FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
IMPROVED PROCESS FOR PREPARING RIMONABANT AND ITS PHARMACEUTICAL
COMPOSITIONS
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh Hall, Ahmedabad 380 009, Gujarat, India
The following specification describes the invention:

IMPROVED PROCESS FOR PREPARAING RIMONABANT AND ITS PHARMACEUTICAL COMPOSITION
FILED OF THE INVENTION
The present invention relates to improved and industrially viable process for the preparation of rimonabant. The present invention also relates to rimonabant in the solid state and, more particularly, to crystalline solvates and amorphous forms of rimonabant having unique physical properties and process for the preparation thereof. The present invention further relates to a pharmaceutical composition of rimonabant, without using wetting agent and process for preparing the same.
BACKGROUND OF THE INVENTION
Rimonabant is first in a new class of drug, called CBl blockers. Rimonabant is a new entrant in the market of weight loss. Rimonabant is a selective CBl endo cannabinoid receptor antagonist indicated for the treatment of obesity. Rimonabant is also having long lasting effect on a patient than any other anti obesity drug.
The pharmacological properties of the rimonabant or its pharmaceutical acceptable salts, which are selective antagonists of the CBl central cannabinoid receptors, have been reported especially in the publication of M. Rinaldi-Carmona et al., FEBS Letters, 1994, 240-244.
Rimonabant is marketed in Europe by Sanofi-Aventis under the brand name ACOMPLIA® containing rimonabant base as an active ingredient of pharmaceutical product. Rimonabant is under approval by US FDA.
1

Rimonabant is 5-(4-chlorophenyl)-l-(2, 4-dichlorophenyl)-4-methyl-N-(piperidin-l-yl) pyrazole-3-carboxamide and its molecular structure is represented by formula I.

Rimonabant was first disclosed in EP 656354 Bl. A process disclosed in said patent for the preparation of rimonabant comprises the following steps :
(a) Condensation of 4-chloro-propiophenone (II) with diethyl oxylate in the presence of lithium hexamethyldisilazamide provided lithium salt (III).
(b) Obtained lithium salt condensed with 2,4-dichlorophenylhydrazine to provide hydrazone, refluxed in excess of acetic acid to yield carboxylate derivative (IV).
(c) The ester of formula (IV) was then converted to their acid (V) by reaction with an alkaline agent such as potassium hydroxide, followed by acidification.
(d) The acid (V) was converted to corresponding acid chloride (VI) by adding thionyl chloride into the suspension of acid in toluene & mixture is heated at reflux temp, for 3 hours.
(e) The compound (VI) was treated with 1-aminopiperidine, followed by column chromatography and crystallization form isopropyl ether to provide pure rimonabant.
The general process steps are represented in Schem-1 below.
SCHEME - 1
2


This process disclosed in EP 656354 Bl, however, suffers with limitations like:
(i) The halogenation of acid (V) at refluxed temp, requires a very high temp i.e. 110°C which is not much in favor of industrial feasibility.
(ii) Furthermore it is observed that while repeating the experiment as per EP 0656354B1, the acid of formula (V) does not get dissolved completely leading to partial conversion of formula (V) to formula (VI) thereby affecting the overall yield with lots of impurities. This in turn demands for the need of using special technique of separating the desired product from the unwanted impurities.
(iii) The special technique (column chromatography) used for the purification of residue requires large amount of solvents and is either to be discarded after use or its recyclability invites purification of the recovered solvents.
(iv) Furthermore, the large amounts of solvents are evaporated into the
atmosphere and therefore, the column chromatography is environmentally unsafe.
(v) All these parameters make the process not only lengthy, cumbersome but also industrially complicated.
3

In an alternate process as disclosed in EP 656354 Bl when reproduced also requires high temperature of reaction, partial conversion of formula(V) to formula(VI), distillation of excess of thionylchloride, azeotropic distillation and long reaction time for the step (e) in addition to low yields
The process of purification or crystallization disclosed in EP 656354 Bl lead to the formation of Form I of rimonabant as revealed in later published patent application WO 03040105 by same applicant. EP 656354 Bl also exemplifies salt of rimonabant such as hydrochloride, hemifumarate, tosylate, mesylate, dihydrogenphosphate etc. Also claims solvate forms of rimonabant but only exemplifies ethanol solvate of rimonabant base and hydrochloride salt, acetone solvate of tosylate salt. However, the prepared solvates were only characterized by their DSC; no other data was given.
EP 656354 Bl also discloses the various dosage form of rimonabant and suggests the use of wetting agent, particularly Sodium lauryl sulfate and optionally micronized rimonabant particularly for the solid composition in the form of tablets.
Another process for preparing rimonabant was disclosed in /. CHEM. SOC, CHEM. COMMUK, 1995, 1549-1550., which also involves laborious column chromatography for the purification of rimonabant with overall yield, of 15%.
A.K. Dutta, H. Sard, W. Ryan, R. K. Razdan, D. R. Compton and B. R. Martin, Med. Chem. Res., 1995, 5: 54-62, reports process for the preparation of rimonabant, schematically represented in scheme - 2.
SCHEME - 2
4


