Indian Patents. 207628:PROCESS FOR PREPARATION OF (S)-CITALOPRAM OXALATE CRYSTALLINE POLYMORPHS

Title of Invention	PROCESS FOR PREPARATION OF (S)-CITALOPRAM OXALATE CRYSTALLINE POLYMORPHS
Abstract	Abstract: The present invention relates to processes for preparation of (S)-citalopram oxalate crystalline polymorphs. Thus, for example, (S)-citalopram is dissolved in acetone, oxalic acid is added to the solution, the resulting mass is stirred for 30 minutes at 0°C and the separated solid is filtered to give (S)-citalopram oxalate crystalline form I.

Full Text	The present invention relates to novel crystalline forms of (S)-citalopram oxalate, to processes for their preparation and to pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION (S)-Citalopram of formula (1): or 1 (S)-[3-(Dimethylamino)propyl]-1 -(4-fluorophenyl)-1,3-dihydro-5-isobenzo furancarbonitrile as well as acid addition salts thereof are valuable antidepressants. EP 0347066 disclosed the therapeutic uses of (S)-citalopram and its salts. In the prior art literature no crystalline forms of (S)-citalopram oxalate were reported We have discovered two novel crystalline forms of (S)-citalopram oxalate. The novel forms have been found to be stable and reproducible and suitable for pharmaceutical preparations. Thus the object of the present invention is to provide stable novel crystalline forms of (S)-citalopram oxalate, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms. DESCRIPTION OF THE INVENTION According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.9, 8.9, 10.8, 13.4, 14.0, 16.3, 17.6, 18.6, 19.1, 19.5, 21.2, 22.8, 23.1, 24.2, 24.5, 25.3, 27.3 degrees. Figure 1 shows typical Form I x-ray powder diffraction pattern. According to another aspect of the present invention, there is provided a process for preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram oxalate is mixed with a suitable solvent. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or Form II of (S)-citalopram oxalate (prepared by the process described below) may be used. The contents may be heated to reflux. The Form I of (S)-citalopram oxalate is separated by filtration. According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in a suitable solvent and oxalic acid is added to the solution. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. The Form I of (S)-citalopram oxalate is precipitated from the solution by the techniques such as cooling, partial removal of the solvent or addition of anti-solvent. According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.6, 10.0, 11.0, 11.9, 15.2, 16.8, 17.8, 20.3, 21.1, 21.4, 22.6, 23.0, 26.4, 28.4 degrees. Figure 2 shows typical Form II x-ray powder diffraction pattern. According to another aspect of the present invention there is provided a process for preparation of the Form II of (S)-citalopram oxalate. Thus (S)-citalopram oxalate is mixed with an alcohol. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or the Form I of (S)-citalopram oxalate may be used. The alcohol is either methanol or ethanol or isopropyl alcohol. The solubility of (S)-citalopram oxalate depends on the alcohol used and volume of the alcohol to (S)-citalopram oxalate. For example, 5 gm of (S)-citalopram oxalate is soluble in 35 ml of methanol at 25°C. If (S)-citalopram oxalate is soluble in the conditions of experiment, the Form II of (S)-citalopram oxalate is precipitated from the solution. The techniques such as cooling, partial removal of the solvent, addition of anti-solvent like diisopropyl ether may be used to precipitate the Form II of (S)-citalopram oxalate. If the (S)-citalopram oxalate is insoluble in the alcohol, after mixing (S)-citalopram oxalate and the alcohol the solid is filtered from the contents to obtain Form II of (S)-citalopram oxalate. According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in an alcoholic solvent and oxalic acid is added to the solution. The alcoholic solvent is either methanol or ethanol or isopropyl alcohol. (S)-citalopram prepared by the process described in, for example, EP 0347066 may be used. The Form II of (S)-citalopram oxalate is precipitated from the solution by the techniques such as partial removal of the solvent or addition of anti-solvent. According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form I or Form II of (S)-citalopram oxalate. The forms of (S)-citalopram oxalate may be formulated in a form suitable for oral administration or injection. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an x-ray powder diffraction pattern of Form I (S)-citalopram oxalate. Figure 2 is an x-ray powder diffraction pattern of Form II (S)-citalopram oxalate. x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation. The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention. Example 1 (S)-Citalopram oxalate (5 gm, obtained as in example 2 of EP 0347066) is mixed with acetone (30 ml), heated to reflux and is cooled to 20°C. The separated crystals are filtered and dried to give Form I of (S)-citalopram oxalate (4.5 gm). Example 2 (S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in acetone (100 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 0°C and the separated solid is filtered and dried to give Form I of (S)-citalopram oxalate (10.5 gm). Example 3 (S)-Citalopram oxalate(5 gm, obtained as in example 2 of EP 0347066) is dissolved in methanol (35 ml) at 25°C. Then diisopropyl ether (50ml) is added to the solution and maintained for 2 hours at 25°C. The separated crystals are filtered and dried to give Form II of (S)-citalopram oxalate (4 gm). Example 4 (S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in isopropyl alcohol (125 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 40°C and cooled to 0°C. The separated solid is filtered and dried to give Form II of (S)-citalopram oxalate (9.5 gm). Example 5 Example 1 is repeated using Form II of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form I of (S)-citalopram oxalate. Example 6 Example 3 is repeated using Form I of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form II of (S)-citalopram oxalate. We claim: 1. A process for the preparation of (S)-citalopram oxalate crystalline polymorph(s), Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 6.9, 8.9, 10.8, 13.4, 14.0, 16.3, 17.6, 18.6, 19.1, 19.5, 21.2, 22.8, 23.1, 24.2, 24.5, 25.3, 27.3 degrees as shown in figure 1; Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 20 at about 6.6, 10.0, 11.0, 11.9, 15.2, 16.8, 17.8, 20.3, 21.1, 21.4, 22.6, 23.0, 26.4, 28.4 degrees as shown in figure 2; as herein described comprising the steps of: a) either, suspending or dissolving (S)-citalopram oxalate in a suitable solvent, or adding oxalic acid to a solution of (S)-citalopram in a suitable solvent; and b) isolating (S)-citalopram oxalate crystalline polymorph (Form I and/or Form II) from the solution obtained in step (a) by the techniques such as cooling, partial removal of the solvent or addition of an anti solvent; wherein the solvent used in step (a) is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, acetonitrile, and an alcoholic solvent such as methanol, ethanol and isopropyl alcohol; and the anti solvent used in step (b) is diisopropyl ether. 2. The process as claimed in claim 1, wherein the process comprising the steps of: a) suspending or dissolving (S)-citalopram oxalate in a suitable solvent; and b) isolating Form I of (S)-citalopram oxalate; wherein the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether and acetonitrile. 3. The process as claimed in claim 2, wherein the suitable solvent is acetone. 4. The process as claimed in claim 2, wherein the suitable solvent is ethyl acetate. 5. The process as claimed in claim 1, wherein the process comprising the steps of: a) adding oxalic acid to a solution of (S)-citalopram in a suitable solvent; and b) isolating Form I of (S)-citalopram oxalate; wherein the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether and acetonitrile. 6. The process as claimed in claim 5, wherein the suitable solvent is acetone. 7. The process as claimed in claim 1, wherein the process comprising the steps of: a) suspending or dissolving (S)-citalopram oxalate in an alcoholic solvent; and b) isolating Form II of (S)-citalopram oxalate; wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol. 8. The process as claimed in claim 7, wherein the alcoholic solvent is methanol. 9. The process as claimed in claim 7, wherein the Form II of (S)-citalopram oxalate is isolated by using diisopropyl ether as an anti-solvent. 10. The process as claimed in claim 1, wherein the process comprising the steps of: a) adding oxalic acid to a solution of (S)-citalopram in an alcoholic solvent; and b) isolating Form II of (S)-citalopram oxalate; wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol. 11. The process as claimed in claim 10, wherein the alcoholic solvent is methanol.

