F0RM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. Title of the invention.

NOVEL POLYMORPHIC FORMS OF (S)-(-)-2-AMINO-6-(N- PROPYLAMINO)-4,5,6,7-TETRAHYDROBENZOTHIAZOLE

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Filed of invention:
The present invention relates to novel polymorphic forms of (S)-(-)-2-Amino-6-(n-
propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) and process of their
preparation. More particularly the present invention discloses four novel
polymorphic forms of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole of formula (I) designated as Form I, II, III and IV. The compound of formula (I) is commonly known as Pramipexole.

Formula (I)
Background of the invention and prior art:
(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole is known as Pramipexole and belongs to a group of 2-amino-6-(substituted)amino-4,5,6,7-tetrahydro benzothiazoles having general formula (A), wherein Ri is hydrogen, alkyl or aralkyl group and R2 is hydrogen. These compounds are first described in US Patent No. 4,843,086. They are useful for treatment of schizophrenia, Parkinson's disease or parkinsonism, and/or hypertension. The processes for the preparation of Pramipexole and its pharmaceutically acceptable salts are known in literature.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes in solid state. Thus, polymorphs are distinct solids sharing the same molecular formula, yet
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each polymorph may have distinct physical properties. Therefore a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures and/or x-ray diffraction pattern. Polymorphs of a compound can be characterized by x-ray diffraction pattern, Infrared Spectrum, DSC etc.
The polymorphic form of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole are not reported in literature. The inventors of present invention have now found that (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole exhibits polymorphism. These polymorphic forms are characterized as Form I, II, III and IV.
Object of the invention:
It is the primary object of the present invention to provide novel polymorphic forms of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I).
Another object of the invention is to provide novel polymorphic forms of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form I, II, III and IV.
Yet another object of the invention is to provide processes for preparation of novel polymorphic forms of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form I, II, III and IV.
Summary of the invention:
According to one aspect of present invention, there is provided a novel polymorph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form I,
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Formula (I)
characterized by PXRD peaks at 9.7,13.0, 16.6, 18.7, 21.9 ± O.2°-20.
According to another aspect the present invention provides the process for the
preparation of Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole of formula (I).
According to another aspect of the invention, there is provided a novel polymorph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form II,

Formula (I)
characterized by PXRD peaks at 7.9,15.8,19.7, 23.7, 24.4 ± 0.2°-29.
According to a further aspect the present invention provides the process for the
preparation of Form II of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole of formula (I).
Formula (I)
characterized by PXRD peaks at 12.0, 21.4, 24.2, 24.7, 25.0 ± O.2°-20.
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According to further aspect of the invention, there is provided a novel polymorph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form III,


According to another aspect the present invention provides the process for the preparation of Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I).
According to yet another aspect of the invention, there is provided a novel polymorph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form IV,

Formula (I)
characterized by PXRD peaks at 15.6, 18.5, 19.9, 20.8, 25.8 ± O.2°-20.
According to further aspect the present invention also provides the process for the preparation of Form IV of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I).
Detailed description of the invention:
The term "(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole", used herein in specification and claims is intended to include Pramipexole and its pharmaceutical^ acceptable salts, and hydrates or solvates thereof in any state of purity unless specifically mentioned.
According the present invention, novel polymorphic form of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form I is characterized by PXRD peaks at 9.7, 13.0, 16.6, 18.7, 21.9 ± O.2°-20. It is further characterized by PXRD peaks at 10.8, 17.3, 17.7, 21.5, 22.4 ± O.2°-20.
The process for the preparation of Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) comprises treating (S)-(-)-2-Amino-
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6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with solvent selected from acetonitrile, acetone, water and mixtures there of to obtain Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Alternatively, Form I can be prepared by treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with solvent selected from ethyl acetate, dichloro methane, methyl isobutyl ketone and the like to obtain solution and adding anti-solvent selected from hexane, diisoproyl ether, diethyl ether, methyl terf-butyl ether, cyclohexane to the said solution to obtain Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Another process for the preparation of Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole comprises treating the solution of acid addition salt of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole, preferably hydrochloride or dihydrochloride salts with base selected from alkali and alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, cesium hydroxide and the like to obtain Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole. The solution of acid addition salt of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole is meant to include any solvent,., in which acid addition salt of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole is soluble. Preferred solvent is selected from water, alcohols such as methanol, ethanol, isopropanol, n-propanol, tert-butanol and mixtures thereof.
Form I obtained by above procedures can be isolated by conventional methods and dried.
In accordance with the present invention, another novel polymorphic form of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form II is characterized by PXRD peaks at 7.9, 15.8, 19.7, 23.7,
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24.4 ± 0.2°-29. It is further characterized by PXRD peaks at 17.9, 18.4, 20.5, 26.0, 27.5 ± O.2°-20.
The process for the preparation of Form II of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) comprises treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with 0.8 to 1.2 M equivalent hydrochloric acid in alcohol selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol and mixtures thereof to obtain Form II of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Preferably, Form II is prepared by treating methanolic solution of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with 1.1 molar equivalent of cone, hydrochloric acid at about 40 to 50°C temperature and subsequently cooling it to obtain Form II of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Form II obtained by above procedure can be isolated by conventional methods and dried.
Yet another aspect of the present invention provides novel polymorphic form of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form III, characterized by PXRD peaks at 12.0, 21.4, 24.2, 24.7, 25.0 ± 0.2°-29. It is further characterized by PXRD peaks at 13.0, 13.3, 13.9, 19.5, 25.6, 28.5 ±0.2°-29.
The process for the preparation of Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) comprises treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with 1.8 to 2.2 M equivalent hydrochloric acid in alcohol selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol and mixtures thereof to obtain Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
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Preferably, Form III is prepared by treating solution of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole in ethanol-water with 20% ethanolic hydrochloric acid solution at 40 to 60°C temperature and subsequently cooling it to obtain Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Form III obtained by above procedure can be isolated by conventional methods and dried.
According to the present invention, yet another novel polymorphic form of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) designated as Form IV is characterized by PXRD peaks at 15.6, 18.5, 19.9, 20.8, 25.8 ± 0.2°-29.. It is further characterized by PXRD peaks at 12.9, 13.7, 24.2, 24.9, 26.6± 0.2°-26.
The process for the preparation of Form IV of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) comprises treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with anhydrous alcohol selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol and mixtures thereof to obtain solution , optionally cooling the said solution and passing HCI gas to obtain Form IV. The said HCI gas is preferably dry.
Alternate process for the preparation of Form IV of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula (I) comprises treating Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with alcohol selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol and mixtures thereof to obtain solution and concentrating the solution to obtain Form IV.
Form IV obtained by above procedures can be isolated by conventional methods and dried.
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(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole used in experimental procedures is prepared in accordance with process know perse or by any method of preparation known to person skilled in art.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Examples:
Example 1: Preparation of Form I
(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (50g) was added to 125 ml of acetonitrile and heated to 80-86°C. The reaction mixture was cooled to about 20-25°C and product was filtered, washed and dried at 45-60°C to obtain 48 g of Form I of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Example 2: Preparation of Form II
A solution of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (8.4g) in Methanol (30ml) was heated the to 40°-42°C followed by addition of cone. HCI (3.3ml) slowly over a period of 20-30 min. at 40°-42°C. The reaction mixture was stirred for 30 min at 40°-42°C. Subsequently the reaction mixture was cooled to 25°-35°C. Material is filtered and air dried at 25°-35°C for 12-15 hours to obtain 6.34 g of Form II of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Example 3: Preparation of Form III
(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (10g) was added to ethanol (90ml) and the reaction mixture is heated to 55-60°C to get a clear solution. The reaction mixture is charcoalized and filtered. Water (90ml) was added to the filtrate and cooled to 0-5°C. -20% Ethanolic HCI (180 ml) was
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added drop wise to the reaction mixture till pH 2. The temperature of the reaction mixture was raised to 25-35°C and stirred for 12-15 hours. The product was filtered and dried at 25-35°C to obtain Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole.
Example 4: Preparation of Form IV
(S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (20 g) is dissolved in methanol (500ml) and hydrochloric acid gas is purged at 0-5°C. The reaction mixture is then stirred and filtered, washed with methanol, dried at 40°C to get (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form IV. The product is filtered, washed and dried at 40°C under vacuum (19.9g)
Example 5: Preparation of Form IV
Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole (20 g) was suspended in ethanol (100 ml) and ethanol was recovered completely under reduced pressure at 40°C to get (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form IV. The product is filtered, washed and dried at 40°C under vacuum (19.9g).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Brief description of the figures:
Figure 1 represents PXRD graph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form I.
Figure 2 represents PXRD graph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form II.
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Figure 3 represents PXRD graph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form III.
Figure 4 represents PXRD graph of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form IV.
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We claim:
1. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula I designated as Form I.
Formula (I)
2. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form I as claimed in claim 1, characterized by PXRD peaks at 9.7, 13.0, 16.6, 18.7, 21.9 ± O.2°-20.
3. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form I as claimed in claim 1 having PXRD pattern as shown in Figure 1.
4. A process for the preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form I comprises treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with solvent selected from acetonitrile, acetone, water and mixtures there of to obtain Form I.
5. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole Form I comprises treating (S)-(-)-2-Amino-6-(n-
propylamino)-4,5,6,7-tetrahydrobenzothiazole with solvent selected from ethyl
acetate, dichloro methane, methyl isobutyl ketone and the like to obtain solution
and adding anti solvent selected from hexane, diisoproyl ether, diethyl ether,
methyl terf-butyl ether, cyclohexane to said solution to obtain Form I.
6. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole Form I comprises treating the solution of acid addition
salt of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with
base to obtain Form I.
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7. A process as claimed in claim 6, wherein said acid addition salt of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole is preferably hydrochloride or dihydrochloride salt.
8. A process as claimed in claim 6, wherein said base is selected from alkali and alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, cesium hydroxide and like.
9. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula I designated as Form II.

Formula (I)
10. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form II
as claimed in claim 9, characterized by PXRD peaks at 7.9, 15.8, 19.7, 23.7, 24.4
± O.2°-20.
11. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form II as
claimed in claim 9 having PXRD pattern as shown in Figure 2
12. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole Form II comprises treating (S)-(-)-2-Amino-6-(n-
propylamino)-4,5,6,7-tetrahydrobenzothiazole with 0.8 to 1.2 M equivalent
hydrochloric acid in alcohol to obtain Form II.
Formula (I)
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13. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula
I designated as Form III.


14. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form III
as claimed in claim 13, characterized by PXRD peaks at 12.0, 21.4, 24.2, 24.7,
25.0 ± 0.2°-29.
15. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form III as claimed in claim 13 having PXRD pattern as shown in Figure 3
16. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form III comprises treating (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with 1.8 to 2.2 M equivalent hydrochloric acid in selective alcohol.
17. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole of formula
I designated as Form IV.

Formula (I)
18. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form IV
as claimed in claim 17, characterized by PXRD peaks at 15.6, 18.5, 19.9, 20.8,
25.8 ± O.2°-20.
19. (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form II as
claimed in claim 17 having PXRD pattern as shown in Figure 4
20. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-
tetrahydrobenzothiazole Form IV comprises treating (S)-(-)-2-Amino-6-(n-
propylamino)-4,5,6,7-tetrahydrobenzothiazole with anhydrous selective alcohol to
obtain solution , optionally cooling the said solution and passing HCI gas to
obtain Form IV.
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21. A process for preparation of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole Form IV comprises treating Form III of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole with selective alcohol to obtain solution and concentrating the solution to obtain Form IV.
22. A process as claimed in any preceding claims, wherein said alcohol is selected from methanol, ethanol, isopropanol, n-propanol, tert-butanol, and mixtures thereof preferably methanol or ethanol.
Dated this 24th day of October 2005

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ABSTRACT
Title : NOVEL POLYMORPHIC FORMS OF (S)-(-)-2-AMINO-6-(N-PROPYLAMINO)-4,5,6,7- TETRAHYDROBENZOTHIAZOLE
The present invention relates to novel polymorphic forms of (S)-(-)-2-Amino-6-(n-propylamino)-4,5,6,7-tetrahydrobenzothiazole designated as Form I, II, III and IV and its process for preparation.
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