CN100441196C - Process for preparing micro Azithromycin powder - Google Patents
Process for preparing micro Azithromycin powder Download PDFInfo
- Publication number
- CN100441196C CN100441196C CNB200610165253XA CN200610165253A CN100441196C CN 100441196 C CN100441196 C CN 100441196C CN B200610165253X A CNB200610165253X A CN B200610165253XA CN 200610165253 A CN200610165253 A CN 200610165253A CN 100441196 C CN100441196 C CN 100441196C
- Authority
- CN
- China
- Prior art keywords
- azithromycin
- solvent
- material solution
- powder
- solution
- 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 process of preparing superfine Azithromycin powder belongs to the field of superfine medicine powder preparing technology. Specifically, the process includes marketable Azithromycin medicine material in organic solvent to obtain Azithromycin solution, adding the Azithromycin solution in counter solvent in certain volume through magnetic stirring at certain temperature to deposit Azithromycin crystal and obtain crystal slurry, ageing at certain temperature, filtering, washing and drying to obtain superfine Azithromycin powder product. The process is simple, safe, low in cost and suitable for industrial production, and the obtained superfine Azithromycin powder has high leaching rate and high solubility.
Description
Technical field
The invention belongs to medicine superfine powder preparation field, the particularly preparation of azithromycin superfine powder.
Background technology
Azithromycin is a kind of novel macrolide antibiotic, and structure is similar to erythromycin, but its antimicrobial spectrum is wider than erythromycin, and antibacterial activity is stronger, and chemical property is also more stable, and especially the stability to acid is higher than erythromycin far away.Its chemistry 9-deoxidation by name-9 α-azepine-9 Alpha-Methyl-9 α-Erythromycin A [CAS83905-01-5].It is at first to be invented by (United States Patent (USP) 4,517,357) such as Bright (United States Patent (USP) 4,474,768) and Kobrehel, is mainly used in the sensitive microbial associated diseases.
The listing dosage form of azithromycin mainly contains peroral dosage forms such as tablet, capsule, dry suspension.According to relevant bibliographical information, this product only has 37% oral administration biaavailability.Trace it to its cause, mainly be since azithromycin be poorly water soluble drugs, enter human body by oral administration after, be difficult to reach good absorption, most of medicine excretes with original shape.For reaching the purpose of drug effect, have to increase the use amount of medicine, so not only just cause very big waste clinically, but also can increase side effect to the intestines and stomach.
For oral formulations, the dissolution rate of medicine activity component in body determined the size of bioavailability.Get rid of other factor affecting, the dissolution rate of solid drugs depends primarily on the size of the granule surface area that contacts with solvent liquid.Therefore, by insoluble drug is carried out micronization,, very important meaning is arranged to improving bioavailability to reduce the drug particles particle diameter and then to increase its specific surface area.
The method of utilizing the ultrasonic emulsification solvent diffusion method to prepare the azithromycin superfine powder has been described: among the Chinese patent CN1634113A under ultransonic condition, the azithromycin alcoholic solution is splashed in the aqueous solution that contains stabilizing agent, become muddy until system, again after the solution system ageing a period of time with muddiness, high speed centrifugation separate solid matter, and washing, drying obtain the azithromycin superfine powder of mean diameter at 500nm.The method relates to ultrasound condition, energy consumption height not only, and only be suitable for the small lot experiment, be difficult to realize suitability for industrialized production.In addition, the introducing of emulsifying agent is made troubles to subsequent processes, and has increased the cost of raw material.Long Tao etc. [preparation of ultra-fine azithromycin and sign. Long Tao etc. chemical industry progress, 2005,24 (7): 763-766] adopt the supersonic airstream crushing technology to carry out the experiment of azithromycin micronization, obtain the azithromycin powder body of mean diameter at 1.13 μ m.The medicament powder that the method obtains is broad particle distribution often, and because high-octane input, is easy to cause the particle agglomeration after the pulverizing.In addition, comminution by gas stream also can cause problems such as dust pollution and electrostatic safety.
