FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule!3)
1. TITLE OF THE INVENTION: "Amorphous form of Rimonabant, process for preparation and compositions thereof
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008,
Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Field of invention:
The present invention relates to an amorphous form of N- piperidino-5-(4- chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide and a process for its preparation. More particularly the invention relates to the preparation of an amorphous form and to pharmaceutical compositions thereof.
Background of invention:
N-piperidino-5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide is an antagonist of the CB i cannabinoid receptors and is also known by the international nonproprietary name as rimonabant represented by formula I.

Rimonabant and its pharmaceutical acceptable salts were described for first time in European patent EP0656354. The method disclosed in this patent describes the preparation of rimonabant in crystalline form.
European patent EP0656354 (1994) makes no reference to the existence of any specific polymorphic forms of rimonabant. However US patent application US20050043356 discloses a new crystalline form of rimonabant named as Form II. Crystalline Rimonabant was prepared following the process disclosed in EPO 656 354 and is termed as crystalline Form -I in subsequent patent. It is reported and we have confirmed that crystalline rimonabant has a tendency to form solvate with methanol, ethanol, isopropyl alcohol and various other organic solvents like ethyl acetate, tetrahydrofuran, methyl cyclohexane, hexane, heptane, isopropyl acetate, acetone, acetonitrile, methyl ethyl ketone, dimethyl formamaide, dimethyl acetamide
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etc. In crystalline rimonabant the solvents gets trapped in the crystals lattice and hence removal of these residual solvent becomes difficult. The solvated form of any drug is not acceptable by any regulated authority for any pharmaceutical use. Further, to get rid of the residual solvent it requires purification or crystallization, which leads to a loss in yield. Alternatively the solvate has to be dried at elevated temperature for prolonged duration. Other desolating techniques known in the art are suspending the solvate in anti-solvent and digesting for extended periods.
It is a well known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties. The amorphous form of a drug may exhibit different dissolution characteristics and in some case different bioavailability patterns compared to crystalline forms.
Further, amorphous and crystalline forms of a drug may have different handling properties, dissolution rates, solubility, and stability.
Furthermore, different physical forms may have different particle size, hardness and glass transition temperatures. Amorphous materials do not exhibit the three-dimensional long-range orders found in crystalline materials, but are structurally more similar to liquids where the arrangement of molecules is random.
Amorphous solids do not give a definitive x-ray diffraction pattern (XRD). In addition, amorphous solids do not give rise to a specific melting point and tend to liquefy at some point beyond the glass transition temperature. Because amorphous solids do not have lattice energy, they usually dissolve in a solvent more rapidly and consequently may provide
r
enhanced bioavailability characteristics such as a higher rate and extent of absorption of the compound from the gastrointestinal tract. Also, amorphous forms of a drug may offer
significant advantages over crystalline forms of the same drug in the manufacturing process
t
of solid dosage form such as compressibility.
Regulatory authorities required to have all possible polymorphic forms of a new drug substance identified prior to approval of a product containing the drug. However, it is well known in the art, the existence of polymorphic forms of any given compound cannot be
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predicted, and there is no standard procedure for proceeding to make a previously unknown polymorphic form. Even after a polymorph has been identified, there is no possibility of predicting whether any additional forms will ever be discovered. This has been described in many recent articles, including A. Goho, Science News, Vol. 166, No. 8, pages 122-123 (August 2004).
Consequently, it would be a significant contribution to the art to provide an amorphous form of rimonabant, having increased solubility, and methods of preparation, pharmaceutical formulations, and methods of use thereof.
The present invention provides an amorphous rimonabant hereinafter referred to as Form A and a process to prepare it. The advantages of the process include simplicity, eco-friendliness and suitability for commercial use. The known processes for making amorphous substances include lyophilization & spray drying. But these are time consuming & expensive. The process of the present invention is surprisingly very simple, economical and eco-friendly.
Summary of the invention
The invention discloses an amorphous rimonabant Form A.
In one aspect the invention discloses a process for the preparation of amorphous rimonabant Form A and isolation of the same from aqueous media.
In another aspect, the invention provides a pharmaceutical composition that contains an amorphous form of rimonabant form A and one or more pharmaceutically acceptable carriers.
Detailed Description
All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art unless defined otherwise. For purposes of the present invention, the following terms are defined below.
The phrase "amorphous rimonabant" is intended to include any amorphous form of rimonabant including but not limited to amorphous rimonabant, an amorphous solid
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dispersion of rimonabant, and amorphous combinations of rimonabant with pharmaceutically acceptable carriers or crystallization inhibitors.
The term "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non- toxic, and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term "composition" includes, but is not limited to, a powder, a suspension, an emulsion
and/or mixtures thereof. A "composition" may contain a single compound or a mixture of
compounds. '
The term "pharmaceutical composition" is intended to encompass a product comprising the active ingredient(s) and pharmaceutically acceptable excipients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, any additional active ingredient(s), and pharmaceutically acceptable excipients.
The term "excipient" means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent, carrier, and so on. The excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes either one, or more than one, such excipient.
In one aspect the present invention provides a stable amorphous rimonabant Form A which is substantially non-hygroscopic and has good flow characteristic.
In another aspect, the present invention provides a process for the preparation of amorphous rimonabant form A. Crystalline rimonabant is prepared using process as disclosed in EPO 656 354. This is then converted to various acid addition salts of rimonabant. The preferred acid for preparing the salt is selected from oxalic acid, mahdelic acid, tartaric acid, citric acid,
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salicylic acid fumaric acid, sulphuric acid, phosphoric acid preferably hydrochloric acid. The acid addition salt of rimonabant is suspended in water and stirred at temperature below 40°C. The pH of the suspension is made alkaline using aqueous ammonia. The resulting suspension is stirred for 2-3 hrs. at a temperature of 25-30° C and filtered. The resulting solid is washed with water and dried under vacuum at below 80°C preferably at 55-60°C to give amorphous rimonabant Form A.
Crystaline rimonabant has the tendency to form solvates with alcohols and other solvent used for crystallization which is difficult to remove by conventional methods of drying, the process of the present invention acts as a very good desolvating process for rimonabant, this form another aspect of the present invention.
Amorphous rimonabant Form A of the present invention is further characterized by X-ray powder diffraction spectrum shown in fig-1, where the vertical axis denotes intensity and the horizontal axis denotes the 26 angle, in degrees.
The XRPD of the amorphous rimonabant Form A was measured on a Rigaku miniflex advance powder X-ray Powder Diffractometer using a Cu K alpha-1 radiation source, and is characterized by its XRPD pattern as shown in fig-1.
Amorphous rimonabant form A of the present invention is further characterized by IR spectrum shown in fig-2.
Amorphous rimonabant form A of the present invention is further characterized by having characteristic IR spectra peaks at about 3407 cm-1, 3305 cm-1, 3144 cm-1, 3049cm-1, 2937cm-1 2803 cm-1,1442cm-1,1409cm-1,1245 cm-1, 863.60, ± 0.2 cm-1.
In another aspect, the present invention provides a pharmaceutical composition containing the amorphous form of rimonabant and one or more pharmaceutical excipients. The pharmaceutical composition may be prepared by uniformly admixing the active ingredient with liquid or solid excipients and then shaping the product into the desired form. The pharmaceutical compositions may be in the form of suspensions, solutions, elixirs, aerosols, or solid dosage forms. Because of their ease of administration, tablets and capsules represent
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a more advantageous oral dosage unit form, in which case solid pharmaceutical excipients are employed.
Pharmaceutical excipients that can be used for the preparation of pharmaceutical compositions include, but are not limited to, hydrophilic polymers such as polyvinylpyrrolidone, gums, cellulose derivatives, cyclodextrins, gelatins, hypromellose phthalate, sugars, polyhydric alcohols, polyethylene glycol, polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohol, propylene glycol derivatives etc.. The use of mixtures of more than one of the pharmaceutical carriers to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, mixtures are all within the scope of this invention without limitation. Those having skill in the pharmaceutical formulation art are well aware of numerous suitable excipients, and useful procedures for making pharmaceutical compositions. ,
Brief description of the drawings
FIG. 1 is an X-ray powder diffraction ("XRPD") pattern for amorphous rimonabant Form A.
FIG. 2 is an Infra red spectrum (IR) for amorphous rimonabant Form A.
The invention is further described by reference to the following examples, which set forth in detail certain aspects and embodiments of the preparation of compounds and compositions of the present invention. It will be apparent to those skilled in the art, that many modifications, both to materials and methods can be practiced without departing from the purpose and intent of this invention. The examples that follow are not intended to limit the scope of the invention as described hereinabove or as claimed below.
EXAMPLES
Example 1
Preparation of Crystalline rimonabant
Crystalline rimonabant was prepared using the process disclosed in EP EP0656354.
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Example 2
Preparation of rimonabant hydrochloride
Crystalline rimonabant (100 gms) was dissolved in ethyl acetate (1.0 ltr.) and stirred at 25-30°C. To the reaction mass HC1 gas dissolved in isopropyl alcohol was added dropwise at room temperature until the pH of reaction mass was 2-3. The resulting precipitate was stirred at 25-30°C for 2 hrs. and filtered. The solid was washed with ethyl acetate and dried under vacuum at 55-60°C to get a 100 gms of rimonabant hydrochloride.
Example 3
Preparation of amorphous rimonabant form A
Rimonabant hydrochloride (100 gms) was suspended in water (1500 ml) at 25-30°C and stirred. The pH of the reaction mass was adjusted to 9 using 10% liquor ammonia solution. The resulting slurry was stirred for 4 hours at 25-30°C filtered the solid and washed with water (500 ml). The solid was dried in vacuum oven at 60°C for 12-14 hrs. to get 90 gms of amorphous rimonabant form A.
Example 4
Preparation of amorphous rimonabant form A
Rimonabant hydrogensulphate (50 gms) was suspended in water (1000 ml) at 25-30°C and stirred. The pH of the reaction mass was adjusted to 9 using 10% liquor ammonia solution. The resulting slurry was stirred for 4 hours at 25-30°C filtered the solid and washed with water (500 ml). The solid was dried in vacuum oven at 60°C for 12-14 hrs. to get 35 gms of amorphous rimonabant form A.

Dr. Gopakumar G. Nair Agent for the Applicant
Dated this 19th day September 2006