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Process for producing multiform crystal of donepezil hydrochloride

a technology of donepezil hydrochloride and multi-form crystals, which is applied in the direction of biocide, cardiovascular disorder, drug compositions, etc., can solve the problems of high volatility of organic solvents, inflammability, and safety to the environment and health, and achieve the same methods and problems, and achieve difficult to secure chemical stability

Inactive Publication Date: 2004-02-19
EISAI CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods therefore have the problems concerning flammability based on high volatility of organic solvents, safety to environment and the health of operators and solvents remaining in the produced donepezil hydrochloride crystal and the like.
These methods therefore have the same problems as above.
It is to be noted that the production method 12) in which "the polymorphic crystals (I) or (II) of donepezil hydrochloride is heated" poses many problems as an industrial production method because decomposition is accelerated in a heating step and it is therefore difficult to secure chemical stability.
However, no simple method for preparing the polymorphic crystal (III) of donepezil hydrochloride directly from donepezil has been developed yet.

Method used

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  • Process for producing multiform crystal of donepezil hydrochloride
  • Process for producing multiform crystal of donepezil hydrochloride
  • Process for producing multiform crystal of donepezil hydrochloride

Examples

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example 1

[0050] 50 g of donepezil was dissolved by stirring in 315 g of ethanol under heating, followed by adding 15.1 g of concentrated hydrochloric acid thereto at the internal temperature of 30.degree. C. Then, it was cooled and continued stirring while keeping the internal temperature at 30.degree. C. Crystals started precipitating about 30 minutes after the concentrated hydrochloric acid was poured into the mixture. After the precipitation started, the mixture was stirred at the internal temperature of 15.degree. C. for 18 hours and then cooled to the internal temperature of 9.degree. C. The crystals were collected by filtration and dried about 4 hours after the cooling was started, to give 52.32 g of polymorphic crystal (III) of donepezil hydrochloride (yield: 95.5%).

example 2

[0051] 50 g of donepezil was dissolved by stirring in 240 g of ethanol under heating, followed by adding 15.1 g of concentrated hydrochloric acid thereto at the internal temperature of 30.degree. C. Then, it was cooled and continued stirring while keeping the internal temperature at about 25.degree. C. Crystals started precipitating about 1 hour after the concentrated hydrochloric acid was poured into the mixture. After the precipitation started, the mixture was stirred at the internal temperature of 25.degree. C. for 17 hours and then cooled to the internal temperature of 9.degree. C. The crystals were collected by filtration and dried about 3 hours after the cooling was started, to give 52.25 g of polymorphic crystal (III) of donepezil hydrochloride (yield: 95.3%).

example 3

[0052] 50 g of donepezil was dissolved by stirring in 320 g of ethanol under heating, followed by adding 15.1 g of concentrated hydrochloric acid thereto at the internal temperature of 30.degree. C. After concentrated hydrochloric acid was poured, 100 mg of seed crystals were added. The mixture was cooled and continued stirring while keeping the internal temperature at about 20.degree. C. Crystals started precipitating immediately after the seed crystals were added. After the precipitation started, the mixture was stirred at the internal temperature of 20.degree. C. for 18 hours and then cooled to the internal temperature of 9.degree. C. The crystals were collected by filtration and dried about 3 hours after the cooling was started, to give 52.90 g of polymorphic crystal (III) of donepezil hydrochloride (yield: 96.5%).

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Abstract

The present invention provides a simple method of producing polymorphic crystal (III), which has high safety to environment and the bodies of operators; is gentle to environment; and can produce at low costs; and has a high refining effect. It is a method of producing polymorphic crystal (III) of donepezil hydrochloride (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine.monohydrochloride) represented by the following structural formula (formula (I)), which comprises dissolving donepezil (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) in ethanol; and adding hydrochloric acid or hydrogen chloride thereto, followed by stirring.

Description

[0001] The present invention relates to a method of industrially producing a highly stable polymorphic crystal (III) of donepezil hydrochloride (chemical name: 1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidi-ne.multidot.monohydrochloride) which is disclosed in JP-A 10-53576 (WO-A 97-46527) and has a superior effect as medicines.PRIOR ART[0002] Donepezil hydrochloride has an acetylcholinesterase inhibitory action and is useful as an agent for treating, preventing or improving various senile dementia especially Alzheimer-type senile dementia, cerebrovascular disorder associated with cerebral apoplexy (cerebral hemorrhage and cerebral infarction), cerebral arteriosclerosis, head injury etc., attention-deficit, logopathy, hypobulia, attention deficit hyperactivity disorders, emotional disorders, memorization disorders, paranoid hallucinatory states, abnormal behavior etc. associated with sequelae of encephalitis, cerebral paralysis etc., etc.[0003] This agent is mostly adminis...

Claims

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Application Information

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IPC IPC(8): A61P9/10A61P25/28A61P43/00C07D211/32
CPCC07D211/32A61P25/00A61P25/28A61P43/00A61P9/00A61P9/10
Inventor IMAI, AKIOSHIMOTANI, AKIHIKO
Owner EISAI CO LTD
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