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Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology

A supercritical anti-solvent, ultra-fine particle technology, applied in the field of preparation of estradiol ultra-fine particles, can solve the problems of low oral bioavailability and low solubility, and achieves improved bioavailability, small particle size, prominent effect of substantive features

Active Publication Date: 2017-02-22
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The solubility of estradiol in water is very low, resulting in a very low oral bioavailability of only about 10%

Method used

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  • Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology
  • Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology
  • Method for preparing estradiol ultrafine particles with supercritical anti-solvent technology

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: single factor method determines the preferred value range of each key parameter

[0033] Instruments and materials

[0034] See Table 1 for experimental materials and Table 2 for experimental equipment.

[0035] Table 1 Experimental materials

[0036] material name Specification Manufacturer Estradiol ≥99％ Wuhan Belka Biomedicine Co., Ltd. CO 2

≥99％ Nanjing Tongqi Gas Company ethanol Analytical pure Nanjing Chemical Reagent Co., Ltd. acetone Analytical pure Nanjing Chemical Reagent Co., Ltd. Dichloromethane Analytical pure Nanjing Chemical Reagent Co., Ltd. Methanol Analytical pure Nanjing Chemical Reagent Co., Ltd. Dimethyl sulfoxide Analytical pure Nanjing Chemical Reagent Co., Ltd.

[0037] Table 2 Experimental Instruments

[0038] device name model Manufacturer Supercritical Particle Preparation System Helix Applied Separations, USA Intell...

Embodiment 2

[0071] Embodiment 2: Orthogonal experiment optimizes optimal parameters within the preferred range of each key parameter

[0072] Orthogonal experimental design and results

[0073] Taking the particle size as the main evaluation index, four factors that have a significant impact on the particle size of estradiol particles are selected, namely, the solution volume flow rate (A), the crystallization pressure (B), the crystallization temperature (C) and the mass concentration of estradiol (D ) for investigation, using the L9(34) orthogonal experimental design to carry out experiments, and its factor levels have been determined by the single factor experiment of Example 1, see Table 4. Other process conditions are CO 2 The exhaust volume flow rate is 3L / min, and the volume ratio of acetone and ethanol is 1:1. The experimental design and results are shown in Table 5.

[0074] Table 4 Orthogonal Experimental Factors and Level Table

[0075]

[0076] Table 5 Orthogonal expe...

Embodiment 3

[0093] A method for preparing estradiol ultrafine particles by a supercritical antisolvent method, comprising the steps of:

[0094] Step S1, dissolving estradiol in an organic solvent to obtain an estradiol solution with a mass concentration of 6 mg / mL;

[0095] Step S2, the CO 2 Pass it into the crystallization kettle at a flow rate of 3L / min, adjust the temperature in the crystallization kettle to 55°C, and the pressure to 8MPa;

[0096] Step S3, continue to introduce CO at a flow rate of 3 L / min 2 , maintaining the temperature and pressure in the crystallization tank constant, while passing the estradiol solution prepared in step S1 into the crystallization tank at a volume flow rate of 1.0 mL / min;

[0097] Step S4, after the estradiol solution is passed through, continue to pass through the CO 2, keep the temperature and pressure in the crystallization kettle constant, and release the pressure after 40 minutes; when the pressure in the crystallization kettle drops to a...

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Abstract

The invention discloses a method for preparing estradiol ultrafine particles with a supercritical anti-solvent technology. The method comprises the steps as follows: step S1, estradiol is dissolved in an organic solvent, and an estradiol solution is prepared; step S2, CO2 is introduced into a crystallization kettle, and the temperature and pressure in the crystallization kettle are adjusted; step S3, CO2 is introduced continuously at a constant flow rate, and the estradiol solution prepared in step S1 is introduced into the crystallization kettle while the temperature and pressure in the crystallization kettle are kept unchanged; Step S4, CO2 is introduced continuously after the introduction of estradiol solution, the temperature and pressure in the crystallization kettle are kept unchanged, the pressure is relieved after a period of time, and after the pressure in the crystallization kettle is reduced to atmospheric pressure, the crystallization kettle is opened for collecting the estradiol ultrafine particles, wherein the sequence of the step S1 and the step S2 can be changed, and the organic solvent is a mixed solvent of acetone and ethanol. With the adoption of the method, estradiol with fine particle size can be prepared, the solubility of estradiol in water is improved, and accordingly, the bioavailability of estradiol is improved.

Description

technical field [0001] The invention relates to the preparation of estradiol ultrafine particles, in particular to a method for preparing estradiol ultrafine particles using supercritical antisolvent technology. Background technique [0002] Supercritical anti-solvent (Supercritical Anti-solvent, SAS) has great potential in the preparation of ultrafine particles, and its operating conditions are mild, which is especially suitable for the miniaturization of biological products, antibiotic drugs and drug carriers. Compared with traditional granulation methods such as spray drying, jet milling, grinding, and freeze drying, its main advantages are that the prepared particles have less residual organic solvents, mild reaction conditions, and can prevent heat-sensitive drugs from being decomposed by heat. , controllable shape, etc. [0003] Supercritical CO 2 The antisolvent process is to dissolve the solute into a suitable solvent (usually an organic solvent) to form a solution...

Claims

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Application Information

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IPC IPC(8): C07J1/00
CPCC07J1/007Y02P20/54
Inventor 王志祥刘尚德缪虹刚王为彦宋雅琴高赵华
Owner CHINA PHARM UNIV
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