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Refining method of cyclophosphamide

A technology of cyclophosphamide and purification method, applied in the field of preparation of cyclophosphamide, can solve the problems of large particle size, unstable cyclophosphamide, complicated process, etc., achieve dense and stable particles, improved solubility and stability, and improved product quality. The effect of uniform particle size

Pending Publication Date: 2022-05-06
ANHUI POLY PHARM CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The process methods of the prior art all obtain cyclophosphamide crystals with improved purity, but the ubiquitous problem is that cyclophosphamide is unstable, because cyclophosphamide can undergo anhydrous and monohydrate transformation at room temperature, resulting in an unstable state
The process is complex and requires freezing solution induction, the cost of this process is very expensive, and the collapsed structure caused by the escape of crystallization water is difficult to obtain the consistency of crystal particles
The products obtained by us after repeated tests by the freezing process generally have large particle sizes, the water solubility has not been improved, and contain freezing-inducing agent impurities, and the purity has not reached the Pharmacopoeia standard

Method used

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  • Refining method of cyclophosphamide
  • Refining method of cyclophosphamide
  • Refining method of cyclophosphamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034]Add 10g of crude cyclophosphamide into a three-necked bottle filled with 60ml of water, stir and heat to 50°C, continue to add 30ml of normal temperature water, stir and keep at 50°C until dissolved, and filter out the insoluble impurities at the bottom of the bottle; When stirring at 45rpm and cooling down to 40°C, reduce the speed to 35rpm, and after cooling down to 30°C, add 60g of ether solution and 1g of Na 2 O·Al 2 o 3 2SiO2 2 9 / 2H 2 O (where the pore size is ≤10nm, the silicon-aluminum ratio is 2:1, and the particle size is ≥1mm), maintain the temperature and continue to stir until the solution is no longer clear and the bottom of the bottle is clearer than the upper part, or the solution appears a little cloudy until the bottom changes again. Clear state; stop stirring at this time, quickly remove the molecular sieve, keep the solution and continue to stir and slightly heat up to 35 ° C, when it can be seen that white turbidity appears along the bottle wall, s...

Embodiment 2

[0037] Add 15g of crude cyclophosphamide into a three-neck bottle filled with 100ml of water, stir and heat to 55°C, continue to add 50ml of room temperature water, stir until dissolved, filter out insoluble impurities at the bottom of the bottle; stir at 40rpm and cool down to 40°C When the temperature is within, reduce the rotation speed to 30rpm, and after cooling down to 30°C, add 120g of ether solution and 1g of Na 2 O·Al 2 o 3 2SiO2 2 9 / 2H 2 O (where the pore size is ≤10nm, the silicon-aluminum ratio is 2:1, and the particle size is ≥1mm), maintain the temperature and continue to stir until the solution is no longer clear, and the bottom of the bottle is clearer than the upper part, stop stirring, quickly remove the molecular sieve, and keep Continue to stir the solution and heat up slightly to 35°C. When it can be seen that white turbidity appears along the bottle wall, stop heating and cool down to room temperature naturally, and the stirring speed drops to 20rpm. ...

Embodiment 3

[0040] Add 10g of crude cyclophosphamide into a three-necked bottle filled with 60ml of water, stir and heat to 50°C, continue to add 30ml of normal temperature water, stir and keep at 50°C until dissolved, and filter out the insoluble impurities at the bottom of the bottle; When stirring at 45rpm and cooling down to 40°C, reduce the speed to 35rpm, and after cooling down to 30°C, add 60g of ether solution and 1g of Na 2 O·Al 2 o 3 2SiO2 2 9 / 2H 2 O (where the pore size is ≤10nm, the silicon-aluminum ratio is 2:1, and the particle size is ≥1mm), maintain the temperature and continue to stir until the solution is no longer clear, and the bottom of the bottle is clearer than the upper part, or the solution appears a little cloudy until the bottom turns Turn into a clear state; stop stirring at this time, quickly remove the molecular sieve, keep the solution and continue to stir and slightly heat up to 35°C, when it can be seen that white turbidity appears along the bottle wall...

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Abstract

The present invention provides a cyclophosphamide refining method, which comprises: adding a cyclophosphamide crude product into water, dissolving, adding diethyl ether and a molecular sieve, stirring, removing the molecular sieve, cooling, crystallizing, carrying out vacuum filtration, and carrying out microwave vacuum low temperature drying, the particle size of the obtained product is less than or equal to 10 [mu] m, and the obtained product has improved water solubility and stability.

Description

technical field [0001] The invention relates to the field of a preparation method of cyclophosphamide, in particular to crystallization, purification and drying of crude cyclophosphamide by a specific method to obtain a stable refined product. Background technique [0002] Cyclophosphamide (Cyclophosphane), according to the 2015 edition of the Chinese Pharmacopoeia, its chemical composition is P-[N,N-bis(β-chloroethyl)]-1-oxo-3-nitrogen-2-phosphocyclohexane -P-oxide-hydrate, calculated as anhydrous, containing not less than 98.0% C7H15Cl2N2O2P, molecular formula C7H15Cl2N2O2p H2O, white crystal or crystalline powder; liquefied when losing crystal water; soluble in water but not very soluble, The aqueous solution is unstable, and its original research is Baxter International Co., Ltd. It is suitable for the treatment of malignant lymphoma, multiple myeloma, lymphocytic leukemia, cervical cancer, prostate cancer, colon cancer, bronchial cancer, solid tumors such as neuroblasto...

Claims

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Application Information

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IPC IPC(8): C07F9/6584
CPCC07F9/65846
Inventor 朱逸凡范敏华周胜军陈辉陆翠军聂良邓
Owner ANHUI POLY PHARM CO LTD