CN105342991A - Preparation technology of dexamethasone sodium phosphate injection for quality improvement - Google Patents

Preparation technology of dexamethasone sodium phosphate injection for quality improvement Download PDF

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Publication number
CN105342991A
CN105342991A CN201510758828.8A CN201510758828A CN105342991A CN 105342991 A CN105342991 A CN 105342991A CN 201510758828 A CN201510758828 A CN 201510758828A CN 105342991 A CN105342991 A CN 105342991A
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dexamethasone
sodium phosphate
dexamethasone sodium
recrystallization
preparation technology
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廖成斌
卢朝成
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Chengdu Zhongmu Biological Pharmaceutical Co Ltd
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Chengdu Zhongmu Biological Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation technology of dexamethasone sodium phosphate injection for quality improvement. The preparation technology comprises the following steps: synthetizing dexamethasone sodium phosphate; sequentially carrying out ring-opening reaction, recrystallization, base-catalyzed hydrolysis, pyrophosphoryl chloride esterification and salt-formation from neutralization to obtain a dexamethasone sodium phosphate solution, and carrying out further recrystallization on the dexamethasone sodium phosphate solution to obtain a dexamethasone sodium phosphate crystal by taking dexamethasone acetate epoxide as a starting material; drying the dexamethasone sodium phosphate crystal, and ball-milling the dried crystal into powder; and dissolving the dexamethasone sodium phosphate powder by water for injection for dilution, adding medicinal propylene glycol, and phosphate buffered solution with the pH being 8.0 to prepare the dexamethasone sodium phosphate injection. With the adoption of the method, the problems that the recrystallization particles are small, the active ingredients of the prepared dexamethasone sodium phosphate injection are rapid in efficacy-decreasing speed existing in the traditional preparation method are solved.

Description

Based on the dexamethasone sodium phosphate injection preparation technology improving quality
Technical field
The present invention relates to medical art, particularly, relating to the dexamethasone sodium phosphate injection preparation technology based on improving quality.
Background technology
Dexamethasone sodium phosphate, chemistry 16 Alpha-Methyl-11 β, 17 α by name, 21 trihydroxy-9 α-fuprednate-Isosorbide-5-Nitrae-diene-3,20-diketone-21-organic phosphate disodium salt, be a kind of Aeroseb-Dex, there is antiinflammatory, antiallergic, rheumatism, immunosuppressive action.The mechanism of action is: (1) antiinflammatory action: can alleviate and prevent tissue to the reaction of inflammation, thus the performance reduced inflammation.Can inflammation-inhibiting cell, comprise macrophage and leukocyte gathering at inflammation part, and suppress phagocytosis, the synthesis of lysosomal release and inflammation chemistry mediator and release.(2) immunosuppressive action: comprise prevent or T suppression cell mediation immunoreation, the anaphylaxis of retardance, reduce the number of T lymphocyte, mononuclear cell, oxyphil cell, reduce the binding ability of immunoglobulin and cell surface receptor, and suppress synthesis and the release of interleukin, thus reduce T lymphocyte to lymphocyte transformation, and alleviate and formerly send out expansion immunoreactive.Also can reduce immunity and check thing by basement membrane, and the concentration of complement component and immunoglobulin can be reduced.
Dexamethasone sodium phosphate is mainly used in anaphylaxis and auto-immune inflammatory disease, be used for connective tissue disease, activeness rheumatism, rheumatoid arthritis, lupus erythematosus, serious bronchial asthma, serious dermatitis, ulcerative colitis, acute leukemia etc., also for some severe infections and poisoning.The Comprehensive Treatment of malignant lymphoma.Within 1 hour after intramuscular injection, blood peak concentration of drug can be reached, and its plasma protein binding rate is low compared with other corticosteroids medicine, therefore clinical its injection inhibitor conventional.
Preparation technology's size of recrystallization particle in recrystallization process of existing dexamethasone sodium phosphate injection is less, be unfavorable for the uniformity of disperseing, and the drug effect of the effective ingredient of the dexamethasone sodium phosphate injection made underspeeds comparatively fast.
Summary of the invention
Technical problem to be solved by this invention is to provide based on improving the dexamethasone sodium phosphate injection preparation technology of quality, to underspeed problem faster to overcome the recrystallization particle that existing preparation method the causes drug effect of the effective ingredient of dexamethasone sodium phosphate injection that is little, that make.
The present invention's adopted technical scheme that solves the problem is: based on the dexamethasone sodium phosphate injection preparation technology improving quality, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Described ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is-10 DEG C ~ 0 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution;
Described recrystallization: add acetone and Tween 80 or ether and Tween 80 in dexamethasone acetate solution, carry out recrystallization and obtain dexamethasone acetate, adopt after recrystallization to revolve and steam except desolventizing, the volume ratio of acetone and Tween 80 is 3-4:1; The volume ratio of ether and Tween 80 is 2-3:1;
Described alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 20 DEG C ~ 30 DEG C, obtains dexamethasone after response time 10min;
Described pyrophosphoryl chloride esterification: the dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 20 DEG C ~ 30 DEG C, the response time, 1h obtained dexamethasone sodium phosphate;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
Reagent used in the present invention is available reagent, wherein HF is Fluohydric acid., and DMF is dimethyl formamide, and the step that the present invention prepares dexamethasone sodium phosphate is simple, raw material is easy to get, reaction condition is gentle, is suitable for suitability for industrialized production, and with low cost, and, the present invention adopts acetone to be used for the recrystallization of dexamethasone acetate, can effectively improve dexamethasone acetate recrystallization ratio, and then improves the yield of final products dexamethasone sodium phosphate; The present invention, by adding phosphate buffered solution in dexamethasone sodium phosphate injection, effectively can avoid the problem that the effective ingredient drug effect of dexamethasone sodium phosphate injection reduces.
Further, in step 1), the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1 ~ 2:92 ~ 95:44 ~ 50.
Further, dexamethasone acetate, Na in step 3) 2cO 3, methanol mol ratio be 1 ~ 2:4 ~ 8:214 ~ 220.
Further, in step 4), the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1 ~ 3:5 ~ 8:19 ~ 25.
Further, in step 5), the mol ratio of dexamethasone phosphate, NaOH, methanol is 1 ~ 2:2 ~ 5:169 ~ 175.
To sum up, the invention has the beneficial effects as follows:
1, to prepare the step of dexamethasone sodium phosphate simple in the present invention, raw material is easy to get, reaction condition is gentle, be suitable for suitability for industrialized production, and with low cost, and the present invention adopts acetone to be used for the recrystallization of dexamethasone acetate, can effectively improve dexamethasone acetate recrystallization ratio, and then improve the yield of final products dexamethasone sodium phosphate.
2, the present invention by adding phosphate buffered solution in dexamethasone sodium phosphate injection, effectively can avoid the problem that the effective ingredient drug effect of dexamethasone sodium phosphate injection reduces.
Detailed description of the invention
Below in conjunction with embodiment, to the detailed description further of invention do, but embodiments of the present invention are not limited thereto.
Embodiment 1:
Based on the dexamethasone sodium phosphate injection preparation technology improving quality, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is-10 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1:92:44;
Described recrystallization: add acetone and Tween 80 in dexamethasone acetate solution, carries out recrystallization and obtains dexamethasone acetate, adopts to revolve to steam except desolventizing after recrystallization, and the volume ratio of acetone and Tween 80 is 3:1;
Alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 20 DEG C, obtains dexamethasone after response time 10min, dexamethasone acetate, Na 2cO 3, methanol mol ratio be 1:4:214;
Described pyrophosphoryl chloride esterification: the dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1:5:19;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 20 DEG C, the response time, 1h obtained dexamethasone sodium phosphate, and the mol ratio of dexamethasone phosphate, NaOH, methanol is 1:2:169;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
Embodiment 2:
Based on the dexamethasone sodium phosphate injection preparation technology improving quality, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Described ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is-5 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1.5:94:48;
Described recrystallization: add acetone and Tween 80 in dexamethasone acetate solution, carries out recrystallization and obtains dexamethasone acetate, adopts to revolve to steam except desolventizing after recrystallization, and the volume ratio of acetone and Tween 80 is 4:1;
Described alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 25 DEG C, obtains dexamethasone after response time 10min, dexamethasone acetate, Na 2cO 3, methanol mol ratio be 1.5:6:216; Described pyrophosphoryl chloride esterification:
The dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, and the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 2:6:22;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 25 DEG C, the response time, 1h obtained dexamethasone sodium phosphate, and the mol ratio of dexamethasone phosphate, NaOH, methanol is 1.5:4:173;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
Embodiment 3:
Based on the dexamethasone sodium phosphate injection preparation technology improving quality, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Described ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is 0 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 2:95:50;
Described recrystallization: add ether and Tween 80 in dexamethasone acetate solution, carries out recrystallization and obtains dexamethasone acetate, adopts to revolve to steam except desolventizing after recrystallization, and the volume ratio of ether and Tween 80 is 2:1;
Described alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 30 DEG C, obtains dexamethasone after response time 10min, dexamethasone acetate, Na 2cO 3, methanol mol ratio be 2:8:220;
Described pyrophosphoryl chloride esterification: the dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 3:8:25;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 30 DEG C, the response time, 1h obtained dexamethasone sodium phosphate, and the mol ratio of dexamethasone phosphate, NaOH, methanol is 2:5:175;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
Embodiment 4:
Based on the dexamethasone sodium phosphate injection preparation technology improving quality, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Described ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is 0 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution, and the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 2:95:50;
Described recrystallization: add ether and Tween 80 in dexamethasone acetate solution, carries out recrystallization and obtains dexamethasone acetate, adopts to revolve to steam except desolventizing after recrystallization, and the volume ratio of ether and Tween 80 is 3:1;
Described alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 30 DEG C, obtains dexamethasone after response time 10min, dexamethasone acetate, Na 2cO 3, methanol mol ratio be 2:8:220;
Described pyrophosphoryl chloride esterification: the dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate, the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 3:8:25;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 30 DEG C, the response time, 1h obtained dexamethasone sodium phosphate, and the mol ratio of dexamethasone phosphate, NaOH, methanol is 2:5:175;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
As mentioned above, the present invention can be realized preferably.

Claims (5)

1., based on the dexamethasone sodium phosphate injection preparation technology improving quality, it is characterized in that, comprise the following steps:
1), the synthesis of dexamethasone sodium phosphate: with dexamethasone acetate epoxy material for initiation material, successively through ring-opening reaction, recrystallization, alkali catalyzed hydrolysis, pyrophosphoryl chloride esterification, be neutralized into reactant salt and obtain dexamethasone sodium phosphate solution, dexamethasone sodium phosphate solution again recrystallization obtains dexamethasone sodium phosphate crystalline solid;
Described ring-opening reaction: with dexamethasone acetate epoxy material for initiation material, add HF, DMF, reaction temperature is-10 DEG C ~ 0 DEG C, and response time 3h carries out ring-opening reaction and obtains dexamethasone acetate solution;
Described recrystallization: add acetone and Tween 80 or ether and Tween 80 in dexamethasone acetate solution, carry out recrystallization and obtain dexamethasone acetate, adopt after recrystallization to revolve and steam except desolventizing, the volume ratio of acetone and Tween 80 is 3-4:1; The volume ratio of ether and Tween 80 is 2-3:1;
Described alkali catalyzed hydrolysis: the dexamethasone acetate obtained is joined Na 2cO 3with in methanol, reaction temperature 20 DEG C ~ 30 DEG C, obtains dexamethasone after response time 10min;
Described pyrophosphoryl chloride esterification: the dexamethasone obtained and pyrophosphoryl chloride, THF are obtained by reacting dexamethasone phosphate;
Describedly be neutralized into reactant salt: the dexamethasone phosphate obtained and NaOH, methanol are reacted, reaction temperature 20 DEG C ~ 30 DEG C, the response time, 1h obtained dexamethasone sodium phosphate;
2) ball milling powdered after the dexamethasone sodium phosphate crystalline solid drying, step 1) obtained;
3), by step 2) the dexamethasone sodium phosphate powder water for injection dissolved dilution prepared, add Proplyleng Glycol, the phosphate buffered solution of pH8.0 makes dexamethasone sodium phosphate injection.
2. the dexamethasone sodium phosphate injection preparation technology based on improving quality according to claim 1, it is characterized in that, in step 1), the mol ratio of dexamethasone acetate epoxy material, HF, DMF is 1 ~ 2:92 ~ 95:44 ~ 50.
3. the dexamethasone sodium phosphate injection preparation technology based on improving quality according to claim 1, is characterized in that, dexamethasone acetate, Na in step 3) 2cO 3, methanol mol ratio be 1 ~ 2:4 ~ 8:214 ~ 220.
4. the dexamethasone sodium phosphate injection preparation technology based on improving quality according to claim 1, it is characterized in that, in step 4), the mol ratio of dexamethasone, pyrophosphoryl chloride, THF is 1 ~ 3:5 ~ 8:19 ~ 25.
5. the dexamethasone sodium phosphate injection preparation technology based on improving quality according to claim 1, it is characterized in that, in step 5), the mol ratio of dexamethasone phosphate, NaOH, methanol is 1 ~ 2:2 ~ 5:169 ~ 175.
CN201510758828.8A 2015-11-10 2015-11-10 Preparation technology of dexamethasone sodium phosphate injection for quality improvement Pending CN105342991A (en)

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Application publication date: 20160224