CN112225715A - Process for refining cromolyn sodium - Google Patents
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- CN112225715A CN112225715A CN202011156230.9A CN202011156230A CN112225715A CN 112225715 A CN112225715 A CN 112225715A CN 202011156230 A CN202011156230 A CN 202011156230A CN 112225715 A CN112225715 A CN 112225715A
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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Abstract
The invention belongs to the technical field of refining of a sodium cromoglycate crude product, and particularly relates to a refining process of sodium cromoglycate. Adding the crude sodium cromoglycate into the mixed solution, and heating to dissolve the crude sodium cromoglycate; adding half of the activated carbon moistened by alcohol, preserving heat and refluxing for 0.5-0.6h, then adding the rest of the activated carbon soaked by alcohol, and continuing preserving heat and refluxing for 0.5-0.6 h; pressing the feed liquid into a crystallization kettle in a nitrogen atmosphere; starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished; and (3) cooling the temperature in the crystallization kettle, standing for crystallization, then performing throw filtration on the filtrate, collecting wet refined product, and drying to prepare the refined sodium cromoglycate. The process for refining the sodium cromoglycate has the advantages that the process parameters are easy to control, the HPLC purity of the refined sodium cromoglycate is more than or equal to 99.8 percent, the yield is more than 90 percent, and unknown single impurity is less than or equal to 0.10 percent.
Description
Technical Field
The invention belongs to the technical field of refining of a sodium cromoglycate crude product, and particularly relates to a refining process of sodium cromoglycate.
Background
Sodium cromoly sodium, distinguished as disodium cromoly, is white crystalline powder, is dissolved in water, is insoluble in ethanol or chloroform, is odorless, tasteless at first, slightly bitter later, easily absorbs moisture, easily discolors when exposed to light, and needs to be stored in a sealed manner and protected from light. Can be used for treating allergic asthma, allergic rhinitis or ulcerative colitis, and has effects in stabilizing mast cell membrane, inhibiting mast cell lysis and degranulation, and preventing release of allergic mediator in response to antigen and antibody. The cromolyn sodium eye drop is used for treating allergic conjunctivitis, vernal conjunctivitis and vernal keratitis. Topical ocular instillation is only effective in reducing the degranulation of mast cells in type I hypersensitivity reactions, thereby slowing the subsequent activation and aggregation of eosinophils, neutrophils, and monocytes.
Patent CN 106957295a discloses a physical concentration method for extracting the crude drug of cromolyn in the residual liquid, and discloses that the collected crude product of cromolyn is decolorized with 70% ethanol solvent and added with activated carbon, refined three to five times, and then dried to obtain the finished product of cromolyn.
U.S. Pat. No. 5,000,000 for the preparation of disodium cromoglycate A pure product of disodium cromoglycate was prepared by "adding ethanol to the resulting brownish yellow mixture and stirring at room temperature for 30min, then filtering, washing the resulting solid with a mixture of 95% ethanol/5% water, and drying the wet solid under vacuum at 50 ℃. "
In the process, 70% ethanol is used as a solvent, and experiments prove that sodium cromoglycate is very easy to separate out under the ethanol concentration, and a large amount of sodium cromoglycate is separated out in activated carbon and a filter during filtration, so that pipelines are easy to block, and the yield is reduced; in order to prevent the sodium cromoglycate from being separated out, the filtration temperature needs to be increased, and the filtration is carried out under the condition of boiling reflux, so that the process safety is reduced; the crystal form of the obtained cromolyn sodium is poor due to the over-fast crystallization, impurities are easily wrapped in precipitates, and the purity of a final product is influenced; the active carbon is added at one time, the decoloring effect is poor, the chromaticity of the finished product is too high, and the sodium cromoglycate eye drops meeting the chromaticity requirement of Chinese pharmacopoeia cannot be prepared.
Disclosure of Invention
The purpose of the invention is: provides a refining process of cromolyn sodium. The refining process parameters are easy to control, the production risk is greatly reduced, the purity of the obtained cromolyn sodium is greatly improved, and the final yield is greatly improved.
The invention relates to a process for refining cromolyn sodium, which comprises the following steps:
(1) putting the crude product of the cromolyn sodium into a refining kettle containing mixed solution of alcohol and purified water, heating to 75-82 ℃, and completely dissolving the crude product of the cromolyn sodium;
(2) adding 50 wt% of activated carbon moistened by alcohol, preserving heat and refluxing for 0.5-0.6h, then adding the rest of activated carbon soaked by alcohol, and continuing preserving heat and refluxing for 0.5-0.6 h;
(3) filtering the feed liquid while the feed liquid is hot and pressing the feed liquid into a crystallization kettle under the nitrogen protection atmosphere, flushing a refining kettle and a pipeline by using alcohol, heating the obtained washing liquid to 73-76 ℃, and pressing the washing liquid into the crystallization kettle together through a filter for crystallization treatment;
(4) starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is completely dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished;
(5) slowly cooling the temperature in the crystallization kettle to below 5 ℃, standing for crystallization for 4-5 hours, putting the filtrate into a centrifuge for spin-filtration, collecting wet refined product after centrifugation, and drying to obtain the refined sodium cromoglycate.
Wherein:
the mass concentration of the alcohol in the step (1) is 55-65%, and the alcohol with the mass concentration of 60% is preferred.
The weight ratio of the alcohol to the purified water in the mixed solution in the step (1) is 1.5-1.8: 1.
The weight ratio of the sodium cromoglycate crude product to the mixed solution in the step (1) is 1:16-25, and preferably, the weight ratio of the sodium cromoglycate crude product to the mixed solution is 1: 24.
And (3) wetting the activated carbon by adopting alcohol with the mass concentration of 60% in the step (2), wherein the weight ratio of the alcohol to the activated carbon is 5: 0.9-1.0.
The weight ratio of the sodium cromoglycate crude product to the active carbon in the step (2) is 1: 0.2.
The heat preservation reflux temperature in the step (2) is 80-82 ℃.
The hot filtration temperature in step (3) is 75-82 ℃.
And (4) heating to 80-82 ℃, wherein the variable-frequency stirring rotating speed is 90-95r/min, and the low-speed stirring rotating speed is 10-20 r/min.
And (4) adding a certain amount of alcohol to control the concentration of the alcohol in the crystallization kettle to be 70-75%, preferably 72-73%.
And (5) reducing the temperature to be below 5 ℃ at the cooling rate of 10-15 ℃/h.
And (5) in the filter throwing process, washing the filter cake twice by using alcohol, wherein the washing time is 20-25min each time.
The drying vacuum degree in the step (5) is-0.085 to-0.090 MPa, the drying temperature is 80 to 90 ℃, and the drying time is 5 to 6 hours.
As a preferred technical scheme, the refining process of cromolyn sodium comprises the following steps:
(1) adding alcohol and purified water into the refining kettle via high-level tank, and stirring for 10-15 min. Opening a feed port to add the sodium cromoglycate crude product, starting stirring, opening a heating valve of a refining kettle, opening a circulating water outlet valve and a circulating water inlet valve of a heat exchanger, raising the temperature in the refining kettle to 75-82 ℃, and completely dissolving the crude product.
(2) Pumping half wet activated carbon, and refluxing for 0.5 hour; then adding the rest half of the activated carbon, continuously preserving the heat for 0.5 hour, and opening a filter heating valve to preheat during the heat preservation reflux period.
(3) Closing the heating valve, opening the kettle bottom valve and the crystallization kettle valve, opening the nitrogen valve, pressing the hot feed liquid (75-82 deg.C) to the crystallization kettle through the filter, adding alcohol into the refining kettle through the high-level tank, heating to about 75 deg.C, and pressing into the crystallization kettle. And (3) emptying the refining kettle, closing a circulating water inlet valve and a circulating water outlet valve of the heat exchanger, opening a press cover of the press filter, removing the active carbon in the press filter, and cleaning the press filter and the filter element by using water.
(4) Starting frequency conversion stirring, after the material liquid is pressed into a crystallization kettle at a refining position, heating to be completely dissolved, opening the high position of alcohol, and dropwise adding the high position alcohol into the crystallization kettle to control the concentration of the alcohol in the crystallization kettle to be 72-73%. After the dropwise addition, the heating valve is closed, the low-speed stirring is started, and the temperature is slowly reduced to the room temperature.
