CN105031963B - A kind of integrated anti-solvent-vacuum evaporation-cooling or the method for crystallising of anti-solvent - Google Patents
A kind of integrated anti-solvent-vacuum evaporation-cooling or the method for crystallising of anti-solvent Download PDFInfo
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Abstract
The invention discloses the vacuum evaporation cooling of a kind of integrated anti-solvent or the method for crystallising of anti-solvent.The method step following steps: (1) preliminary antisolvent crystallisation: aminoacid material to be crystallized is placed in crystallizer, adding aqueous solvent makes it fully dissolve, and is warming up to 30～80 DEG C, anti-solvent is joined in crystallizer, it is sufficiently stirred for, makes solute partially crystallizable in solution separate out；Material to be crystallized；(2) vacuum evaporation cooling or antisolvent crystallisation: continue stirring, gained solid-liquid system is evaporated under absolute pressure is 20～60kPa, gained solid-liquid system cooled down or adds the anti-solvent identical with step (1), promoting crystal continued growth；Repeat step (2) 1～3 times；(3) filtration drying: employing is filtered, washs, is dried, and prepares crystalline product.The inventive method has simple operation, productivity is high and is easily achieved the advantage that commercial scale produces, and can obtain narrow particle size distribution, crystalline product that particle diameter is big.
Description
Technical field
A kind of method that the present invention relates to antisolvent crystallisation, particularly relate to the vacuum evaporation cooling of a kind of integrated anti-solvent or the method for crystallising of anti-solvent, by the crystallite dimension in regulation and control antisolvent crystallisation, the crystal product that prepared sizes narrowly distributing, particle diameter are big, is particularly suitable for the anti-solvent water-soluble amino acid crystallizing system having anti-solvent normal boiling point less than water.
Background technology
High-purity aminoacid is various active biology, the important synthesis material of medical components.Crystallization is the effective ways obtaining high-purity aminoacid solid product, and crystal particle diameter, distribution and crystal formation have particularly important impact to the quality of crystal product.To this end, prepare particle diameter amino acid crystals big, narrowly distributing, modern biotechnology, medicine and functional health care product are produced significant.
Antisolvent crystallisation be a kind of efficiently, environmental protection, energy-conservation Isolation and purification method, by solute being dissolved in water or other organic solvents, be subsequently adding the dissolubility that certain solvent makes solute in former solvent and reduce, so that the crystallization process that solute separates out.The solvent added is referred to as anti-solvent or precipitant, and anti-solvent can be gas, it is also possible to be liquid.The mechanism of antisolvent crystallisation is that other solvent molecule that the original solvent molecule with solute molecule effect is partly or entirely newly added in the solution replaces, and makes the free energy of solution system be greatly improved, causes solution supersaturation to make solute separate out.Select solvent and the anti-solvent being suitable for, it is possible to obtain higher yields and higher crystalline product purity.Antisolvent crystallisation has operation, and temperature is low, less energy consumption, is widely used in the PRODUCTION TRAITS field of medicine and fine chemicals.
Crystal size and distribution thereof are the key indexs of crystalline product, during antisolvent crystallisation, anti-solvent adds and in mixed process, outburst nucleation is easily caused because local mixing is uneven, thus cause crystal size little and distribution width, impurity is the most easily carried secretly in crystal product simultaneously, affects the purity of product.The growth of conservative control crystal, to obtain bigger mean diameter and narrower distribution, can not only improve content and the product quality of active ingredient, and can make product separation, wash, pack, transport and preserve the improvement obtained in various degree.Therefore, in industrial processes, the control of crystal particle diameter and distribution thereof is particularly significant.
Existing antisolvent crystallisation product quality control method is mainly degree of supersaturation control, nucleated directly controls and multiparameter regulation and control.Owing to saturation is the direct driving force of crystal growth, degree of supersaturation is the least, and growth rate is the slowest, advantageously forms that granule is big, narrow particle size distribution crystalline product；Degree of supersaturation is the biggest, outburst nucleation easily occurs and then affect crystalline product quality in crystal growing process.During antisolvent crystallisation, addition speed or rate of temperature fall by controlling anti-solvent make degree of supersaturation be maintained at a stable scope, in order to the growth of crystalchecked.Owing in antisolvent crystallisation, the membership that adds of anti-solvent inevitably causes the big degree of supersaturation of regional area, thus cause outburst nucleation, make the increase of crystal little granule, particle size distribution uneven, affect its product quality.
Summary of the invention
The present invention is directed to the problem that the little granule crystal of product is more, particle size distribution is uneven that existing antisolvent crystallisation technology exists, thering is provided a kind of easy and simple to handle, purity is high, yield is high integrated anti-solvent-vacuum evaporation-cooling or the method for crystallising of anti-solvent, gained crystalline product particle diameter is big, narrowly distributing.
The present invention to aminoacid by vacuum evaporation cooling (or anti-solvent) circulation operation, it is achieved dissolving short grained to crystal and the control of crystal growth, thus obtain that particle diameter is big, the crystalline product of narrowly distributing.This particle diameter is big, the crystal product of narrowly distributing can not only improve purity and crystallization process yield, and beneficially product separation, wash, pack, transport and preserve.
The principle of the present invention is as follows: when anti-solvent relative solvent boiling point is relatively low, uses vacuum evaporation that the solvent strength in crystal solution phase system can be made to increase, thus promotes that solute dissolves.First dissolve owing to the little granule of crystal has bigger specific surface area, and then pass through to lower the temperature or continue to add anti-solvent acquisition large-size crystals, be achieved in the minimizing of crystal short grained crystal, the increase of oarse-grained crystal.By being evaporated in vacuo cooling (or anti-solvent) circulation operation, it is achieved dissolving short grained to crystal and the control of crystal growth, final acquisition particle diameter is big, the crystalline product of narrowly distributing.For aminoacid material to be crystallized, relevant process conditions are one of key measures of the present invention.
The object of the invention is achieved through the following technical solutions:
The vacuum evaporation cooling of a kind of integrated anti-solvent or the method for crystallising of anti-solvent, it is characterised in that comprise the steps:
(1) preliminary antisolvent crystallisation: be placed in crystallizer by aminoacid material to be crystallized, adds aqueous solvent and makes it fully dissolve, and controlling solution concentration is 10g/L～500g/L；It is warming up to 30～80 DEG C, anti-solvent is joined in crystallizer, control anti-solvent and solvent volume ratio for 1:4～2:1, be sufficiently stirred for, make solute partially crystallizable in solution separate out, obtain crystallized stock；
(2) vacuum evaporation cooling or antisolvent crystallisation: continue stirring, step (1) gained solid-liquid system is evaporated under absolute pressure is 20～60kPa, after control evaporation capacity is the 1/40～1/4 of step (1) described anti-solvent addition, by anti-solvent identical with step (1) to the cooling of gained solid-liquid system or addition, promote crystal continued growth；
Repeat step (2) 1～3 times, make crystalline product reach predetermined crystallite dimension；
(3) filtration drying: take out crystalline solid after being filtered by step (2) gained solid-liquid system；Adding step (1) described identical anti-solvent washing crystal solid, control anti-solvent addition is 1～2 times of solid crystal quality；Crystalline product is prepared after being dried 24 hours；
The normal boiling point temperature of the anti-solvent selected is less than the normal boiling point of solvent；Described anti-solvent is water-soluble alcohol.
For realizing the object of the invention further, it is preferable that described aminoacid is glycine, 5 ' sodium inosinate or 5 ' disodium 5'-ribonucleotide.
Preferably, step (2) crystallisation by cooling process control crystallization temperature reduces by 5～50 DEG C.
Preferably, during step (2) antisolvent crystallisation, anti-solvent addition is the 1/5～1/2 of step (1) described anti-solvent addition.
Preferably, step (1) controls solution concentration is 50g/L～200g/L.
Preferably, step (2) controls evaporation capacity is the 1/20～1/10 of step (1) described anti-solvent addition.
Preferably, described water-soluble alcohol is ethanol
Relative to prior art, present invention have the advantage that
(1) present invention is evaporated in vacuo and can efficiently control crystal product small particles ratio, overcomes in antisolvent crystallisation that uneven the caused crystallite dimension of local concentration produced in anti-solvent adition process is little, the problem of skewness.
(2) present invention is by simple and convenient vacuum evaporation cooling (or anti-solvent) circulation operation, realize dissolving short grained to crystal and the control of crystal growth, product purity and crystallization process yield can not only be significantly improved, and beneficially product separation, wash, pack, transport and preserve, thus effectively realize that particle diameter is big, the crystalline product industrialized production of narrowly distributing.
(3) present invention controls particle diameter and the particle diameter distribution of crystallized stock by the way of adding anti-solvent, being evaporated in vacuo and cool down, and technical process easily realizes, low cost, it is simple to continuous prodution.
