CN107556352A - A kind of method for crystallising for preparing the big granularity azithromycin of grade - Google Patents
A kind of method for crystallising for preparing the big granularity azithromycin of grade Download PDFInfo
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Abstract
The present invention relates to a kind of method for crystallising for preparing the big granularity azithromycin of grade；Paeoniflorin crystallization product is white crystal, and product pattern is the acuminous water chestnut column in one end, and heap density is preferable, reaches more than 0.58g/mL；Good fluidity, angle of repose can be less than 36 °；Method is that azithromycin crude product and acetone solvent are added in the crystallizer with stirring after heating for dissolving, add water and reach and azithromycin crystal seed growing the grain is added after supersaturation, then water is added dropwise by crystal growth, after water droplet adds, filtering crystals, azithromycin crystal product is obtained after drying.This method uses constant temperature dissolved method, and technological process is simple, and the big granularity azithromycin product of grade is obtained by controlling the growth of crystal seed and crystal, product granularity is big, without it is broken, purity is high, heap density is high, good fluidity, easily realize industrialized production.
Description
Technical field
The invention belongs to Chemical Engineering pharmaceutical technology field, and in particular to a kind of grade big granularity azithromycin of preparing
Method for crystallising
Background technology
Azithromycin (- 9 α of 9- deoxidations-- 9 α of the Alpha-Methyl of azepine-9-Erythromycin A) is third generation macrolide antibiotics.
Chemical structural formula is：
Azithromycin suppresses bacterioprotein synthesis and kills bacterium by hindering bacterium to turn peptide process.To gram sun
Property bacterium, part Gram-negative bacteria, Chlamydia, mycoplasma etc. have stronger antibacterial action, evident in efficacy to respiratory tract infection.Ah
Miramycin bioavilability is high, antibacterial activity in vivo is strong, and tissue permeability is strong, evident in efficacy, security and good by patience.The U.S.
Patent US4517359 and US4474768 describe azithromycin.
Pharmacokinetic shows that azithromycin biological half-life is very long, has good Clinical practice value.Zitromax
Element mainly has a tablet and injection, considers medication convenience, and the applicability of tablet is more preferable.And tablet is close to the granularity of product, heap
The requirement of degree and mobility is higher, and these powder characteristics of azithromycin product are influenceed very big by refined and method for crystallising.At present,
Report both domestic and external is primarily upon the purifying process for purification in azithromycin, and US0082527 reports use methanol or acetone and water
Purifying process for purification；CN1304407C reports absorb-elute and is evaporated under reduced pressure and the process for purification of dissolved purifying azithromycin；
CN104262429 reports purifies azithromycin by extraction and acid-base neutralization reaction；CN105001283B, which is reported, passes through second
The method of the polishing purification azithromycin recrystallized again with acetone and water after alcohol and water crystallization；CN101418026B reports one kind
Crystal formation and the controllable crystallization processes of granularity, by solvent and acid-base reaction speed, prepared sizes scope 20~180 microns Ah
Miramycin product.Summarize and find that the purification process of elution evaporation or extraction acid-base neutralization reaction is cumbersome, it is difficult to realize work
Industry.And these methods have not focused on granularity, pattern and the coalescence feelings of product both for the purity of azithromycin product
Condition, presently commercially available Azithromycin Raw Material are essentially all agglomerate, and product heap density is small, and mobility is bad, and heap density exists
0.42g/mL~0.54g/mL, the angle of repose for characterizing mobility are generally higher than 42 °.So developed there is an urgent need to us and optimize work
It is higher that skill obtains heap density, the preferable azithromycin product of mobility.
Obtained azithromycin product is industrially produced as shown in figure 1, being easily agglomerate at present, and it is broken very tight
Weight, granule size is at 30~200 microns, and granularity is too small to easily cause caking and agglomeration phenomena, and coalescence can cause solvent preservation, pure
Spend low；And coalescence and the broken mobility and heap density that can influence particle, the mobility of product is bad, and heap density is also low.Pin
To these problems, it is necessary to develop a kind of technique so that product granularity is larger, does not coalesce, and mobility and heap density are higher.
The content of the invention
To solve the deficiency of above-mentioned technology, it is an object of the invention to provide a kind of big granularity azithromycin of grade for preparing
Method for crystallising, prepared paeoniflorin crystallization product are white crystal, and product pattern is the acuminous water chestnut column in one end, crystal
The single big grain particles of scattered grade are not gathered into；Product purity height can reach 99.8%；There is no Fragmentation Phenomena；Heap is close
Degree is preferable, can reach more than 0.58g/mL；Good fluidity, angle of repose can be less than 36 °；It is very easy to filtering and dries；Adopt
With dilution crystallization method, crystallization processes are simple, high income, and product purity is high.
A kind of method for crystallising for preparing the big granularity azithromycin of grade, it is characterised in that：
Azithromycin crude product is dissolved by heating with acetone, adds water to reach supersaturation, growing the grain after crystal seed is added before going out crystalline substance, followed by
Continuous to be added dropwise water-soluble analysis, crystal further growth is into grade, the filtered grade Zitromax for being dried to obtain brilliant white and not coalescing
Plain product.
Technical scheme is as follows：
A kind of method for crystallising for preparing the big granularity azithromycin of grade, azithromycin crude product and acetone solvent are added to
After being dissolved by heating in crystallizer with stirring, add after water reaches supersaturation and add azithromycin crystal seed growing the grain, then water is added dropwise and allows
Crystal growth, after water droplet adds, filtering crystals, azithromycin crystal product is obtained after drying.
Described azithromycin and the mass ratio of acetone solvent are 1:2~5.
Described heating for dissolving temperature is 30~50 DEG C.
Described addition water reaches supersaturation, and the quality for adding water is 0.5~2 times of azithromycin gross mass.
Described crystal seed adds 0.5%~2% that quality is azithromycin gross mass；10~40min of growing the grain.
For described dropwise addition water by crystal growth, the quality that water is added dropwise is 2~6 times of azithromycin gross mass；Water is added dropwise
Time is 5~10h.
The main granularity of particle prepared by the method for crystallising of the present invention for preparing the big granularity azithromycin of grade reaches 1.5
More than millimeter, product purity is high, and particle does not coalesce and mobility is very good.In medicine production, the heap density of particle, particle
Size, mobility are critically important powder indexs.The increase of heap density, mobility improve the storage for being advantageous to product, transport, so
It is a critically important target of crystallization process that azithromycin particles characteristic, which can be improved,.The azithromycin product prepared by the present invention
Particle is that single dispersing does not coalesce, and the main granularity of product can reach more than 1.5 millimeters；There is no Fragmentation Phenomena；Heap density is preferable, can
To reach more than 0.58g/mL；Good fluidity, angle of repose can be less than 38 °.The azithromycin crude product purity used in the present invention
It is 95.6%, purity is higher than 99.5% after being prepared into the big granularity product of grade, and the method for crystallising of the present invention is permanent
Warm dilution crystallization, technique is simple, easily realizes industrialized production.
Brief description of the drawings
Azithromycin Raw Material product stereoscan photograph commercially available Fig. 1
The stereoscan photograph of the products obtained therefrom of Fig. 2 embodiments 1；
Fig. 3 is the stereoscan photograph of the products obtained therefrom of embodiment 2；
Fig. 4 is the stereoscan photograph of the products obtained therefrom of embodiment 3.
Fig. 5 is the stereoscan photograph of the products obtained therefrom of embodiment 4.
Specific implementation method
Below by by the embodiment of embodiment form, comprise the following steps that：Add in the crystallizer with stirring
Enter azithromycin crude product and acetone solvent, the azithromycin crude product of 1 part of quality, the quality for adding acetone is 2~5 parts, rise temperature
Spend to 30~50 DEG C, it is ensured that azithromycin solid is completely dissolved, and azithromycin gross mass is added after adding 0.5~2 part of quality water
0.5%~2% azithromycin crystal make crystal seed 10~40min of growing the grain, continue that the water of 2~6 parts of quality of water is added dropwise, during dropwise addition
Between control be 5~10h, mixing speed control can reach that suspension is uniform, and after completion of dropwise addition, filtering crystals are dry in system
It is dry to obtain azithromycin product.The above of the present invention is described in further detail.But this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following examples.All technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
5g azithromycins and 10g part acetone are added in the crystallizer with stirring, are heated to 50 DEG C of insulations, azithromycin is complete
After portion's dissolving, 2.5g water is added, after stable system, adds 0.5% azithromycin crystal of azithromycin gross weight as crystalline substance
Kind, constant temperature growing the grain 30min, 10g water is slowly added dropwise, whole time for adding is controlled in about 5h, and after adding water, filtration drying obtains
Product.As shown in Figure 2, as can be seen from the figure the granularity of single crystal product is more than 1.4 millimeters to the SEM photograph of product, production
Product even particle size distribution；Heap density 0.58g/mL；37.2 ° of angle of repose；It is 99.7% to detect product purity by liquid phase.
Embodiment 2
10g azithromycins and 50g acetone are added in the crystallizer with stirring, temperature control is incubated at 30 DEG C, treats Archie
Mycin all after dissolving, adds 20g water, after stable system, add 2% azithromycin crystal of azithromycin gross weight as
Crystal seed, constant temperature growing the grain 10min, 60g water is slowly added dropwise, whole time for adding control is in about 10h, after adding water, filtration drying
Obtain product.As shown in Figure 3, as can be seen from the figure the granularity of single crystal product is more than 1.6 millis to the SEM photograph of product
Rice, Granularity Distribution are uniform；Heap density 0.59g/mL；36.5 ° of angle of repose；It is 99.8% to detect product purity by liquid phase.
Embodiment 3
8g azithromycins and 32g acetone are added in the crystallizer with stirring, temperature control is incubated at 50 DEG C, treats Zitromax
After plain all dissolvings, 12g water is added, after stable system, add 1% azithromycin crystal of azithromycin gross weight as crystalline substance
Kind, constant temperature growing the grain 40min, 40g water is slowly added dropwise, whole time for adding is controlled in about 8h, and after adding water, filtration drying obtains
Product.As shown in Figure 4, as can be seen from the figure the granularity of single crystal product is more than 1.5 millimeters to the SEM photograph of product, production
Product even particle size distribution；Heap density 0.60g/mL；37.9 ° of angle of repose；It is 99.8% to detect product purity by liquid phase.
Embodiment 4
6g azithromycins and 18g acetone are added in the crystallizer with stirring, temperature control is incubated at 40 DEG C, treats Zitromax
After plain all dissolvings, add 6g water, after stable system, add 1.5% azithromycin crystal of azithromycin gross weight as
Crystal seed, constant temperature growing the grain 20min, 24g water is slowly added dropwise, whole time for adding is controlled in about 9h, and after adding water, filtration drying obtains
To product.The granularity of single crystal product is more than 1.7 millimeters, and Granularity Distribution is uniform；Heap density 0.58g/mL；Angle of repose
38.0°；It is 99.6% to detect product purity by liquid phase.
Embodiment 5
4g azithromycins and 14g acetone are added in the crystallizer with stirring, temperature control is incubated at 35 DEG C, treats Zitromax
After plain all dissolvings, 6.4g water is added, after stable system, the 0.8% azithromycin crystal for adding azithromycin gross weight is worked as
Make crystal seed, constant temperature growing the grain 25min, 22g water is slowly added dropwise, whole time for adding control is in about 7h, after adding water, filtration drying
Obtain product.The granularity of single crystal product is more than 1.4 millimeters, and Granularity Distribution is uniform；Heap density 0.57g/mL；Angle of repose
35.80°；It is 99.8% to detect product purity by liquid phase.
Embodiment 6
10g azithromycins and 25g acetone are added in the crystallizer with stirring, temperature control is incubated at 45 DEG C, treats Archie
Mycin all after dissolving, adds 8g water, and after stable system, the 1.2% azithromycin crystal for adding azithromycin gross weight is worked as
Make crystal seed, constant temperature growing the grain 15min, 35g water is slowly added dropwise, whole time for adding control is in about 8h, after adding water, filtration drying
Obtain product.The granularity of single crystal product is more than 1.5 millimeters, and Granularity Distribution is uniform；Heap density 0.59g/mL；Angle of repose
36.50°；It is 99.6% to detect product purity by liquid phase.
Claims (6)
1. a kind of method for crystallising for preparing the big granularity azithromycin of grade, it is characterized in that：The azithromycin necessarily matched is thick
Product and acetone solvent are added in the crystallizer with stirring after heating for dissolving, are added after water reaches supersaturation and are added azithromycin crystalline substance
Kind growing the grain, then water is added dropwise by crystal growth, after water droplet adds, filtering crystals, azithromycin crystal product is obtained after drying.
2. method for crystallising as claimed in claim 1, it is characterised in that described azithromycin and the quality proportioning of acetone solvent
Scope is 1:2~5.
3. method for crystallising as claimed in claim 1, it is characterised in that described addition water reaches supersaturation, adds the quality of water
For 0.5~2 times of azithromycin gross mass.
4. method for crystallising as claimed in claim 1, it is characterised in that the quality of water is added dropwise by crystal growth in described dropwise addition water
For 2~6 times of azithromycin gross mass, the time that water is added dropwise is 5~10h.
5. method for crystallising as claimed in claim 1, it is characterised in that described Seed charge is azithromycin gross mass
0.5%~2%.
6. the crystal of the big granularity azithromycin of grade prepared by claim 1 method；It is characterized in that product pattern has for one end
The water chestnut column of tip；Heap density reaches more than 0.58g/mL；Good fluidity, angle of repose can be less than 36 °.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108690106A (en) * | 2018-06-27 | 2018-10-23 | 天津大学 | Two water azithromycin sphaerocrystals of one kind and preparation method thereof |
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|---|---|---|---|---|
| CN1973844A (en) * | 2006-12-15 | 2007-06-06 | 北京化工大学 | Process for preparing micro Azithromycin powder |
| CN102417531A (en) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | Method for preparing azithromycin monohydrate |
| CN104892697A (en) * | 2015-05-05 | 2015-09-09 | 黄石世星药业有限责任公司 | Azithromycin production technology |
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2017
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| CN1973844A (en) * | 2006-12-15 | 2007-06-06 | 北京化工大学 | Process for preparing micro Azithromycin powder |
| CN102417531A (en) * | 2011-12-20 | 2012-04-18 | 浙江国邦药业有限公司 | Method for preparing azithromycin monohydrate |
| CN104892697A (en) * | 2015-05-05 | 2015-09-09 | 黄石世星药业有限责任公司 | Azithromycin production technology |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108690106A (en) * | 2018-06-27 | 2018-10-23 | 天津大学 | Two water azithromycin sphaerocrystals of one kind and preparation method thereof |
| CN108690106B (en) * | 2018-06-27 | 2021-06-18 | 天津大学 | Dihydrate azithromycin spherical crystal and preparation method thereof |
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