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Method for producing aripiprazole crystallite

An aripiprazole and microcrystal technology, which is applied in the field of preparation of aripiprazole microcrystals, can solve problems such as excessive crystal grain size, and achieve the effects of simple process, no equipment and small crystal grain size.

Active Publication Date: 2008-05-07
重庆凯林制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The obvious disadvantage of this method is that the prepared crystals are too large in size and still need to be ground to achieve good bioavailability

Method used

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  • Method for producing aripiprazole crystallite
  • Method for producing aripiprazole crystallite
  • Method for producing aripiprazole crystallite

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Add 20g of aripiprazole and 240ml of ethanol into a three-necked reaction flask with a reflux condenser, heat to reflux under stirring, stop heating after the aripiprazole is completely dissolved, adjust the line speed to 500 m / min, and add 1°C 37ml of low-temperature water, cooled rapidly with ice-water mixture for 30min, suction filtered, washed, the obtained crystals were placed in a desiccator at 80°C, and dried under reduced pressure for 10 hours to obtain 19.2g of powdery aripiprazole crystals, with a yield of 96%. mp: 138.5-139.4°C, measured its powder X-ray diffraction pattern, the results are shown in Figure 1. Determination of its differential calorimetry scan and thermogravimetric diagram, the results are shown in Figure 3

[0029] The mensuration of aripiprazole crystallite particle size: get the crystallization that present embodiment obtains in right amount, take water as dispersant, measure with Mastersizer 2000 laser particle size analyzer, volume averag...

Embodiment 2

[0034] Add 20g of aripiprazole, 190ml of ethanol and 50ml of water into a three-necked reaction flask with a reflux condenser, heat to reflux under stirring, stop heating after the aripiprazole is completely dissolved, adjust the line speed to 500 m / min, and simultaneously Add 37ml of low-temperature water at 1°C, cool down rapidly with ice-water mixture for 30min, filter with suction, wash, and dry the obtained crystals in a desiccator at 90°C for 11 hours to obtain 19.4g of powdery aripiprazole crystals, yield 97%, mp: 138.4-139.1°C. Measure its particle diameter according to the method for embodiment 1,: volume average particle diameter volume average particle diameter 24.991um, d(0.9)=44.377, d(0.5)=22.868, d(0.1)=8.901, its particle size spectrum is shown in the figure 2.

[0035] The range of crystallite size is shown in Table 2.

[0036] Table 2 particle size and volume ratio

[0037] Granularity (um)

Embodiment 3

[0039] Add 20g of aripiprazole, 190ml of ethanol and 50ml of ethyl acetate into a three-necked reaction flask with a reflux condenser, heat to reflux under stirring, stop heating after the aripiprazole is completely dissolved, and adjust the line speed to 500 m / min At the same time, 37ml of low-temperature water at 1°C was added, and the temperature was rapidly cooled with ice-water mixture for 30 minutes, suction filtered, washed, and the obtained crystals were placed in an ebullating bed at 85°C, and boiled and dried for 1 hour to obtain powdered aripiprazole crystals 19.1, yield 95.5%, mp: 138.4-139.4°C,. Measure its particle diameter by the method for embodiment 1: volume average particle diameter 25.827um, d(0.9)=45.128, d(0.5)=23.156, d(0.1)=9.253

[0040] The range of crystallite size is shown in Table 3.

[0041] Table 3 particle size and volume ratio

[0042] Granularity (um)

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Abstract

The invention belongs to the chemical filed, in particular to an aripiprazole minicrystal preparation method, and comprises the steps as follow: aripiprazole rough products and ethanol or ethanol and non-alcohol solvent are mixed and heated to back flow into aripiprazole for full dissolution; water with low temperature is added into the solution; and the solution is cooled, and crystal is participated quickly; and then the solution is filtered under 30 to 130 DEG C and depressurized and dried for 1 to 20 hours, thereby obtaining the minicrystal. The gain diameter of the crystal ranges from 100 to 10 micrometers with the average grain diameter of 35 micrometers or smaller. The minicrystal obtained with the invention is suitable to be used for preparing oral solid preparation such as tablet, thereby improving the biological utilization degree of the minicrystal.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a preparation method of aripiprazole (aripiprazole) microcrystals Background technique [0002] Aripiprazole, the chemical name is 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydroquinolone or 7-{ 4-[4-(2,3-Dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-2(1H)-quinolone, a SARS drug used in the treatment of schizophrenia type of psychiatric drugs. [0003] Aripiprazole is a kind of poorly soluble drug, and small particle size is required when it is made into oral preparations such as tablets or other solid preparations including fast-melting formulations, and the particle size of aripiprazole crystals is controlled in the micron range ( 1 ~ 100um), in order to improve the bioavailability of its activity. Methods for preparing micron-sized crystals include physical grinding, rapid crystallization, and the like. [0004] CN1463191A discloses a B-type crystal and A-t...

Claims

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Application Information

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IPC IPC(8): C07D215/227
Inventor 秦咏梅朱昌肃邓国辉张志跃
Owner 重庆凯林制药有限公司
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