(f) HBr/ AcOH, 5° C to RT, 1.5 hr, 95%,
(g) NaH/ THF, 0°C, ethyl acetoacetate, reflux 1 hr, 42%,
(h) Na/ethanol, 0°C, 2,4-dichlorodiazonium chloride, H20,24 hr, 0°C,
(i) NaOH, ethanol, reflux 1.5 hr, 45%;
(j) Oxalyl chloride/CH2C12, rt;
(k) TEA, 1-aminopiperidine, rt; 1.5 hr,
The process as disclosed also leads to several disadvantage such as low yield (66%; from formula (V) to formula (I)) column chromatography, additional reagent specially dried solvent.
In an alternate approach of resolving the drawbacks as described above WO2006021652 discloses the use of carbohydrazide derivative for the preparation of rimonabant condensing with 1,5-dibromopentane with the overall yield of 48% only.,
WO 03040105 discloses crystalline form II of rimonabant base and process for preparing the same and also discloses the composition of rimonabant and wetting
5

agent can be added to other pharmaceutically acceptable excipients but this prior art does not discloses any example related to the composition.
Recently published application WO 06/087732 describes novel forms of rimonabant hydrochloride designated as Form II, III & Form IV and novel amorphous forms of rimonabant hydrochloride, and processes for their preparation.
Different therapeutic applications of rimonabant have been described in US634474, US 6642258, WOO 158450, and WOO 185092 which describes the preparation of pharmaceutical composition using micronised form of rimonabant without mentioning the appropriate quantity of Lactose monohydrate(example 4) in absence of wetting agent as against the quantitative details of the composition along with wetting agent(example 1-3). In addition to it in the absence of dissolution profile of example 1-3 or example 4 will lead to undue experimentation for a person skilled in art.
W09843636 discloses the hydrophobic character of the rimonabant or its pharmaceutical acceptable salts. These compounds are soluble in alcohols and glycols and more particularly in polyethylene glycols (PEG). Prior art also discloses that this problem can be overcome during formulation by using micronized form of rimonabant along with wetting agent i.e. sodium alkyl sulphate. The micronization of rimonabant as required in W09843636 for preparing pharmaceutical compositions unjustifiably increases the time cycle for the manufacturing process. It also requires undue utilities like milling and sifting, which increases the cost of preparing the final product in addition to environmental hazards. Wetting agent is a surfactant, a substance capable of reducing the surface tension of a liquid in which it is dissolved. The effect of surfactant over the intestinal membrane is more complex. It has been shown that most surfactants interact with the absorbing membranes (Bermejo, D. M. and Ruiz-Garcia, A., Business Briefing: Pharmatech 2003; pages 1-7). Permeability
6

