津大学 | Preparation method of rifampicin II crystal form |
| CN103819487A (en) * | 2014-02-07 | 2014-05-28 | 天津大学 | Novel rifampin crystal form and preparing method thereof |
| CN106800564A (en) * | 2015-11-26 | 2017-06-06 | 中国科学院沈阳科学仪器股份有限公司 | A kind of process for purification of rifampin bulk drug |
-
2008
- 2008-05-21 CN CNA2008100997096A patent/CN101279977A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102079749A (en) * | 2010-11-25 | 2011-06-01 | 河北欣港药业有限公司 | Method for producing rifampicin raw material medicines with densities of less than or equal to 0.3g/ml and more than or equal to 0.8g/ml |
| CN102079749B (en) * | 2010-11-25 | 2012-07-04 | 河北欣港药业有限公司 | Method for producing rifampicin raw material medicines with densities of less than or equal to 0.3g/ml and more than or equal to 0.8g/ml |
| CN103755723A (en) * | 2014-02-07 | 2014-04-30 | 天津大学 | Method for preparing rifampicin I crystal form |
| CN103772413A (en) * | 2014-02-07 | 2014-05-07 | 天津大学 | Preparation method of rifampicin II crystal form |
| CN103819487A (en) * | 2014-02-07 | 2014-05-28 | 天津大学 | Novel rifampin crystal form and preparing method thereof |
| CN103755723B (en) * | 2014-02-07 | 2016-04-20 | 天津大学 | A kind of preparation method of rifampicin I crystal form |
| CN103819487B (en) * | 2014-02-07 | 2016-08-24 | 天津大学 | A kind of rifampicin crystal and preparation method thereof |
| CN106800564A (en) * | 2015-11-26 | 2017-06-06 | 中国科学院沈阳科学仪器股份有限公司 | A kind of process for purification of rifampin bulk drug |
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Open date: 20081008 |