(5) Opening a chilled water valve, slowly reducing the temperature in the crystallization kettle to be below 5 ℃, standing for crystallization for 4-5 hours, closing a water chilling unit, and closing a chilled water inlet valve and a chilled water outlet valve. Laying a filter bag in a centrifuge, putting feed liquid into the centrifuge, starting the centrifuge for filtration, washing a filter cake twice by using alcohol, washing for 20 minutes each time, closing the centrifuge after centrifugation is finished, taking out the filter bag, collecting wet refined products, and conveying the wet refined products to a drying post for drying.
In the step (4), the feed liquid filtered into the crystallization kettle is precipitated due to the temperature reduction, and the precipitate crystals are too small and powdery due to the too fast precipitation, so the precipitate is dissolved completely by heating, and is slowly precipitated again. The alcohol is added dropwise, and the concentration of the alcohol is adjusted to 72-73% because the crystallization effect and the yield reach the best equilibrium state under the concentration. The concentration is low, so that the water content is high, the cromolyn sodium is dissolved in water, and the yield is reduced; the concentration is too high, and the polarity of the solvent is changed, so that the sodium cromoglycate is separated out too fast and is easy to wrap impurities.
Controlling slow cooling in the step (5), wherein the rapid cooling can cause the sodium cromoglycate to be rapidly separated out; cooling to 5 ℃, standing for crystallization and crystal growth, ensuring the maximum precipitation of the product and improving the yield; meanwhile, the crystal particles are large, so that the purity is easily improved and the filter-throwing operation is easy.
Compared with the prior art, the invention has the following beneficial effects:
(1) the refining process of the cromolyn sodium provided by the invention has the advantages that the process parameters are easy to control, the risk in the production process is reduced, the yield and the purity of the obtained cromolyn sodium are greatly improved, and the crystal form of the product is good.
(2) According to the refining process of the sodium cromoglycate, the active carbon is added in two times, so that the chromaticity of the prepared sodium cromoglycate is obviously reduced, and the sodium cromoglycate eye drops meeting the chromaticity requirement of Chinese pharmacopoeia can be prepared.
(3) By adopting the process for refining, the HPLC purity of the refined cromolyn sodium is not less than 99.8%, the yield is higher than 90%, and unknown single impurity is not more than 0.10%.
Drawings
FIG. 1 is a high performance liquid chromatogram of cromolyn sodium prepared in comparative example 1;
FIG. 2 is a high performance liquid chromatogram of the fine sodium cromoglycate prepared in example 1;
FIG. 3 is a high performance liquid chromatogram of the fine sodium cromoglycate prepared in example 2;
FIG. 4 is a high performance liquid chromatogram of the fine sodium cromoglycate prepared in example 3.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
The refining process of cromolyn sodium described in this example 1 comprises the following steps:
(1) putting the crude product of the cromolyn sodium into a refining kettle containing mixed solution of alcohol and purified water, heating to 75 ℃, and completely dissolving the crude product of the cromolyn sodium;
(2) adding 50 wt% of activated carbon moistened by alcohol, preserving heat and refluxing for 0.5h, then adding the rest of activated carbon soaked by alcohol, and continuing preserving heat and refluxing for 0.5 h;
(3) filtering the feed liquid while the feed liquid is hot and pressing the feed liquid into a crystallization kettle under the nitrogen protection atmosphere, flushing a refining kettle and a pipeline by using alcohol, heating the obtained washing liquid to 73 ℃, and pressing the washing liquid into the crystallization kettle together through a filter for crystallization treatment;
(4) starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is completely dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished;
(5) and (3) cooling the temperature in the crystallization kettle to 4 ℃, standing for crystallization for 4 hours, putting the filtrate into a centrifuge for filtration, collecting wet refined products after centrifugation, and drying to obtain 8.6Kg of refined sodium cromoglicate.
Wherein:
the mass concentration of the alcohol in the step (1) is 60%.
The weight ratio of the alcohol to the purified water in the mixed solution in the step (1) is 1.7:1, and 136.0kg of edible alcohol and 80.0kg of purified water are added.
The weight ratio of the sodium cromoglycate crude product to the mixed solution in the step (1) is 1:24, and the mass of the sodium cromoglycate crude product is 9 kg.
And (3) wetting the activated carbon by adopting alcohol with the mass concentration of 60% in the step (2), wherein the weight ratio of the alcohol to the activated carbon is 5:0.9, adding 10kg of alcohol, and wetting 1.8kg of activated carbon.
The weight ratio of the sodium cromoglycate crude product to the active carbon in the step (2) is 1: 0.2.
The heat preservation reflux temperature in the step (2) is 80 ℃.
The hot filtration temperature in step (3) was 75 ℃.
And (4) heating to 82 ℃, wherein the variable-frequency stirring rotating speed is 90r/min, and the low-speed stirring rotating speed is 10 r/min.
And (4) adding a certain amount of alcohol into the crystallization kettle to control the concentration of the alcohol in the crystallization kettle to be 72%.
The temperature reduction rate of 10 ℃/h in the step (5) is reduced to 4 ℃.
And (5) in the filter throwing process, washing the filter cake twice by using alcohol, wherein the washing time is 20min each time.
The drying vacuum degree in the step (5) is-0.090 MPa, the drying temperature is 90 ℃, and the drying time is 5 h.
Yield equation: yield is equal to 100% of the number of the fine sodium cromoglycate/the number of the crude sodium cromoglycate.
8.6Kg of refined sodium cromoglycate was prepared by the method described in example 1, with a yield of 8.6/9 × 100% to 95.6%, as shown in FIG. 2, with a purity of 99.99%; the obtained cromolyn sodium is made into solution, and compared with standard yellow green, the color number is 0.5-1.
Example 2
The refining process of cromolyn sodium described in this example 2 comprises the following steps:
(1) putting 9kg of the crude sodium cromoglycate into a refining kettle containing 128kg of edible alcohol and 80kg of purified water, heating to 78 ℃, and completely dissolving the crude sodium cromoglycate;
(2) adding 1.8kg of 50 wt% of activated carbon moistened by 9kg of alcohol, carrying out heat preservation and reflux for 0.55h, then adding the rest of activated carbon soaked by the alcohol, and continuing to carry out heat preservation and reflux for 0.55 h;
(3) filtering the feed liquid while the feed liquid is hot and pressing the feed liquid into a crystallization kettle under the nitrogen protection atmosphere, flushing a refining kettle and a pipeline by using alcohol, heating the obtained washing liquid to 74 ℃, and pressing the washing liquid into the crystallization kettle together through a filter for crystallization treatment;
(4) starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is completely dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished;
(5) and (3) cooling the temperature in the crystallization kettle to 4 ℃, standing for crystallization for 5 hours, putting the filtrate into a centrifuge for spin filtration, collecting wet refined products after centrifugation, and drying to obtain 8.4kg of refined sodium cromoglycate.
Wherein:
the mass concentration of the alcohol in the step (1) is 58%.
The weight ratio of the alcohol to the purified water in the mixed solution in the step (1) is 1.6:1, and 128Kg of edible alcohol and 80Kg of purified water are added.
The weight ratio of the sodium cromoglycate crude product to the mixed solution in the step (1) is 1:23, and the mass of the sodium cromoglycate crude product is 9 Kg.
And (3) wetting the activated carbon by adopting alcohol with the mass concentration of 60% in the step (2), wherein the weight ratio of the alcohol to the activated carbon is 5:1, adding 9kg of alcohol, and wetting 1.8kg of the activated carbon.
The weight ratio of the sodium cromoglycate crude product to the active carbon in the step (2) is 1: 0.2.
The heat preservation reflux temperature in the step (2) is 81 ℃.
The hot filtration temperature in step (3) was 80 ℃.
And (4) heating to 82 ℃, wherein the variable-frequency stirring rotating speed is 95r/min, and the low-speed stirring rotating speed is 20 r/min.
And (4) adding a certain amount of alcohol into the crystallization kettle to control the concentration of the alcohol in the crystallization kettle to be 72%.
The temperature reduction rate of 15 ℃/h in the step (5) is reduced to 4 ℃.
And (5) in the filter throwing process, washing the filter cake twice by using alcohol, wherein the washing time is 25min each time.
The drying vacuum degree in the step (5) is-0.090 MPa, the drying temperature is 85 ℃, and the drying time is 5.5 h.
8.4Kg of refined sodium cromoglycate was prepared by the method described in example 2, with a yield of 8.4/9 × 100% — 93.3%, as shown in FIG. 3, with a purity of 100.00%; the obtained cromolyn sodium is made into solution, and compared with standard yellow green, the color number is 0.5-1.
Example 3
The refining process of cromolyn sodium in this example 3 comprises the following steps:
(1) putting the crude product of the cromolyn sodium into a refining kettle containing mixed solution of alcohol and purified water, heating to 82 ℃, and completely dissolving the crude product of the cromolyn sodium;
(2) adding 50 wt% of activated carbon moistened by alcohol, preserving heat and refluxing for 0.6h, then adding the rest of activated carbon soaked by alcohol, and continuing preserving heat and refluxing for 0.6 h;
(3) filtering the feed liquid while the feed liquid is hot and pressing the feed liquid into a crystallization kettle under the nitrogen protection atmosphere, flushing a refining kettle and a pipeline by using alcohol, heating the obtained washing liquid to 76 ℃, and pressing the washing liquid into the crystallization kettle together through a filter for crystallization treatment;
(4) starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is completely dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished;
(5) and (3) cooling the temperature in the crystallization kettle to 3 ℃, standing for crystallization for 4.5 hours, putting the filtrate into a centrifuge for spin filtration, collecting wet refined products after centrifugation, and drying to obtain the refined sodium cromoglycate.
Wherein:
the mass concentration of the alcohol in the step (1) is 61%.
The weight ratio of the alcohol to the purified water in the mixed solution in the step (1) is 1.8:1, 144Kg of edible alcohol and 80Kg of purified water are added.
The weight ratio of the sodium cromoglycate crude product to the mixed solution in the step (1) is 1:25, and the mass of the sodium cromoglycate crude product is 9 Kg.
And (3) wetting the activated carbon by adopting alcohol with the mass concentration of 60% in the step (2), wherein the weight ratio of the alcohol to the activated carbon is 5:0.95, adding 9.5kg of alcohol, and wetting 1.8kg of the activated carbon.
The weight ratio of the sodium cromoglycate crude product to the active carbon in the step (2) is 1: 0.2.
The heat preservation reflux temperature in the step (2) is 82 ℃.
The hot filtration temperature in step (3) was 81 ℃.
And (4) heating to 82 ℃, wherein the variable-frequency stirring rotating speed is 93r/min, and the low-speed stirring rotating speed is 15 r/min.
And (4) adding a certain amount of alcohol to control the concentration of the alcohol in the crystallization kettle to be 73%.
The temperature reduction rate of 12 ℃/h in the step (5) is reduced to 3 ℃.
And (5) in the filter throwing process, washing the filter cake twice by using alcohol, wherein the washing time is 22min each time.
The drying vacuum degree in the step (5) is-0.085 MPa, the drying temperature is 80 ℃, and the drying time is 6 hours.
8.5Kg of refined sodium cromoglycate was prepared by the method described in example 3, with a yield of 8.5/9 × 100% — 94.4%, as shown in FIG. 4, with a purity of 99.99%; the obtained cromolyn sodium is made into solution, and compared with standard yellow green, the color number is 0.5-1.
Comparative example 1
The refining process of cromolyn sodium in comparative example 1 comprises the following steps:
the mixture ratio: the crude sodium cromoglycate is ethanol (70 percent) and active carbon is 1:28: 0.25.
Adding the crude product of the cromolyn sodium, ethanol and active carbon into a refining tank, heating and refluxing for 2 hours, filtering, adding 2 times of ethanol (95%) into the filtrate, cooling to 0 ℃, separating out crystals, performing spin filtration, washing with ethanol, and drying to obtain the cromolyn sodium; the total yield was 57.6%. The purity is shown in figure 1, and the purity is 99.00%.
Claims (10)
1. A refining process of cromolyn sodium is characterized by comprising the following steps: the method comprises the following steps:
(1) putting the crude product of the cromolyn sodium into a refining kettle containing mixed solution of alcohol and purified water, heating to 75-82 ℃, and completely dissolving the crude product of the cromolyn sodium;
(2) adding 50 wt% of activated carbon moistened by alcohol, preserving heat and refluxing for 0.5-0.6h, then adding the rest of activated carbon soaked by alcohol, and continuing preserving heat and refluxing for 0.5-0.6 h;
(3) filtering the feed liquid while the feed liquid is hot and pressing the feed liquid into a crystallization kettle under the nitrogen protection atmosphere, flushing a refining kettle and a pipeline by using alcohol, heating the obtained washing liquid to 73-76 ℃, and pressing the washing liquid into the crystallization kettle together through a filter for crystallization treatment;
(4) starting variable frequency stirring, heating the feed liquid in the crystallization kettle until the feed liquid is completely dissolved, dripping quantitative alcohol into the crystallization kettle, stopping heating and starting low-speed stirring after dripping is finished;
(5) and (3) cooling the temperature in the crystallization kettle to below 5 ℃, standing for crystallization for 4-5 hours, putting the filtrate into a centrifuge for spin-filtration, collecting wet refined products after centrifugation, and drying to obtain the refined sodium cromoglycate.
2. The refining process of cromolyn sodium as claimed in claim 1, wherein: the weight ratio of the alcohol to the purified water in the mixed solution in the step (1) is 1.5-1.8: 1.
3. The refining process of cromolyn sodium as claimed in claim 1, wherein: the weight ratio of the sodium cromoglycate crude product to the mixed solution in the step (1) is 1: 16-25.
4. The refining process of cromolyn sodium as claimed in claim 1, wherein: wetting the activated carbon by adopting 60% alcohol in mass concentration in the step (2), wherein the weight ratio of the alcohol to the activated carbon is 5: 0.9-1.0; the weight ratio of the sodium cromoglycate crude product to the active carbon is 1: 0.2.
5. The refining process of cromolyn sodium as claimed in claim 1, wherein: the heat preservation reflux temperature in the step (2) is 80-82 ℃.
6. The refining process of cromolyn sodium as claimed in claim 1, wherein: the hot filtration temperature in step (3) is 75-82 ℃.
7. The refining process of cromolyn sodium as claimed in claim 1, wherein: and (4) heating to 80-82 ℃, wherein the variable-frequency stirring rotating speed is 90-95r/min, and the low-speed stirring rotating speed is 10-20 r/min.
8. The refining process of cromolyn sodium as claimed in claim 1, wherein: and (4) adding a certain amount of alcohol into the crystallization kettle to control the concentration of the alcohol in the crystallization kettle to be 70-75%.
9. The refining process of cromolyn sodium as claimed in claim 1, wherein: reducing the temperature to below 5 ℃ at a cooling rate of 10-15 ℃/h in the step (5), and standing for crystallization for 4-5 h; in the filter-swinging process, the filter cake is washed by alcohol twice, and each washing time is 20-25 min.
10. The refining process of cromolyn sodium as claimed in claim 1, wherein: the drying vacuum degree in the step (5) is-0.085 to-0.090 MPa, the drying temperature is 80 to 90 ℃, and the drying time is 5 to 6 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5508451A (en) * | 1994-07-07 | 1996-04-16 | Hoechst Celanese Corporation | Process for the preparation of dialkali metal cromoglycates |
| CN106946829A (en) * | 2017-05-27 | 2017-07-14 | 湖北华丹医药科技股份有限公司 | A kind of method that utilization raffinate produces nasmil bulk drug |
| CN106957295A (en) * | 2017-05-27 | 2017-07-18 | 湖北华丹医药科技股份有限公司 | A kind of method that utilization raffinate extracts nasmil bulk drug |
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2020
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5508451A (en) * | 1994-07-07 | 1996-04-16 | Hoechst Celanese Corporation | Process for the preparation of dialkali metal cromoglycates |
| CN106946829A (en) * | 2017-05-27 | 2017-07-14 | 湖北华丹医药科技股份有限公司 | A kind of method that utilization raffinate produces nasmil bulk drug |
| CN106957295A (en) * | 2017-05-27 | 2017-07-18 | 湖北华丹医药科技股份有限公司 | A kind of method that utilization raffinate extracts nasmil bulk drug |
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