Full Text

The present invention relates to novel crystalline forms of (S)-citalopram oxalate, to processes for their preparation and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION (S)-Citalopram of formula (1):

or 1 (S)-[3-(Dimethylamino)propyl]-1 -(4-fluorophenyl)-1,3-dihydro-5-isobenzo furancarbonitrile as well as acid addition salts thereof are valuable antidepressants. EP 0347066 disclosed the therapeutic uses of (S)-citalopram and its salts. In the prior art literature no crystalline forms of (S)-citalopram oxalate were reported
We have discovered two novel crystalline forms of (S)-citalopram oxalate. The novel forms have been found to be stable and reproducible and suitable for pharmaceutical preparations.
Thus the object of the present invention is to provide stable novel crystalline forms of (S)-citalopram oxalate, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form I, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.9, 8.9, 10.8, 13.4, 14.0, 16.3, 17.6, 18.6, 19.1, 19.5, 21.2, 22.8, 23.1, 24.2, 24.5, 25.3, 27.3 degrees. Figure 1 shows typical Form I x-ray powder diffraction pattern.

According to another aspect of the present invention, there is provided a process for preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram oxalate is mixed with a suitable solvent. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or Form II of (S)-citalopram oxalate (prepared by the process described below) may be used. The contents may be heated to reflux. The Form I of (S)-citalopram oxalate is separated by filtration.
According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in a suitable solvent and oxalic acid is added to the solution. The suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, dioxane and acetonitrile. The Form I of (S)-citalopram oxalate is precipitated from the solution by the techniques such as cooling, partial removal of the solvent or addition of anti-solvent.
According to one aspect of the present invention, there is provided a novel crystalline form of (S)-citalopram oxalate, designated as Form II, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 6.6, 10.0, 11.0, 11.9, 15.2, 16.8, 17.8, 20.3, 21.1, 21.4, 22.6, 23.0, 26.4, 28.4 degrees. Figure 2 shows typical Form II x-ray powder diffraction pattern.
According to another aspect of the present invention there is provided a process for preparation of the Form II of (S)-citalopram oxalate. Thus (S)-citalopram oxalate is mixed with an alcohol. (S)-Citalopram oxalate prepared by the process described in, for example, EP 0347066 or the Form I of (S)-citalopram oxalate may be used. The alcohol is either methanol or ethanol or isopropyl alcohol. The solubility of (S)-citalopram oxalate depends on the alcohol used and volume of the alcohol to (S)-citalopram oxalate. For example, 5 gm of (S)-citalopram oxalate is soluble in 35 ml of methanol at 25°C. If (S)-citalopram oxalate is soluble in the conditions of experiment, the Form II of (S)-citalopram oxalate is precipitated from the solution. The techniques such as cooling, partial removal of the solvent, addition of anti-solvent like diisopropyl ether may be used to precipitate the Form II of (S)-citalopram oxalate. If the (S)-citalopram

oxalate is insoluble in the alcohol, after mixing (S)-citalopram oxalate and the alcohol the solid is filtered from the contents to obtain Form II of (S)-citalopram oxalate.
According to another aspect of the present invention, there is provided an alternative process for the preparation of Form I of (S)-citalopram oxalate. Thus, (S)-citalopram is dissolved in an alcoholic solvent and oxalic acid is added to the solution. The alcoholic solvent is either methanol or ethanol or isopropyl alcohol. (S)-citalopram prepared by the process described in, for example, EP 0347066 may be used. The Form II of (S)-citalopram oxalate is precipitated from the solution by the techniques such as partial removal of the solvent or addition of anti-solvent.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form I or Form II of (S)-citalopram oxalate. The forms of (S)-citalopram oxalate may be formulated in a form suitable for oral administration or injection.
BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is an x-ray powder diffraction pattern of Form I (S)-citalopram oxalate. Figure 2 is an x-ray powder diffraction pattern of Form II (S)-citalopram oxalate.
x-Ray powder diffraction spectrum was measured on a Siemens D5000 x-ray powder diffractometer having a copper-Ka radiation.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Example 1
(S)-Citalopram oxalate (5 gm, obtained as in example 2 of EP 0347066) is mixed with acetone (30 ml), heated to reflux and is cooled to 20°C. The separated crystals are filtered and dried to give Form I of (S)-citalopram oxalate (4.5 gm).
Example 2
(S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in acetone (100 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 0°C and the separated solid is filtered and dried to give Form I of (S)-citalopram oxalate (10.5 gm).

Example 3 (S)-Citalopram oxalate(5 gm, obtained as in example 2 of EP 0347066) is dissolved in methanol (35 ml) at 25°C. Then diisopropyl ether (50ml) is added to the solution and maintained for 2 hours at 25°C. The separated crystals are filtered and dried to give Form II of (S)-citalopram oxalate (4 gm).
Example 4 (S)-Citalopram (10 gm, obtained as in example 2 of EP 0347066) is dissolved in isopropyl alcohol (125 ml) and oxalic acid dihydrate (5 gm) is added to the solution. The contents are maintained for 30 minutes at 40°C and cooled to 0°C. The separated solid is filtered and dried to give Form II of (S)-citalopram oxalate (9.5 gm).
Example 5 Example 1 is repeated using Form II of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form I of (S)-citalopram oxalate.
Example 6
Example 3 is repeated using Form I of (S)-citalopram oxalate instead of (S)-citalopram oxalate (obtained as in example 2 of EP 0347066) to give Form II of (S)-citalopram oxalate.