(4) by using the inventive method that amino acid crystals par particle size increase by more than 20%, particle diameter distribution standard variance can be made to reduce by more than 25%, it is achieved particle diameter is big, prepared by the amino acid crystals product of narrowly distributing.
Accompanying drawing explanation
Fig. 1 is the FB(flow block) of the method for crystallising of the vacuum evaporation cooling of the present invention integrated anti-solvent or anti-solvent.
Fig. 2 is embodiment 2IMP crystalline product displaing micro picture.
Fig. 3 is comparative example 2IMP crystalline product optical microphotograph picture.
Fig. 4 is embodiment 1 glycine crystallization product optical microphotograph picture.
Fig. 5 is comparative example 1 glycine crystallization product optical microphotograph picture.
Detailed description of the invention
For being best understood from the present invention, below in conjunction with embodiment, the invention will be described further, but it should be recognized that the scope of protection of the presently claimed invention is not limited to the scope that embodiment is stated.
Embodiment 1
Weighing 20g glycine, graduated cylinder measures 100mL water, and the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, and under the mixing speed of 300r/min, stirring makes glycine fully dissolve.Add anti-solvent dehydrated alcohol 300mL with the adding rate of 3mL/min, solution has crystal separate out, be sufficiently stirred for 10min, in order to crystal fully grows.Reducing system pressure is 30mL to 45 55kPa, volatilised liq volume, is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.Then it is respectively adopted crystallisation by cooling (being i.e. cooled to 50 DEG C) or antisolvent crystallisation (i.e. continuing to add anti-solvent dehydrated alcohol 170mL with the adding rate of 3mL/min) two ways promotes crystal growth.And then reduction system pressure is 10mL to 35 45kPa, volatilised liq volume, it is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.In buchner funnel reduce pressure sucking filtration obtain Glycine crystals, add 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be at 60 DEG C be dried 24 hours, prepare Glycine crystals product.
Gained Glycine crystals product carries out morphology observations on Olympus BX41 polarizing microscope, and as shown in Figure 4, result shows that crystal product has preferable crystal morphology.In Malvern Mastersizer 2000, record the average crystal grain diameter using anti-solvent vacuum evaporation cooling or anti-solvent to prepare be respectively 300.1 and 325.4 μm, standard variance respectively ± 85.9 and ± 79.5 μm.
Embodiment 2
Weighing 20g 5 ' sodium inosinate (IMP), graduated cylinder measures 200mL water, and the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, and under the mixing speed of 300r/min, stirring makes IMP fully dissolve.Add anti-solvent dehydrated alcohol 300mL with the adding rate of 3mL/min, solution has crystal separate out, be sufficiently stirred for 10min, in order to crystal fully grows.Reducing system pressure is 30mL to 40 50kPa, volatilised liq volume, is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.Being cooled to 50 DEG C, reducing system pressure is 10mL to 30 40kPa, volatilised liq volume, is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.In buchner funnel reduce pressure sucking filtration obtain IMP crystal, add 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be at 60 DEG C be dried 24 hours, prepare IMP crystal product.As shown in Figure 2.
It is 164.4 μm that gained IMP product records average crystal grain diameter in Malvern Mastersizer 2000, and standard variance is ± 85.9 μm.Products obtained therefrom is (as shown in Figure 3 with direct antisolvent crystallisation method (as described in comparative example 2), average crystal grain diameter is 113.6 μm, standard variance is ± 119.7 μm) contrast understand: by the inventive method implement gained IMP product mean diameter add about 51 μm, standard variance reduces about 34 μm, is indicated above the inventive method and can obtain the crystalline product that crystallite dimension is bigger, be more evenly distributed.
Embodiment 3
Weighing 20g 5 ' disodium 5'-ribonucleotide (I+G), measure 200mL water, the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, and under the mixing speed of 300r/min, stirring makes I+G fully dissolve.Add anti-solvent dehydrated alcohol 300mL with the adding rate of 3mL/min, solution has crystal separate out, be sufficiently stirred for 10min, in order to crystal fully grows.Reducing system pressure is 30mL to 40 50kPa, volatilised liq volume, is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.Being cooled to 50 DEG C, reducing system pressure is 10mL to 30 40kPa, volatilised liq volume, is sufficiently stirred for 5min, in order to the short grained abundant dissolving of crystal.In buchner funnel reduce pressure sucking filtration obtain I+G crystal, add 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be at 60 DEG C be dried 24 hours, prepare I+G crystal product.
In Malvern Mastersizer 2000, record the I+G average crystal grain diameter using anti-solvent vacuum evaporation cooling (or anti-solvent) prepared and standard variance is 99.4 ± 44.9 μm.
Comparative example 1
Weighing 20g glycine, measure 90mL water, the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, 300r/min mixing speed under stirring make glycine fully dissolve.Anti-solvent dehydrated alcohol 270mL is added with the adding rate of 3mL/min, then the sucking filtration that reduces pressure in buchner funnel obtains Glycine crystals, add 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be at 60 DEG C be dried 24 hours, prepare Glycine crystals product.
On instrument same as in Example 1, use the pattern of identical enlargement ratio observation Glycine crystals product, as shown in Figure 5.Comparative example 1 product, the crystallite dimension of comparative example product is less, and intercrystalline size difference is bigger.Comparative example 1 products obtained therefrom size is measured as 243.1 ± 101.3 μm in Malvern Mastersizer 2000.
Comparative example 2
Weighing 20g IMP, measure 190mL water, the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, 300r/min mixing speed under stirring make IMP fully dissolve.Adding anti-solvent dehydrated alcohol 270mL with the adding rate of 3mL/min, the sucking filtration that then reduces pressure in buchner funnel obtains IMP crystal, adds 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be to be dried 24 hours at 60 DEG C, prepare IMP crystal product.
Comparative example 2 products obtained therefrom size is measured as 113.6 ± 119.7 μm in Malvern Mastersizer 2000.
Comparative example 3
Weighing 20g I+G, measure 190mL water, the two joins in crystallization kettle after being sufficiently mixed, warming-in-water to 60 DEG C, 300r/min mixing speed under stirring make I+G fully dissolve.Adding anti-solvent dehydrated alcohol 270mL with the adding rate of 3mL/min, the sucking filtration that then reduces pressure in buchner funnel obtains I+G crystal, adds 30mL absolute ethanol washing, absolute pressure be 40kPa, temperature be to be dried 24 hours at 60 DEG C, prepare I+G crystal product.
Comparative example 3 products obtained therefrom size is measured as 57.9 ± 60.4 in Malvern Mastersizer 2000.
Embodiment 13 gained crystalline product compares with comparative example 13 crystalline product respectively, the corresponding comparative example 1 of embodiment 1, the corresponding comparative example 2 of embodiment 2, and the corresponding comparative example 3 of embodiment 3 is shown in Table 1.As shown in Table 1, embodiment 13 is vacuum evaporation cooling or anti-solvent is cycled to used in antisolvent crystallisation, and comparative example 13 is and is directly added into antisolvent crystallisation.Glycine in embodiment 13, the mean diameter of IMP and I+G are all noticeably greater than comparative example 13, and embodiment 13 Plays difference is respectively less than comparative example 14, be indicated above that embodiment is bigger than the product granularity of comparative example, distribution of sizes evenly.So using the inventive method can significantly increase crystalline product particle diameter, reduce particle size distribution inequality, thus obtain the preferable crystalline product of quality.
Table 1 embodiment and comparative example Contrast on effect
Table 1 is cycled to used in antisolvent crystallisation for vacuum evaporation cooling or anti-solvent and contrasts the addition crystallization of direct anti-solvent.As it can be seen from table 1 when anti-solvent relative solvent boiling point is relatively low, uses vacuum evaporation that the solvent strength in crystal solution phase system can be made to increase, thus promote that solute dissolves.First dissolve owing to the little granule of crystal has bigger specific surface area, and then add anti-solvent acquisition large-size crystals by cooling or continuation, be achieved in the short grained minimizing of crystal, oarse-grained increase.Being cooled down by vacuum evaporation or anti-solvent circulation operation, it is achieved dissolving short grained to crystal and the control of crystal growth, final acquisition particle diameter is big, the crystalline product of narrowly distributing.
Crystal size and distribution thereof are the key indexs of crystalline product, during antisolvent crystallisation, anti-solvent adds and in mixed process, outburst nucleation is easily caused because local mixing is uneven, thus cause crystal size little and distribution width, impurity is the most easily carried secretly in crystal product simultaneously, affects the purity of product.The growth of conservative control crystal, to obtain bigger mean diameter and narrower distribution, can not only improve content and the product quality of active ingredient, and can make product separation, wash, pack, transport and preserve the improvement obtained in various degree.The inventive method vacuum evaporation can efficiently control crystal product small particles ratio, overcomes the problems such as the local concentration problem of non-uniform produced in solvent or anti-solvent adition process, temperature controlled hysteresis effect problem, rising temperature for dissolving little granule energy consumption are high and the scope of application is narrower during antisolvent crystallisation.
The present invention circulates operation by simple and convenient vacuum evaporation cooling or anti-solvent, it is achieved dissolving short grained to crystal and the control of crystal growth, prepares that particle diameter is big, the amino acid crystals of narrowly distributing.Use the inventive method can not only improve purity and crystallization process yield, and beneficially product separation, wash, pack, transport and preserve, significant to the production of modern biotechnology, medicine and functional health care product.
Claims (7)
1. an integrated anti-solvent vacuum evaporation cooling or the method for crystallising of anti-solvent, it is characterised in that comprise the steps:
(1) preliminary antisolvent crystallisation: be placed in crystallizer by aminoacid material to be crystallized, adds aqueous solvent and makes it the most molten
Solving, controlling solution concentration is 10g/L～500g/L；It is warming up to 30～80 DEG C, anti-solvent is joined in crystallizer, control the most molten
Agent and solvent volume ratio for 1:4～2:1, is sufficiently stirred for, makes solute partially crystallizable in solution separate out, obtain crystallized stock；
(2) vacuum evaporation cooling or antisolvent crystallisation: continue stirring, by step (1) gained solid-liquid system in absolute pressure
It is to evaporate, after control evaporation capacity is the 1/40～1/4 of step (1) described anti-solvent addition, by gained solid-liquid under 20～60kPa
System cools down or adds the anti-solvent identical with step (1), promotes crystal continued growth；
Repeat step (2) 1～3 times, make crystalline product reach predetermined crystallite dimension；
(3) filtration drying: take out crystalline solid after being filtered by step (2) gained solid-liquid system；Add step (1) described
Identical anti-solvent washing crystal solid, control anti-solvent addition is 1～2 times of solid crystal quality；After being dried 24 hours
Prepare crystalline product；
The normal boiling point temperature of the anti-solvent selected is less than the normal boiling point of solvent；Described anti-solvent is water-soluble alcohol.
Integrated anti-solvent the most according to claim 1 vacuum evaporation cooling or the method for crystallising of anti-solvent, its feature exists
In: described aminoacid is glycine, 5 ' sodium inosinate or 5 ' disodium 5'-ribonucleotide.
3. being evaporated in vacuo cooling or the method for crystallising of anti-solvent according to the integrated anti-solvent described in claim 1 and 2, it is special
Levy and be: step (2) crystallisation by cooling process control crystallization temperature reduces by 5～50 DEG C.
Integrated anti-solvent the most according to claim 1 vacuum evaporation cooling or the method for crystallising of anti-solvent, its feature exists
In: during step (2) antisolvent crystallisation, anti-solvent addition is the 1/5～1/2 of step (1) described anti-solvent addition.
Integrated anti-solvent the most according to claim 1 vacuum evaporation cooling or the method for crystallising of anti-solvent, its feature exists
In: it is 50g/L～200g/L that step (1) controls solution concentration.
Integrated anti-solvent the most according to claim 1 vacuum evaporation cooling or the method for crystallising of anti-solvent, its feature exists
In: it is the 1/20～1/10 of step (1) described anti-solvent addition that step (2) controls evaporation capacity.
Integrated anti-solvent the most according to claim 1 vacuum evaporation cooling or the method for crystallising of anti-solvent, its feature exists
In: described water-soluble alcohol is ethanol.
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| CN106748849A (en) * | 2016-12-02 | 2017-05-31 | 天津科技大学 | A kind of glycine batch crystallization process granularity regulates and controls method |
| CN108031142A (en) * | 2017-12-13 | 2018-05-15 | 上海合全药物研发有限公司 | A kind of device and method that a large amount of crystallite kinds are prepared using wet-milling of simplification |
| CN110857474B (en) * | 2018-08-24 | 2023-04-18 | 武汉远大弘元股份有限公司 | Method for treating L-cysteine hydrochloride monohydrate |
| KR102282384B1 (en) * | 2019-11-20 | 2021-07-27 | 씨제이제일제당 주식회사 | Purification method of nucleic acid |
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Effective date of registration: 20211230 Address after: 151199 No. 199, Baxian North Road, Zhaodong City, Suihua City, Heilongjiang Province Patentee after: ZHAODONG XINGHU BIOTECHNOLOGY Co.,Ltd. Address before: 510640 No. five, 381 mountain road, Guangzhou, Guangdong, Tianhe District Patentee before: SOUTH CHINA University OF TECHNOLOGY |