Indian Patents. 212397:PROCESS FOR PREPARATION OF FINASTERIDE CRYSTALLINE POLYMORPHS

Title of Invention	PROCESS FOR PREPARATION OF FINASTERIDE CRYSTALLINE POLYMORPHS
Abstract	The present invention provides a process for the preparation of finasteride crystalline polymorphs, thus, for example, finasteride is dissolved in methanol, heated to 55°C and then stirred for 15 minutes. The solution is slowly cooled to O˚C, stirred for 1 hour 30 minutes at O˚C and then filtered the separated crystals to give crystalline form H1 of finasteride.

Full Text	The present invention relates to novel crystalline forms of finasteride, to processes for their preparation and pharmaceutical compositions containing them. BACKGROUND OF THE INVENTION Finasteride of formula (1): or (5a,17P)-N-(1,1-Dimethylethyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide is used for the treatment of benign prostatic hypertrophy and its therapeutic uses are disclosed in US 4,760,071. Two crystalline forms of finasteride, Form I and Form II, are disclosed in EP 0599376. We have discovered two novel crystalline forms of finasteride. The novel forms have been found to be stable and reproducible. These novel forms do not automatically convert into other crystalline forms of finasteride. The novel forms of finasteride are, thus, suitable for pharmaceutical preparations. Thus the object of the present invention is to provide stable novel crystalline forms of finasteride, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms. SUMMARY OF THE INVENTION According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H1, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.8. 6.8, 7.3, 9.0, 9.4, 10.7, 13.9. 14.9, 15.9, 17.3, 18.2, 19.0, 20.1 degrees. Figure 1 shows typical Form HI x-ray powder diffraction pattern. According to another aspect of the present invention there is provided a process for preparation of the Form H1 of finasteride comprising the steps of: a) mixing finasteride and an alcohol; b) maintaining at about 40°C to 60°C for about 10 minutes to 1 hour; c) cooling slowly to about 0°C to 5°C; d) maintaining for about 1 hour to 3 hours at about 0°C to 5°C; e) filtering the solid separated. The alcohol is methanol, ethanol or isopropyl alcohol; or mixture thereof. According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H2, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.4, 9.9, 12.1,14.5,15.2,16.2.19.3. 29,0 degrees. Figure 2 shows typical Form H2 x-ray powder diffraction pattern. According to another aspect of the present invention there is provided a process for preparation of the Form H2 of finasteride comprising the steps of: a) dissolving finasteride in dioxane; b) maintaining at about 70°C to 80°C for about 10 minutes to 30 minutes; c) cooling the solution slowly to about 20°C to 25°C; d) maintaining at about 20°C to 25°C for about 2 hours to 4 hours; e) filtering the solid separated. The previously known forms or finasteride prepared by a known method may be used in the above processes. According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form HI or Form H2 of finasteride. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction pattern of Form H1 finasteride. Figure 2 is a x-ray powder diffraction pattern of Form H2 finasteride. x-Ray powder diffraction spectrum was measured on a Siemens diffractometer, DETAILED DESCRIPTION OF THE INVENTION According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form HI, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.8, 6.8, 7.3, 9,0, 9.4, 10.7,13.9, 14.9. 15.9,17.3, 18.2, 19.0, 20.1 degrees. Figure 1 shows typical Form HI x-ray powder diffraction pattern. According to another aspect of the present invention, there is provided a process for preparation of the Form H1 of finasteride. Thus finasteride is mixed with an alcohol. The suitable alcohol is methanol or ethanol or isopropyl alcohol; or mixture thereof. The previously known forms or finasteride prepared by a known method may be used. The contents are maintained at about 40°C to 60°C for about 10 minutes to 1 hour and then cooled slowly in about 3 hours to about 0°C to 5°C. The contents are maintained for about 1 hour to 3 hours at about 0°C to 5°C, preferably for about 1.5 hours at 0°C. The Form HI of finasteride is separated by filtration. According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H2, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.4, 9.9, 12.1,14.5, 15.2,16.2,19,3, 29.0 degrees. Figure 2 shows typical Form H2 x-ray powder diffraction pattern. According to another aspect of the present invention there is provided a process for preparation of the Form H2 of finasteride. Thus finasteride is dissolved in dioxane, the solution is heated to about 70°C to 80°C and maintained at this temperature for about 10 minutes to 30 minutes. The solution is cooled slowly, in about 3 hours, to about 20°C to 25°C and maintained at the same temperature for about 2 hours to 4 hours. The separated crystals are filtered to give Form H2 of finasteride. The previously known forms or finasteride prepared by a known method may be used in the process. According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form HI or Form H2 of finasteride. The forrns of finasteride may be formulated in a form suitable for oral administration or injection. 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 Finasteride (10 gm) (obtained by a known method) is dissolved in methanol (25 ml), heated to 55°C and maintained at this temperature for 15 minutes. The solution is slowly cooled to 0°C in 3 hours and maintained at 0°C for 1.5 hours. The separated crystals are filtered at 0°C to give 8.5 gm of Form H1 of finasteride. Example 2 Finasteride (10 gm) (obtained by a known method) is dissolved in isopropyl alcohol (40 ml), heated to 55°C and maintained at this temperature for 15 minutes. The solution is slowly cooled to 0°C in 3 hours and maintained at 0°C for 1.5 hours. The separated crystals are filtered at 0°C to'give 8.5 gm of Form HI of finasteride. Example 3 Finasteride (10 gm) (obtained by a known method) is dissolved in dioxane (50 ml), heated the solution to 80°C and maintained at 80°C for 15 minutes. The solution is slowly cooled to 25°C, maintained for 3 hours at 25°C and the solid separated is filtered to give 9 gm of Form H2 of finasteride. Example 4 Example 1 is repeated using Form H2 of finasteride instead of finasteride to give Form HI of finasteride. Example 5 Example 3 is repeated using Form HI of finasteride instead of finasteride to give Form H2 of finasteride. We claim: 1. A process for the preparation of tiie finasteride crystalline polymorph, form H1, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.8, 6.8, 7.3, 9.0. 9.4, 10.7, 13.9, 14.9, 15.9. 17.3, 18.2, 19.0 and 20.1 degrees as shown in figure 1; form H2, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.4, 9.9, 12.1, 14.5, 15.2, 16.2. 19.3, 29.0 degrees as shown in figure 2; as herein described comprising the steps of: a) suspending or dissolving finasteride in an organic solvent; b) maintaining at about 40°C to 80°C for about 10 minutes to 1 hour; and c) isolating finasteride crystalline polymorph (form HI and/or form H2) from the solution obtained in step (b) at about 0 - 25°C; wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol and dioxane. 2. The process as claimed in claim 1, wherein the process comprising the steps of: a) mixing finasteride and an alcohol solvent; b) maintaining at about 40°C to 60°C for about 10 minutes to 1 hour; c) cooling slowly to about 0°C to 5°C; d) maintaining for about 1 hour to 3 hours at about 0°C to 5°C; and e) collecting the separated finasteride crystalline form HI by filtration; wherein the alcohol is methanol or ethanol or isopropyl alcohol. 3. The process as claimed in claim 2, wherein the alcohol is methanol. 4. The process as claimed in claim 2, wherein the alcohol is isopropyl alcohol. 5. The process as claimed in claim 1, wherein the process comprising the steps of. a) dissolving finasteride in dioxane; b) maintaining at about 70°C to 80°C for about 10 minutes to 30 minutes; c) cooling the solution slowly to about 20°C to 25°G; d) maintaining at about 2Q°C to 25°C for about 2 hours to 4 hours; and e) collecting the separated finasteride crystalline form H2 by filtration.

Full Text

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

or (5a,17P)-N-(1,1-Dimethylethyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide is used for the treatment of benign prostatic hypertrophy and its therapeutic uses are disclosed in US 4,760,071.
Two crystalline forms of finasteride, Form I and Form II, are disclosed in EP 0599376.
We have discovered two novel crystalline forms of finasteride. The novel forms have been found to be stable and reproducible. These novel forms do not automatically convert into other crystalline forms of finasteride.
The novel forms of finasteride are, thus, suitable for pharmaceutical preparations.
Thus the object of the present invention is to provide stable novel crystalline forms of finasteride, processes for preparation of the novel crystalline forms and pharmaceutical compositions containing these novel crystalline forms.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H1, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.8. 6.8, 7.3, 9.0, 9.4, 10.7, 13.9. 14.9, 15.9, 17.3, 18.2, 19.0, 20.1 degrees. Figure 1 shows typical Form HI x-ray powder diffraction pattern.

According to another aspect of the present invention there is provided a process for preparation of the Form H1 of finasteride comprising the steps of:
a) mixing finasteride and an alcohol;
b) maintaining at about 40°C to 60°C for about 10 minutes to 1 hour;
c) cooling slowly to about 0°C to 5°C;
d) maintaining for about 1 hour to 3 hours at about 0°C to 5°C;
e) filtering the solid separated.
The alcohol is methanol, ethanol or isopropyl alcohol; or mixture thereof.
According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H2, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.4, 9.9, 12.1,14.5,15.2,16.2.19.3. 29,0 degrees. Figure 2 shows typical Form H2 x-ray powder diffraction pattern.
According to another aspect of the present invention there is provided a process for preparation of the Form H2 of finasteride comprising the steps of:
a) dissolving finasteride in dioxane;
b) maintaining at about 70°C to 80°C for about 10 minutes to 30 minutes;
c) cooling the solution slowly to about 20°C to 25°C;
d) maintaining at about 20°C to 25°C for about 2 hours to 4 hours;
e) filtering the solid separated.
The previously known forms or finasteride prepared by a known method may be used in the above processes.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form HI or Form H2 of finasteride.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a x-ray powder diffraction pattern of Form H1 finasteride. Figure 2 is a x-ray powder diffraction pattern of Form H2 finasteride. x-Ray powder diffraction spectrum was measured on a Siemens diffractometer,
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form HI, characterized by an x-ray powder diffraction pattern having peaks expressed as 29 at about 5.3, 5.8, 6.8, 7.3, 9,0, 9.4, 10.7,13.9, 14.9. 15.9,17.3, 18.2, 19.0, 20.1 degrees. Figure 1 shows typical Form HI x-ray powder diffraction pattern.

According to another aspect of the present invention, there is provided a process for preparation of the Form H1 of finasteride. Thus finasteride is mixed with an alcohol. The suitable alcohol is methanol or ethanol or isopropyl alcohol; or mixture thereof. The previously known forms or finasteride prepared by a known method may be used. The contents are maintained at about 40°C to 60°C for about 10 minutes to 1 hour and then cooled slowly in about 3 hours to about 0°C to 5°C. The contents are maintained for about 1 hour to 3 hours at about 0°C to 5°C, preferably for about 1.5 hours at 0°C. The Form HI of finasteride is separated by filtration.
According to one aspect of the present invention, there is provided a novel crystalline form of finasteride, designated as Form H2, characterized by an x-ray powder diffraction pattern having peaks expressed as 26 at about 5.4, 9.9, 12.1,14.5, 15.2,16.2,19,3, 29.0 degrees. Figure 2 shows typical Form H2 x-ray powder diffraction pattern.
According to another aspect of the present invention there is provided a process for preparation of the Form H2 of finasteride. Thus finasteride is dissolved in dioxane, the solution is heated to about 70°C to 80°C and maintained at this temperature for about 10 minutes to 30 minutes. The solution is cooled slowly, in about 3 hours, to about 20°C to 25°C and maintained at the same temperature for about 2 hours to 4 hours. The separated crystals are filtered to give Form H2 of finasteride. The previously known forms or finasteride prepared by a known method may be used in the process.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising Form HI or Form H2 of finasteride. The forrns of finasteride may be formulated in a form suitable for oral administration or injection.
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
Finasteride (10 gm) (obtained by a known method) is dissolved in methanol (25 ml), heated to 55°C and maintained at this temperature for 15 minutes. The solution is slowly cooled to 0°C in 3 hours and maintained at 0°C

for 1.5 hours. The separated crystals are filtered at 0°C to give 8.5 gm of Form H1 of finasteride.
Example 2 Finasteride (10 gm) (obtained by a known method) is dissolved in isopropyl alcohol (40 ml), heated to 55°C and maintained at this temperature for 15 minutes. The solution is slowly cooled to 0°C in 3 hours and maintained at 0°C for 1.5 hours. The separated crystals are filtered at 0°C to'give 8.5 gm of Form HI of finasteride.
Example 3 Finasteride (10 gm) (obtained by a known method) is dissolved in dioxane (50 ml), heated the solution to 80°C and maintained at 80°C for 15 minutes. The solution is slowly cooled to 25°C, maintained for 3 hours at 25°C and the solid separated is filtered to give 9 gm of Form H2 of finasteride.
Example 4 Example 1 is repeated using Form H2 of finasteride instead of finasteride to give Form HI of finasteride.
Example 5 Example 3 is repeated using Form HI of finasteride instead of finasteride to give Form H2 of finasteride.

We claim:
1. A process for the preparation of tiie finasteride crystalline polymorph, form
H1, characterized by an x-ray powder diffraction pattern having peaks
expressed as 29 at about 5.3, 5.8, 6.8, 7.3, 9.0. 9.4, 10.7, 13.9, 14.9, 15.9.
17.3, 18.2, 19.0 and 20.1 degrees as shown in figure 1; form H2,
characterized by an x-ray powder diffraction pattern having peaks expressed
as 29 at about 5.4, 9.9, 12.1, 14.5, 15.2, 16.2. 19.3, 29.0 degrees as shown
in figure 2; as herein described comprising the steps of:
a) suspending or dissolving finasteride in an organic solvent;
b) maintaining at about 40°C to 80°C for about 10 minutes to 1 hour; and
c) isolating finasteride crystalline polymorph (form HI and/or form H2) from
the solution obtained in step (b) at about 0 - 25°C;
wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol and dioxane.
2. The process as claimed in claim 1, wherein the process comprising the steps of:
a) mixing finasteride and an alcohol solvent;
b) maintaining at about 40°C to 60°C for about 10 minutes to 1 hour;
c) cooling slowly to about 0°C to 5°C;
d) maintaining for about 1 hour to 3 hours at about 0°C to 5°C; and
e) collecting the separated finasteride crystalline form HI by filtration;
wherein the alcohol is methanol or ethanol or isopropyl alcohol.
3. The process as claimed in claim 2, wherein the alcohol is methanol.
4. The process as claimed in claim 2, wherein the alcohol is isopropyl alcohol.
5. The process as claimed in claim 1, wherein the process comprising the steps of.

a) dissolving finasteride in dioxane;
b) maintaining at about 70°C to 80°C for about 10 minutes to 30 minutes;

c) cooling the solution slowly to about 20°C to 25°G;
d) maintaining at about 2Q°C to 25°C for about 2 hours to 4 hours; and
e) collecting the separated finasteride crystalline form H2 by filtration.

Documents:

775-chenp-2003-abstract.pdf

775-chenp-2003-claims filed.pdf

775-chenp-2003-claims granted.pdf

775-chenp-2003-correspondnece-others.pdf

775-chenp-2003-correspondnece-po.pdf

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

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

775-chenp-2003-drawings.pdf

775-chenp-2003-form 1.pdf

775-chenp-2003-form 19.pdf

775-chenp-2003-form 3.pdf

775-chenp-2003-form 4.pdf

775-chenp-2003-form 5.pdf

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Patent Number

212397

Indian Patent Application Number

775/CHENP/2003

PG Journal Number

07/2008

Publication Date

15-Feb-2008

Grant Date

03-Dec-2007

Date of Filing

21-May-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	RAJI, Reddy, Rapolu	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,
3	RATHNAKAR, Reddy, Kura	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	SUBASH CHANDER, Reddy, Kesireddy	Hetero Drugs Limited (R & D), Plot No. B-80 & 81, A.P.I.E., Balanagar, Hyderabad 500 018,

PCT International Classification Number

C07J 73/00

PCT International Application Number

PCT/IN2003/000060

PCT International Filing date

2003-03-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA