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Method for preparing ezetimibe ultrafine particles by supercritical compression anti-solvent precipitation method

A technology for compressing antisolvent and ezetimibe, applied in the field of medicine, can solve the problems of poor absorption and low bioavailability, and achieve the effects of reducing particle size, improving solubility and high safety

Active Publication Date: 2019-06-07
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, ezetimibe is almost insoluble in water, poorly absorbed in the body, and has low bioavailability

Method used

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  • Method for preparing ezetimibe ultrafine particles by supercritical compression anti-solvent precipitation method
  • Method for preparing ezetimibe ultrafine particles by supercritical compression anti-solvent precipitation method
  • Method for preparing ezetimibe ultrafine particles by supercritical compression anti-solvent precipitation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Accurately weigh 250mg of ezetimibe API, prepare 10mL of 25mg / mL ezetimibe-ethanol solution; set the crystallization temperature to 44°C on the operation panel of the supercritical anti-solvent granulation system, and preheat the system for 60 minutes ; After preheating, CO is introduced into the system 2 and maintain CO 2 The volume flow rate is within the range of 3.5-4.5L / min, and the pressure is slowly increased to a crystallization pressure of 8MPa; the previously prepared sample solution is injected into the crystallization kettle at a sample flow rate of 1.1mL / min by a high-efficiency liquid phase pump; After the sample is completed, continue to pass CO 2 After 90 minutes, stop the air intake, slowly release the pressure until the pressure in the crystallization tank is equal to the atmospheric pressure; close the system, and collect the product from the crystallization tank. The particle size of the obtained ezetimibe ultrafine particles is 8.576 μm, and the a...

Embodiment 2

[0049] Accurately weigh 100 mg of ezetimibe API, prepare 10 mL of ezetimibe-ethanol solution at 10 mg / mL; set the crystallization temperature to 42°C on the operation panel of the supercritical anti-solvent granulation system, and preheat the system for 60 minutes ; After preheating, CO is introduced into the system 2 and maintain CO 2 The volume flow rate is within the range of 3.5-4.5L / min, and the pressure is slowly increased to a crystallization pressure of 12MPa; the previously prepared sample solution is injected into the crystallization kettle at a sample flow rate of 0.5mL / min by using a high-efficiency liquid phase pump; After the sample is completed, continue to pass CO 2 After 90 minutes, stop the air intake, slowly release the pressure until the pressure in the crystallization tank is equal to the atmospheric pressure; close the system, and collect the product from the crystallization tank. The particle size of the obtained ezetimibe ultrafine particles is 8.185 ...

Embodiment 3

[0051] Accurately weigh 300 mg of ezetimibe raw material drug, prepare 10 mL of ezetimibe-ethanol solution of 30 mg / mL; set the crystallization temperature to 38°C on the operation panel of the supercritical anti-solvent granulation system, and preheat the system for 60 minutes ; After preheating, CO is introduced into the system 2 and maintain CO 2 The volume flow rate is within the range of 3.5-4.5L / min, and the pressure is slowly increased to a crystallization pressure of 16MPa; the previously prepared sample solution is injected into the crystallization kettle at a sample flow rate of 2.0mL / min using a high-efficiency liquid phase pump; After the sample is completed, continue to pass CO 2 After 90 minutes, stop the air intake, slowly release the pressure until the pressure in the crystallization tank is equal to the atmospheric pressure; close the system, and collect the product from the crystallization tank. The particle size of the prepared ezetimibe ultrafine particle...

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Abstract

The invention relates to the method for preparing ezetimibe ultrafine particles by supercritical compression anti-solvent precipitation; the method comprises: dissolving crude ezetimibe in an organic solvent to prepare ezetimibe solution; introducing CO2 into a crystallizer under certain volumetric flow, adjusting inner temperature and pressure of the crystallizer, and maintaining a stable state; introducing the prepared ezetimibe solution into the crystallizer at preset sample-injecting flow speed; after sample injecting, introducing CO2 continuously with the inner temperature and pressure of the crystallizer maintained constant during the whole process, and relieving after a period of time; after the inner pressure of the crystallizer drops to atmospheric pressure, opening the crystallizer to collect ezetimibe ultrafine particles, and performing a series of characterization analysis. Compared with non-treated active pharmaceutical ingredients, the ezetimibe ultrafine particles prepared herein has particle size reduced by about 80% with crystal form unchanged. Technically, the method has the advantages of good mildness of operation conditions, greenness, high efficiency, nearly zero solvent residues and the like.

Description

【Technical field】 [0001] The invention relates to the field of medicine, in particular to a method for preparing ezetimibe ultrafine particles by using a supercritical compression anti-solvent precipitation method. 【Background technique】 [0002] The supercritical anti-solvent method (Supercritical Anti-solvent, SAS) was first proposed by Gallgher et al. in 1989. The basic principle is to dissolve the solute that needs to be granulated in an appropriate solvent to form a solution of a certain concentration, and then add it to the solution. Pass into supercritical fluid, at this time supercritical fluid will compete with solute for organic solvent. Due to the supercritical fluid's extremely high solubility for organic solvents, it can be miscible with solvents in any proportion, so the solute will instantly reach a large degree of supersaturation and crystallize to form ultrafine particles. According to the specific equipment and operation methods, the supercritical anti-sol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D205/08
CPCC07D205/08Y02P20/54
Inventor 王志祥王为彦陈震徐文博宋雅琴高赵华
Owner CHINA PHARM UNIV