We claim:
1. A process for the preparation of (S)-citalopram oxalate crystalline
polymorph(s), Form I, characterized by an x-ray powder diffraction pattern
having peaks expressed as 29 at about 6.9, 8.9, 10.8, 13.4, 14.0, 16.3, 17.6,
18.6, 19.1, 19.5, 21.2, 22.8, 23.1, 24.2, 24.5, 25.3, 27.3 degrees as shown in
figure 1; Form II, characterized by an x-ray powder diffraction pattern having
peaks expressed as 20 at about 6.6, 10.0, 11.0, 11.9, 15.2, 16.8, 17.8, 20.3,
21.1, 21.4, 22.6, 23.0, 26.4, 28.4 degrees as shown in figure 2; as herein
described comprising the steps of:
a) either, suspending or dissolving (S)-citalopram oxalate in a suitable solvent, or adding oxalic acid to a solution of (S)-citalopram in a suitable solvent; and
b) isolating (S)-citalopram oxalate crystalline polymorph (Form I and/or Form II) from the solution obtained in step (a) by the techniques such as cooling, partial removal of the solvent or addition of an anti solvent;
wherein the solvent used in step (a) is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether, acetonitrile, and an alcoholic solvent such as methanol, ethanol and isopropyl alcohol; and the anti solvent used in step (b) is diisopropyl ether.
2. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) suspending or dissolving (S)-citalopram oxalate in a suitable solvent; and
b) isolating Form I of (S)-citalopram oxalate;
wherein the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether and acetonitrile.
3. The process as claimed in claim 2, wherein the suitable solvent is acetone.
4. The process as claimed in claim 2, wherein the suitable solvent is ethyl acetate.
5. The process as claimed in claim 1, wherein the process comprising the steps of:

a) adding oxalic acid to a solution of (S)-citalopram in a suitable solvent; and
b) isolating Form I of (S)-citalopram oxalate;

wherein the suitable solvent is selected from the group consisting of acetone, ethyl acetate, methyl tert-butyl ether and acetonitrile.
6. The process as claimed in claim 5, wherein the suitable solvent is acetone.
7. The process as claimed in claim 1, wherein the process comprising the steps of:

a) suspending or dissolving (S)-citalopram oxalate in an alcoholic solvent; and
b) isolating Form II of (S)-citalopram oxalate;
wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol.
8. The process as claimed in claim 7, wherein the alcoholic solvent is
methanol.
9. The process as claimed in claim 7, wherein the Form II of (S)-citalopram
oxalate is isolated by using diisopropyl ether as an anti-solvent.
10. The process as claimed in claim 1, wherein the process comprising the steps
of:
a) adding oxalic acid to a solution of (S)-citalopram in an alcoholic solvent;
and
b) isolating Form II of (S)-citalopram oxalate;
wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol and isopropyl alcohol.
11. The process as claimed in claim 10, wherein the alcoholic solvent is
methanol.

Documents:

744-chenp-2003-abstract.pdf

744-chenp-2003-claims duplicate.pdf

744-chenp-2003-claims original.pdf

744-chenp-2003-correspondnece-others.pdf

744-chenp-2003-correspondnece-po.pdf

744-chenp-2003-description(complete) duplicate.pdf

744-chenp-2003-description(complete) original.pdf

744-chenp-2003-drawings.pdf

744-chenp-2003-form 1.pdf

744-chenp-2003-form 3.pdf

744-chenp-2003-form 4.pdf

744-chenp-2003-form 5.pdf

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Patent Number

207628

Indian Patent Application Number

744/CHENP/2003

PG Journal Number

44/2007

Publication Date

02-Nov-2007

Grant Date

19-Jun-2007

Date of Filing

19-May-2003

Name of Patentee

M/S. HETERO DRUGS LIMITED

Applicant Address

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

Inventors:

#	Inventor's Name	Inventor's Address
1	PARTHASARADHI, Reddy, Bandi	Hetero House, 8-3-166/7/1, Erragadda, Hyderabad 500 018, Andhrapradesh.

PCT International Classification Number

C 07 D 307/87

PCT International Application Number

PCT/IN2003/000066

PCT International Filing date

2003-03-24

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA