Indian Patents. 206274:PROCESS FOR PREPARATION OF ZIPRASIDONE HYDROCHLORIDE CRYSTALLINE POLYMORPHS

Title of Invention	PROCESS FOR PREPARATION OF ZIPRASIDONE HYDROCHLORIDE CRYSTALLINE POLYMORPHS
Abstract	The present invention relates to processes for preparation of ziprasidone hydrochloride monohydrate crystalline polymorphs, thus, for example,ziprasidone free base is stirred with methanol, dimethylformamide, chloroform and cony. Hydrochloric acid, heated to 60°C until to form a clear solution and then subjected to vacuum drying to give ziprasidone hydrochloride monohydrate form II

Full Text	The present invention provides novel crystalline forms of ziprasidone hydrochloride monohydrate, processes for their preparation and pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION Ziprasidone of formula (1): or 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and its salts are antipsychotic agents. Ziprasidone hydrochloride and related compounds and their therapeutic uses are disclosed in US 4,831,031. The crystalline forms of ziprasidone mesylate were reported in WO 97/42190, WO 97/42191. It has now been discovered that ziprasidone hydrochloride monohydrate can be prepared in three stable crystalline forms having good dissolution characteristics. The object of the present invention is to provide stable novel crystalline forms of ziprasidone hydrochloride monohydrate, processes for preparing these forms and pharmaceutical compositions containing them. DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form I, characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 10.9, 13.9. 15.9, 16.4, 17.5, 19.2, 20.6, 21.3, 21.9, 24.2. 24.7, 24.9, 25.7, 25.9 and 28.9 degrees. Figure 1 shows typical form I x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form I. Thus, a mixture of ziprasidone free base, hydrochloric acid and water is heated to about 45°C to 100°C; and ziprasidone hydrochloride monohydrate form I is isolated by filtration or centrifugation. Preferably, the mixture of ziprasidone free base, hydrochloric acid and water is heated to about 55°C to 65°C; and ziprasidone hydrochloride monohydrate form I is isolated by filtration or centrifugation. In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form II, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 10.9, 11.3, 18.1, 19.5, 21.9, 23.7, 24.4, 24.8 and 26.2 degrees. Figure 2 shows typical form II x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form II. Thus, ziprasidone free base, an alcohol or a mixture of alcohols, dimethylformamide, a chlorinated solvent, hydrochloric acid and water are mixed to form a solution of ziprasidone hydrochloride; and the solvents are removed by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II. Water may be directly mixed or it may be mixed, for example, as an aqueous solution of hydrochloric acid. The alcohols are selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. The preferable alcohols are methanol and ethanol. The chlorinated solvents are selected from the group consisting of methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride. The preferable ester solvents are chloroform and methylene dichloride. In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form III, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 10.9, 14.8, 15.9, 18.1, 19.5, 21.8, 24.3, 24.9, 25.9 and 26.5 degrees. Figure 3 shows typical form III x-ray powder diffraction spectrum. In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form III. Thus ziprasidone free base, an ether solvent or a mixture of ether solvents, dimethylformamide, hydrochloric acid and water are mixed to form a solution of ziprasidone hydrochloride; and ziprasidone hydrochloride monohydrate form III is isolated from the solution. Water may be directly mixed or it may be mixed, for example, as an aqueous solution of hydrochloric acid. The ether solvents are selected from the group consisting of diethyl ether, diisopropyl ether and tert-butyl methyl ether. The preferable ether solvent is diethyl ether. Ziprasidone free base used in the above processes can be obtained from the previously known methods. In accordance with the present invention, there is provided a pharmaceutical composition comprising a crystalline form of ziprasidone hydrochloride monohydrate and pharmaceutically acceptable carrier or diluent. The crystalline form includes form I, form II or form III. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form 1. Figure 2 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form II. Figure 3 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form III. 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 present invention. Example 1 Ziprasidone free base (10 gm), conc, hydrochloric acid (10 ml) and water (150 ml) are mixed and the reaction mass is heated to 60°C and stirred for 4 hours at 60°C to 65°C. The contents are cooled to 25°C, filtered, washed with water and dried to give 10 gm of ziprasidone hydrochloride monohydrate form I. Example 2 Ziprasidone free base (2.5 gm), methanol (100 ml), dimethylformamide (100 ml), chloroform (25 ml) and conc, hydrochloric acid (1.5 ml) are mixed at 25°C. The contents are heated to 60°C and stirred for 10 minutes at 60°C to 65°C and the clear solution thus obtained is subjected to vacuum drying at 70°C for 40 hours to give ziprasidone hydrochloride monohydrate form II in near quantitative yield. Example 3 Ziprasidone free base (3.0 gm), methanol (120 ml), dimethylformamide (100 ml), chloroform (30 ml) and conc, hydrochloric acid (1.5 ml) are mixed at 25°C. The contents are heated to 60°C and stirred for 10 minutes at 60°C to 65°C and the clear solution thus obtained is subjected to spray drying to give ziprasidone hydrochloride monohydrate form II. Example 4 Ziprasidone free base(5.0 gm) is added to diethyl ether (50 ml) and heated to reflux temperature. Then dimethylformamide (145 ml) is added and the contents are stirred for 2 hours under reflux. Then conc, hydrochloric acid (2.5 ml) and water (3 ml) are added, and the solution is cooled to 25°C. The separated crystals are filtered to give 3.5 gm of ziprasidone hydrochloride monohydrate form III. We claim: 1. A process for the preparation of ziprasidone hydrochloride monohydrate crystalline polymorph, form II, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 10.9, 11.3, 18.1, 19.5, 21.9, 23.7, 24.4, 24.8 and 26.2 degrees as shown in figure 2; form III, characterized by an x-ray powder diffraction spectrum having peaks expressed as 26 at about 10.9, 14.8, 15.9, 18.1, 19.5, 21.8, 24.3, 24.9, 25.9 and 26.5 degrees as shown in figure 3; as herein described comprising the steps of: a) mixing ziprasidone free base, hydrochloric acid and water in presence of an organic solvent or a mixture of organic solvents; b) heating the reaction mixture obtained in step (a) to about 45°C to the reflux temperature of the solvent used; and c) either isolating ziprasidone hydrochloride monohydrate form III from the solution obtained in step (b) by filtration or centrifugation, or removing the solvents from the solution obtained in step (b) by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II; wherein the organic solvent used in step (a) is selected from the group consisting of an alcohol solvent such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol; dimethylformamide; a chlorinated solvent such as methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; and an ether solvent such as diethyl ether, diisopropyl ether and tert-butyl methyl ether. 2. The process as claimed in claim 1, wherein the process comprising the steps of: a) mixing ziprasidone free base, an alcohol or a mixture of alcohols, dimethylformamide, a chlorinated solvent, hydrochloric acid and water at about 45°C to 100°C to form a ziprasidone hydrochloride solution; and b) removing the solvents from the solution obtained in step (a) by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II; 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 methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride. 3. The process as claimed in claim 2; wherein the solvents are removed by the vacuum drying or spray drying. 4. The process as claimed in claim 2, wherein the alcohol is methanol. 5. The process as claimed in claim 2, wherein the chlorinated solvent is chloroform. 6. The process as claimed in claim 1, wherein the process comprising the steps of: a) mixing ziprasidone free base, an ether solvent or a mixture of ether solvents, dimethylformamide, hydrochloric acid and water at reflux to form a ziprasidone hydrochloride solution; and b) isolating ziprasidone hydrochloride monohydrate form III form the solution obtained in step (a) at 25 - 30°C by filtration or centrifugation; wherein the ether solvent is selected from the group consisting of diethyl ether, diisopropyl ether and tert-butyl methyl ether. 7. The process as claimed in claim 6, wherein the ether solvent is diethyl ether.

Full Text

The present invention provides novel crystalline forms of ziprasidone hydrochloride monohydrate, processes for their preparation and pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION Ziprasidone of formula (1):

or 5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one and its salts are antipsychotic agents. Ziprasidone hydrochloride and related compounds and their therapeutic uses are disclosed in US 4,831,031.
The crystalline forms of ziprasidone mesylate were reported in WO 97/42190, WO 97/42191.
It has now been discovered that ziprasidone hydrochloride monohydrate can be prepared in three stable crystalline forms having good dissolution characteristics.
The object of the present invention is to provide stable novel crystalline forms of ziprasidone hydrochloride monohydrate, processes for preparing these forms and pharmaceutical compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form I, characterized by an x-ray powder diffraction spectrum having peaks expressed as 29 at about 10.9, 13.9. 15.9, 16.4, 17.5, 19.2, 20.6, 21.3, 21.9, 24.2. 24.7, 24.9, 25.7, 25.9 and 28.9 degrees. Figure 1 shows typical form I x-ray powder diffraction spectrum.

In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form I. Thus, a mixture of ziprasidone free base, hydrochloric acid and water is heated to about 45°C to 100°C; and ziprasidone hydrochloride monohydrate form I is isolated by filtration or centrifugation. Preferably, the mixture of ziprasidone free base, hydrochloric acid and water is heated to about 55°C to 65°C; and ziprasidone hydrochloride monohydrate form I is isolated by filtration or centrifugation.
In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form
II, characterized by an x-ray powder diffraction spectrum having peaks
expressed as 26 at about 10.9, 11.3, 18.1, 19.5, 21.9, 23.7, 24.4, 24.8 and 26.2
degrees. Figure 2 shows typical form II x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form II. Thus, ziprasidone free base, an alcohol or a mixture of alcohols, dimethylformamide, a chlorinated solvent, hydrochloric acid and water are mixed to form a solution of ziprasidone hydrochloride; and the solvents are removed by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II. Water may be directly mixed or it may be mixed, for example, as an aqueous solution of hydrochloric acid. The alcohols are selected from the group consisting of methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol. The preferable alcohols are methanol and ethanol. The chlorinated solvents are selected from the group consisting of methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride. The preferable ester solvents are chloroform and methylene dichloride.
In accordance with the present invention, there is provided a novel crystalline form of ziprasidone hydrochloride monohydrate, designated as form
III, characterized by an x-ray powder diffraction spectrum having peaks
expressed as 26 at about 10.9, 14.8, 15.9, 18.1, 19.5, 21.8, 24.3, 24.9, 25.9 and
26.5 degrees. Figure 3 shows typical form III x-ray powder diffraction spectrum.
In accordance with the present invention, a process is provided for preparation of ziprasidone hydrochloride monohydrate form III. Thus ziprasidone free base, an ether solvent or a mixture of ether solvents, dimethylformamide, hydrochloric acid and water are mixed to form a solution of ziprasidone

hydrochloride; and ziprasidone hydrochloride monohydrate form III is isolated from the solution. Water may be directly mixed or it may be mixed, for example, as an aqueous solution of hydrochloric acid. The ether solvents are selected from the group consisting of diethyl ether, diisopropyl ether and tert-butyl methyl ether. The preferable ether solvent is diethyl ether.
Ziprasidone free base used in the above processes can be obtained from the previously known methods.
In accordance with the present invention, there is provided a pharmaceutical composition comprising a crystalline form of ziprasidone hydrochloride monohydrate and pharmaceutically acceptable carrier or diluent. The crystalline form includes form I, form II or form III.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form 1.
Figure 2 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form II.
Figure 3 is a x-ray powder diffraction spectrum of ziprasidone hydrochloride monohydrate form III.
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 present invention.
Example 1
Ziprasidone free base (10 gm), conc, hydrochloric acid (10 ml) and water (150 ml) are mixed and the reaction mass is heated to 60°C and stirred for 4 hours at 60°C to 65°C. The contents are cooled to 25°C, filtered, washed with water and dried to give 10 gm of ziprasidone hydrochloride monohydrate form I.
Example 2
Ziprasidone free base (2.5 gm), methanol (100 ml), dimethylformamide (100 ml), chloroform (25 ml) and conc, hydrochloric acid (1.5 ml) are mixed at 25°C. The contents are heated to 60°C and stirred for 10 minutes at 60°C to 65°C and the clear solution thus obtained is subjected to vacuum drying at 70°C

