CN102134236B - Preparation method of fine clarithromycin powder - Google Patents
Preparation method of fine clarithromycin powder Download PDFInfo
- Publication number
- CN102134236B CN102134236B CN 201110089808 CN201110089808A CN102134236B CN 102134236 B CN102134236 B CN 102134236B CN 201110089808 CN201110089808 CN 201110089808 CN 201110089808 A CN201110089808 A CN 201110089808A CN 102134236 B CN102134236 B CN 102134236B
- Authority
- CN
- China
- Prior art keywords
- clarithromycin
- powder
- solution
- recrystallization
- fine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Abstract
The invention relates to a preparation method of fine medicament powder, in particular to a preparation method of fine clarithromycin powder, which is characterized by comprising the following steps: firstly dissolving clarithromycin in an inert organic solvent to form a clarithromycin solution; secondly, adding the clarithromycin solution in an anti-solvent solution for recrystallization to generate clarithromycin crystals; and thirdly, filtering, washing and drying the clarithromycin crystals. The method has the following advantages: in the recrystallization process, crystallization and fining are completed by one step, thus simplifying the technical process, being easy to control the recrystallization operation conditions, and having good reaction repeatability; the clarithromycin powder after fining has high purity and is easy to separate, the average grain diameter of the fine clarithromycin crystals is controllable, the grain fineness distribution is narrow, and the recrystallization time is short and is easy to control, thus being beneficial to industrialized production.
Description
Technical field
The present invention relates to the preparation method of micronized drug powder, the preparation method of especially fine clarithromycin powder.
Background technology
Erythromycin is the first-generation macrolide antibiotics that the nineteen fifty-two gift comes company to release, with the leading macrolide antibiotics of s-generation erythromycin such as clarithromycin, Azythromycin and Roxithromycin etc. in the international market portion just growing steadily in recent years, account for 90% of the whole macrolide antibiotics market share.Clarithromycin (Clarithromycin) is one of at present the most surging erythromycin series medicine, clinically is usually used in treating respiratory tract, skin soft tissue and urogenital infections.Its great advantage is that the infectious diseases Macrocyclolactone lactone kind medicine that penicillin medicine can be treated can be treated equally, and does not almost have irritated effect, fully can be as the substitute of penicillin medicine.Because administration number of times is few, the course of treatment is shorter relatively, belongs to a line medication.On American-European market, become hospital with the clinical commonly used drug that is only second to cynnematin in the anti-infective.
The main formulation of erythromycin series medicine comprises at present: oral tablet, capsule; The injection of injection etc.In use can cause gastrointestinal reaction, anaphylaxis, liver damage, thrombophlebitis, untoward reactions such as unsuitable intramuscular injection.Therefore the inhaling type treatment that directly arrives target organ is present a kind of new route of administration.The medicine that sucks can arrive diseased region rapidly by higher concentration, therefore effect directly, onset is rapid, local drug concentration height, and used drug dose is few far beyond the systemic administration amount is avoided or has been reduced the issuable side effect of whole body administration.It is the novel form that present many countries fall over each other to research and develop.For the agent of gas (powder) mist, granular size is the key factor that can the decision medicine arrive site of action, because drug particles is more little of the easy more segmental bronchus that enters, brings into play the effect of expansion bronchus fast, and its bioavailability is also just high more.Therefore, micronization of clarithromycin is to improve the key point of its bioavailability.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of fine clarithromycin powder, this method technology is easy, cost is lower, can also control clarithromycin crystal grain size and its size-grade distribution.
For achieving the above object, the technical solution used in the present invention is.
A kind of preparation method of fine clarithromycin powder, its special feature is, comprise the steps, earlier clarithromycin is dissolved in inert organic solvents, form clarithromycin solution, then this clarithromycin solution is added in the anti-solvent solution and carry out recrystallization, generate the clarithromycin crystallization, will get final product after the filtration of clarithromycin crystal process, washing, the drying again.
Wherein inert organic solvents is at least a in acetone, trichloromethane and the ethanol.
Wherein anti-solvent solution is a water.
Wherein recrystallization process carries out in the reactor that band stirs, and stirring velocity is 100-2000r/min, and the recrystallization process temperature is 0-60 ℃, and the time is 2-60min, and the volumetric ratio of clarithromycin solution and anti-solvent solution is 1: 1 to 1: 40 in the recrystallization process.
Method of the present invention has following advantage, in the recrystallization process, crystallization and one step of miniaturization finish, and have simplified technological process, the recrystallization operational condition is easy to control, the favorable reproducibility of reaction, clarithromycin powder purity height and separate easily after the miniaturization, fine clarithromycin crystalline median size is controlled, narrow particle size distribution, the recrystallization time is short, and separate easily helps suitability for industrialized production.
Description of drawings
Accompanying drawing 1 is the stereoscan photograph of raw material clarithromycin medicament powder.
Accompanying drawing 2 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 1 method.
Accompanying drawing 3 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 2 methods.
Accompanying drawing 4 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 3 methods.
Accompanying drawing 5 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 4 methods.
Accompanying drawing 6 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 5 methods.
Accompanying drawing 7 is the stereoscan photograph of the clarithromycin powder that obtains according to embodiment 6 methods.
Embodiment
The invention provides a kind of method for preparing clarithromycin, comprise the steps:
(1) clarithromycin is dissolved in inert organic solvents, forms clarithromycin solution;
(2) described clarithromycin solution is added anti-solvent and carry out recrystallization, generate the clarithromycin crystallization;
(3) with the clarithromycin crystal that obtains in the step (2), through obtaining finished product after filtration, washing, the drying.
Wherein said inert organic solvents refers to clarithromycin is had the organic solvent of certain dissolving power, and anti-solvent refers to that clarithromycin is not had solubility property or the minimum solvent of solubility property.Inert organic solvents and anti-solvent in whole recrystallization process chemical reaction does not take place or the possibility that reacts minimum.
Clarithromycin bulk drug used among the present invention can be buied from the market, and as shown in Figure 1, its granularity records by stereoscan photograph, and minor axis is 20 microns or bigger bar-shaped or platy shaped particle, and size-grade distribution is also inhomogeneous.Its purity is preferably greater than 70%, more preferably greater than 80%, most preferably greater than 98%.
In the first step of the present invention, clarithromycin is dissolved in inert organic solvents, dissolving is meant that clarithromycin forms basic clear soln in solvent.In solution of the present invention, clarithromycin can any suitable concentration exist, as long as it can satisfy the dissolved requirement.Be preferably formed nearly saturated solution.This moment, temperature did not need special requirement, but should carry out being lower than under the boiling point of solvent, as was less than or equal to 70 ℃, preferably less than 60 ℃, more preferably at 50-60 ℃.The first step of the inventive method can be carried out under water bath with thermostatic control.
The clarithromycin solution that forms in the first step of the present invention can be any material solution that comprises clarithromycin, comprise the final stock liquid that contains clarithromycin that obtains of reaction, perhaps any clarithromycin that will obtain is dissolved in the suitable solvent and the clarithromycin solution that obtains.If the mother liquor of synthetic clarithromycin, condition is that clarithromycin has suitable concentration, and impurity wherein is not to the not influence of follow-up crystallisation process (for example can change Property of Acid and Alkali of Solution, do not react with anti-solvent, to clarithromycin dissolving or reaction etc.).
Inert organic solvents includes but not limited to, the arbitrary proportion mixture of acetone, trichloromethane, trichloromethane and acetone, can also arbitrary proportion in this inert organic solvents be mixed into ethanol, also can be only with ethanol as inert organic solvents.Specifically, described inert organic solvents is, but is not limited to the mixture of the mixture of acetone, trichloromethane, ethanol, acetone and trichloromethane, acetone and alcoholic acid mixture, ethanol and trichloromethane, acetone/trichloromethane/alcoholic acid mixture.Preferably, inert solvent is acetone, trichloromethane, ethanol, wherein more preferably acetone.
Contain in the alcoholic acid mixture above-mentioned, ethanol accounts for amount (volume ratio) suggestion of mixture less than 50%, preferably less than 30%.
In the present invention, the anti-solvent in second step refers to that clarithromycin is not had solvability or the minimum solvent of solubility property.Include, but are not limited to water.
