CN108031142A - Simplified device and method for preparing large amount of micro-crystal seeds by wet grinding - Google Patents
Simplified device and method for preparing large amount of micro-crystal seeds by wet grinding Download PDFInfo
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- CN108031142A CN108031142A CN201711327860.6A CN201711327860A CN108031142A CN 108031142 A CN108031142 A CN 108031142A CN 201711327860 A CN201711327860 A CN 201711327860A CN 108031142 A CN108031142 A CN 108031142A
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- crystallization kettle
- wet
- crystallite
- solvent
- crystallization
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000001238 wet grinding Methods 0.000 title claims abstract description 25
- 239000013081 microcrystal Substances 0.000 title claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 74
- 230000008025 crystallization Effects 0.000 claims abstract description 74
- 239000013078 crystal Substances 0.000 claims abstract description 47
- 239000002904 solvent Substances 0.000 claims abstract description 22
- 239000000725 suspension Substances 0.000 claims abstract description 21
- 239000012296 anti-solvent Substances 0.000 claims abstract description 18
- 239000007787 solid Substances 0.000 claims abstract description 17
- 239000000047 product Substances 0.000 claims abstract description 16
- 238000001816 cooling Methods 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 12
- 238000001704 evaporation Methods 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 4
- 238000005070 sampling Methods 0.000 claims abstract description 4
- 235000013336 milk Nutrition 0.000 claims description 25
- 239000008267 milk Substances 0.000 claims description 25
- 210000004080 milk Anatomy 0.000 claims description 25
- 239000011521 glass Substances 0.000 claims description 6
- 230000008020 evaporation Effects 0.000 claims description 4
- 238000010606 normalization Methods 0.000 claims description 4
- 238000003921 particle size analysis Methods 0.000 claims description 4
- 230000006698 induction Effects 0.000 claims description 3
- 238000010926 purge Methods 0.000 claims description 3
- 230000002269 spontaneous effect Effects 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 230000004310 photopic vision Effects 0.000 claims 1
- 238000009738 saturating Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000003860 storage Methods 0.000 abstract description 4
- 238000005406 washing Methods 0.000 abstract description 2
- 238000007664 blowing Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 10
- 229960001138 acetylsalicylic acid Drugs 0.000 description 10
- 239000008187 granular material Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 238000009826 distribution Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000009837 dry grinding Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000010904 focused beam reflectance measurement Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000036186 satiety Effects 0.000 description 1
- 235000019627 satiety Nutrition 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
- B01D9/0054—Use of anti-solvent
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0059—General arrangements of crystallisation plant, e.g. flow sheets
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0063—Control or regulation
Landscapes
- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a simplified device for preparing a large number of micro-seeds by wet grinding, which comprises a crystallization kettle, a circulating pump and a wet grinder which are connected in series to form a circulating loop. In addition, the invention also discloses a simplified method for preparing a large number of micro-crystal seeds by wet grinding, which comprises the steps of firstly adding a solution of a crude product of an active pharmaceutical ingredient X into a crystallization kettle; then the supersaturation degree of the solution reaches 20 percent; adding <1% solid crystal seed to induce crystallization; starting a circulating pump and a wet grinder, generating a large amount of microcrystal seeds to form suspension, and sampling to confirm that the microcrystal seeds meet the process requirements; closing a bottom valve of the crystallization kettle, and blowing the circulating pipeline by using nitrogen to transfer the suspension to the crystallization kettle; continuously adding an anti-solvent into the crystallization kettle, cooling or evaporating the solvent until crystals are completely separated out at the crystallization end point, filtering, washing and drying to obtain the product. The invention achieves the purpose of simplifying the production equipment for preparing the microcrystal seed suspension containing a large number of microcrystal seeds, is not limited by the size of a crystallization kettle and has higher flexibility. While also reducing the need for storage and the addition of large quantities of seeds.
Description
Technical field
The present invention relates to a kind of pharmaceutical granulation equipment, and in particular to a kind of crystallite kind preparation facilities, more particularly to a kind of letter
The device that a large amount of crystallite kinds are prepared using wet-milling of change；Moreover, it relates to a kind of simplification is prepared using wet-milling
The method of a large amount of crystallite kinds.
Background technology
In the production process of active pharmaceutical ingredient (API), addition crystal seed is the means that generally use to ensure to crystallize
The high duplication of process, and crystallite kind is due to the specific surface area of its particle and bigger with smaller, then more conducively crystal growth.
Prepare crystallite kind and dry grinding method can be used（Dry grinding）With wet lapping method（Wet-milling）Two methods.Dry grinding is usually present dust control
The problem of processed.Wet-milling can avoid this problem, and Chinese patent application CN200780009100.9 discloses one kind by micro- grinding
With micro- seed crystals produce crystallization organic microparticle compositions method and apparatus and its application, but the patent application use
Wet grinding needs two reaction kettles, including a crystallization kettle, the crystal seed of a suitable size to prepare kettle.Elder generation is needed according to technique
A certain amount of crystal seed and anti-solvent are added in crystal seed prepares kettle, obtains crystallite kind suspension by wet-milling, then crystallite kind is hanged
Supernatant liquid is transferred in the crystallization kettle for having contained API solution.Since crystal seed amount in different crystallization process and the volume of suspension will
The difference asked may be larger, this matching to two kettle sizes in crystallization workshop is more demanding.And no matter dry grinding or wet-milling
The a large amount of crystal seeds of storage may all be faced（Up to 20%）The problem of.This area urgent need to resolve problem above.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of device that a large amount of crystallite kinds are prepared using wet-milling of simplification,
The device is combined with the method for adding dry crystal seed and wet-milling, is hanged so as to reach the crystallite kind for simplifying and preparing and containing a large amount of crystallite kinds
The purpose of the production equipment of supernatant liquid, and limited from crystallization kettle size, flexibility is higher.Also reduce storage at the same time and addition is big
Measure the needs of crystal seed.For this reason, a kind of method that a large amount of crystallite kinds are prepared using wet-milling the present invention also provides simplification.
In order to solve the above technical problems, the present invention adopts the following technical scheme that：
A kind of simplification of present invention offer prepares the device of a large amount of crystallite kinds using wet-milling, including is connected into a circulation loop
Crystallization kettle, circulating pump and wet milk.
As currently preferred technical solution, one end of the crystallization kettle is connected with the circulating pump by pipeline, separately
One end is connected with wet milk by pipeline；The circulating pump is connected with the wet milk by pipeline.
As currently preferred technical solution, the top of the crystallization kettle is equipped with charge door.
As currently preferred technical solution, the loop direction of the crystallization kettle, circulating pump and wet milk is：From crystallization
Bottom portion, to circulating pump, to wet milk, again arrive at the top of crystallization kettle.
As currently preferred technical solution, the crystallization kettle bottom discharge mouth pipeline is equipped with glass transparent visor.
In addition, the present invention also provides a kind of method that a large amount of crystallite kinds are prepared using wet-milling of simplification, this method uses
Above device, this method comprises the following steps：
（1）The solution of active pharmaceutical ingredient X crude products is added into crystallization kettle or adds X crude solids and appropriate solvent, stirring makes
Solution is made in its dissolving；
（2）Degree of supersaturation is reached certain value by cooling down, evaporating solvent or add appropriate anti-solvent but do not produce spontaneous knot
It is brilliant（Such as the degree of supersaturation of 2-30%）；
（3）Mass percent is added into crystallization kettle<1%（Preferably 0.5%）Solid crystal seeds induction crystallization；The quality percentage
Than being percentage of the crystal seed quality relative to the X crude product qualities of normalization；
（4）Open the circulation pump and wet milk, observe gradually has a large amount of crystallite kinds to produce to form suspension at this time, and sampling confirms micro-
Crystal seed size meets technological requirement；Crystallization kettle bottom valve is closed, suspension is all transferred back to crystallization with nitrogen purge circulation line
Kettle；
（5）Continue through cooling, evaporation solvent or separated out to crystallization kettle addition anti-solvent to terminal crystal whole is crystallized, filtering,
X wet products are washed, are dried to obtain final X products.
As currently preferred technical solution, step（2）In, described to make degree of supersaturation reach 2-30%, satiety at this time
Step is determined with degree（4）The total amount of crystallite kind after wet-milling.
As currently preferred technical solution, step（4）In, described observe gradually has a large amount of crystallite kinds to produce to be formed
Suspension, passes through the online granularity of set glass transparent visor or plum Teller-support benefit on crystallization kettle bottom discharge mouth pipeline
Analyzer, which is observed gradually, has a large amount of crystallite kinds to produce to form suspension；The online particle size analysis of the plum Teller-support benefit
Instrument is installed in crystallization kettle or in circulation loop.
As currently preferred technical solution, if desired for a greater amount of crystallite kinds, that is, the crystal seed amount needed, which exceedes, to be situated between surely
The available degree of supersaturation of sector width, then in step（3）And step（4）Between increase following steps：It is brilliant adding a small amount of solid
Plant and continue crystallization process until producing enough by cooling down, evaporating solvent or addition anti-solvent after degree of supersaturation completely release
Solid amount as crystal seed, to be then then turned on circulating pump and wet milk, the solid of generation be all ground into granule size
Satisfactory crystallite kind.
As currently preferred technical solution, step（2）Cooling, evaporation solvent add appropriate anti-solvent and produce
Degree of supersaturation determines the number of crystallite kind total amount, step（5）Continue to cool down, evaporate solvent or add remaining anti-solvent.
Compared with prior art, the beneficial effects of the invention are as follows：A crystallization kettle is used only with regard to that can prepare crystallite in the present invention
Plant and complete to crystallize, achieve the purpose that to simplify the production equipment for preparing the crystallite kind suspension containing a large amount of crystallite kinds.Omitting
While crystal seed prepares the use of kettle, the suspension containing a large amount of crystallite kinds can be still produced to reach promotion crystal growth
With the purpose of control crystal size, limited from crystallization kettle size, flexibility is higher.And decrease the big of storage and addition
Measure the needs of crystal seed.The present invention greatly reduces production cost, simplifies preparation process, effectively overcomes traditional wet-milling processes needs
Two reaction kettles there are the defects of.
Brief description of the drawings
The present invention is further described with reference to the accompanying drawings and examples.
Fig. 1 is a kind of structure diagram of the device that a large amount of crystallite kinds are prepared using wet-milling of simplification of the present invention.
The reference numerals are as follows in figure：
1 is crystallization kettle, and 2 be circulating pump, and 3 be wet milk, and 4 be charge door.
Embodiment
In conjunction with the accompanying drawings, the present invention is further explained in detail.These attached drawings are simplified schematic diagram, only with
Illustration illustrates the basic structure of the present invention, therefore it only shows composition related to the present invention.
With reference to Fig. 1, a kind of device that a large amount of crystallite kinds are prepared using wet-milling of simplification of the present invention, including crystallization kettle 1, follow
Ring pump 2 and wet milk 3, are connected into a circulation loop, loop direction is by crystallization kettle 1, circulating pump 2 and wet milk 3：Crystallization kettle
1 bottom, circulating pump 2, wet milk 3, arrive the top of crystallization kettle 1 again.One end of crystallization kettle 1 is connected with circulating pump 2 by pipeline, another
End is connected with wet milk 3 by pipeline；Circulating pump 2 is connected with wet milk 3 by pipeline.The top of crystallization kettle 1 is equipped with charge door
4.1 bottom discharge mouth pipeline of crystallization kettle is equipped with glass transparent visor, or crystallization kettle 1 or is equipped with plum in the circulation loop
The online particle size analysis instrument of Teller-support benefit（FBRM）Probe.
A kind of method that a large amount of crystallite kinds are prepared using wet-milling of simplification of the present invention, is included the following steps：
（1）The solution of active pharmaceutical ingredient X crude products is added into crystallization kettle 1 or adds X crude products and appropriate good solvent, stirring makes it
Solution is made in dissolving；Good solvent refers to that compound has the solvent of high-dissolvability wherein（Can be water or various organic molten
Agent）, corresponding anti-solvent is exactly the compound low solvent of solubility wherein.
（2）Then degree of supersaturation is made to reach certain value by cooling down, evaporating solvent or the appropriate anti-solvent of addition（For example, 2-
30% degree of supersaturation）But do not produce spontaneous crystallization（I.e. degree of supersaturation is no more than Metastable zone width）, degree of supersaturation at this time determines
Determine（4）Walk wet-milling after crystallite kind total amount, concrete numerical value should be determined by technique research and development with ensure product granule size and
Distribution reaches requirement；
（3）Then mass percent is added from charge door 4<1%（Such as 0.5%）Solid crystal seeds induction crystallization；The quality hundred
It is percentage of the crystal seed quality relative to the X crude product qualities of normalization to divide ratio；The crystal seed ratio mentioned in text is entirely crystal seed
Quality relative to the X crude product qualities of normalization percentage.
（4）Open the circulation pump 2 and wet milk 3, can pass through set glass transparent on 1 bottom discharge mouth pipeline of crystallization kettle at this time
The online particle size analysis instrument of visor or plum Teller-support benefit（FBRM）It was observed that gradually there are a large amount of crystallite kinds to produce to form suspension
Liquid.FBRM probes can be installed in crystallization kettle and also be mountable in circulation loop, for tracking the quantity and grain of the generation of crystallite kind
Footpath.Since crystal seed is the template of crystal growth, to product granularity size and very big shadow is distributed with the granule size and total amount of crystal seed
Ring.During technique research and development product granularity size and distribution symbol can be produced to develop by adjusting seed size size and total amount
Close desired technique.Sampling confirms that crystallite kind size meets technological requirement after suspension is formed during production.Close 1 bottom of crystallization kettle
Suspension, crystallization kettle 1 is all transferred back to nitrogen by valve from 1 exit purge circulation line of crystallization kettle.Crystallite kind total amount is by
（2）The degree of supersaturation of step determines, and can easily reach more than 10%.If desired for a greater amount of crystallite kinds（The crystal seed amount needed surpasses
Cross the available degree of supersaturation of Metastable zone width）, a small amount of solid crystal seeds can added（If mass percent is 0.5%）And treated
It is total up to producing enough solids by cooling down, evaporating solvent or add anti-solvent continuation crystallization process after saturation degree release completely
Amount as crystal seed, to be then then turned on circulating pump 2 and wet milk 3, the solid of generation be all ground into granule size symbol at this time
Close desired crystallite kind.
（5）Continue to cool down, evaporate solvent or addition anti-solvent to all precipitations of crystallization terminal crystal.Filtering, washing X are wet
Product, are dried to obtain final X products.Step（2）Cooling, the degree of supersaturation for evaporating solvent or adding appropriate anti-solvent and producing are determined
The number of crystallite kind total amount, step are determined（5）Continue to cool down, evaporate solvent or add remaining anti-solvent.
In order to be more clearly understood that the technology contents of the present invention, spy enumerates specific examples below detailed description.However, tool
Body embodiment is merely for illustration, rather than limitation of the present invention.
Embodiment
Embodiment 1：
The present embodiment uses aspirin to be crystallized for model compound using apparatus and method described in the invention to control
The granule size of the product arrived, detailed process are as follows：Aspirin is dissolved in 70 °C of ethanol/water first（Volume ratio 3/5）It is mixed
Close in solution, be cooled to 55 °C and add the crystal seed of opposite crude product quality 0.5%（250-500 microns）, keep 2 it is small when treat solid
Separate out, degree of supersaturation discharges completely.Open the circulation pump and wet milk for a period of time after, close crystallization kettle bottom valve, treat to starch in pipeline
Liquid is all transferred back to crystallization kettle, and the slurries obtained at this time are crystallite kind suspension.Continue to be cooled to 25 °C, keep 4 it is small when after
Filtering.Thus method can obtain 100-200 microns of aspirin product.And distribution smaller than the crystal grain of crystal seed is narrower.
Embodiment 2：
The present embodiment uses aspirin to be crystallized for model compound using apparatus and method described in the invention to control
The granule size of the product arrived, detailed process are as follows：Aspirin is dissolved in 70 °C of ethanol/water first（Volume ratio 3/5）It is mixed
Close in solution, be cooled to 55 °C and add the crystal seed of opposite crude product quality 0.5%（250-500 microns）, keep 2 it is small when treat solid
Separate out, degree of supersaturation discharges completely.Slow cooling to 35 °C, open the circulation pump and wet milk for a period of time after, close crystallization kettle
Bottom valve, treats that slurries are all transferred back to crystallization kettle in pipeline, and the slurries obtained at this time are crystallite kind suspension.Continue to be cooled to
25 °C, keep 4 it is small when after filter.Thus method can obtain 50-130 microns of aspirin product.It is smaller than the crystal grain of crystal seed
And distribution is narrower.
Embodiment 3：
The present embodiment uses aspirin to be crystallized for model compound using apparatus and method described in the invention to control
The granule size of the product arrived, detailed process are as follows：Aspirin is dissolved in 45 °C of acetone first, adds actual total dosage
20% water（Actual total dosage of water is 27L/kg aspirin）Solution is set to produce degree of supersaturation as anti-solvent, with respect to crude product
The crystal seed of quality 0.5%（250-500 microns）, open the circulation pump and wet milk for a period of time after, close crystallization kettle bottom valve, treat pipe
Slurries are all transferred back to crystallization kettle in road, and the slurries obtained at this time are crystallite kind suspension.Continue to add remaining 80% water,
Then be cooled to 25 °C, keep 4 it is small when after filter.Thus method can obtain 50-150 microns of aspirin product.Compare crystal seed
Crystal grain it is smaller and distribution it is narrower.
Claims (10)
1. the device that a large amount of crystallite kinds are prepared using wet-milling of a kind of simplification, it is characterised in that including being connected into a circulation
Crystallization kettle, circulating pump and the wet milk in circuit.
2. device according to claim 1, it is characterised in that one end of the crystallization kettle passes through pipeline with the circulating pump
It is connected, the other end is connected with wet milk by pipeline；The circulating pump is connected with the wet milk by pipeline.
3. device according to claim 1, it is characterised in that the top of the crystallization kettle is equipped with charge door.
4. device according to claim 1, it is characterised in that the loop direction of the crystallization kettle, circulating pump and wet milk
For：From crystallization kettle bottom, to circulating pump, to wet milk, again at the top of crystallization kettle.
5. device according to claim 1, it is characterised in that it is saturating that the crystallization kettle bottom discharge mouth pipeline is equipped with glass
Photopic vision mirror.
6. a kind of method that a large amount of crystallite kinds are prepared using wet-milling of simplification, this method is used such as any one of claim 1-4
The device, it is characterised in that this method comprises the following steps：
（1）The solution of active pharmaceutical ingredient X crude products is added into crystallization kettle or adds X crude solids and appropriate good solvent, stirring
Make its dissolving that solution be made；
（2）Degree of supersaturation is reached certain value by cooling down, evaporating solvent or add appropriate anti-solvent but do not produce spontaneous knot
Crystalline substance, i.e. degree of supersaturation are no more than Metastable zone width；
（3）Mass percent is added into crystallization kettle<1% solid crystal seeds induction crystallization；The mass percent is crystal seed quality
Relative to the percentage of the X crude product qualities of normalization；
（4）Open the circulation pump and wet milk, observe gradually has a large amount of crystallite kinds to produce to form suspension at this time, and sampling confirms micro-
Crystal seed size meets technological requirement；Crystallization kettle bottom valve is closed, with nitrogen from crystallization kettle exit purge circulation line by suspension
All it is transferred back to crystallization kettle；
（5）Continue through cooling, evaporation solvent or separated out to crystallization kettle addition anti-solvent to terminal crystal whole is crystallized, filtering,
X wet products are washed, are dried to obtain final X products.
7. method as claimed in claim 6, it is characterised in that step（2）In, it is described degree of supersaturation is reached 2-30%, at this time
Degree of supersaturation determine step（4）The total amount of crystallite kind after wet-milling.
8. method as claimed in claim 6, it is characterised in that step（4）In, described observe gradually has a large amount of crystallite kinds to produce
Life forms suspension, passes through the online of set glass transparent visor on crystallization kettle bottom discharge mouth pipeline or plum Teller-support benefit
Particle size analysis instrument, which is observed gradually, has a large amount of crystallite kinds to produce to form suspension；The online particle of the plum Teller-support benefit
Analyzer is spent to be installed in crystallization kettle or in circulation loop.
9. method as claimed in claim 6, it is characterised in that if desired for a greater amount of crystallite kinds, that is, the crystal seed amount needed surpasses
The available degree of supersaturation of Metastable zone width is crossed, then in step（3）And step（4）Between increase following steps：It is a small amount of adding
Solid crystal seeds simultaneously continue crystallization process up to production after degree of supersaturation completely release by cooling down, evaporating solvent or addition anti-solvent
Raw enough solid amounts are as crystal seed, to be then then turned on circulating pump and wet milk, the solid of generation is all ground granulating
Spend the satisfactory crystallite kind of size.
10. method as claimed in claim 6, it is characterised in that step（2）Cooling, evaporation solvent add appropriate anti-solvent
And produce degree of supersaturation determine crystallite kind total amount number, step（5）Continue to cool down, evaporate solvent or remaining anti-molten
Agent adds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711327860.6A CN108031142A (en) | 2017-12-13 | 2017-12-13 | Simplified device and method for preparing large amount of micro-crystal seeds by wet grinding |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711327860.6A CN108031142A (en) | 2017-12-13 | 2017-12-13 | Simplified device and method for preparing large amount of micro-crystal seeds by wet grinding |
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| CN108031142A true CN108031142A (en) | 2018-05-15 |
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| CN201711327860.6A Pending CN108031142A (en) | 2017-12-13 | 2017-12-13 | Simplified device and method for preparing large amount of micro-crystal seeds by wet grinding |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110158156A (en) * | 2019-06-28 | 2019-08-23 | 青岛科技大学 | A kind of crystal seed preparation method for crystallization process |
| CN114163484A (en) * | 2021-12-10 | 2022-03-11 | 浙江金华康恩贝生物制药有限公司 | Amikacin sulfate crystallization method using wet grinder |
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| CN114163484B (en) * | 2021-12-10 | 2024-01-05 | 浙江金华康恩贝生物制药有限公司 | Amikacin sulfate crystallization method using wet mill |
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