for 40 hours to give ziprasidone hydrochloride monohydrate form II in near quantitative yield.
Example 3 Ziprasidone free base (3.0 gm), methanol (120 ml), dimethylformamide (100 ml), chloroform (30 ml) and conc, hydrochloric acid (1.5 ml) are mixed at 25°C. The contents are heated to 60°C and stirred for 10 minutes at 60°C to 65°C and the clear solution thus obtained is subjected to spray drying to give ziprasidone hydrochloride monohydrate form II.
Example 4 Ziprasidone free base(5.0 gm) is added to diethyl ether (50 ml) and heated to reflux temperature. Then dimethylformamide (145 ml) is added and the contents are stirred for 2 hours under reflux. Then conc, hydrochloric acid (2.5 ml) and water (3 ml) are added, and the solution is cooled to 25°C. The separated crystals are filtered to give 3.5 gm of ziprasidone hydrochloride monohydrate form III.

We claim:
1. A process for the preparation of ziprasidone hydrochloride monohydrate
crystalline polymorph, form II, characterized by an x-ray powder diffraction
spectrum having peaks expressed as 26 at about 10.9, 11.3, 18.1, 19.5,
21.9, 23.7, 24.4, 24.8 and 26.2 degrees as shown in figure 2; form III,
characterized by an x-ray powder diffraction spectrum having peaks
expressed as 26 at about 10.9, 14.8, 15.9, 18.1, 19.5, 21.8, 24.3, 24.9, 25.9
and 26.5 degrees as shown in figure 3; as herein described comprising the
steps of:
a) mixing ziprasidone free base, hydrochloric acid and water in presence of an organic solvent or a mixture of organic solvents;
b) heating the reaction mixture obtained in step (a) to about 45°C to the reflux temperature of the solvent used; and
c) either isolating ziprasidone hydrochloride monohydrate form III from the solution obtained in step (b) by filtration or centrifugation, or removing the solvents from the solution obtained in step (b) by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II;
wherein the organic solvent used in step (a) is selected from the group consisting of an alcohol solvent such as methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol; dimethylformamide; a chlorinated solvent such as methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; and an ether solvent such as diethyl ether, diisopropyl ether and tert-butyl methyl ether.
2. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) mixing ziprasidone free base, an alcohol or a mixture of alcohols, dimethylformamide, a chlorinated solvent, hydrochloric acid and water at about 45°C to 100°C to form a ziprasidone hydrochloride solution; and
b) removing the solvents from the solution obtained in step (a) by the techniques such as vacuum drying, spray drying, freeze drying and lyophilization to form ziprasidone hydrochloride monohydrate form II;

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 methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride.
3. The process as claimed in claim 2; wherein the solvents are removed by the
vacuum drying or spray drying.
4. The process as claimed in claim 2, wherein the alcohol is methanol.
5. The process as claimed in claim 2, wherein the chlorinated solvent is chloroform.
6. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) mixing ziprasidone free base, an ether solvent or a mixture of ether
solvents, dimethylformamide, hydrochloric acid and water at reflux to
form a ziprasidone hydrochloride solution; and
b) isolating ziprasidone hydrochloride monohydrate form III form the
solution obtained in step (a) at 25 - 30°C by filtration or centrifugation;
wherein the ether solvent is selected from the group consisting of diethyl ether, diisopropyl ether and tert-butyl methyl ether.
7. The process as claimed in claim 6, wherein the ether solvent is diethyl ether.

Documents:

916-chenp-2003-abstract.pdf

916-chenp-2003-claims filed.pdf

916-chenp-2003-claims granted.pdf

916-chenp-2003-correspondnece-others.pdf

916-chenp-2003-correspondnece-po.pdf

916-chenp-2003-description(complete)filed.pdf

916-chenp-2003-description(complete)granted.pdf

916-chenp-2003-drawings.pdf

916-chenp-2003-form 1.pdf

916-chenp-2003-form 3.pdf

916-chenp-2003-form 4.pdf

916-chenp-2003-form 5.pdf

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Patent Number

206274

Indian Patent Application Number

916/CHENP/2003

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

23-Apr-2007

Date of Filing

11-Jun-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	MURALIDHARA, Reddy, Dasari	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
5	SRINIVAS, Reddy, Itiyala

PCT International Classification Number

C07 D 417/12

PCT International Application Number

PCT/IN2003/000154

PCT International Filing date

2003-04-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA