FORM 2

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

1. Title of the invention. - A NOVEL CRYSTALLINE FORM OF
CLONIDINE HYDROCHLORIDE

2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: 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:
Field of the invention:
The present invention relates to a novel crystalline form of Clonidine hydrochloride designated herein as AL-form and its preparation.

Background of the invention:
The chemical name of Clonidine hydrochloride is 2-[(2, 6-dichlorophenyl)imino]-2-imidazoline hydrochloride and molecular formula is C0H9CI2N3.HCI and molecular weight is 266.55. The drug Clonidine hydrochloride is being sold by Boehringer under tradename CATAPRES® as a tablet.
Clonidine (Catapres) is an antihypertensive drug that is effective in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). It has also been used to treat Tourette syndrome by reducing tics, improving hyperactivity and decreasing obsessive-compulsive symptoms. Clonidine is an alpha-adrenergic stimulating agent that acts on presynaptic neurons to inhibit norepinephrine activity.
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. The polymorphic and pseudopolymorphic solids display different physical properties, including those due to packing, and various thermodynamic, spectroscopic, interfacial

and mechanical properties (See H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, N.Y., 1999, pp. 1-2). Polymorphic and pseudopolymorphic forms of the drug substance (also known as the "active pharmaceutical ingredient" (API)), as administered by itself or formulated as a drug product (also known as the final or finished dosage form, or as the pharmaceutical composition) are well known and may affect, for example, the solubility, stability, flowability, fractability, and compressibility of drug substances and the safety and efficacy of drug products, (see, e.g., Knapman, K Modem Drug Discoveries, March 2000: 53). Polymorphs of a compound can be characterized by x-ray diffraction pattern, infrared spectrum, DSC etc.
Clonidine hydrochloride was first reported in U.S. Patent No. 3,202,660, which disclose its process for preparation. Presently no polymorphic forms of Clonidine hydrochloride are reported in literature. Surprisingly inventors of present invention have found that Clonidine hydrochloride exists in substantially crystalline form.
One important physical property that can vary between two polymorphic forms is solubility, which can affect the bioavailability of the drug. Therefore there is a need to develop new polymorphic forms of a drug since it provides new opportunity to improve the performance characteristics of a pharmaceutical product.
Object of the invention:
It is therefore an object of the present invention to provide a novel crystalline form of Clonidine hydrochloride designated herein as AL-form.
Another object of the present invention is to provide a process for the preparation of a novel crystalline form of Clonidine hydrochloride designated herein as AL-form.

Another object of the present invention is to provide a process for the preparation of a novel crystalline form of Clonidine hydrochloride designated herein as AL-form having purity more than 99.5 %.
A further object of the present invention is to provide process for the preparation of a novel crystalline form of Clonidine hydrochloride herein as AL-form, which is operationally simple, cost-effective, easy to handle and feasible at commercial scale.
Summary of the Invention:
Accordingly, the present invention provides a novel crystalline form of Clonidine hydrochloride designated herein as AL-form.
Another aspect of the present invention provides a novel crystalline form of Clonidine hydrochloride designated herein as AL-form, characterized by powder X-ray diffraction peaks at 9.92, 12.64, 13.18, 14.71, 16.98, 22.34, 23.30, 24.74, 25.38 and 26.46 2-9 values.
In another aspect, the present invention provides a process for the preparation of a novel crystalline form of Clonidine hydrochloride designated herein as AL-form comprising steps of:
(i) refluxing charcoalized solution of crude Clonidine hydrochloride in
methanol
(ii) filtering the solution obtain in step (i)
(iii) removing methanol
(iv) adding alcoholic solvent in the residue obtain in step (iii)
(v) removing alcoholic solvent
(vi) adding alcoholic solvent in the residue obtain in step (v)

(vii) stirring the reaction mixture obtain in step (vi)
(viii) filtering the reaction mixture obtain in step (vii)
(ix) washing solid material obtain in step (viii) with alcoholic solvent
(x) drying solid material obtain in step (ix)
Brief description of the figure:
Fig-1 illustrates an X-ray diffraction diagram of novel crystalline form of Clonidine hydrochloride designated herein as AL-form.
Detailed description of the invention:
Accordingly, the present invention provides a novel crystalline form of Clonidine hydrochloride designated herein as AL-form which is characterized by powder X-ray diffraction spectrum which is substantially the same as shown in Fig-1.
A novel crystalline form of Clonidine hydrochloride designated herein as AL-form is characterized by powder X-ray diffraction peaks at 9.92, 12.64, 13.18, 14.71, 16.98, 22.34, 23.30, 24.74, 25.38 and 26.46 2-9 values.
Another preferred embodiment of the present invention provides a novel crystalline form of Clonidine hydrochloride designated herein as AL-form comprising steps of:
(i) refluxing charcoalized solution of crude Clonidine hydrochloride in methanol
(ii) filtering the solution obtain in step (i)
(iii) removing methanol
(iv) adding alcoholic solvent in the residue obtain in step (iii)
(v) removing alcoholic solvent

(vi) adding alcoholic solvent in the residue obtain in step (v)
(vii) stirring the reaction mixture obtain in step (vi)
(viii) filtering the reaction mixture obtain in step (vii)
(ix) washing solid material obtain in step (viii) with alcoholic solvent
(x) drying solid material obtain in step (ix)
The starting material crude Clonidine hydrochloride can be prepared by the process disclosed in patent application number 680/MUM/2007 as well as from the process disclosed in prior art.
The process in step (i) is carried out at a reflux temperature for 1 hr to 3 hrs.
The meaning of term "charcoalized solution" used herein above includes treating of
charcoal with the solution crude Clonidine hydrochloride in methanol.
The meaning of term "filtering the solution" used in step (ii) includes filtering the solution obtain in step (i) through hyflo bed at room temperature or refluxing temperature.
The meaning of term "removing methanol" used herein above includes distilling of methanol from the solution under vacuum or atmospheric pressure.
The meaning of term "alcoholic solvent" used herein above includes all alcoholic solvent except methanol. The alcoholic solvent are selected from ethanol, butanol, propanol, isopropanol and like or mixture thereof. The preferred alcoholic solvent is isopropanol.
The meaning of term "removing" used herein above includes distilling of alcoholic solvent or isopropanol completely from the solution under vacuum or atmospheric pressure.

The process in step (vii) is carried out at room temperature for 1 hr to 3 hrs.
The meaning of term "drying" used herein above includes drying of solid material under vacuum or atmospheric pressure.
The process in step (x) is carried out at 40-80°C.
Yet another aspect of the present invention provides a process for the preparation of a novel crystalline form of Clonidine hydrochloride designated herein as AL-form comprising steps of:
(i) refluxing solution of crude Clonidine hydrochloride in methanol
(ii) removing methanol
(iii) adding alcoholic solvent in the residue obtain in step (ii), optionally
removing alcoholic solvent and further adding alcoholic solvent
(iv) stirring the reaction mixture obtain in step (iii)
(v) filtering and washing with alcoholic solvent
(vi) drying solid material obtain in step (v)
The process in step (i) involves treatment of charcoal with the solution crude Clonidine hydrochloride in methanol to obtain charcoalized solution and charcoalized solution refluxed for 1 hr to 3 hrs at reflux temperature. The reaction mixture is filtered through hyflo bed at room temperature or refluxing temperature.
The meaning of term "removing methanol" used herein above includes distilling of methanol from the solution under vacuum or atmospheric pressure.

The meaning of term "alcoholic solvent" used herein above includes all alcoholic solvent except methanol. The alcoholic solvent are selected from ethanol, butanol, propanol, isopropanol and like or mixture thereof. The preferred alcoholic solvent is isopropanol.
The meaning of term "removing" used herein above includes distilling of alcoholic solvent completely from the solution under vacuum or atmospheric pressure.
The process in step (iv) is carried out at room temperature for 1 hr to 3 hrs.
The meaning of term "drying" used herein above includes drying of solid material under vacuum or atmospheric pressure.
Unexpectedly, the present inventors observed a novel crystalline form of Clonidine hydrochloride designated herein as AL-form with purity more than 99.5%.
Moreover, the process of the present invention has following advantages:
• It provides a process which is economical, operational and industrially applicable.
• The process is simple and easy to handle and does not require special handling care or critical temperature conditions.
• It reduces the time period of the reaction.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.

Example 1
Process for crude Clonidine hydrochloride (Patent application number
680/MUM/2007)
Stage-I: Preparation of N-(2,6-dichlorophenyl)formamide
2, 6-Dichloroaniline (100 g) in a mixture of acetic anhydride (175 ml) and formic acid (52 ml) was heated at 30-80°C for 1-10 hrs. D.M. Water (600 ml) was added to reaction mixture and then the solid material was filtered and washed with D.M.Water (400 ml) and Dichloromethane (200 ml). The material was dried at 40-80°C. Yield: 110 g (97.5%) HPLC purity: -99.8%
Stage-II: Preparation of crude Clonidine Hydrochloride
Sulfuryl chloride (51 ml) was added to a pre cooled mixture of N-(2, 6-dichlorophenyl) formamide (100 g) in thionyl chloride (500 ml). The reaction mixture was heated to 40-60°C for 4-15 hrs. D.M.Water (1000 ml) was added to the reaction mixture at 0-50°C and then Dichloromethane (700 ml) was added to the reaction mixture and then stirred for 15-30 minutes. Organic layer was separated and cooled to 0-10°C. Ethylene diamine (70 ml) was added to the reaction mixture and stirred for 2-24 hrs. The reaction mixture was filtered and the filtrate was washed with D.M.Water (200 ml). The organic layer was added IPA HC1 (-16.0 %) (80-90 ml) and then cooled to obtain crude Clonidine hydrochloride. The solid product was filtered and washed with Dichloromethane (100 ml X 2). The solid product was dried at 40-80°C. Yield: 90-100 g (64.3%) HPLC purity: -99.9%

Stage-Ill: Purification of Clonidine Hydrochloride
A solution of crude Clonidine Hydrochloride (50 g) in Methanol (350 ml) was charcoalized for 60-120 minutes refluxing temperature. The reaction mixture was filtered through hyflo bed at room temperature. Methanol was then distilled out under vacuum at 30-60°C. Isopropanol (100 ml) was then added to the residual mass and then distilled out under vacuum. Isopropanol (100 ml) was added to the residual mass and then the mixture was stirred for 60-120 minutes then solid material was filtered, washed with Isopropanol (50 ml) and dried under vacuum at 40-80°C to obtain crystalline AL-form of Clonidine hydrochloride.
Yield: 40-45 g (80.0 %)
HPLC purity: -99.9%
X-ray powder diffraction pattern demonstrates the crystalline nature of AL-form of
Clonidine hydrochloride (Fig-1).

We claim:
1. A process for the preparation of crystalline AL-form of Clonidine
hydrochloride comprising steps of:
(i) refluxing charcoalized solution of crude Clonidine hydrochloride in
methanol
(ii) filtering the solution obtain in step (i)
(iii) removing methanol from filtrate obtain in step (ii)
(iv) adding alcoholic solvent in the residue obtain in step (iii)
(v) removing alcoholic solvent from solution obtain in step (iv)
(vi) adding alcoholic solvent in the residue obtain in step (v)
(vii) stirring the reaction mixture obtain in step (vi)
(viii) filtering the reaction mixture obtain in step (vii)
(ix) washing solid material obtain in step (viii) with alcoholic solvent
(x) drying solid material obtain in step (ix)
2. The process of claim 1, wherein the reaction in step (i) is carried out at a reflux temperature for 1 hr to 3 hrs.
3. The process of claim 1, wherein alcoholic solvent in step (iv), step (v), step (vi) or step (ix) are selected from ethanol, butanol, propanol, isopropanol or mixture thereof
4. The process of claim 3, wherein the alcoholic solvent in step (iv), step (v), step (vi) or step (ix) is isopropanol.
5. The process of claim 1, wherein reaction in step (vii) is carried out at room temperature for 1 hr to 3 hrs.

6. A process for the preparation of a novel crystalline form of Clonidine
hydrochloride designated herein as AL-form comprising steps of:
(i) refluxing solution of crude Clonidine hydrochloride in methanol
(ii) removing methanol
(iii) adding alcoholic solvent in the residue obtain in step (ii), optionally
removing alcoholic solvent and further adding alcoholic solvent
(iv) stirring the reaction mixture obtain in step (iii)
(v) filtering and washing with alcoholic solvent
(vi) drying solid material obtain in step (v)
7. The process of claim 6, wherein alcoholic solvent in step (iii) is selected from ethanol, butanol, propanol, isopropanol or mixture thereof.
8. A crystalline AL-form of Clonidine hydrochloride.
9. A crystalline AL-form of Clonidine hydrochloride characterized by the X-ray powder diffraction peaks 9.92, 12.64, 13.18, 14.71, 16.98, 22.34, 23.30, 24.74, 25.38 and 26.46 2-9 values.

ABSTRACT
The present invention relates to a novel crystalline form of Clonidine hydrochloride designated as form I comprising steps of:
(i) refluxing charcoalized solution of crude Clonidine hydrochloride in
methanol
(ii) filtering the solution obtain in step (i)
(iii) removing methanol obtain in step (i)
(iv) adding alcoholic solvent in the residue obtain in step (iii)
(v) removing alcoholic solvent from solution obtain in step (iv)
(vi) adding alcoholic solvent in the residue obtain in step (v)
(vii) stirring the reaction mixture obtain in step (vi)
(viii) filtering the reaction mixture obtain in step (vii)
(ix) washing solid material obtain in step (viii) with alcoholic solvent
(x) drying solid material obtain in step (ix)