Summary of the invention
At the deficiency that exists on the prior art, the method for preparing micro Azithromycin powder that the object of the present invention is to provide that a kind of technology is simple, handling safety, cost are low, is easy to industrial amplification production further wishes to solve controllable granularity, the controlled problem of pattern.
The present invention is under stirring condition, and the solution of azithromycin raw material is added carrying out precipitated crystal in the undissolved anti-solvent of azithromycin, can make micronized azithromycin granule, and the method need not any surfactant and emulsifying agent.
Specifically, the present invention relates to a kind of method for preparing micro Azithromycin powder, its characterization step comprises:
1) commercially available azithromycin is dissolved in organic solvent, prepares certain density azithromycin material solution;
2) set recrystallization temperature, the volume ratio according to certain solution and anti-solvent adds the azithromycin material solution in the anti-solvent, and it is fully mixed, and through stirring a period of time, paeoniflorin crystallization is precipitated out, and obtains slurry;
3) with step 2) in gained paeoniflorin crystallization serosity carry out ageing at a certain temperature;
4) gained serosity in the step 3) is obtained azithromycin micronization product through filtration, washing, drying.
In above-mentioned steps 2) in, anti-solvent recrystallization process is carried out in having the reactor of agitating device, all adopt and pour the azithromycin material solution in the anti-solvent feed way rapidly, make mixed system reach higher degree of supersaturation, help short grained generation in moment.
Be used for that azithromycin material solution of the present invention comprises that any commercially available azithromycin that meets pharmacopeia regulation is dissolved in suitable solvent and the azithromycin solution that obtains.
In above-mentioned solution, normally used organic solvent comprises methanol, ethanol, chloroform, acetone or their mixture, preferred alcohol.And, the above-mentioned the 1st) step described in " dissolving " be meant that azithromycin forms basic clear solutions in solvent.
In the present invention, because azithromycin is in partial solvent, especially dissolubility is bigger in ethanol, when utilizing saturated solution to carry out recrystallization, moment is separated out a large amount of crystal, the chance showed increased of colliding between granule causes particle agglomeration serious, so the azithromycin material solution should not adopt saturated concentration.The material solution concentration that the present invention chooses azithromycin is the 5%-95% of azithromycin saturated concentration under the uniform temp, preferred 20%-50%.
It is miscible to be used for anti-solvent of the present invention and to be water and all and solvent phase, but to the insoluble organic or inorganic solvent of azithromycin, considers that from economy, cleaning raw material angle preferred anti-solvent is a water.
Mixing speed used in the present invention is 300rpm-3000rpm, and mixing speed is high more, and is strong more to the reinforcement of transmittance process and micro mixing, the easy more granule that obtains narrow diameter distribution, rotating speed is low more, and this invigoration effect is weak more, the particle that obtains is big more, and particle size distribution is wide more.But speed of agitator is excessive, can cause higher energy consumption.Therefore, the rotating speed of the preferred recrystallization process of the present invention is 800rpm-1000rpm.
Among the present invention, mixing time is 1s-120s, and the proper extension mixing time helps azithromycin solution and mixes more fully with anti-solvent, improve the yield of product, but the long meeting of mixing time causes crystal to grow up.Therefore, the preferred mixing time of the present invention is 50s-60s.
Selective freezing temperature of the present invention is 5 ℃-50 ℃, experimentation shows: when carrying out anti-solvent recrystallization in ethanol-water system, crystallization temperature does not almost have crystal to separate out when being controlled at below 5 ℃, there is the crystallization induction time in the time of 5 ℃-10 ℃, and when controlling higher crystallization temperature, the azithromycin crystal can be separated out rapidly, but temperature when too high rate of crystalline growth also can obviously increase, be unfavorable for obtaining the little granule of granularity.Therefore, the preferred crystallization temperature of the present invention is 10 ℃-25 ℃.
Among the present invention, the material solution of azithromycin and the volume ratio of anti-solvent are the key factors that influences product particle size and pattern, have only the anti-solvent volume of strict control solution than within the specific limits, just can prepare the granule of azithromycin ultra-fine grain and the spherical secondary structure of the self assembly with porous surface, inner hollow.It is 1 that the present invention selects the anti-solvent volume ratio of solution: 2-1: 50, preferred 1: 10-1: 20.
In order to make all controlled azithromycin powder body of granularity and pattern, in the described step 3) of method of the present invention, at the powder body of required different grain size that obtains and pattern, the ageing temperature and the digestion time that are adopted are different.Obtain the azithromycin ultra-fine grain and need the ageing long period under higher temperature, the present invention selects the ageing temperature and time to be respectively 40 ℃-70 ℃ and 1h-5h, be preferably 50 ℃-60 ℃ and 2h-3h, can obtain the azithromycin superfine powder of mean diameter about 500nm this moment; In addition, obtain having porous surface, the granule of the spherical secondary structure of the self assembly of inner hollow, need under room temperature (about about 20 ℃) condition, the digestion time that control is short, it is 50s-300s that the present invention selects digestion time, be preferably 1min-2min, can get the granule with self assembly spherical secondary structure of particle diameter between 10-20 μ m, this granule has porous surface, hollow structure inside, pattern that this is special and structures shape this powder body have good dispersibility and flowability, have very high specific surface area simultaneously.
In sum, can find out that the pointed method technology of the present invention is simple, not relate to hazardous environments such as dangerous materials and high pressure in all operations, handling safety, and cost is low, be easy to industrial amplification production, volume ratio by control material solution and anti-solvent can obtain controllable granularity, the controlled micro Azithromycin powder of pattern.
Description of drawings
For further introducing the present invention, show used description of drawings is as follows by embodiment:
Fig. 1 is the electron scanning micrograph of azithromycin crude drug.
Fig. 2 is the electron scanning micrograph of the azithromycin superfine powder of method preparation of the present invention.
Fig. 3 is 800 times of electron scanning micrographs with the spherical secondary structure azithromycin of self assembly powder granule of method preparation of the present invention.
Fig. 4 is 8000 times of electron scanning micrographs of a damaged structure with the spherical secondary structure azithromycin of self assembly powder granule of method preparation of the present invention.
Fig. 5, the 6th, 1000 times of electron scanning micrographs with the spherical secondary structure azithromycin of self assembly powder granule of method preparation of the present invention.
Fig. 7 is the electron scanning micrograph of secondary structure azithromycin granule of the almost spherical of method of the present invention preparation.
Fig. 8 is the infrared spectrogram before and after the azithromycin micronization, and wherein, curve A is the infrared spectrum of crude drug, and curve B is the infrared spectrum of ethanol/water system recrystallization product.
The specific embodiment
Embodiment 1
Adopt commercially availablely, meet the azithromycin raw material medicine of pharmacopeia regulation, shown in scanning electron microscope among Fig. 1 (SEM) photo, particle diameter between 20-100 μ m, be that granule size is inhomogeneous, the irregular granule of pattern.The azithromycin crude drug is dissolved in the dehydrated alcohol, be mixed with concentration and be 0.2g/ml (when being 20 ℃ azithromycin in ethanol saturated concentration about 50%) azithromycin material solution (being the alcoholic solution of azithromycin raw material in the present embodiment).By water bath with thermostatic control control recrystallization temperature is 18 ℃.Get the alcoholic solution 10ml of above-mentioned azithromycin, add rapidly and be equipped with in the reactor of the anti-solvent of 200ml (being water in the present embodiment), promptly, the volume ratio of azithromycin material solution and anti-solvent is 1: 20, in the control mixing speed is to stir 1min under the condition of 1000rpm, obtains the paeoniflorin crystallization serosity.The gained slurry at 60 ℃ of ageing 3h, is used the vacuum pump sucking filtration then, and wash filter cake 2-5 time with water, dry under 50-60 ℃ of condition, promptly get azithromycin micronization product.By SEM observation, as shown in Figure 2, product pellet is even, and mean diameter is at 500nm, and wherein at least 80% particle diameter is at 300-800nm.
Embodiment 2
Operating parameter is identical with embodiment 1, and the temperature that only different is changes recrystallization is 30 ℃.By SEM observation, the particle morphology of gained azithromycin micronization product is similar to embodiment 1, but the mean diameter of particle wherein has 80% above particle diameter at least between 0.5-3 μ m about 1 μ m.
Embodiment 3
Operating parameter is identical with embodiment 1, and the volume ratio that only different is changes azithromycin material solution and anti-solvent (being water in the present embodiment) is 1: 10.By SEM observation products obtained therefrom, the product pellet particle diameter is substantially between 0.5-1 μ m, but the reunion situation is serious.
Embodiment 4
The azithromycin crude drug is dissolved in the dehydrated alcohol, be mixed with concentration and be 0.08g/ml (when being 20 ℃ azithromycin in ethanol saturated concentration about 20%) azithromycin material solution (being the alcoholic solution of azithromycin raw material in the present embodiment).Adopting the volume ratio of azithromycin material solution and anti-solvent (being water in the present embodiment) is 1: 10, and recrystallization temperature is 20 ℃.With recrystallization gained serosity ageing 1min under room temperature (about 20 ℃) condition, carry out vacuum filtration then, wash filter cake 2-5 time with water, dry under 50-60 ℃ of condition, promptly get azithromycin micronization product.By SEM observation, as Fig. 3, shown in 4, gained azithromycin powder body is the granule with spherical secondary structure of self assembly of porous surface, and particle size distribution is between 10-20 μ m; From the particulate SEM of single breakage as shown in Figure 4 as can be seen, the particle surface rough porous, inside is hollow structure.By its special pattern and structures shape, this granule has good flowability and very high specific surface area, and the BET test has further confirmed this observed result.Result of extraction shows that dissolution rate and the dissolubility of this azithromycin powder body in water obviously is better than crude drug.
Embodiment 5
Operating parameter is identical with embodiment 4, and only different is that the change digestion time is 2min.By SEM observation products obtained therefrom as shown in Figure 5, still be spherical secondary structure granule, microstructure changes to some extent, surface porosity porous, but particle diameter increase, more than 80% between 25-30 μ m.
Embodiment 6
Operating parameter is identical with embodiment 4, and only different is that the change digestion time is 5min.By SEM observation products obtained therefrom as shown in Figure 6, be similarly spherical secondary structure granule, microstructure further changes, particle diameter also further increases, between 29-34 μ m, and be made of the bigger primary particle of particle diameter more than 80%, the change of this structure causes particulate specific surface to descend to some extent.
Embodiment 7
Operating parameter is identical with embodiment 4, the concentration that only different is changes the azithromycin alcoholic solution be 0.02g/ml (when being 20 ℃ azithromycin in ethanol saturated concentration about 5%).By SEM observation products obtained therefrom, be the secondary structure granule (as shown in Figure 7) of almost spherical, particle diameter is about 10 μ m, but it is more open to reunite, and easily broken, most of shaping particles is imperfect, and the obvious change of the primary particle that constitutes second particle is big, and the specific surface area of gained dry powder obviously reduces.
See Fig. 8, the micro Azithromycin powder by method preparation of the present invention detects through infrared spectrum, can find out that its infrared spectrum is consistent with the spectrogram of azithromycin crude drug, proves that anti-solvent recrystallization process does not change the chemical property of azithromycin.
Measure by the result of extraction that carries out in water, the azithromycin behind the micronization all has the dissolubility of dissolution rate and Geng Gao faster than crude drug.
Claims (4)
1. method for preparing micro Azithromycin powder, its characterization step comprises:
1) azithromycin is dissolved in methanol, ethanol, chloroform, acetone or their mixture, preparation azithromycin material solution, described material solution concentration is the 5%-95% of azithromycin saturated concentration under the uniform temp;
2) setting recrystallization temperature is 5 ℃-50 ℃, volume ratio according to certain solution and anti-solvent, the azithromycin material solution is added in the anti-solvent, the volume ratio of azithromycin material solution and anti-solvent is 1: 2-1: 50, through stirring 1s-120s it is fully mixed, paeoniflorin crystallization is precipitated out, obtains slurry;
3) with step 2) in gained paeoniflorin crystallization serosity carry out ageing at 40 ℃-70 ℃, digestion time is 1h-5h;
4) with the filtration of the process of the slurry after the ageing in the step 3), washing, the dry azithromycin micronization product that gets.
2. the method for preparing micro Azithromycin powder according to claim 1 is characterized in that: described anti-solvent is that water and all and azithromycin material solution are miscible, but with the insoluble organic or inorganic solvent of azithromycin.
3. the method for preparing micro Azithromycin powder according to claim 1 is characterized in that: mixing speed is 300rpm-3000rpm described step 2).
4. method for preparing micro Azithromycin powder, its characterization step comprises:
1) azithromycin is dissolved in methanol, ethanol, chloroform, acetone or their mixture, preparation azithromycin material solution, described material solution concentration is the 5%-95% of azithromycin saturated concentration under the uniform temp;
2) setting recrystallization temperature is 5 ℃-50 ℃, volume ratio according to certain solution and anti-solvent, the azithromycin material solution is added in the anti-solvent, the volume ratio of azithromycin material solution and anti-solvent is 1: 2-1: 50, through stirring 1s-120s it is fully mixed, paeoniflorin crystallization is precipitated out, obtains slurry;
3) with step 2) in gained paeoniflorin crystallization serosity carry out ageing in room temperature, digestion time is 50s-300s;
4) with the filtration of the process of the slurry after the ageing in the step 3), washing, the dry azithromycin micronization product that gets.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610165253XA CN100441196C (en) | 2006-12-15 | 2006-12-15 | Process for preparing micro Azithromycin powder |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610165253XA CN100441196C (en) | 2006-12-15 | 2006-12-15 | Process for preparing micro Azithromycin powder |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1973844A CN1973844A (en) | 2007-06-06 |
| CN100441196C true CN100441196C (en) | 2008-12-10 |
Family
ID=38124378
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200610165253XA Expired - Fee Related CN100441196C (en) | 2006-12-15 | 2006-12-15 | Process for preparing micro Azithromycin powder |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100441196C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105294791A (en) * | 2014-06-10 | 2016-02-03 | 无锡康福特药物科技有限公司 | Ultrafine powder of macrolide drug and preparation method for ultrafine powder |
| CN104324008A (en) * | 2014-09-18 | 2015-02-04 | 山东省药学科学院 | Industrial preparation method of micronized iloperidone |
| CN107556352B (en) * | 2017-09-05 | 2020-07-24 | 天津大学 | Crystallization method for preparing millimeter-grade large-particle-size azithromycin |
| CN112479867B (en) * | 2020-12-30 | 2024-03-29 | 武汉诺安药业有限公司 | Chemical preparation method for micronization of adapalene |
| CN114699386B (en) * | 2022-04-14 | 2023-05-23 | 深圳职业技术学院 | Azithromycin composition and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6068859A (en) * | 1994-05-06 | 2000-05-30 | Pfizer Inc. | Controlled-release dosage forms of Azithromycin |
| CN1606433A (en) * | 2001-12-21 | 2005-04-13 | 辉瑞产品公司 | Methods for wet granulating azithromycin |
| CN1634113A (en) * | 2004-10-29 | 2005-07-06 | 中国地质大学（武汉） | Method for preparing azithromycin superfine powder by ultrasound homogenization dissolvent diffusion method |
| JP2006045117A (en) * | 2004-08-04 | 2006-02-16 | Pfizer Japan Inc | Stable composition with suppressed bitter taste and comprising azithromycin compound as effective ingredient |
-
2006
- 2006-12-15 CN CNB200610165253XA patent/CN100441196C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6068859A (en) * | 1994-05-06 | 2000-05-30 | Pfizer Inc. | Controlled-release dosage forms of Azithromycin |
| CN1606433A (en) * | 2001-12-21 | 2005-04-13 | 辉瑞产品公司 | Methods for wet granulating azithromycin |
| JP2006045117A (en) * | 2004-08-04 | 2006-02-16 | Pfizer Japan Inc | Stable composition with suppressed bitter taste and comprising azithromycin compound as effective ingredient |
| CN1634113A (en) * | 2004-10-29 | 2005-07-06 | 中国地质大学（武汉） | Method for preparing azithromycin superfine powder by ultrasound homogenization dissolvent diffusion method |
Non-Patent Citations (6)
| Title |
|---|
| 超声乳化溶剂扩散法制备阿奇霉素超细粉体. 龙涛等.武汉大学学报（理学版），第50卷第6期. 2004 |
| 超声乳化溶剂扩散法制备阿奇霉素超细粉体. 龙涛等.武汉大学学报（理学版），第50卷第6期. 2004 * |
| 超细阿奇霉素的制备及表征. 龙涛等.化工进展，第24卷第7期. 2005 |
| 超细阿奇霉素的制备及表征. 龙涛等.化工进展，第24卷第7期. 2005 * |
| 高压均质法制备阿奇霉素超微粉体. 王龙艳等.化工时刊，第19卷第9期. 2005 |
| 高压均质法制备阿奇霉素超微粉体. 王龙艳等.化工时刊，第19卷第9期. 2005 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1973844A (en) | 2007-06-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100441196C (en) | Process for preparing micro Azithromycin powder | |
| CA2732952C (en) | Crystalline microparticles of an active substance, method for producing the same and use thereof in medicaments | |
| CN100448447C (en) | Preparation of superfine prednisolone powder | |
| CN105061459A (en) | Preparation method of clopidogrel hydrogen sulfate I crystal form spherical crystal | |
| CN104650091A (en) | Micronization and crystal form of ticagrelor and preparation method and pharmaceutical application of crystal form of ticagrelor | |
| US6979735B1 (en) | Agglomerates by crystallization | |
| CN104887633B (en) | A kind of razaxaban tablet and preparation method thereof | |
| CN100448879C (en) | Method for preparing unformed cefuroxime axetil | |
| CN100490796C (en) | Methodc for preparing sub-micron gemfibrozil medicament powder | |
| CN101292958B (en) | Method of preparing ultra-fine danazol powder | |
| CN101780046B (en) | Itraconazole composite powder and preparation method thereof | |
| EP1497308B1 (en) | Method for producing steroid crystals, crystals obtained by said method and their use in pharmaceutical formulations | |
| CN113845423B (en) | Pharmaceutical auxiliary material sodium stearyl fumarate with uniform sheet-shaped structure and preparation method thereof | |
| CN108586565A (en) | A kind of purification process of small grain size danazol | |
| CN105012237A (en) | Fluticasone furoate nasal spray and preparation method thereof | |
| CN114681404B (en) | Repaglinide granule pharmaceutical composition and preparation method thereof | |
| CN101973967B (en) | Method for preparing negative pressure anti-solvent of water-soluble nano-taxol powder | |
| CN109232389A (en) | A kind of crystallization preparation method of small grain size nifedipine | |
| CN104324008A (en) | Industrial preparation method of micronized iloperidone | |
| CN106309371B (en) | Cefixime nano dispersion and preparation method thereof | |
| CN101390838A (en) | Method for preparing micronization medicine | |
| CN108727448A (en) | Spiramvcin class antibiotic spheroidal crystal and preparation method thereof | |
| CN110563635A (en) | New method for micronizing raw material medicines of dihydropyridine antihypertensive drugs | |
| CN104140378A (en) | Special superfine powder lyophilized N-Acetyl-L-Glutamine preparation and preparation method thereof | |
| CN109970664B (en) | Co-crystal product of pyrazinamide and fumaric acid and ultrasonic-microwave coupling 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: 20081210 Termination date: 20141215 |
|
| EXPY | Termination of patent right or utility model |