The method according to this invention comprises the recrystallization condition of rotating speed, temperature, volume ratio, the clarithromycin powder that obtains having required narrow size distribution by adjusting.The recrystallization temperature of clarithromycin solution and anti-solvent is 0-60 ℃, and preferred 5-50 ℃, more preferably 10-20 ℃, the reaction times is 2-60min; Preferred 5-30min, more preferably 5-10min.The second step recrystallization process may carry out in the reactor that band stirs.Stirring velocity is not particularly limited, as long as it can reach and make clarithromycin solution and anti-solvent uniform mixing.For specific reactor, high more helping more of stirring velocity reacts.Usually, stirring velocity is 100-2000r/min, preferred 500-1500r/min, more preferably 700-900r/min.The volumetric ratio of described clarithromycin solution and anti-solvent is 1: 1-1: 40, preferred 1: 8-1: 20.
By the clarithromycin powder that above-mentioned crystallization obtains, can be further according to for example post-processing steps such as washing, drying that comprise known to a person of ordinary skill in the art.For example, in embodiments of the invention, can utilize vacuum pump to carry out suction filtration and separate, after washing with water simultaneously and carrying out vacuum-drying, can obtain fine clarithromycin powder.
To the scope of about 10 μ m, preferably about 500nm is to about 5 μ m at about 500nm for the clarithromycin powder that the present invention also provides the method according to this invention to obtain, its median size.The method according to this invention can obtain the clarithromycin powder of specified particle size, being suitable for different needs, the granularity of the clarithromycin powder that for example obtains can for about 500nm to the scope of about 1 μ m, preferred 500nm, 800nm.In also can scope for 1 μ m to 10 μ m, preferred 1 μ m, 3 μ m, 5 μ m.
And, clarithromycin according to the present invention is different from the clarithromycin material powder of prior art, the particle size distribution that the present invention obtains is narrow, preferably at least about 50%, more preferably at least about 70%, most preferably at least about 90% particle in the particle size range of the same order of magnitude.
Embodiment 1
The clarithromycin 4g that will buy from market is dissolved in the 50ml acetone solvent, places water bath with thermostatic control, is heated to 25 ℃ clarithromycin is dissolved in acetone, and being mixed with concentration is the clarithromycin raw material soup of 0.08g/ml.The acetone soln of gained clarithromycin and 1: 2 by volume ratio of anti-aqueous solvent are added respectively in the container with electronic stirring by peristaltic pump, the control recrystallization temperature is 25 ℃, mixing speed is 600r/min, and the reaction times is 10min, promptly obtains the magma of clarithromycin.Carry out vacuum filtration then and separate, the filter cake water washs 3 times, and carries out vacuum-drying 12 hours under 50 ℃, can obtain fine clarithromycin powder.Granularity Distribution is even, and median size is about 6 μ m, and pattern is a rod-shpaed particle, and wherein at least 80% particle diameter is between 5 μ m-7 μ m.
Embodiment 2
Other parameter constant, the acetone soln of gained clarithromycin and 1: 10 by volume ratio of anti-aqueous solvent are added respectively in the container with electronic stirring by peristaltic pump, the control recrystallization temperature is 15 ℃, mixing speed is 300r/min, reaction times is 5min, it is similar with embodiment 1 to obtain the product pattern, but the median size of minor axis is about 3 μ m.The particle diameter that at least 80% particle is wherein arranged is at 2.5～3.5 μ m.
Embodiment 3
Other parameter is identical with embodiment 2, is 1000r/min and change mixing speed, and it is similar with embodiment 1 to obtain the product pattern, but the median size of minor axis is about 1.5nm.The particle diameter that at least 80% particle is wherein arranged is at 1～2 μ m.
Embodiment 4
Other parameter is identical with embodiment 3, is 0～5 ℃ and change recrystallization temperature, and it is similar with embodiment 1 to obtain the product pattern, but the median size of minor axis is about 1.0 μ m.The particle diameter that at least 80% particle is wherein arranged is at 0.8nm～1.2 μ m.
