FORM2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
NOVEL POLYMORPHIC FORM C OF ANHYDROUS
PRAMIPEXOLE DlHYDROCHLORIDE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400051.
3. PREAMBLE TO THE DESCRD7TION
The present invention provides a novel polymorphic Form C of anhydrous
pramipexole dihydrochlonde. The invention also relates to pharmaceutical compositions that include the anhydrous pramipexole dihydrochlonde and one or more pharmaceutically acceptable carriers, excipients or diluents.
The following specification particularly describes the invention and the manner
in which it is to be performed.
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4. DESCRIPTION
The present invention provides a novel polymorphic Form C of anhydrous pramipexole dihydrochioride. The invention also relates to pharmaceutical compositions that include the anhydrous pramipexole dihydrochioride and one or more pharmaceutically acceptable carriers, excipients or diluents.
Pramipexole of Formula I is chemically (S)-2-amino-4,5,6,7-tetra-hydro-6-(propylamino)benzothiazole and is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease. Pramipexole is commercially available in the form of dihydrochioride salt as monohydrate.

Formula I
US patent No. 4,886,812 discloses pramipexole or an acid addition salt thereof. The '812 patent further provides various processes for the preparation of pramipexole.
Journal of medical chemistry, 30, 494-498, (1987), describes a process for the preparation of optically pure pramipexole. It also discloses a process for resolution of racemic 2,6-diamino intermediate using L-(+)-tartaric acid as chiral auxiliary. The so obtained single enantiomer precursor is further converted to pramipexole by a two-step reaction, which involves N-acylation and reduction.
PCT patent application No. WO 02/022590 provides a process for preparation of pramipexole which involves reacting 6-substituted 2-amino-4,5,6,7-tetrahydrobenzothiazole with an amine in the presence of a reducing agent. The 6-substituted group may be an alkoxy, alkylenedioxy or an oxo group.
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PCT patent application No. WO 02/022591 provides a process for resolution of pramipexole, which involves reacting racemic pramipexole with a acid to form a monobasic acid addition salt which is further converted into the dibasic acid addition salt.
PCT patent application No. WO 02/022591 discloses polymorphic Forms A and B of anhydrous pramipexole dihydrochloride.
The present inventors have now found a novel polymorphic Form C of anhydrous pramipexole dihydrochloride.
The term "compound of Formula I or acid addition salt thereof in the present invention refers to a compound of Formula I or its monobasic or dibasic acid addition salt. The acid addition salt can be selected from inorganic or organic acid addition salt. The dibasic acid addition salt can be a mixed acid addition salt of two different acids. The term also includes hydrates, solvates and enantiomers of compound of Formula I or acid addition salt thereof.
In one of the aspect of the present invention there is provided a novel polymorphic Form C of anhydrous pramipexole dihydrochloride.
In another aspect of the of the present invention there is provided a polymorphic Form C of anhydrous pramipexole dihydrochloride having a characteristic XRD pattern as depicted in Figure I.
Embodiments of the polymorphic Form C may include one or more of the following features. For example, the polymorphic Form C of anhydrous pramipexole dihydrochloride may include 2theta values at 6.58, 6.82, 11.62, 11.94, 12.20, 12.72, 13.18, 13.54, 13.78, 15.02, 15.46, 16.84, 17.10, 17.80, 18.10, 18.34, 19.38, 19.96, 20.46, 20.72, 21.24, 21.70, 22.98, 23.20, 23.52, 24.10, 24.76, 25.68, 26.44, 26.76, 27.14, 27.46, 27.76, 28.36, 29.08, 29.36,
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29.54, 30.70, 31.50, 31.86, 31.96, 32.66, 33.64, 34.70, 34.90, 35.96, 37.28, 37.56, 38.12, 38.38, 38.70.
In yet another aspect of the of the present invention there is provided a polymorphic Form C of anhydrous pramipexole dihydrochloride having a characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure II.
In yet another aspect there is provided a process for the preparation of polymorphic Form C of anhydrous pramipexole dihydrochloride. Pramipexole free base can be obtained by any process known in the art. The process includes:
a) treating mixture of pramipexole base and organic solvent with dry HCI,
b) isolating pramipexole dihydrochloride from the reaction mixture and thereof.
The non-limiting examples of organic solvents include alcohols, haloalkanes, esters, ethers, aromatic solvents and other such as acetonitrile. The halogenated solvent includes halo (C1-C6) alkanes such as methylene chloride, chloroform, carbon tetrachloride, 1,1,1-trichloroethylene, 1,1,2-trichloroethylene and the like. The dry HCI is slowly purged in the reaction mixture at 0° C or lower till the pH is 5 or below.. The isolation is carried at lower temperature in the range of 10°C to upto -20°C.
Isolation of Pramipexole may include, for example, one or more of filtration, filtration under vacuum, distillation, distillation under vacuum, evaporation, decantation and centrifugation. The process may include further forming of the product so obtained into a finished dosage form.
The process may include further drying of the product obtained.
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The anhydrous form C of pramipexole dihydrochloride may have, for example, a purity of 99% or more when measured by HPLC and a moisture content of about 0.25 %w/w or less.
In yet another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of polymorphic form C of anhydrous pramipexole dihydrochloride and one or more pharmaceutically acceptable carriers, excipients or diluents.
Figure I depicts XRD of Form C of anhydrous pramipexole dihydrochloride.
Figure II depicts DSC of Form C of anhydrous pramipexole dihydrochloride.
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, model 2200, target: Cu K (a), Divergence slits 1.0, Receiving slit 0.3 mm, Scatter slit 1°, Power: 40 KV, Scanning speed: 5 deg/min step: 0.02 deg, Wave length: 1.5406 A & scan range of 2.5-40.
DSC of the samples were determined by using Metller Toledo DSC 822 e, scan temperature 30-350° C. Pan 40 ml. (Aluminium pan).
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.
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Example 1 Preparation of Form C of pramipexole dihvdrochloride
To the mixture of Pramipexole free base (60.01 g) in ethanol (360ml), the dry HCI
was purged at 0 °C to attain the phi around 2. The precipitated solid was filtered,
washed and dried to give Pramipexole dihvdrochloride.
Yield: 75g
HPLC Purity: 99.6%
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WE CLAIM:
1. Polymorphic Form C of anhydrous pramipexole dihydrochloride.
2. A polymorphic Form C of anhydrous pramipexole dihydrochloride having a characteristic XRD pattern as depicted in Figure I.
3. A polymorphic Form C of anhydrous pramipexole dihydrochloride having characteristic Differential Scanning Calorimetric (DSC) thermogram as depicted in Figure II.
4. A process of preparation of pramipexole dihydrochloride of claim 1, comprising:

a) treating mixture of pramipexole base and organic solvent with dry HCI,
b) isolating pramipexole dihydrochloride from the reaction mixture and thereof.

5. Anhydrous pramipexole dihydrochloride of claim 1, having purity 99% or more when measured by HPLC.
6. Anhydrous pramipexole dihydrochloride of claim 5, having purity greater than 99.6%.
7. Anhydrous pramipexole dihydrochloride of claim 1, having moisture content of about 0.25 % w/w or less.
8. Anhydrous pramipexole dihydrochloride of claim 7, having moisture content of about 0.23%w/w.
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9. A pharmaceutical composition that includes a therapeutically effective amount of polymorphic form C of anhydrous pramipexoie dihydrochloride of claim 1, and one or more pharmaceutically acceptable carriers, excipients or diluents.
Dated this26th day of Feb,2007 For Wockhardt Limited

(Mandar kodgule) Authorized Signatory
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