enhancement and local damage are closely related sequelae of the interaction of surfactants with the intestinal wall (Swenson, E.S., Milisen, W.B., Curatolo, W., Pharm. Res. 1994 Aug; 11(8), pages 1132-42). Ingested surfactants may facilitate penetration or absorption of potentially toxic or pathogenic compounds, which in turn may result in adverse effects on the other organs (Lieberman, H.A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed, Vol. 1 , page 261). The surfactant can facilitate their own entry and that of other material into the body, which thus enters in to the systemic circulation (Lieberman, H.A., Rieger, M. M. and Banker, G. S., Eds., Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed., Vol. 1, page 264).
Polysorbate 60 or 80 affects the integrity of intestinal mucosa (Lieberman, H.A.,
Rieger, M.M. and Banker, G.S., Eds., Pharmaceutical Dosage Forms: Disperse
Systems, 2nd ed., Vol. 1, page 261). Polysorbate 80 may increase the absorption of
fat-soluble substances (www.lactose.co.uk/milkalleriey/foodadditives400.html).
Further, polysorbate 80 containing pharmaceutical compositions have found to cause
allergy in various patients
(http://www.hci.utah.edu/patientdocs/hci/drugd/docetaxel.htm). Polysorbate 20 and polysorbate 40 should also be avoided in formulations as they are banned in certain countries (http://www.lactose.co.uk/milkallergv/foodadditives400.html).
It is perceptible from the above mentioned prior arts that according to the known process for the preparation of rimonabant and its polymorphic forms and the pharmaceutical dosage forms thereof, there are more than one underlying problems associated with each reported process and its dosage form. Hence, there is a long felt need to develop a new process for preparing rimonabant and its pharmaceutical composition to take care of the mentioned problems.
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Thus, there is a demand for an improved process for synthesizing rimonabant, which is cost effective, commercially viable with higher yields and composition thereof which is safe and efficacious at the same time being cost and time effective on large scale of manufacturing.
The present inventors have surprisingly found an improved process for the preparation of rimonabant and its crystalline solvates and amorphous form.
Further it has also been surprisingly found that a stable pharmaceutical composition of rimonabant can also be prepared even without using micronized form of rimonabant and without incorporating wetting agent.
SUMMARY OF THE INVENTION
Thus according to one general aspect of the present invention, there is provided an improved process for the preparation of rimonabant of formula (I) comprising:
(a) halogenating 5-(4-chlorophenyl)-l-(2,4-dichlorphenyl)- 4 -methyl-pyrazole-3-
carboxylic acid (V) in aprotic solvent and in the presence of a cosolvent to obtain acid
chloride of formula (VI); and
(b) adding 1-aminopiperiddine and base to the acid chloride of formula (VI) in aprotic solvent to obtain formula (I); and
(c) isolating rimonabant.
According to another general aspect of the present invention, there is provided an
improved process for the preparation of rimonabant of formula (I) comprising:
(a) activating 5-(4-chlorophenyl)-l-(2,4-dichlorphenyl)- 4 -methyl-pyrazole-3-
carboxylic acid (V) using activating agent such as DiyclohexylCarbodimide or
Carbonyldimidazole
8

(b) adding 1-aminopiperiddine and base to the activated acid of formula (V) or adding the reaction mixture obtained in step a to a mixture containing 1-aminopiperidine and base,
(c) Isolating rimonabant
In another aspect, the present invention provides crystalline methanol solvate of rimonabant base.
In another aspect, the present invention provides crystalline isopropanol solvate of rimonabant base.
In another aspect, the present invention provides the use of crystalline methanol or isopropanol solvate for the preparation of pure Form I of rimonabant base.
In another aspect, the present invention provides novel amorphous form of rimonabant base.
In yet another aspect, the present invention provides a pharmaceutical dosage form of rimonabant with or without micronization of rimonabant and without wetting agent.
In yet another aspect the present invention provides a process for preparing the said pharmaceutical dosage form of rimonabant.
BREIF DESCRIPTION OF FIGURES
Fig. 1: X-ray powder diffraction pattern (XRPD) of Form I of rimonabant base. Fig. 2: X-ray powder diffraction pattern (XRPD) of amorphous form of rimonabant base.
Fig. 3: X-ray powder diffraction pattern (XRPD) of crystalline methanol solvate of rimonabant base.
9

Fig. 4: X-ray powder diffraction pattern (XRPD) of crystalline isopropanol solvate of
rimonabant base. Fig. 5: Differential Scanning Calorimetry (DSC) of Form I of rimonabant base. Fig. 6: Differential Scanning Calorimetry (DSC) of amorphous form of rimonabant base.
DETAIL DESCRIPTION OF THE INVENTION
In one aspect the present invention provides process for the preparation of rimonabant of formula (I) comprises the following steps:
(a) halogenating 5-(4-chlorophenyl)-l-(2,4-dichlorphenyl)- 4 -methyl-pyrazole-3-
carboxylic acid (V) in aprotic solvent and in the presence of a cosolvent to obtain acid
chloride of formula (VI); and
(b) adding 1-aminopiperiddine and base to the acid chloride of formula (VI) in aprotic solvent to obtain formula (I); and
(c) isolating rimonabant.
In step (a), preferably halogenation is chlorination; it can be conducted in chlorinated or non-chlorinated aprotic solvent but are not limited to chloroform, dichloromethane, dichloroethane, chlorobenzene, 1,1,1 -trichloroethane, ethyl acetate, methyl acetate, tetrahydrofuran, dioxane, toluene, methylcyclohexane or mixture thereof, more preferably toluene.
Chlorination can be carried out by using known chlorinating agent e.g. thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, or other commercial chlorinating agents, more preferably using thionyl chloride.
The cosolvent is preferably an aprotic polar solvent, such as dimethylformamide (DMF), dimethylacetamide, and N-methyl pyrolidone, most preferably DMF. In the presence of a cosolvent, the above mentioned acid (V) can be converted almost entirely into an acid chloride (VI).
10

The "solvent ratio" (v/v) of solvent and cosolvent is most prominent factor for the desired conversion of acid to acid chloride, it may vary from 100:1 to 100:10. Further, it has been observed that minimum solvent ratio for almost conversion in preferred range is 100:1. The desired conversion can be preferably in the range of 90 % -100%, more preferably 95% -100%.
The chlorination can be operated at temperature ranging from about 50°C to 80°C, preferably between 60°C to 70°C, preferably in an inert gas atmosphere such as nitrogen. The reaction time may vary, depending upon temperature, as well as specific solvents, but exemplary time can be expected to be generally in the range of about 30 minutes to 4 hours.
After the chlorination "substantially pure" acid chloride is isolated by any conventional method known to person skilled in art such as distillation, extraction etc.
As used herein, the term "substantially pure" refers to acid chloride having HPLC purity greater than 90% or 93% free from impurities, more often greater than 94%, or 95%free from impurities, and normally greater than 96% free from impurities.
In step (b), mixture of 1-aminopiperidine and base such as triethylamine added drop wise to the solution of acid chloride (VI) in aprotic solvent while keeping the reaction temperature in the -10° C to +20° C range and the reaction is allowed to continue until completed. Completion of the reaction may be determined by testing a sample from the reaction mixture by appropriate analytical techniques such as thin layer chromatography or high performance liquid chromatography. The mixture of 1-aminopiperidne and base may be dissolved or suspended in aprotic solvent and aprotic solvent used in step (a) and (b) may be same or different.
11

In step (c), isolating rimonabant refers to pure rimonabant obtained by any or all of the process carried out after the completion of reaction, such as distillation, extraction , subjecting residual mass or isolated residue/ product to purification by dissolving or suspending in at least one solvent selected from ether, methyl-isobutylketone, n-hexane, and cyclohexane, wherein ether is selected from diisopropyl ether, diethyl ether, tert-butyl methyl ether, petroleum ether,, distillation, filtration, drying.
The acid of formula (V) can be prepared by any method known to one of skill in art. See for example EP 656354 B1.
According to another general aspect of the present invention, there is provided an improved process for the preparation of rimonabant of formula (I) comprising:
(a) activating 5-(4-chlorophenyl)-l-(2,4-dichlorphenyl)- 4 -methyl-pyrazole-3-
carboxylic acid (V) using activating agent such as DiyclohexylCarbodimide or
Carbonyldimidazole
(b) adding 1-aminopiperiddine and base to the activated acid of formula (V) or adding the reaction mixture obtained in step a to a mixture containing 1-aminopiperidine and base,
(c) isolating rimonabant
The term Activating means reacting formula (V) with appropriate reagent other than halogenating agents.
Base as described herein above is selected from the group consisting of organic or inorganic base such as sodium carbonate, triethylamine.
According to another aspect, the crystalline solvate of rimonabant base constituting the object of the present invention can be prepared with process comprising:
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(i) Rimonabant base is dissolved by heating in solvent selected from the
group consisting of methanol and isopropanol and stirred for 30 minutes
to 1 hour at boiling temperature of solvent,
(ii) The clear solution is obtained after filtration is cooled to boiling
temperature of solvent to 25° C-35° C and stirred at same temp, for 30
min. to 1 hour,
(iii) Cool the mass further to 0° C-05° C and stir for 1 hour, then product is
filtered off, washed with same solvent and dried under vacuum to obtain
pure solvate form of rimonabant base.
As used herein, the term "pure" refers to compound having purity greater than 96% or 97% free from impurities, more often greater than 97%, or 98%free from impurities, and normally greater than 99% free from other impurities.
The crystalline methanol solvate of rimonabant base is characterized by XRPD pattern depicted in fig. 3 and expressed in following table 1:
Table 1