Embodiment 5
To be dissolved in from the clarithromycin that market is buied the trichloromethane solvent, and place water bath with thermostatic control, and be heated to 25 ℃ clarithromycin is dissolved in trichloromethane, being mixed with concentration is the clarithromycin raw material soup of 0.05g/ml.The raw material medicine solution of gained clarithromycin and 1: 10 by volume ratio of anti-aqueous solvent are added respectively in the container with electronic stirring by peristaltic pump, the control recrystallization temperature is 25 ℃, mixing speed is 600r/min, and the reaction times is 10min, promptly obtains the magma of clarithromycin.Carry out vacuum filtration then and separate, the filter cake water washs 3 times, and carries out vacuum-drying 12 hours under 50 ℃, can obtain fine clarithromycin powder.Granularity Distribution is even, and median size is about 3.0 μ m, and pattern is a rod-shpaed particle, and wherein at least 80% particle diameter is between 2.5 μ m-3.5 μ m.
Embodiment 6
To be dissolved in from the clarithromycin that market is buied acetone and the ethanol mixed solvent, wherein the volume ratio of ethanol and acetone is 1: 9.Place water bath with thermostatic control, be heated to 25 ℃ clarithromycin is dissolved in acetone and ethanol mixed solvent, being mixed with concentration is the clarithromycin raw material soup of 0.05g/ml.
The raw material soup of gained clarithromycin and 1: 10 by volume ratio of anti-aqueous solvent are added respectively in the container with electronic stirring by peristaltic pump, the control recrystallization temperature is 15 ℃, mixing speed is 1000r/min, and the reaction times is 5min, promptly obtains the magma of clarithromycin.Carry out vacuum filtration then and separate, the filter cake water washs 3 times, and carries out vacuum-drying 12 hours under 50 ℃, can obtain fine clarithromycin powder.Granularity Distribution is even, and median size is about 2 μ m, and pattern is a rod-shpaed particle, and wherein at least 80% particle diameter is between 1.5 μ m-2.5 μ m.
By the description of above embodiment with in conjunction with concrete experimental data and accompanying drawing, we can draw as drawing a conclusion: use method of the present invention and can prepare fine clarithromycin powder.The particle diameter of gained powder is significantly less than the powder that obtains with ordinary method, can control particle in required average particle size range as required, and the epigranular of powder, narrow distribution.What need proposition especially is that the micronization technology of the clarithromycin medicament powder that adopts all is to utilize ordinary method to obtain again it being carried out micronization processes on the oarse-grained basis at present.According to the proposed method, realized that the preparation of clarithromycin and micronization carry out simultaneously, do not needed to carry out again processing treatment.Even can directly make inhaling type powder inhalation etc., thereby the route of administration that exploitation makes new advances.In actual medical applications, brought beyond thought on the basis of existing technology effect at aspects such as bioavailability, solvabilities.And, reduced the possibility that side reaction takes place, thereby the high purity and the quality of the finished product have been guaranteed owing to only relate to one or both inert organic solvents in the whole process.
The fine clarithromycin powder color and luster that obtains according to the inventive method is pure white, surface smoothness, uniform particles, purity height and good fluidity.Meet the requirement of Pharmacopoeia of People's Republic of China (version in 2010).Its solubility property of medicament powder after the micronization is significantly improved.Sucking treatment in addition is a kind of new administering mode in the present clarithromycin clinical treatment, and document shows: the agent of gas (powder) mist requires the suitable particle diameter of its powder in the scope of 0.5 μ m--5 μ m.The particle diameter of crystal grain is more little, and the deposition that medicine arrives lung is many more, and just the easy more segmental bronchus that enters is brought into play the effect of expansion bronchus fast, thereby made bioavailability of medicament also high more.The clarithromycin drug powder of the inventive method preparation satisfies above-mentioned requirements.
