Indian Patents. 202800:A NOVEL PROCESS FOR AMORPHOUS FORM OF DONEPEZIL HYDROCHLORIDE

Title of Invention	A NOVEL PROCESS FOR AMORPHOUS FORM OF DONEPEZIL HYDROCHLORIDE
Abstract	The present invention provides a novel process for the preparation of amorphous from of donepezil hydrochloride. Amorphous donepezil hydrochloride is prepared by dissolving done pezil hydrochloride in a mixture of an alcoholic solvent and a chlorinated solvent; and removing the solvents for example by vacuum driying.

Full Text	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]-1 H-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 US 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 figure 1. One aspect of the present invention provides a process for the preparation of amorphous donepezil hydrochloride. Amorphous donepezi. 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 Figure 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-Ka 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. We claim: 1. A process for preparation of amorphous donepezii hydrochloride, which comprises: a) dissolving donepezii hydrochloride in a mixture of an alcohol and a chlorinated solvent; and b) removing the solvents from the solution by vacuum drying, distillation, freeze drying or spray drying; wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol and the chlorinated solvent is selected from the group consisting of chloroform, methylene dichloride, carbontetrachloride and ethylene 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.

Full Text

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]-1 H-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 US 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 figure 1.

One aspect of the present invention provides a process for the preparation of amorphous donepezil hydrochloride. Amorphous donepezi. 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
Figure 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-Ka 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.

We claim:
1. A process for preparation of amorphous donepezii hydrochloride, which comprises:
a) dissolving donepezii hydrochloride in a mixture of an alcohol and a
chlorinated solvent; and
b) removing the solvents from the solution by vacuum drying, distillation,
freeze drying or spray drying;
wherein the alcohol is selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol and the chlorinated solvent is selected from the group consisting of chloroform, methylene dichloride, carbontetrachloride and ethylene 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.

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Patent Number

202800

Indian Patent Application Number

1370/CHENP/2003

PG Journal Number

05/2007

Publication Date

02-Feb-2007

Grant Date

31-Oct-2006

Date of Filing

01-Sep-2003

Name of Patentee

M/S. HETERO DRUGS LIMITED

Applicant Address

Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018

Inventors:

#	Inventor's Name	Inventor's Address
1	PARTHASARADHI, Reddy, Bandi	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018
2	RATHNAKAR, Reddy, Kura	Hetero Drugs Limited (R & D), Plot No B-80 & 81 A.P.I.E. Balanagar, Hyderabad-500 018
3	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018
4	NARASA, Reddy, Bolla	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018
5	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018

PCT International Classification Number

C07D211/20

PCT International Application Number

PCT/IN2003/000136

PCT International Filing date

2003-04-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA