CN115974958B - Method for improving clarity of dexamethasone sodium phosphate - Google Patents
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- CN115974958B CN115974958B CN202310059717.2A CN202310059717A CN115974958B CN 115974958 B CN115974958 B CN 115974958B CN 202310059717 A CN202310059717 A CN 202310059717A CN 115974958 B CN115974958 B CN 115974958B
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- 229960002344 dexamethasone sodium phosphate Drugs 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 22
- PLCQGRYPOISRTQ-FCJDYXGNSA-L dexamethasone sodium phosphate Chemical compound [Na+].[Na+].C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP([O-])([O-])=O)(O)[C@@]1(C)C[C@@H]2O PLCQGRYPOISRTQ-FCJDYXGNSA-L 0.000 title 1
- VQODGRNSFPNSQE-CXSFZGCWSA-N dexamethasone phosphate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COP(O)(O)=O)(O)[C@@]1(C)C[C@@H]2O VQODGRNSFPNSQE-CXSFZGCWSA-N 0.000 claims abstract description 74
- 229960004833 dexamethasone phosphate Drugs 0.000 claims abstract description 22
- 238000001914 filtration Methods 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 13
- 230000008025 crystallization Effects 0.000 claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 62
- 238000003756 stirring Methods 0.000 claims description 42
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 16
- 239000012982 microporous membrane Substances 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 229910052719 titanium Inorganic materials 0.000 claims description 16
- 239000010936 titanium Substances 0.000 claims description 16
- 239000000706 filtrate Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 11
- 239000003610 charcoal Substances 0.000 claims description 10
- 229940105082 medicinal charcoal Drugs 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004042 decolorization Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 26
- 230000001276 controlling effect Effects 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- KLCDQSGLLRINHY-UHFFFAOYSA-N 1-phenyldiazenylnaphthalen-2-amine Chemical compound NC1=CC=C2C=CC=CC2=C1N=NC1=CC=CC=C1 KLCDQSGLLRINHY-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- 244000088401 Pyrus pyrifolia Species 0.000 description 2
- 235000001630 Pyrus pyrifolia var culta Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960003657 dexamethasone acetate Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004879 turbidimetry Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for improving clarity of dexamethasone sodium phosphate, which takes dexamethasone phosphate as a raw material, and obtains the dexamethasone sodium phosphate through decolorization, filtration, salifying at a flow rate of 5-10L/h and crystallization. The clarity of the dexamethasone sodium phosphate prepared by the method is obviously improved, the solution is stable within 72 hours after the dexamethasone sodium phosphate is dissolved, the dexamethasone sodium phosphate is simple and controllable, the cost is saved, and the production efficiency is high.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a method for improving clarity of dexamethasone sodium phosphate.
Background
Dexamethasone sodium phosphate is a drug of adrenocortical hormone, and has the chemical name: 16 alpha-methyl-11 beta, 17 alpha, 21-trihydroxy-9 alpha-fluoropregna-1, 4-diene-3, 20-dione-21-phosphate disodium salt, having the formula: c 22H28FNa2O8 P with a molecular weight of 516.41 and a chemical structural formula as follows:
Dexamethasone sodium phosphate has antiinflammatory, antiallergic, antirheumatic, and immunosuppression effects. Most of dexamethasone sodium phosphate in the current market is used in a preparation, namely, 0.9% sodium chloride injection is needed to be added, and the problems of poor stability, unqualified solution clarity, small amount of precipitation and the like exist in the preparation.
With respect to a plurality of synthesis methods of dexamethasone sodium phosphate, patent CN112094311A discloses a synthesis method of dexamethasone sodium phosphate, the method comprises esterification, hydrolysis and extraction and purification by toluene, the process is complicated, a solvent toluene is used, toluene in centrifugal waste liquid has a certain harm to the environment, and mass production is inconvenient. Patent CN105348358A also discloses a synthesis method of dexamethasone sodium phosphate, which takes dexamethasone acetate as a main raw material, and prepares the dexamethasone sodium phosphate through ring opening, recrystallization, hydrolysis, esterification and salification.
In the production process, the dexamethasone sodium phosphate has poor stability and even is unqualified, related insoluble substances are needed to exist in the solution, and aiming at the prior technical problems, no solution method for improving the clarity of the dexamethasone sodium phosphate is disclosed in the prior art, so that a method for improving the clarity of the dexamethasone sodium phosphate, which is easy to operate, needs to be developed.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a method for improving the clarity of dexamethasone sodium phosphate, which can effectively improve the clarity of dexamethasone sodium phosphate, reduce the cost of waste liquid treatment and raw materials and improve the production efficiency.
The invention provides the following technical scheme:
a method for improving clarity of dexamethasone sodium phosphate comprises the following specific steps:
(1) Dexamethasone phosphate is taken as a starting raw material, medicinal carbon is added into methanol to decolorize and dissolve the dexamethasone phosphate, the molar ratio of the dexamethasone phosphate to the methanol to the medicinal carbon is 1 (110-130) (1-3), and the decolorizing temperature is 30-40 ℃;
(2) Filtering, adding alkali liquor under stirring to adjust the pH value to 10-13, crystallizing in an organic solvent, and centrifuging to obtain dexamethasone sodium phosphate.
As a preferred embodiment, the mole ratio of the dexamethasone phosphate, the methanol and the medicinal charcoal in the step (1) is 1:118:2.
As a preferred embodiment, the decolorization temperature in step (1) is 35 to 40 ℃.
As a preferred embodiment, the filtering material in the step (2) is one of polypropylene, titanium microporous membrane and nonwoven filter cloth, preferably 1 μm titanium microporous membrane.
As a preferred embodiment, the step (2) is carried out by stirring in a stainless steel reaction vessel at a stirring speed of 30 to 60r/min, preferably at a stirring speed of 30 to 45r/min.
As a preferred embodiment, the lye in step (2) is one of sodium carbonate solution, sodium hydroxide solution, preferably sodium hydroxide solution.
As a preferred embodiment, the sodium hydroxide solution has a mass concentration of 15% to 25%, preferably 18% to 22%.
As a preferred embodiment, the pH value in the step (2) is 12 to 13.
As a preferred embodiment, in step (2), the alkali solution is added dropwise to the crystallization vessel at a drop rate of 5 to 20L/h, preferably 5 to 10L/h, and at a drop temperature of 10 to 20℃and preferably 10 to 13 ℃.
In a preferred embodiment, the organic solvent in the step (2) includes any one of methanol, ethanol and acetone, and in a preferred embodiment, the organic solvent is methanol, and the mass concentration is preferably 70% -90%.
In a preferred embodiment, the organic solvent is acetone, preferably at a mass concentration of 70% to 90%, more preferably 72% to 78%.
As a preferred embodiment, the crystallization temperature in step (2) is 10 to 20℃and preferably 12 to 15 ℃.
As a preferred embodiment, the centrifugal rotational speed in step (2) is 800 to 2000 rpm, preferably 1800 to 2000 rpm.
Compared with the prior art, the invention has the beneficial effects that:
The invention has high production efficiency and controllable process, is suitable for industrialized production of dexamethasone sodium phosphate, effectively improves the clarity of the dexamethasone sodium phosphate, reduces the cost of waste liquid treatment and raw materials, and improves the production efficiency.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are merely some embodiments of the present invention, but not all embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Adding 0.092mol of dexamethasone phosphate 44.3g,11mol of methanol 352g and 0.17mol of medicinal carbon 2g into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a 1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 30r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 5ml/min, dropwise adding 18% sodium hydroxide solution, adjusting the pH to 12, after the dropwise adding, stirring for 30 minutes, crystallizing in 72% methanol at 13 ℃, stirring for crystallization, centrifuging at the rotation speed of 1800r/min, and drying to obtain 46.5g of dexamethasone sodium phosphate.
Example 2
Adding 44.4g of dexamethasone phosphate, 384g of 12mol of methanol and 3.4g of 0.28mol of medicinal carbon into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 30r/min, controlling the pot temperature to 10-13 ℃, dropwise adding 18% sodium hydroxide solution at a flow rate of 7ml/min, adjusting the pH to 12.5, stirring for 30 minutes after dropwise adding, crystallizing and stirring at a temperature of 12 ℃ in 79% methanol, centrifuging at a rotation speed of 1800r/min, and drying to obtain 47.1g of dexamethasone sodium phosphate.
Example 3
Adding 44.9g of dexamethasone phosphate of 0.095mol, 403.2g of methanol of 12.6mol and 3g of medicinal charcoal of 0.25mol into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a titanium microporous membrane of 1 mu m, controlling the stirring rotation speed of the filtrate to be 32r/min, controlling the pot temperature to be 10-13 ℃, dropwise adding 18% sodium hydroxide solution at a flow rate of 7ml/min, adjusting the pH value to be 12.5, stirring for 30 minutes, crystallizing in acetone of 75% at a temperature of 13 ℃, stirring for crystallization, centrifuging and crystallizing at a rotation speed of 1900r/min, and drying to obtain 46.8g of dexamethasone sodium phosphate.
Example 4
Adding 84.8g of dexamethasone phosphate, 691.2g of 21.6mol of methanol and 4.3g of 0.36mol of medicinal carbon into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a 1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 32r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 9ml/min, dropwise adding 20% sodium hydroxide solution, adjusting the pH to 13, stirring for 30 minutes after dropwise adding, crystallizing in 76% methanol at 14 ℃, stirring for crystallization, centrifuging and crystallizing at the rotation speed of 1900r/min, and drying to obtain 89.9g of dexamethasone sodium phosphate.
Example 5
Adding 85.6g of dexamethasone phosphate of 0.18mol, 713.6g of methanol of 22.3mol and 4.6g of medicinal carbon of 0.38mol into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 34r/min, controlling the pot temperature to 10-13 ℃ and the flow rate to 9ml/min, dropwise adding 22% sodium hydroxide solution, adjusting the pH to 12.5, stirring for 30 minutes, crystallizing in 73% acetone at 12 ℃, stirring for crystallization, centrifuging at 2000r/min, and drying to obtain 89.9g of dexamethasone sodium phosphate.
Example 6
45.2G of 0.096mol dexamethasone phosphate, 396.8g of 12.4mol methanol and 2.64g of 0.22mol medicinal charcoal are added into a flask, the temperature is raised to 35-40 ℃, the heat is preserved for 30 minutes, the mixture is filtered through a1 mu m titanium microporous membrane, the stirring rotation speed of the filtrate is controlled to 34r/min, the tank temperature is 10-13 ℃, the flow rate is controlled to 9ml/min, 18% sodium hydroxide solution is dropwise added, the pH value is adjusted to 13, the mixture is stirred for 30 minutes after the dropwise addition, the mixture is stirred and crystallized at 13 ℃ in 75% methanol, the centrifugal rotation speed is 2000r/min, and the mixture is dried to obtain 48.8g of dexamethasone sodium phosphate.
Example 7
84.5G of 0.178mol dexamethasone phosphate, 691.2g of 21.6mol methanol and 4.3g of 0.36mol medicinal charcoal are added into a flask, the temperature is raised to 35-40 ℃, the heat is preserved for 30 minutes, the mixture is filtered through a1 mu m titanium microporous membrane, the stirring rotation speed of the filtrate is controlled to be 30r/min, the tank temperature is controlled to be 10-13 ℃, the flow rate is controlled to be 5ml/min, 20% sodium hydroxide solution is dripped, the pH value is regulated to be 13, the dripping is completed, the mixture is stirred for 30 minutes, the mixture is stirred and crystallized at 13 ℃ in 77% methanol, the centrifugal rotation speed is 2000r/min, and the mixture is dried to obtain 88.6g of dexamethasone sodium phosphate.
Comparative example 1
45.2G of dexamethasone phosphate of 0.096mol, 396.8g of methanol of 12.4mol and 2.69g of medicinal charcoal of 0.24mol are added into a flask, the temperature is raised to 35-40 ℃, the temperature is kept for 30 minutes, filtering is carried out, 25% sodium hydroxide solution is dripped into the flask at the temperature of 10-13 ℃ and the temperature of 85r/min, the pH is adjusted to 11, stirring is carried out for 30 minutes, crystallization is carried out in acetone at the temperature of 16 ℃, the centrifugal rotation speed is 1200r/min, and 47.9g of dexamethasone sodium phosphate is obtained after drying.
Comparative example 2
45.2G of dexamethasone phosphate of 0.096mol, 396.8g of methanol of 12.4mol and 2.69g of medicinal charcoal of 0.24mol are added into a flask, the temperature is raised to 35-40 ℃, the temperature is kept for 30 minutes, the filtration is carried out, 15% sodium hydroxide solution is dripped into the flask at the tank temperature of 10-13 ℃ and the temperature of 85r/min, the pH is regulated to 10, the stirring is carried out for 30 minutes, the crystallization is carried out in 15 ℃ of ethanol, the centrifugal speed is 1100r/min, and 46.7g of dexamethasone sodium phosphate is obtained after drying.
Comparative example 3
Adding 0.092mol of dexamethasone phosphate 44.3g,11mol of methanol 352g and 0.17mol of medicinal charcoal 2g into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering, dropwise adding 20% sodium hydroxide solution at the tank temperature of 10-13 ℃ and 85r/min, adjusting to pH 13, stirring for 30 minutes, crystallizing in methanol 17 ℃ with stirring, centrifuging at the rotational speed of 1200r/min, and drying to obtain 46.4g of dexamethasone sodium phosphate.
Experimental example clarity investigation of dexamethasone sodium phosphate
According to the clarity inspection method of 2020 edition of Chinese pharmacopoeia, the dexamethasone sodium phosphate samples prepared in examples 1-7 are precisely weighed, dissolved in purified water, placed in glass tubes for turbidimetry matched with the same amount of purified water for 0h, 24h, 36h, 48h, 60h and 72h, and respectively placed under the condition that umbrella canopy lamps are vertically and simultaneously placed in a darkroom, the illuminance is 1000lx, and the turbidity of the sample solution is not more than that of the purified water when observed and compared in the horizontal direction. If turbidity is developed, the turbidity is respectively placed in a paired turbidity comparing glass tube with the same amount of turbidity standard liquid No. 1, the turbidity standard liquid is vertically and simultaneously placed under a umbrella shed lamp in a darkroom, the illuminance is 1000lx, and the turbidity of the sample solution is not more than that of the turbidity standard liquid No. 1 when the sample solution is observed and compared from the horizontal direction. Otherwise, 10ml of the sample solution is taken and placed in a 25ml Nashi cuvette, 10ml of purified water is taken and placed in another 25ml Nashi cuvette, and the two tubes are simultaneously placed on a white background and are subjected to perspective from top to bottom or are simultaneously placed in front of the white background for head-up observation; the test tube solution should be of a darker color than the control tube. If color development is carried out, then the color development and the yellow No. 2 standard colorimetric solution are arranged on a white background, perspective is carried out from top to bottom, or the looking-up is carried out before the white background is arranged at the same place; the color of the sample tube solution is not deeper than that of the yellow No. 2 standard colorimetric solution, and the product solution finally placed for 72 hours is clear and colorless, such as turbidity, and is not deeper than that of the No. 1 turbidity standard solution, such as color, and is not deeper than that of the yellow No. 2 standard colorimetric solution.
TABLE 1 clarity determination of dexamethasone sodium phosphate
According to the clarity measurement results of dexamethasone sodium phosphate in table 1, compared with comparative examples 1-3, the clarity of the products prepared by the methods described in examples 1-7 is examined, the clarity of the solution is better and more stable, the salt forming flow rate and the rotating speed have important influence on the clarity, in addition, the rotating speed control during centrifugation also has influence on the clarity, and the dexamethasone sodium phosphate prepared by the method has the advantages of improved clarity, stable quality, simple preparation process and improved production efficiency.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: adding 0.092mol of dexamethasone phosphate 44.3g,11mol of methanol 352g and 0.17mol of medicinal carbon 2g into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 30r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 5ml/min, dropwise adding 18% sodium hydroxide solution, adjusting the pH to 12, after the dropwise adding, stirring for 30 minutes, crystallizing in 72% methanol at 13 ℃, stirring for crystallization, centrifuging at the rotation speed of 1800r/min, and drying to obtain 46.5g of dexamethasone sodium phosphate.
2. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: adding 44.4g of dexamethasone phosphate, 384g of 12mol of methanol and 3.4g of 0.28mol of medicinal carbon into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 30r/min, controlling the pot temperature to 10-13 ℃, dropwise adding 18% sodium hydroxide solution at a flow rate of 7ml/min, adjusting the pH to 12.5, stirring for 30 minutes after dropwise adding, crystallizing and stirring at a temperature of 12 ℃ in 79% methanol, centrifuging at a rotation speed of 1800r/min, and drying to obtain 47.1g of dexamethasone sodium phosphate.
3. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: adding 44.9g of dexamethasone phosphate of 0.095mol, 403.2g of methanol of 12.6mol and 3g of medicinal charcoal of 0.25mol into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a titanium microporous membrane of 1 mu m, controlling the stirring rotation speed of the filtrate to 32r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 7ml/min, dropwise adding 18% sodium hydroxide solution, adjusting the pH to 12.5, stirring for 30 minutes, crystallizing in acetone of 75% at 13 ℃, stirring for crystallization, centrifuging the filtrate to 1900r/min, and drying to obtain 46.8g of dexamethasone sodium phosphate.
4. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: adding 84.8g of dexamethasone phosphate, 691.2g of 21.6mol of methanol and 4.3g of 0.36mol of medicinal carbon into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 32r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 9ml/min, dropwise adding 20% sodium hydroxide solution, adjusting the pH to 13, stirring for 30 minutes after dropwise adding, crystallizing in 76% methanol at 14 ℃, stirring for crystallization, centrifuging at the rotation speed of 1900r/min, and drying to obtain 89.9g of dexamethasone sodium phosphate.
5. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: adding 85.6g of dexamethasone phosphate of 0.18mol, 713.6g of methanol of 22.3mol and 4.6g of medicinal carbon of 0.38mol into a flask, heating to 35-40 ℃, preserving heat for 30 minutes, filtering by a1 mu m titanium microporous membrane, controlling the stirring rotation speed of the filtrate to 34r/min, controlling the pot temperature to 10-13 ℃, controlling the flow rate to 9ml/min, dropwise adding 22% sodium hydroxide solution, adjusting the pH to 12.5, stirring for 30 minutes, crystallizing in 73% acetone at 12 ℃, stirring for crystallization, centrifuging at 2000r/min, and drying to obtain 89.9g of dexamethasone sodium phosphate.
6. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: 45.2g of 0.096mol dexamethasone phosphate, 396.8g of 12.4mol methanol and 2.64g of 0.22mol medicinal charcoal are added into a flask, the temperature is raised to 35-40 ℃, the heat is preserved for 30 minutes, the mixture is filtered through a1 mu m titanium microporous membrane, the stirring rotation speed of the filtrate is controlled to 34r/min, the pot temperature is 10-13 ℃, the flow rate is controlled to 9ml/min, 18% sodium hydroxide solution is dropwise added, the pH value is adjusted to 13, the mixture is stirred for 30 minutes, the mixture is stirred and crystallized in 75% methanol at 13 ℃, the centrifugal rotation speed is 2000r/min, and the mixture is dried to obtain 48.8g of dexamethasone sodium phosphate.
7. A method for improving clarity of dexamethasone sodium phosphate, which is characterized by comprising the following specific steps: 84.5g of 0.178mol dexamethasone phosphate, 691.2g of 21.6mol methanol and 4.3g of 0.36mol medicinal charcoal are added into a flask, the temperature is raised to 35-40 ℃, the heat is preserved for 30 minutes, the mixture is filtered through a1 mu m titanium microporous membrane, the stirring speed of the filtrate is controlled to be 30r/min, the pot temperature is 10-13 ℃, the flow rate is controlled to be 5ml/min, 20% sodium hydroxide solution is dropwise added, the pH value is adjusted to be 13, the mixture is stirred for 30 minutes, the mixture is stirred and crystallized at 13 ℃ in 77% methanol, the centrifugal speed is 2000r/min, and the mixture is dried to obtain 88.6g of dexamethasone sodium phosphate.
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| CN112094311A (en) * | 2020-10-16 | 2020-12-18 | 西安国康瑞金制药有限公司 | Process for preparing dexamethasone sodium phosphate by one-step method |
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| Title |
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| 微孔钛滤器在制药业中的应用;宋春福;稀有金属材料与工程(第第4期期);21 * |
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