Claims (1)
1. the preparation method of a fine clarithromycin powder, it is characterized in that, comprise the steps: earlier clarithromycin to be dissolved in inert organic solvents, form clarithromycin solution, then this clarithromycin solution is added in the anti-solvent solution and carry out recrystallization, generate the clarithromycin crystallization, will get final product after the filtration of clarithromycin crystal process, washing, the drying again;
Wherein inert organic solvents is at least a in acetone, trichloromethane and the ethanol;
Wherein anti-solvent solution is a water;
Wherein recrystallization process carries out in the reactor that band stirs, and stirring velocity is 100-2000r/min, and the recrystallization process temperature is 0-60 ℃, and the time is 2-60min, and the volumetric ratio of clarithromycin solution and anti-solvent solution is 1:1 to 1:40 in the recrystallization process.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110089808 CN102134236B (en) | 2011-04-15 | 2011-04-15 | Preparation method of fine clarithromycin powder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110089808 CN102134236B (en) | 2011-04-15 | 2011-04-15 | Preparation method of fine clarithromycin powder |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102134236A CN102134236A (en) | 2011-07-27 |
| CN102134236B true CN102134236B (en) | 2013-07-24 |
Family
ID=44294183
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110089808 Expired - Fee Related CN102134236B (en) | 2011-04-15 | 2011-04-15 | Preparation method of fine clarithromycin powder |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102134236B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113802186B (en) * | 2021-08-17 | 2022-12-09 | 中国药科大学 | Clarithromycin spherical crystal and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186428A (en) * | 1995-04-13 | 1998-07-01 | 阿斯特拉公司 | Preparation of respirable particles |
| US5844105A (en) * | 1996-07-29 | 1998-12-01 | Abbott Laboratories | Preparation of crystal form II of clarithromycin |
-
2011
- 2011-04-15 CN CN 201110089808 patent/CN102134236B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186428A (en) * | 1995-04-13 | 1998-07-01 | 阿斯特拉公司 | Preparation of respirable particles |
| US5844105A (en) * | 1996-07-29 | 1998-12-01 | Abbott Laboratories | Preparation of crystal form II of clarithromycin |
Non-Patent Citations (2)
| Title |
|---|
| 孙京国，等.《克拉霉素的合成进展》.《有机化学》.2002,第22卷(第12期),951-963. * |
| 梁建华,等.《克拉霉素的晶型及其转换》.《北京理工大学学报》.2007,第27卷(第4期),374-376. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102134236A (en) | 2011-07-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105121434B (en) | Canagliflozin monohydrate and its crystal formation, their preparation method and purposes | |
| CN105541870B (en) | A kind of former preparation method and its pharmaceutical preparation for developing quality brizolina | |
| CN104857517B (en) | A kind of miscellaneous Shandong amine soft capsule of grace and preparation method thereof | |
| CN104086569B (en) | A kind of preparation method of cefotaxime sodium | |
| CN105440057B (en) | A kind of method for preparing cefoperazone sodium | |
| CN101896477B (en) | The five crystal forms of the nicousamide, the preparation methods, the pharmaceutical compositions and the uses thereof | |
| JP7007300B2 (en) | New crystalline form of dapagliflozin and its manufacturing method and application | |
| CN102134236B (en) | Preparation method of fine clarithromycin powder | |
| CN104644637A (en) | Piperacillin sodium tazobactam sodium preparation for injection and preparation method thereof | |
| CN114031560B (en) | Preparation method of letermovir sodium salt | |
| US8871927B2 (en) | Method for purifying Ceftizoxime sodium | |
| CN108440569A (en) | The preparation method of Ceftriaxone Sodium sphaerocrystal | |
| CN104045656A (en) | Cefoxitin sodium superfine-powder preparation and preparation method thereof | |
| CN104817557B (en) | A kind of stable crystal form of moxifloxacin hydrochloride and preparation method thereof | |
| CN108066320A (en) | A kind of preparation method of roxithromycin microcapsule formulation | |
| CN106432277A (en) | Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition | |
| CN103087138B (en) | Ginsenoside C-K monohydrate crystal and preparation method thereof | |
| CN113912653A (en) | Method for improving bulk density of beta-nicotinamide mononucleotide crystal powder | |
| CN101897663A (en) | Stable tegafur injection formula and preparation process thereof | |
| CN104151275A (en) | Preparation method of andrographolide compound | |
| CN114642637B (en) | Pure naphthoquinone compound nano particle and preparation method of carrier-free surfactant-free nano particle | |
| CN104725377B (en) | A kind of crystal formation of moxifloxacin hydrochloride and preparation method thereof | |
| CN1566076A (en) | Synthetic method for superfine sulfuric acid and salbutamol | |
| CN105902543B (en) | A kind of high-purity mezlocillin sodium preparation and preparation method thereof | |
| CN107773530B (en) | Miriplatin medicinal composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130724 Termination date: 20200415 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |