Method for preparing donepezil hydrochloride crystal form I

A technology for donepezil hydrochloride and nepazil hydrochloride, applied in the field of preparing donepezil hydrochloride crystal form I, can solve the problems of increasing drying temperature, prolonging drying time, unable to reduce the minimum requirement of residual solvent, etc., to ensure stability and suitable for industrialization Production, the effect of shortening the drying time

Active Publication Date: 2010-12-08
ZHEJIANG HUAHAI PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the process of preparing donepezil hydrochloride crystal form I with methanol / isopropyl ether as the crystallization solvent, methanol is a good solvent and isopropyl ether is an anti-solvent. In the drying process, if the drying conditions and drying temperature are not well controlled, first use high temperature Drying and heating up too quickly, methanol will first volatilize from the mixed system, causing a relative excess of isopropyl ether in the mixed system, changing the saturation concentration of the solvent in the mixed system, causing crystallization of donepezil hydrochloride, and the precipitated crystals will be isopropyl ether. The inclusion of propyl ether, this inclusion of isopropyl ether can not reduce the minimum requirements for drug registration for residual solvents by prolonging the drying time and increasing the drying temperature

Method used

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  • Method for preparing donepezil hydrochloride crystal form I
  • Method for preparing donepezil hydrochloride crystal form I
  • Method for preparing donepezil hydrochloride crystal form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: Preparation of the wet product of nepezil hydrochloride crystal form I

[0026] Add 20kg of donepezil base and 80L of methanol into the reaction kettle, heat to 40°C and stir to dissolve. Cool to 0-20°C, add 5.8kg concentrated hydrochloric acid / 20L methanol, control the temperature at 0-20°C, add 200L isopropyl ether after addition, stir at 0-20°C for 10-20min, filter to obtain hydrochloric acid Donepezil crystal form I wet product 40kg.

Embodiment 2

[0027] Embodiment 2: prepare the wet product of nepezil hydrochloride crystal form I

[0028] Add 20kg of donepezil hydrochloride, 80L of methanol, and 2kg of water into the reaction kettle, then heat to 40°C and stir to dissolve, cool to 0-20°C, add 200L of isopropyl ether, after the addition is complete, stir at 0-20°C for 10-20min, filter, Obtain 40kg of donepezil hydrochloride crystal form I wet product.

Embodiment 3

[0029] Example 3: Preparation of Nepezil Hydrochloride Form I Finished Product

[0030] The wet product of donepezil hydrochloride form I obtained in Example 2 was vacuum-dried at 40°C, 50°C and stepwise temperature rise conditions, and the vacuum degree was controlled within the range of -0.07Mpa to -0.1Mpa, and measured after a certain period of time The residual amount of the solvent of isopropyl ether and methyl alcohol, result is shown in table I, table II, table III respectively:

[0031] Table I (40°C)

[0032]

[0033] Table II (50°C)

[0034]

[0035] Table III (stepwise temperature rise)

[0036] time

[0037] 16

[0038] Judging from the data results in Table I and Table II, directly increase the drying temperature to 40°C and 50°C, and keep the temperature constant. After drying for 16 hours, the residual amount of isopropyl ether remains basically constant. The residues did not change much. The results in Table III show that by stepw...

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Abstract

The invention relates to a method for preparing a donepezil hydrochloride crystal form I. The method comprises the following steps of: separating the donepezil hydrochloride crystal form I from a solvent system which contains methanol and isopropyl ether; and separating and drying the donepezil hydrochloride crystal form I to obtain a finished product. The method is characterized in that: the drying temperature is controlled in the range of between 25 and 60 DEG C by stepped temperature rise. The scheme provided by the invention can effectively control the residual quantity of the isopropyl ether in the donepezil hydrochloride crystal form I to be less than 100 ppm.

Description

technical field [0001] The invention relates to a method for preparing crystal form I of donepezil hydrochloride. Background technique [0002] Donepezil hydrochloride is an acetylcholinesterase inhibitor developed by Japan's Eisai Company for the treatment of Alzheimer's dementia (AD). It has the advantages of high selectivity, small dose, long half-life, small adverse reactions, and no liver toxicity. Its chemical The name is: 1-benzyl-4-[(5,6-dimethoxyindanon-2-yl)methyl]piperidine hydrochloride. The structural formula of donepezil hydrochloride is as follows: [0003] [0004] WO9746527 reports the preparation method of five crystal forms of donepezil hydrochloride, I, II, III, IV and V. Wherein the peaks in the powder X-ray diffraction pattern of donepezil hydrochloride crystalline form I are: 9.94, 10.60, 12.66, 13.12, 13.66, 13.86, 14.92, 15.26, 16.08, 16.86, 17.50, 17.58, 18.42, 19.28, 19.80, 19.94, 21.22 , 22.00, 22.54, 22.98, 23.60, 23.78, 23.92, 26.46, 28.02...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/32
Inventor 蹇锋何达云
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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