Preparation method of dexamethasone sodium phosphate_industrial additives

Background and overview^[1]

Dexamethasone sodium phosphate, chemical name is 16α-methyl-11β, 17α, 21 trihydroxy-9α-fluprogester-1,4-diene-3,20-dione-21-phosphate di Sodium salt is an adrenocortical hormone drug with anti-inflammatory, anti-allergic, anti-rheumatic, and immunosuppressive effects. The mechanism of action is: (1) Anti-inflammatory effect: It can reduce and prevent tissue response to inflammation, thereby reducing the manifestations of inflammation. It can inhibit the accumulation of inflammatory cells, including macrophages and leukocytes, at inflammatory sites, and inhibit phagocytosis, the release of lysosomes, and the synthesis and release of chemical mediators of inflammation. (2) Immunosuppressive effects: including preventing or inhibiting cell-mediated immune responses, delayed allergic reactions, reducing the number of T lymphocytes, monocytes, and eosinophils, and reducing the binding of immunoglobulins to cell surface receptors ability, and inhibits the synthesis and release of interleukins, thereby reducing the transformation of T lymphocytes into lymphocytes and reducing the expansion of primary immune responses. It can also reduce the passage of immune check substances through the basement membrane and reduce the concentration of complement components and immunoglobulins.

Preparation^[1-2]

Report 1,

The preparation method of dexamethasone sodium phosphate for injection includes the following steps:

1) Synthesis of dexamethasone sodium phosphate: Using dexamethasone acetate epoxy as the starting material, it sequentially undergoes ring-opening reaction, recrystallization, alkali-catalyzed hydrolysis, pyrophosphoryl chloride esterification, and neutralization to form a salt. The reaction produces a dexamethasone sodium phosphate solution, which is recrystallized again to obtain dexamethasone sodium phosphate crystals;

Ring-opening reaction: Use dexamethasone acetate epoxy as the starting material, add HF and DMF, the reaction temperature is -10°C, and the reaction time is 3 hours to perform a ring-opening reaction to obtain a dexamethasone acetate solution. Dexamethasone acetate The molar ratio of epoxy, HF and DMF is 1:92:44;

The recrystallization: adding methanol to the dexamethasone acetate solution for recrystallization to obtain dexamethasone acetate;

The base-catalyzed hydrolysis: add the obtained dexamethasone acetate to Na₂CO₃ and methanol, the reaction temperature is 20°C, and the reaction time is 10 minutes. Dexamethasone, the molar ratio of dexamethasone acetate, Na₂CO₃, and methanol is 1:4:214;

The esterification of pyrophosphoryl chloride: react the obtained dexamethasone with pyrophosphoryl chloride and THF to obtain dexamethasone phosphate, and the molar ratio of dexamethasone, pyrophosphoryl chloride and THF is 1:5:19; The neutralization salt-forming reaction: react the obtained dexamethasone phosphate with NaOH and methanol at a reaction temperature of 20°C and a reaction time of 1 hour to obtain dexamethasone sodium phosphate. The molar ratio of dexamethasone phosphate, NaOH and methanol is: 1:2:169;

2). Dry the dexamethasone sodium phosphate crystals obtained in step 1) and ball-mill them into powder;

3) Evenly mix dexamethasone sodium phosphate with glucose, disodium hydrogen phosphate, and sodium dihydrogen phosphate to form a composite carbon black. The weight ratio of dexamethasone sodium phosphate and disodium hydrogen phosphate is 1::0.01 ;

4) Dissolve the mixed composition in step 3) into the prescribed water for injection, then add the prescribed amount of ethanol, add activated carbon, and keep it at 60°C for 30 minutes.

Report 2,

Preparation of freeze-dried powder injection:

(1)Prescription

Dexamethasone Sodium Phosphate 2g

Sorbitol 1000g water-based amino resin

Sodium bisulfite 2g

Add water for injection to 5000ml

1000 bottles

(2) Preparation method

Solution preparation: Take the prescribed amount of sorbitol and sodium bisulfite, dissolve it in 70% of the total preparation amount of water for injection that has been purged with nitrogen, adjust the pH to 8.0-8.4 with a pH adjuster, and add the prescribed amount of dexamethasone phosphate Stir and dissolve the sodium, add 0.05% activated carbon in the prepared amount and stir at room temperature for 30 minutes, filter until clear, use 0.22μm microporous filter membrane to sterilize and filter, then set aside;

Freeze-drying: Take the above-mentioned fine filtrate and put it into 10ml tube bottles at 5ml per bottle (2mg specification). Place the tube bottles on the product chamber of the freeze-drying machine and keep them at -45°C for 5 hours. Turn on the water trap. Turn on the refrigeration switch of the machine. After the pre-freezing and heat preservation is completed, turn on the vacuum pump. When the vacuum reading drops below 20 Pa, gradually increase the plate temperature to -5°C and keep it warm for 12 hours. Then raise the temperature to 0°C and continue to keep it warm for 3 hours. When the product temperature is close to the plate temperature, continue to raise the plate temperature to 30°C and keep it warm for 4 hours. When the product temperature is close to the plate temperature again, stop the freeze-drying, vacuum capping, plugging, and packaging.