Crystalline Methanol Solvate of Rimonabant Base
Pos. [°2Th.| d-spacing[A] Rel. Int. [%1
7.3738 11.98895 4.35
9.4106 9.39818 20.78
10.6295 8.32304 12.73
13.5886 6.51649 100.00
14.6404 6.05065 18.24
15.3796 5.76143 7.64
16.2637 5.45019 27.57
17.2300 5.14663 3.50
17.8947 4.95695 8.06
19.1518 4.63431 4.88
20.8598 4.25855 10.18
21.2492 4.18139 14.42
22.5582 3.94162 37.86
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23.8339 3.73346 17.96
24.7881 3.59187 6.79
25.4073 3.50572 3.40
27.3619 3.25957 32.34
29.1349 3.06512 15.80
30.6684 2.91526 8.17
34.0722 2.63142 8.15
34.8282 2.57601 7.85
36.9799 2.43092 4.98
The crystalline isopropanol solvate of rimonabant base is characterized by XRPD pattern depicted in fig. 4 and expressed in following table 2:
Table 2

Crystalline Isoproponal solvate of Rimonabant Base
Pos. [°2Th.| d-spacing[A| Rel. Int. [%]
6.5438 13.50757 34.32
8.2934 10.66153 51.24
10.0890 8.76769 18.82
12.0601 7.33876 59.45
13.1668 6.72428 20.47
14.1057 6.27875 64.02
14.5876 6.07239 5.09
15.4263 5.74410 19.76
15.8365 5.59624 4.85
16.5408 5.35951 28.99
16.6252 5.33247 34.67
16.9960 5.21697 6.39
17.7486 4.99742 12.66
17.9562 4.84697 50.53
18.3042 4.94010 5.21
18.8116 4.71736 17.63
18.9944 4.67237 23.55
19.2199 4.61804 13.14
19.8758 4.46711 4.62
20.2665 4.38186 11.12
20.4398 4.34150 19.41
21.1516 4.20046 100.00
21.7484 4.08653 49.82
22.4697 3.95695 13.14
22.9395 3.87697 16.33
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23.4945 3.78663 3.79
24.2143 3.67567 42.72
24.5559 3.62530 8.64
25.0323 3.55738 13.49
25.9611 3.43218 10.65
26.2741 3.39200 12.31
26.5092 3.36245 28.99
27.3833 3.25707 11.36
28.0750 3.17837 13.85
28.4515 3.13716 26.86
28.7900 3.10105 19.53
29.4436 3.03368 3.08
30.1143 2.96763 4.85
30.6119 2.92051 17.63
31.1345 2.87268 11.12
31.5345 2.83715 8.88
32.3076 2.77100 13.96
32.9037 2.72215 4.73
33.4626 2.67795 10.65
33.9560 2.64016 4.85
34.9462 2.56758 5.68
35.8148 2.50728 4.50
36.4233 2.46677 4.26
36.7798 2.44368 10.65
38.3624 2.34644 6.86
According to another aspect, pure Form I rimonabant base constituting the object of the present invention can be prepared with process comprising:
(1) Dissolving or suspending amorphous or crystalline solvate of rimonabant base selected from methanol or isopropanol by heating in solvent such as dichloromethane
(2) Distill out the solvent and adding solvent A in the residual mass and continue the distillation.
(3) The obtained residual mass is added with same solvent used herein above step (2) and stirred for 1 hour at 25° C-35° C, and isolating pure Form-I.
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Solvent A herein described above is selected from the group consisting of ether such as diisopropyl ether, diethyl ether, tert-butyl methyl ether, petroleum ether , ketones such as methyl-isobutylketone, alkanes such as n-hexane, n-heptane, and cycloalkane such as cyclohexane. More preferred solvent A is diisopropyl ether.
The pure crystalline Form I of rimonabant base is characterized by XRPD pattern depicted in fig. 1.
According to another aspect of present invention there is provided a novel amorphous rimonabant, which is free of crystalline forms.. Figure 2 illustrates an XRPD pattern for this form, where the halo shape of the pattern illustrates the substantial absence of crystalline structure. Peaks and bumps are particularly missing in the regions characteristic of crystalline form. Additionally, pure amorphous rimonabant base has a DSC thermogram as depicted in Fig. 6.
A novel amorphous form of rimonabant base constituting the object of the present invention can be prepared with process comprising: Rimonabant base or solvate form of rimonabant base or pure form I of rimonabant base is dissolved in any suitable solvent, in which rimonabant base is getting dissolved. Then spray drying the material to provide amorphous rimonabant base.
Method and condition for the measurement of X-ray diffraction patterns.
(1) Method of the measurement:
X-ray diffraction patterns were measured on each 400 - 450 mg of the sample of rimonabant base by the following condition.
(2) Condition of measurement:

