# Patent

## Title
Process for amorphous form of donepezil hydrochloride

## Abstract

The present invention provides a novel process for the preparation of amorphous form of donepezil hydrochloride.

## Background
FIELD OF THE INVENTION
The present invention provides a novel process for the preparation of amorphous form of donepezil hydrochloride.
BACKGROUND OF THE INVENTION
Donepezil hydrochloride of formula (1):




or 2,3-Dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride is useful for prevention and treatment of alzheimer disease. The therapeutic uses of donepezil hydrochloride and related compounds are disclosed in EP 296560. Amorphous form of donepezil hydrochloride is mentioned in U.S. Pat. No. 6,140,321.

We have discovered a simple novel process for the preparation of amorphous form of donepezil hydrochloride.
The object of the present invention is to provide a novel process for the preparation of the amorphous form of donepezil hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The amorphous donepezil hydrochloride is characterized by having broad x-ray diffraction spectrum as in FIG. 1.
One aspect of the present invention provides a process for the preparation of amorphous donepezil hydrochloride. Amorphous donepezil hydrochloride is prepared by dissolving donepezil hydrochloride in a mixture comprising an alcoholic solvent and a chlorinated solvent; and removing the solvents from the solution. The solvents can be removed by techniques such as vacuum drying, lyophilization, distillation under vacuum, freeze drying, spray drying, etc. The alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. Methanol is a preferred solvent. The suitable chlorinated solvents are chloroform, methylene dichloride, carbontetrachloride and ethylene dichloride. Methylene dichloride and chloroform are preferred solvents.



BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a x-ray powder diffraction spectrum of amorphous donepezil hydrochloride.



x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Kα radiation.
The following examples further illustrate the invention.
EXAMPLE 1
Donepezil hydrochloride (10 gm, obtained by the process described in example 4 of EP 296560) is dissolved in the mixture of methanol (50 ml) and chloroform (50 ml). The solution is subjected to vacuum drying at about 40° C. for 10 hours to give 9.1 gm of amorphous donepezil hydrochloride.
EXAMPLE 2
Example 1 is repeated by subjecting the solution to spray drying instead of vacuum drying using nitrogen gas to give amorphous donepezil hydrochloride.
EXAMPLE 3
Crystalline donepezil hydrochloride (10 gm) is dissolved in the mixure of ethanol (60 ml) and chloroform (50 ml). The solution is subjected to vacuum drying at about 45° C. for 9 hours to give 9.2 gm of amorphous donepezil hydrochloride.
EXAMPLE 4
Example 3 is repeated by subjecting the solution to spray drying using nitrogen gas instead of vacuum drying to give amorphous donepezil hydrochloride.

## Claims

1. A process for preparation of amorphous donepezil hydrochloride, which comprises:
a) dissolving donepezil hydrochloride in a mixture of an alcohol and a chlorinated solvent; and
b) removing the solvents from the solution;

wherein the alcohol is selected from the group consisting of methanol, ethanol, and isopropyl alcohol, and the chlorinated solvent is selected from the group consisting of chloroform, and methylene dichloride.

2. A process according to claim 1, wherein the solvents are removed by vacuum drying.

3. A process according to claim 1, wherein the solvents are removed by spray drying.

4. A process according to claim 1, wherein the alcohol is methanol or ethanol and the chlorinated solvent is methylene dichloride or chloroform.

5. A process for preparation of amorphous donepezil hydrochloride, which comprises:
a) dissolving donepezil hydrochloride in a mixture of an alcohol and a chlorinated solvent; and
b) removing the solvents from the solution;

wherein the alcohol is selected from the group consisting of methanol and ethanol, and the chlorinated solvent is chloroform.

6. A process according to claim 5, wherein the solvents are removed by vacuum drying.

7. A process according to claim 5, wherein the solvents are removed by spray drying.