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Preparation method of fudosteine crystals

A fodosteine ​​and crystallization technology, which is applied in the field of preparation of fodosteine ​​crystallization, can solve the problems of uneven particle size distribution, high dissolution temperature, and the product is not easy to dry, and achieves the effect of uniform particle size distribution

Active Publication Date: 2017-02-22
迪嘉药业集团股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although the above-mentioned crystallization method is simple in principle, its actual operation is relatively complicated, and appropriate operating parameters are often required to achieve the purpose of refining and purifying
In CN200910167947, water is used as the solvent for cooling crystallization of fudosteine. Although the solvent is cheap and easy to obtain, its dissolution temperature is too high, which will easily lead to the increase of impurities and the product is not easy to dry
At the same time, fudosteine ​​is easily soluble in water, resulting in excessive material loss in its mother liquor
In CN201110062912, water and methanol system are used for refining. Although the product purity can reach 99.5%, it has disadvantages such as excessive methanol consumption, high dissolution temperature, and low crystallization temperature, and the production cost is relatively high
Both CN201410554898 and CN201511002173 use water-ethanol system for cooling and crystallization, but the cooling and crystallization process is not easy to control, and explosive nucleation is prone to occur, resulting in inconsistent quality between product batches
In CN200510059733, acetone is used for elution and crystallization, although the operating conditions are relatively mild, but its yield is low, and a large amount of acetone organic solvent is used simultaneously, which has a certain impact on the environment
In CN201310377145, ethanol is used as eluting agent, but it does not control the ethanol addition process, resulting in subsequent crystallization time of up to 10 hours, thereby increasing the production cycle
[0006] Due to various problems in the refining method, domestic fudosteine ​​products have problems such as poor crystal habit, uneven particle size distribution, and poor product stability between batches.
Compared with foreign products, domestic fodosteine ​​products still have a large gap, and cannot meet the different needs of customers
In addition, in the production process of domestic fudosteine, there are problems such as difficulty in product filtration and product agglomeration, which not only increases the labor intensity of workers, but also requires an additional crushing and granulation process to eliminate product agglomeration

Method used

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  • Preparation method of fudosteine crystals
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  • Preparation method of fudosteine crystals

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 50 g of fudosteine ​​into a three-necked flask filled with 100 ml of water, stir and dissolve at 40°C, and then filter and decolorize after stirring continuously for 30 minutes; Cool the filtrate to 10°C, add 0.25g seed crystals to the crystallizer, and grow the crystals for 2 hours, then add 400ml of n-propanol to the crystallizer at a flow rate of 10ml / min, and then grow the crystals for 3 hours; Suction filter, wash the filter cake with n-propanol, and dry under normal pressure at 40°C for 12 hours. The final product yield is 88.7%, and the HPLC purity is 99.93%, and the crystal habit of the product is flake (such as figure 1 shown), with a primary particle size of 212 microns (as figure 2 shown).

Embodiment 2

[0026] Add 30 g of fudosteine ​​into a three-necked flask filled with 30 ml of water, stir and dissolve at 50°C, and then filter and decolorize after stirring continuously for 60 minutes; Cool the filtrate to 20°C, add 0.3g seed crystals to the crystallizer, and grow the crystals for 1 hour, then add 300ml of n-propanol to the crystallizer at a rate of 2 ml / min, and then grow the crystals for 1 hour ; Suction filtration, and the filter cake was washed with n-propanol, and dried under normal pressure at 45°C for 10 hours. The yield of the final product is 90.2%, the HPLC purity is 99.91%, the crystal habit of the product is flaky, and the main particle size is 189 microns.

Embodiment 3

[0028] Add 40 g of fudosteine ​​into a three-necked flask filled with 50 ml of water, stir and dissolve at 45°C, and then filter and decolorize after stirring continuously for 50 minutes; Cool the filtrate to 15°C, add 0.28g seed crystals to the crystallizer, and grow the crystals for 1.5 hours, then add 400ml of isopropanol to the crystallizer at a flow rate of 5 ml / min, and then grow the crystals for 2 hours ; Suction filtration, and wash the filter cake with isopropanol, and dry under normal pressure at 50°C for 8 hours. The final product yield is 90.2%, and the HPLC purity is 99.91%. The crystal habit of the product is flaky, and the main particle size is 215 microns.

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Abstract

The invention relates to a preparation method of fudosteine crystals, and belongs to the technical field of crystals. The technical scheme of the invention is that the preparation method of the fudosteine crystals of which the main grain sizes are ranged from 180 to 220 microns comprises the following steps: 1, adding the fudosteine to water, wherein the solution solid-liquid ratio is 0.5g / ml to 1.0g / ml, and continuously stirring and dissolving for 30 to 60 minutes at the temperature of 40 to 50 DEG C; 2, carrying out filtration and decolorization; moving a filtrate into a crystallizer, lowering the temperature to 10-20 DEG C, wherein the cooling rate is 5-20 DEG C / h, adding crystal seeds to the crystallizer, cultivating the crystals for 1-2 hours; then carrying out fed-batch of organic solvents of which the weights are 4 to 10 times of that of water in initial solutions to the crystallizer, wherein the fed-batch rate is 2-10 mL / min, and cultivating the crystals for 1-3 hours; 3, filtering, and washing filter cakes by using washing solvents, finally drying products, thus obtaining the fudosteine products with uniform size distribution.

Description

technical field [0001] The invention relates to a method for preparing fudosteine ​​crystals, belonging to the technical field of crystallization. Background technique [0002] The chemical name of Fudosteine ​​is (-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid, and the molecular formula is C 6 h 13 NO 3 S, molecular weight 179.24, CAS number 13189-98-5, white or light yellow crystalline powder, easily soluble in water, slightly soluble in acetic acid, almost insoluble in ethanol. Its chemical structural formula is shown in the following formula. [0003] [0004] Fudosteine ​​is a new type of expectorant drug jointly developed and marketed by Mitsubishi Pharmaceutical Co., Ltd. and SS Pharmaceutical Co., Ltd. of Japan. It has a good inhibitory effect on the formation of goblet cells and the production of fucoidin in the trachea of ​​patients with respiratory diseases, and has a good antitussive and phlegm-reducing effect. Fudosteine ​​is widely used in the tre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/28C07C323/58
CPCC07B2200/13C07C319/28C07C323/58
Inventor 王冠姜凯王超刘世超
Owner 迪嘉药业集团股份有限公司
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