Target Cu

16
Filter Nickel
Voltage 45 KV
Current 40 mA
Slit DS-1/2, RS 0.02
Scan Speed 0.16°/Min
Range 2-40° 29
Step/Sample 0.008
Condition for the measurement DSC

Instrument METTLER STAR SW 8.10
Sample weight 1.5390 ±l mg
Heating Range 10°C/Min.
Flow rate of N2 50 ml/ Min.
Scan range 25 °C - 250 °C
According to another aspect of the invention there is provided a pharmaceutical dosage form of rimonabant containing either of its crystalline form, solvate form, or amorphous form, optionally in the mixture with other form(s) of rimonabant in admixture with pharmaceutically acceptable excipient(s). Rimonabant in the present invention can be used either in micronised or in a non micronised form to prepare pharmaceutical dosage form.
According to preferred aspect of the invention there is provided a pharmaceutical dosage form of rimonabant form I without micronization of rimonabant and without using wetting agent in admixture with pharmaceutically acceptable excipient(s) which exhibited excellent dissolution characteristics that were also found to be comparable with respect to the marketed formulation.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires
17

otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The term "rimonabant" used herein includes rimonabant free base, pharmaceutically acceptable salts, solvates, enantiomers or mixtures thereof.
The term "micronization" used herein means the process of reducing the average diameter of a solid material's particles and used when the particles that are produced are only a few micrometers in diameter.
The term "dosage form" as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosages, each unit containing a predetermined quantity of active material in association with the required excipients. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units. The dosage form used herein selected from tablets, capsule, sachets, pellets, beads, microspheres, microcapsules, pills, powders, lozenges, granules, solution, emulsion or suspension preferably in the form of tablet or capsule.
The dosage form of the present invention comprises the rimonabant in a range of about 1 mg to about 300 mg.
A tablet may be prepared by wet granulation, dry granulation, melt granulation, extrusion spheronization or direct compression, of the active ingredient(s) with a carrier and other excipients in a manner known to those skilled in the art.
Compressed tablets may be prepared by compressing in a suitable machine, after dry mixing the active ingredient with other pharmaceutically acceptable excipients or optionally granulating with the binder solution using- suitable granulation technique
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known to the skilled in the art. Molded tablets may be made on a suitable machine. A mixture of the powdered compound moistened with an inert liquid diluent is suitable in the case of oral solid dosage forms (e.g., powders, capsules, and tablets). If desired, tablets may be coated by standard techniques known to skilled in the art. The compound of this invention may be formulated into typical disintegrating tablets, or into controlled or extended release dosage forms. The preferred mode for preparation of tablet dosage form of present invention is compression of granules prepared by wet granulation.
Pharmaceutically acceptable excipients are known in the art and include diluents or fillers, binders, disintegrants, anti-adherents, lubricants. The proper excipient(s) are selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. The pharmaceutical dosage form tablet or capsule of the present invention is prepared using active ingredient rimonabant and pharmaceutically acceptable excipients selected from the group comprising of diluents, disintegrants, binders, anti-adherents, lubricants, and other pharmaceutically acceptable excipients but without wetting agent.
As used herein, the term "diluents" is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of dosage form. If desired, more than one diluent can be used. Diluents can be selected from the group comprising of lactose monohydrate , starch, maize starch, dibasic calcium phosphate anhydrous, tribasic calcium phosphate, kaolin, sucrose, mannitol, precipitated calcium carbonate, sorbitol, mannitol , cellulose derivatives including powdered cellulose, micro crystalline cellulose and other materials known to one of ordinary skill in the art.
The binder used in the composition of the present invention can be one or more compounds which are capable of densifying rimonabant by converting it into larger
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and dense particle with better flow properties. Binders can be selected from the group comprising of polyvinylpyrrolidone, hydroxyethylcellulose, HPMC, acacia, alginic acid, HPC, carboxymethylcellulose sodium, dextrin , ethyl cellulose, methylcellulose, shellac, zein compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, synthetic resin, pregelatinized starch and other materials known to one of ordinary skill in the art.
Disintegrants can be selected from the group comprising starch, sodium starch glycolate or croscarmellose sodium, crospovidone, alginic acid, carboxymethyl cellulose sodium, Guar gum and other materials known to one of ordinary skill in the art.
Anti-adherents agent may be used to prevent the tablet from sticking to the tablet punch and die wall and may be selected from talc, kaolin, finely divided silicon dioxide, glyceryl monostearate, and the like
The lubricant employed in the composition of the present invention can be one or more compound which are capable of preventing the problems associated with the preparation of dry forms, such as sticking and/or sizing problems which occurs in the machines during compression or filing. Lubricants can be selected from the group comprising of stearic acid, polyethylene glycol, magnesium stearate, calcium stearate, talc, zinc stearate, hydrogenated castor oil, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.
Solvents are selected from the group comprising of methanol, methyl isobutyl ketone, ethyl acetate , water and Methylene chloride.
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The dosage form of the present invention comprises the ingredients in the following proportion. Quantity of rimonabant can be based upon the requirement of human
dosage

Ingredient Minimum (%) Maximum (%)
Binder 0.5 10
Disintegrant 1 15
Diluent 5 90
Lubricant 0.2 5
Solvent* QS QS
* Does not remain in final dosage form
The pharmaceutical dosage form of the present invention containing rimonabant is
prepared according to the following steps:
(a) All excipients are passed through suitable sieve.
(b) Prepare the solution of rimonabant and binder in suitable solvent.
(c) Prepare the granules by suitable granulation technique using solution obtained form step (b).
(d) Dry the wet granules at suitable temperature and sieve the dried granules.
(e) Lubricate the granules of step (e) with lubricant
(f) Compress the granules obtained in step (f) into tablets or fill the granules into capsules.
(g) Optionally film coating the tablet
Having described the invention, the invention is further illustrated by the following non-limiting examples. The examples are merely illustrative and do not limit the teaching of this invention and it would be obvious that various modifications or changes in the procedural steps as well as compositions by those skilled in the art without departing from the scope of the invention and shall be consequently encompassed within the ambit and spirit of this approach and scope thereof.
Example-1
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Preparation of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride.
500 ml of toluene was charged with 50 gm. of 5-(4-chlorophenyl)-l-(2, 4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid in a flask followed by the addition of 5 ml of Dimethyl formamide at temp 25-30°C under stirring. 30 ml of Thionyl chloride was added to the above mixture at temp 25-30°C. The mixture was heated up to 60-70°C and stirred for 2-3 hrs at the same temperature and then cooled it to 50-60°C. The solvent was distilled out under vacuum at temp. 50°C-60°C and 50 ml of Toluene was added to the obtained residue, followed by distillation under vacuum at temp. 55°C-60°C. (Yield: 50 gm, 95%, purity - 97%)
Example-2
Preparation of N-piperidino-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide (rimonabant)
500 ml of Dichloromethane was charged under N2 atm in to the flask and cooled it to 0-5°C. 14.5 gm each of 1-Amino piperidine & triethyl amine was added to dichloromethane at temp 0-5°C. Then charged a solution of 50 gm of 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride drop wise in 250 ml of Dichloromethane over a period of 1-2 hrs at 0-5°C followed by continuous stirring for 2 hrs at same temperature. Check the TLC to confirm the completion of reaction. The obtained reaction mass was poured into 1.0 Lt of ice water and layer were separated. Aq. layer was extracted with 2 x 125 ml of MDC at temp 15-20°C and the organic layer was washed first with 2 x 125 ml of 5% solution of NaHC03, and then washed with 2 x 125 ml of R.O.water at temp 25±5°C and dried over 25 gm of anhydrous sodium sulphate, solvent was distilled out under vacuum at temp. 40-45°C and MDC traces were removed with 2 x 25 ml of Diisopropyl Ether. The resulting mass was charged with 200 ml Diisopropyl ether at temp 40-45°C and then cooled to 30-35°C with stirring for 30 min. Further cooled
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with continuous stirring for 1 hr at temp 0-5°C, and then filtered off the solid and washed with 2 x 25 ml of chilled DIPE and dried under vacuum at 55-60°C for 2-3 hrs. (Yield 50 gm, 86%, purity = 99%)
Example 3
Preparation of crystalline methanol solvate of rimonabant base.
25 gm. rimonabant base was suspended in 225 ml. of methanol and heated to reflux to obtain the clear solution. 2.5 gm of activated charcoal was added to reaction mass and stirred for 30 min. at the same temp. After that the reaction mass was filtered though hyflow bed and washed with 25 ml. of hot methanol. The filtrate was cooled to 30°C and stirred for 30 min. at 30-35°C. and finally filtered the material and washed with 25 ml. of chilled methanol. The product was dried at 60°C for 2-3 hrs. (Yield 21 gm, 84%, purity = 99.9%)
Example 4
Preparation of crystalline isopropanol solvate of rimonabant base.
10 gm. rimonabant base was suspended in 50 ml. of isopropanol and heated to reflux to obtain the clear solution. One gm of activated charcoal was added to reaction mass and stirred for 30 min. at the same temp. After that the reaction mass was filtered though hyflow bed and washed with 29 ml. of hot isopropanol. The filtrate was cooled to 30°C and stirred for 30 min. at 30-35°C. and finally filtered the material and washed with 25 ml. of chilled isopropanol. The product was dried at 60°C for 2-3 hrs. (Yield 9.7 gm, 97%, purity = 99.9%)
Example 5
Preparation of pure Form I of rimonabant base.
62 gm of rimonabant isopropanol solvate was charged with 248 ml of Dichloromethane at temp. 30-35°C, and stirred for 30 min to get clear solution. Dichloromethane was distilled out under vacuum at temp 30-35°C and residue was
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added with 2 x 62 ml of diisopropyl ether, which was further distilled out under vacuum at temp 30-35°C. The resulted residue was charged with 248 ml of diisopropyl ether with stirring for 1 hr at 30-35°C, and then cooled to 0-5°C with continuously stirring for 1 hr. subsequently the product was filtered out and washed with 62 ml of chilled diisopropyl ether and finally dried at 60°C for 4-5 hrs. (Yield: 59 gm, 95%, purity = 99.97%)
Example 6
Preparation of Amorphous rimonabant base.
10 gm of rimonabant was charged with 200 ml of Dichloromethane at temp. 25-30°C and stirred for 15 min to get clear solution. The obtained solution was passed through spray drier and collected solid, (weight: 3 gm)
Example 7
Pharmaceutical composition of rimonabant:

S.No. Ingredients B. No 026/027
Mg/ tablets % w/w
1. Rimonabant 20.00 6.667
2. Lactose monohydrate 150.00 50.000
3. Maize starch 50.00 16.667
4. Povidone K-30 4.00 1.333
5. Croscarmellose Sodium 27.00 9.000
6. Microcrystalline cellulose 48.00 16.000
7. Magnesium Stearate 1.00 0.333
8. Methylene chloride * Q.S. ~
9. Purified water * Q.S. --
Total weight 300.00 100.000
1. All excipient except mg stearate were sifted through # 40 and magnesium stearate through # 60,
2. Binder preparation: rimonabant and Povidone K-30 were dissolved in Methylene chloride.
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3. Lactose Monohydrate, Maize Starch and 50 % of total quantity of Croscarmellose Sodium were added in fluid bed processor.
4. Binder was sprayed over blend of step 3 and granulated, granules were dried, sized
5. Remaining quantity of Croscarmellose Sodium and Microcrystalline Cellulose were mixed in sized granules.
6. Mixture obtained from step 5 was lubricated with Magnesium Stearate and compressed into tablets and tablets were film coated.
Example 8
Comparison of Dissolution profile with the marketed formulation (Acomplia®) by Sanofi-Aventis:
Dissolution method:

Apparatus USP Type II (Paddle)
Paddle RPM 75
Volume 900 ml
Detection wavelength 254 nm by UV
Media pH 6.2 Phosphate buffer with 0.2% SLS
Dissolution Data:

S.No. Batch No. Manufactured by % drug Dissolved
10 min 15 min 30 min 45 min
1 026 Torrent 102.30 101.70 101.50 101.60
2 027 Torrent 102.33 100.13 104.63 99.23
3 267011 Sanofi-Aventis (Reference Product Acomplia®) 98.5 100.1 100.3 100.4


Dated this on 10th October, 2006

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ABSTRACT
The present invention describes improved and industrially viable process for the preparation of Rimonabant and also discloses Rimonabant in the solid state and, more particularly, to crystalline solvates and amorphous forms of Rimonabant having unique physical properties and process for the preparation thereof. The present invention further describes a pharmaceutical composition of Rimonabant, without using wetting agent and process for preparing the same.