Title of Invention

NEW PROCESS FOR PREPARATION OF BILOGICALLY ACTIVE BENZISOXAZOLE

Abstract

The invention is for an improved process for of production of risperidone of formula (I) which comprises the steps of: (a) reacting a halo compound with an oxime in a solvent and a base at 10-40°C; (b) refluxing the reaction mixture of step (a) for 4- 10 hours; (c) adding base to the cooled refluxed mixture of step (b) while maintaining the temperature at 20-40°C for 10-18 hours; (d) filtering and drying the risperidone thus obtained and (e) optionally purifying risperidone obtained in step (d). The invention also discloses a new polymorphic variety of risperidone namely, risperidone form T1 having its characteristic X-ray diffraction pattern and IR data.

Full Text

BACKGROUND OF THE INVENTION 1. FIELD OF THE INVENTION The invention relates to an improved process for the preparation of biologically active risperidone (I) i.e. 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)- piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one and also a new polymorphic variety of this compound. 2. DESCRIPTION OF THE RELATED ART Schizophrenia is one of the most severe and debilitating major psychiatric diseases. The introduction of antipsychotic drugs was indisputably a great advance in the pharmacotherapy of mental disorders. The typical antipsychotic drugs are not effective in all patients. Patients with chronic schizophrenia are either unresponsive or only partially responsive to their antipsychotic drugs. In addition, antipsychotics are ineffective against other dimensions of schizophrenic pathology, namely the negative symptoms of the deficit state and neurocognitive deficits. Lastly, typical antipsychotic drugs have an extensive side-effect profile, with the majority of patients experiencing one or more of the acute extrapyramidal syndromes and patients in an unenviable position in which they can expect only some symptoms to respond to treatment, along with uncomfortable and possibly disabling side-effects. Risperidone ( I ) i.e. 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidin-1- yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one has been introduced in the wake of clozapine induced toxicity. Risperidone, a benzisoxazol derivative, is an antipsychotic agent, which combines potent serotonin 5HT2 and dopamine D2 receptor antagonism. Another advantage offered by risperidone is a faster onset of antipsychotic action, a lower incidence of extrapyramidal effects and possibly greater efficacy against the negative symptoms of schizophrenia. The cardiovascular effects of risperidone reflect its a-adrenergic antagonistic activity, comprising a dose-related decrease in blood pressure and reflex tachycardia on single, but not multiple dose administration. Patients with schizophrenia appear to be more tolerant of the hypotensive effect of risperidone than healthy volunteers. (Drug 1992; Journal of Chromatography, 1993). Risperidone (I) i.e. 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl) -piperidin-1-yl] ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidin-4-one can be prepared by the various processes. According to the process disclosed in ES 2074966, 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one, compound (II) is converted into dibenzyl amine derivative. The dibenzyl group is removed and converted into primary amine i.e. compound (III). On the other hand diflourobenzyl ketone i.e. compound (IV) is converted into its oxime by oximation. The oxime was further cyclized to give benzisoxazol ring. Upon the sequence of the reaction, pyran ring (6 membered oxygen containing ring) is opened to have iodo group on one arm and hydroxy group on the other arm as shown in compound (V). Hydroxy group is then converted into good leaving group for example mesylate group to give compound (VI). The condensation reaction of compound (VI) and compound (III), using sodium bicarbonate in acetonitrile under reflux condition gave risperidone. The above reaction Scheme-I is shown below: The process of Scheme-I involves multiple process steps such as conversion of chloro-compound (II) into its dibenzyl-protected amine followed by conversion to primary amine (III). It requires highly expensive catalytic reduction procedure, wherein costlier palladium on carbon is used as catalyst. Also, the overall yield of the reaction sequence is poor. Further, the ratio of "syn : anti" in the intermediate oxime is around 3:1, from which the unrequired anti form, which is 25 % w/w, is required to be removed by column chromatography. It may be appreciated that the said drug which is in high demand requires production in high volumes to meet the same. Hence, for production of the active pharmaceutical ingredient (API) i.e. bulk drug in higher quantities, the seperation of anti isomer by column chromatography is highly time consuming, resource oriented in terms of the cost of the eluents, silica gel etc. besides the inherent disadvantage of the laborious column chromatographic separation process at the production level. For conversion of hydroxy group to good leaving group i.e. mesylate, mesityl chloride is used in this synthetic route. The use of fuming, corrosive, lacrymetric mesityl chloride needs to be avoided as it is hazardous and not easy to handle. The solvent used in the scheme (I), is acetonitrile, which again is a harmful solvent to human and has limitations based on regulatory requirements. In the hydrogenation process the reagent used is Pd / C, which is flammable. in WO 01/085731, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H- pyrido[1,2-a]pyrimidine-4-one, which is obtained by reduction of 3-(2- chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidine-4-one, is treated with benzisoxazol derivative (VII) i.e. 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole to give risperidone (I) as shown in Scheme II. However, in this sequence the reduction is carried out in acidic medium . To carry out the reduction, it would require pressure vessel with special grade of material of construction having higher capacity in order to carry out the reaction at production scale, which will in-turn involve higher capital investment. X is a good leaving group halogen and preferably chlorine. It need to be noted that according to the European pharmacopoea the purity requirement is minimum 99.7%, whereas purity of the bulk drug prepared according to Scheme II of WO 01/85731 is 99% . In addition, it uses Dimethyl formamide (DMF) for purification at the extreme last step. Dimethyl formamide is harmful to human and very difficult solvent to remove from bulk drug. As DMF is diificult to remove, organic volatile impurities (OVI) limit for DMF set by the regulatory requirement is difficult to achieve in the bulk API. In ES 2050069, 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H- pyrido[1,2-a]pyrimidine-4-one, is treated with (2,4-difluorophenyl)-(4- piperidinyl)methanone in the presence of acetonitrile, NaHCO3 and Kl as shown in Scheme III wherein L represents chlorine. The condensation product is then converted into oxime followed by cyclization into risperidone. This process, which follows a linear route, gives less yield as the oxime formation and cyclization to form benzisoxazol, is carried out separately, after the condensation reaction. Acetonitrile, used in this scheme, is costlier and harmful solvent to human and has limitations based on regulatory requirement with respect to organic volatile impurities. Also, it entails effluent disposal/treatment problems. The reaction steps mentioned in EP- 196132 as shown in scheme IV for production of risperidone result in poor yield. Also, Teva (WO 02/12200 and WO 02/14286), have disclosed preparation of risperidone according to Scheme IV shown above and have recommended the solvent as acetonitrile, in the last step. Acetonitrile, as mentioned earlier, is costlier and is the harmful solvent to human and has limitations based on regulatory requirement with respect to organic volatile impurities. Also, it entails effluent disposal / treatment problems. Though, there are more than one procedure for preparation of risperidone by various routes as discussed above, there are more than one underlying problems associated with each of the processes. These problems have not been so far handled completely. Hence, there is a long felt need to develop a new process to take care of the mentioned problems. Thus, there is a demand for a cost-effective process for synthesizing risperidone on commercial scale with higher yields, while reducing number of process steps and avoiding harmful solvents, which are subject to stringent control by regulatory authorities. The need was felt for a method using simple raw materials which are non-hazardous, non-fuming and easy-to-handle on a commercial scale. The process also need to dispense with the use of harmful reagents such as mesityl chloride to make it more eco-friendly. Further, method has to be simple i.e. without involving laborious separation steps by column chromatography. It is an aim of the present invention to solve the problems associated with the prior art and to provide a simple, efficient and cost effective method for production of risperidone. According to one aspect of the present invention, there is provided an efficient process for the preparation of risperidone, which provides obvious benefits with respect to economics, generation of minimal effluents, lesser number of process steps, less reactor occupancy, higher purity of the product with convenience to operate on a commercial scale SUMMARY OF THE INVENTION The first object of the invention is to provide an improved, cost-effective process for synthesis of the risperidone in high yield. The second object of the invention is to provide a process for synthesis of risperidone that avoids harmful solvents used hitherto in its synthesis. The third object of the invention to provide for a process for purification of risperidone with a minimal amount of organic volatile impurities (OVI) in the purified product. Another object of the invention is to optimise the particle size of risperidone for use as active ingredient in a tablet formulation. Yet another object of the invention is to provide a new polymorphic variety of resperidone identified as resperidone-T and characterised by it X-ray diffraction and IR data. The present invention accordingly provides for a process for the production of risperidone of formula (I), which comprises the steps of : a) reacting halo compound (VIII) in a solvent and a base at 10 - 40 °C ; (b) refluxing the reaction mixture of step (a) for 4-10 hours; (c) adding base to the cooled refluxed mixture of step (b) and maintaining the temperature at 20-40°C for 10-18 hours; (d) filtering and drying the risperidone thus obtained and (e) optionally purifying risperidone obtained in step (d) by using one or more solvents. BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING Fig.1 of the accompanying drawing gives the X-ray diffraction pattern of Risperidone form T1 as obtained according to one embodiment of the instant invention. DETAILED DESCRIPTION OF THE INVENTION The present invention provides an improved process for preparing the biologically active benzisoxazole, risperidone (I) as discussed herein :- The compound (VIII) which is a HCI salt of compound (II), is prepared according to a procedure known in the art. The oximation of compound (IX) gives the syn-and-anti isorners (X) and (XI) respectively of the oxime, according to the procedure known in the art. The chloro compound (VIM) obtained in Reaction A is finally reacted with the mixture of oximes in the presence of a solvent and a base to give a target compound risperidone (I). The condensation and cyclization of the condensed product is carried out simultaneously in Reaction C thereby helping to reduce the reactor occupancy (time cycle for the manufacturing process) and thus reducing the overhead and increasing the productivity. The procedure according to the instant invention does not require isolation of the condensed product or the oxime and the final risperidone is obtained directly without chromatographic seperation in a very high yield and purities as required under the pharmacopeal standard. The reaction also avoids the use of lacrymatric reagents such as mesityl chloride and gives high yield. Further the expensive reagents such as palladium on carbon is not used. It also dispenses with the use of acetonitrile and DMF in the production process. The reaction is carried out in solvents comprising of protic solvents such as alcohols, water, and aprotic solvents such as esters, acetonitrile aromatic hydrocarbons (toluene, xylene (s)), Dimethyl sulfoxide (DMSO), N-methyl pyrrolidone, N, N-dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbon, ethers or mixtures thereof. The alcohols that can be used as solvant for the reaction are methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, isobutyl alcohol or mixtures thereof. The esters that can be used as solvant for the reaction are comprising of methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof. The aromatic hydrocarbons that can be used as solvant for the reaction are comprising of toluene, o-xylene, m-xylene, p-xylene and xylenes. The ketones that can be used as solvant for the reaction are comprising of acetone, methylethylketone, methylisobutyl ketone or mixtures thereof, The ethers that can be used as solvant for the reaction are comprising of linear ethers such as diisopropyl ether, tert. butylmethyl ether, cyclic ethers such as tetrahydro furan, dioxane or mixtures thereof. The preferable alcohols for use as solvant for the reaction are comprising of ethanol, n-propyl alcohol, isopropyl alcohol, t-butyl alcohol, isobutyl alcohol or mixtures thereof. The preferable esters for use as solvant for the reaction are comprising of n-butyl acetate, n-propyl acetate, ethyl acetate or mixtures thereof. The preferable ketones for use as solvant for the reaction are comprising of methylethylketone, methylisobutyl ketone or mixtures thereof. The preferable ethers for use as solvant for the reaction are linear ethers such as diisopropyl ether, tert. butylmethyl ether, cyclic ethers such as tetrahydro furan, dioxane or mixtures thereof. The most preferable alcohols for use as solvant for the reaction are comprising of ethanol, isopropyl alcohol or mixtures thereof. The most preferable esters for use as solvant for the reaction are comprising of n-butyl acetate, n-propyl acetate or mixtures thereof. The most preferable ketones for use as solvant for the reaction are methylethylketone. The most preferable ethers for use as solvant for the reaction are linear ethers such as tert. butylmethyl ether, cyclic ethers such as dioxane. The base usable for the reaction is comprising of inorganic and organic base. The inorganic base is comprising of alkali or alkaline earth metal carbonates, bicarbonates, hydroxides, alkoxides, hydrides or combinations thereof. The organic base is comprising of N,N-diethylethanamine, 4- ethylmorpholine, N-(1-methylethyl)-2-propanamine and the like amines. Alkali metal bases comprises of sodium, potassium and the like. Alkaline earth metal bases comprises calcium and the like. The preferred bases comprise of sodium or potassium carbonate, bicarbonate, hydroxide and hydride. The most preferred bases comprise of sodium or potassium carbonate, bicarbonate, and hydroxide. Reaction C as mentioned above can be carried out in the temperature range of 10 - 40 °C. The preferred range is 20 - 35 °C. The purity of risperidone produced by the process of the instant invention is more than 99% which satisfies the regulatory requirement of the bulk drug. If the purity of the risperidone is not satisfactory, it can be further purified and / or crystallized by using one or more solvents. The solvents for the same comprises of alcohols, esters, acetonitrile, aromatic hydrocarbons (toluene, xylene(s)), Dimythyl sulfoxide (DMSO), N-methyl pyrrolidone, N,N- dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbon, ethers or mixtures thereof. The preferred solvent for purification and/or crystalization comprises of esters, alcohols or mixtures thereof. The more preferred solvent for purification and/or crystalization comprises of esters or mixtures thereof. The examples of esters useful for the purpose may be selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and tert butyl acetate. The examples of alcohols useful as solvent for the purpose may be selected from methyl alcohol, ethyl alcohol, n- propyl alcohol, isopropyl alcohol, isobutyl alcohol, tert. butyl alcohol. One of the ester solvents for purification and/or crystalization as mentioned above is butyl acetate. Choice of butyl acetate is preferred because of reduced volume of the required solvent which in turn governs reactor size, utilities associated with it and also the reaction time. Further due to the higher boiling point of butyl acetate the recovery of the solvent is effective and efficient. The formation of various polymorphs are dependent upon choice of solvent for crystallization, process of crystallization etc. The desired polymorphic form can be obtained by choice of appropriate solvent as mentioned below : The solvent for obtaining the desired polymorphic form of risperidone comprises of alcohols, esters, acetonitrite, aromatic hydrocarbons (toluene, xylene (s), Dymethyl sulfoxide (DMSO), N-methyl pyrrolidone, N, N- dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbon, linear acyclic ethers or mixtures thereof. The solvent for obtaining the polymorhic form A comprises of propyl acetate and higher homologous esters. One of the ester solvents for obtaining the polymorphic form A is butyl acetate. Choice of butyl acetate as solvent is preferred because reduced volume of the required solvent which in turn governs reactor size, utilities associated with it and also the reaction time . Further due to the higher boiling point the recovery of the solvent is effective and efficient. The purification process can also be carried out by using the mixture of isopropyl alcohol and dimethylformamide in the ratio of 99:1 to 1:99. Preferred mixture is isopropyl alcohol and dimethylformamide in the ratio of 60:40 to 99:1. The most preferred mixture is isopropyl alcohol and dimethylformamide in the ratio of 95:5. As can be seen from the experimental data with higher % of dimethylformamide, the traces of Organic Volatile Impurities (OVI) in the form of dimethylformamide remains even after the purification and drying of the product. The purification can as well lead to the desired polymorph, including Form A. The present invention further provides for a new polymorphic form of risperidone namely, form T1 obtained by isolation of this polymorphic variety through purification of crude risperidone obtained by the process of this invention with use of isopropyl alcohol and dimethyl formamide in the ratio 95:5 as purification solvent. Risperidone form T1 is characterized by XRD pattern as given in Fig-1 of the accompanying drawings. Risperidone Form T1 is characterized by the following physiochemical data: A. Powder X-ray diffraction pattern (ref. Table I given below) with peaks at about 2 Theta Values (Lattice spacing in angstroms (D)): 6.888 (12.822), 10.51 (8.411), 11.305 (7.821), 14.040 (6.3030), 14.683 (6.028), 18.320 (4.838), 18.831 (4.708), 19.619 (4.521), 21.154 (4.196), 23.038 (3.857), 27.426 (3.2494), 28.275 (3.1537), 28.867 (3.0904), 32.888 (2.7212) ± 0.2 degrees two-theta. In the following section preferred embodiments are described by way of examples to illustrate the process of this invention. However, this is not intended in any way to limit the scope of the present invention. PREPARATORY EXAMPLE PREPARATION OF RISPERIDONE Example 1 In one liter four neck round bottom flask 250 ml of isopropyl alcohol was taken at room temperature i.e. 20 to 35 °C. To the reaction flask, 25 gm of (2,4- difluorophenyl)(4-piperidinyl) methanone oxime was added followed by addition of 30 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2- a]pyrimidin-4-one hydrochloride and 75 gm of sodium Carbonate. To it 3.75 gm of Potassium Iodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°C), and the temperature maintained for next 4 hours. The reaction mixture was then cooled to room temperature (20 -35 °C). Potassium hydroxide solution (30 gm KOH in 60 ml water) was prepared separately and cooled to 15°C. Potassium hydroxide solution was added slowly to the reaction mixture and stirred at 30-40°C for 6 hours. The reaction mixture is quenched slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 2 lit. water at room temperature (20 -35 DC). The mixture stirred at room temperature (20 -35 °C) for 1 hour and 30 minutes. The product filtered and washed with 500 ml of water till neutral pH to get 43 gm of wet resperidone, which was further dried at 65 °C for 6hours to get 32.0 gm of dry respiredone with 99.4% purity ( by HPLC ). Example 2 In 250 ml four neck round bottom flask, 100 ml of isopropyl alcohol (IPA) was taken at room temperature i.e. 25 to 30 °C. To the reaction flask, 10 gm of (2,4- difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2- a]pyrimidin-4-one hydrochloride and 15 gm of sodium carbonate. To it 1.0 gm of potassium iodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20 -35 °C). Sodium hydroxide solution (8.5 gm NaOH in 8.5 ml water) was prepared separately and cooled to 15°C. Sodium hydroxide solution was added slowly to the reaction mixture and stirred at 25-30°C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 ml water at room temperature (20 -35 °C). Stirred the mixture at room temperature (20 -35 °C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 12.2 gm of wet crude Risperidone, which was further dried at 65 °C for 6hours to get 11.5 gm of dry Risperidone. HPLC PURITY = 97.5% Example 3 In 250 ml four neck round bottom flask 100 ml of Isopropyl alcohol was taken at room temperature i.e. 20 to 35 °C. To the reaction flask, 10 gm of (2,4- difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2- a]pyrimidin-4-one hydrochloride and 5.9 gm of sodium hydroxide. To it 1.0 gm of Potassium Iodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20 -35 °C). Sodium hydroxide solution (8.5 gm NaOH in 8.5 ml water) was prepared separately and cooled to 15°C. Sodium hydroxide solution was added slowly to the reaction mixture and stirred at 25-30°C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 ml water at room temperature (20 -35 °C). Stirred the mixture at room temperature (20 -35 °C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 8.5 gm of wet crude Risperidone, which was further dried at 65 °C for 6hours to get 7.0 gm of dry Risperidone. HPLC PURITY= 94.74% Example 4 In 250 ml four neck round bottom flask 100 ml of isopropyl alcohol was taken at room temperature i.e. 20 to 35 °C. To the reaction flask, 10 gm of (2,4- difluorophenyl-)(4-piperidinyl) methanone, oxime was added followed by addition of 11 gm of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl!-4H-pyrido[1,2- a]pyrimidin-4-one hydrochloride and 15 gm of sodium carbonate . To it 1.0 gm of Potassium Iodide was added. Reaction mixture was stirred for 5-10 minutes. The reaction mixture was slowly heated to reflux (80-82°C), and maintained the temperature for next 5 hours. The reaction mixture was then cooled to room temperature (20 -35 °C). Piperidine 18 gm was charged slowly to the reaction mixture and stirred at 25- 30°C for 12 hours. Quench the reaction mixture slowly by addition of the reaction mixture in a 5 lit. 4-neck round bottom flask containing 750 ml water at room temperature (20 -35 °C). Stirred the mixture at room temperature (20 -35 °C) for 2 hour and 30 minutes. Filtered the product and washed with 240 ml of water till neutral pH to get 8.3 gm of wet crude Risperidone, which was further dried at 65 °C for 6hours to get 7.5 gm of dry Risperidone. PURIFICATION OF RISPERIDONE Example 5 In 1 lit 4 neck round bottom flask containing 575 ml n-butyl acetate, 38.4 gm of risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 65°C to obtain clear solution. To the reaction mixture activated charcoal slurry (11.5 gm in 50 ml n-butyl acetate) was added followed by refluxing at 80°C for one hour. The reaction mixture was filtered through hyflow bed and the hyflow bed washed with a hot (50 - 65 °C) n-butyl acetate (115 ml). The filtrate was cooled to 0 to 5°C and maintain 0 to 5°C for one hour and 30 minutes. The solid obtained was filtered at 0 to 5°C and washed with n-butyl acetate (30 ml at 0 to 5°C) to get 38.5 gm of wet, pure risperidone, which was further dried at 65°C for 6 hours to give 26.5 gm of final risperidone with 99.9% purity (by HPLC). Example 6 Risperidone (36.3 gm) was taken in a 4 neck flask containing 180 ml methanol at room temperature and heated to reflux till clear solution is obtained. To it activated charcoal slurry (3.6 gm in 36 ml methanol) was added and refluxed for 45 minutes. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with hot methanol (144 ml). The clear filtrate was concentrated under vacuum thereby leaving 144 ml of volume in flask and filtered followed by washing the material with 36 ml ethyl acetate at room temperature to get wet weight: 32 gm. The wet material was taken in the flask and added 112 ml of ethyl acetate followed by heating to reflux and maintained the refluxing for 30 minutes. Cooled to room temperature and stirred for 30 minutes at room temperature. Filtered the product and washed with ethyl acetate. The procedure is repeated again to get 30 gm of wet material. Dried at 65° C for 6 hours to get 28 gm of risperidone having HPLC purity as 99.9%. Example 7A Purification of Risperidone by mix of I.P.A: DMF (80:20) In 160 lit Reactor containing 28 lit I.P.A ,7.0 lit D.M.F., 3.5 kg of crude Risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal slurry (0.525 kg in a mix. Of 2.8 lit I.P.A + 0.7 lit D.M.F. ) was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a mix. Of hot I.P.A (5.6 lit). + 1.4 lit D.M.F. The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (7.0 lit). The wet material was again charged in a mix of I.P.A 12.0 lit+ D.M.F 3.0 lit and heated to80-85°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (6.0 lit). Wet material was dried at 65 °C for 24 hours under vacuum to give 2.350 kg of final Risperidone. OVI (D.M.F)= 873 PPM Related impurity ( single) = 0.09% (total)= 0.09% XRD= matches with form A Example 7B Purification of Risperidone by mix of I.P.A: DMF (90:10) In 0.5 lit 4 neck round bottom flask containing 180 ml I.P.A , 26 ml D.M.F., 20 gm of crude risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal slurry (3 gm in 16 ml of I.P.A) was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a hot I.P.A (32 ml). The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (40 ml ). The wet material was again charged in a mix of I.P.A 90 ml+ D.M.F 10 ml and heated to80-82°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (40 ml ). Wet material was dried at 65 °C for 12hours under vacuum to give 16.1 gm of final Risperidone. Related impurity ( single) = nil (total)= nil OVI (D.M.F)= 574 PPM M.R.= 168-169°C XRD= matches with form A Example 7C Purification of crude Risperidone by mix of I.P.A: DMF (60:40) In 0.5 lit 4 neck round bottom flask containing 124 ml I.P.A ,104 ml D.M.F., 20 gm of crude risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal 3 gm was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a hot I.P.A (32 ml). The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (40 ml). The wet material was again charged in a mix of I.P.A 60 ml+ D.M.F 40 ml and heated to80-82°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (40 ml ). Wet material was dried at 65 °C for 12hours under vacuum to give 14 gm of final Risperidone. Related impurity ( single) = nil (total)= nil OVI(D.M.F.) = 3877 PPM M.R.= 168-169°C XRD= matches with form A Example 7D Purification of crude Risperidone by mix of I.P.A: DMF (40:60) In 0.5 lit 4 neck round bottom flask containing 72 ml I.P.A ,156 ml D.M.F., 20 gm of crude risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal 3 gm was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a hot I.P.A (32 ml). The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (40 ml). The wet material was again charged in a mix of I.P.A 40 ml+ D.M.F 60 ml and heated to80-82°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (40 ml). Wet material was dried at 65 °C for 12hours under vacuum to give 13 gm of final Risperidone. Related impurity ( single) = nil (total)= nil OVI (D.M.F.) = 3358 PPM M.R.=167-168°C XRD= Matches with form A Example 7E Purification of crude Risperidone by mix of I.P.A: DMF (20:80) In 0.5 lit 4 neck round bottom flask containing 52 ml I.P.A ,160 ml D.M.F., 20 gm of crude risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal slurry (3 gm in 16 ml of D.M.F ) was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a hot D.M.F (32 ml). The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (40 ml ). The wet material was again charged in a mix of I.P.A 20ml+ D.M.F 80 ml and heated to80-85°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (40 ml ). Wet material was dried at 65 °C for 12hours under vacuum to give 11.5 gm of final Risperidone. Related impurity ( single) = 0.09% (total)=0.21% OVI (DMF)= 3700 PPM M.R.= 167-168X DSC= Matches with form A Example 7F Purification of crude Risperidone by mix of I.P.A: DMF (10:90) In 0.5 lit 4 neck round bottom flask containing 26 ml I.P.A ,186 ml D.M.F., 20 gm of crude risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated "charcoal slurry (3 gm in 16 ml of D.M.F ) was added followed by refluxing at 80-82°C for one hour. The reaction mixture was filtered through hyflow bed and washed the hyflow bed with a hot D.M.F (32 ml). The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (40 ml ). The wet material was again charged in a mix of I.P.A 10 ml + D.M.F 90 ml and heated tc>80-85°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (40 ml ). Wet material was dried at 65 °C for 12hours under vacuum to give 11.5 gm of final Risperidone. Related impurity ( single) = 0.14% (total)= 0.24% OVI(DMF)=3151 ppm M.R.= 167-168°C DSC= Matches with form A Example 7G Purification of crude Risperidone by mix of I.P.A: DMF (95:5) In 500 lit reactor containing 100 lit I.P.A ,5.39 lit D.M.F., 9.8 kg of crude Risperidone was added at room temperature (20 -35 °C). The reaction mixture was heated to 70°C to obtain clear solution. To the reaction mixture activated charcoal slurry (1.47 kg in 8 lit of I.P.A. ) was added followed by refluxing at 80- 82°C for one hour. The reaction mixture was filtered through hyflow bed and washed with hot mixture of 18.62 lit I.P.A + 0.98 lit D.M.F. The filterate was cooled to 0 to 5°C and maintain 0 to 5°C for two hour. The solid obtained was filtered at 0 to 5°C and washed with I.P.A (19.6 lit). The wet material was again charged in a mix of 74.48 lit I.P.A + 3.92 lit D.M.F and heated to80-85°c for 30 minutes. Reaction mass was cooled to 25-30°c and maintained for 2 hr. The solid obtained was filtered and washed with I.P.A (19.6 lit). Wet material was dried at 65 °C for 12hours under vacuum to give 7.1 kg of final Risperidone. Related impurity ( single) = 0.09% (total)= 0.24% OVI (DMF)= 246.3 ppm XRD= matches with data from Table I; Form T1. The Examples 7 A to 7G given above will indicate that the level of organic volatile impurities (OVI) can be reduced by reducing the preparation of DMF in the solvent mix as tabulated below : Example 8 Obtaining the particle size After drying, material obtained by the process of Example 7A to 7G can be passed through gyratory sifter having mesh no. 40. Thereafter, it is subjected to Air-jet Milling Machine. The material is again passed through gyratory sifter of mesh no. 100. Finally, the material is blended in a blender and it is further taken up for preparation of pharmaceutical dosage form, wherein the particle size of above mentioned specification are obtained. Risperidone is low dosage drug i.e. the dose is 0.5mg or 1mg or 2mg or 3mg or 4mg or 5mg or 6mg. For low dosage drugs, it is advisable to have better distribution of particles, which also further controls the dose uniformity. The distribution of particles depends upon number of particles in the pharmaceutical dosage form. The number of particles, in turn, is dependent upon particle size distribution because for the given dosage form, if the particle size is higher, there would be only less number of particles in the pharmaceutical composition. Thus, the innovator i.e. Janssen have recommended the following particle size for the pharmaceutical composition (Risperdal: Review of Chemistry, Manufacturing, and Controls (Freedom of Information, FOI), dated 8th March, 1994, Department of Health and Human Services, Food & Drug Administration (FDA), NDA 20-272, USFDA). To achieve finer particle size as recommended, it needs more equipment, usage of special milling instrument such as fluid energy mill etc, along with associated utilities and manpower. To obtain particle size of these narrow limits, repetition of milling is occasionally demanded and also there is loss of the active pharmaceutical ingredient (API) due to the various process steps associated with this, including sifting. Sifting of API generally gives rise to escaping of the finer particles in to air, with potential inhalation hazard. Surprisingly, it has been found by the inventor of the instant invention, that the particle size given in the following Table IV, which is having coarse particle size, is also sufficient to comply the necessary requirement to prepare the effective pharmaceutical dosage form towards patient use. The particle size according to the instant invention as given in Table IV is higher compared to the particle size recommended by Janssen as mentioned in Table III. Thus, this aspect of the instant invention is beneficial with respect to equipment usage, utilities, manpower, the need of special milling equipment can avoid loss of API and help to reduce inhalation hazard etc. For the determination of the formulation prepared from the instant invention, the study was taken up wherein, a randomized 1 period, 1 treatment, 1 way parallel, pilot bioavailability study of two brands of risperidone 1) Risperidone (test; formulation according to the instant invention) tablet of 1 mg and 2) Rispedal (reference; formulation (from market) of Janssen Pharmaceuticals) tablet of 1 mg was administered as 1x 1 mg in healthy volenteers, under fasting conditions. The result is as given in Table V as under: Observation : The pharmacokinetic parameters i.e Cmax, tmax and AUC(0-inf) of test volunteer as well as reference volunteer fall within the therapeutic range as mentioned in the literature ( May-Lynn Huang et.al.; Clinical Pharmacology & Therapeutics, Sept. 1993) shown in the Table VI. Inspite of the higher particle size of the API for the formulation of the instant invention, formulation is found to be comparable with the innovator's formulation (from the market ), which is for therapeutic use for mammals. As shown in the table the formulation of the instant invention is acceptable as pharmaceuticle dosage form for mammals. Using Risperidone obtained from the above referred process the final dosage form is prepared from the ingredients comprising of Risperidone, lactose, microcrystalline cellulose, magnesium sterate, water and other excipient known to the person skilled in the art followed by coating of the same. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to these skilled in the art and are intended to be included within the scope of the present invention. We Claim: 1. A process for the production of risperidone of formula (I), which comprises the steps of : a) condensing a halo compound (VIII) in a solvent and a base at 10 - 40°C; (b) refluxing the reaction mixture of step (a) for 4-10 hours; (c) adding base to the cooled refluxed mixture of step (b) and maintaining the reaction for 10-18 hours; (d) filtering and drying the risperidone thus obtained and (e) optionally purifying risperidone obtained in step (d) by using one or more solvents. 2. The process as claimed in claim 1, wherein the purification process optionally comprises isolation of desired polymorph of risperidone in a known manner. 3. The process as claimed in claim 1 or 2 wherein the material thus obtained is subjected to milling and sifting to desired particle size for use in pharmaceutical formulations. 4. The process as claimed in claim 1, wherein solvent used in step (a) is selected from the group comprising of protic solvents and aprotic solvents or mixtures thereof. 5. The process as claimed in claim 4, wherein protic solvent used is selected from the group comprising of alcohols and water. 6. The process as claimed in claim 5, the alcoholic solvent used is selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t- butyl alcohol and isobutyl alcohol or mixtures thereof. 7. The process as claimed in claim 6, wherein the alcoholic solvent used is selected from the group comprising of ethanol, n-propyl alcohol, isopropyl alcohol, t-butyl alcohol and isobutyl alcohol or mixtures thereof. 8. The process as claimed in claim 7, wherein the said alcoholic solvent is selected from ethanol, isopropyl alcohol or mixtures thereof. 9. The process as claimed in claim 4, wherein aprotic solvent used is selected from the group comprising of esters, acetonitrile, aromatic hydrocarbons, dimethyl sulfoxide, N-methyl pyrrolidone, N, N-dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbon and ethers or mixtures thereof. 10. The process as claimed in claim 9, wherein esters used as aprotic solvent are selected from the group comprising of methyl acetate, ethyl acetate, n-butyl acetate and n-propyl acetate or mixtures thereof. 11. The process as claimed in claim 10, wherein said esters are selected from n-butyl acetate, n- propyl acetate and ethyl acetate or mixtures thereof. 12. The process as claimed in claim 11, wherein the said esters are selected from n-butyl acetate and n-propyl acetate or mixtures thereof. 13. The process as claimed in claim 9, wherein said aromatic hydrocarbons are selected from the group comprising of toluene, o-xylene, m-xylene, p-xylene and xylenes. 14. The process as claimed in claim 9, wherein said ketones are selected from the group comprising of acetone, methylethylketone and methylisobutyl ketone or mixtures thereof. 15. The process as claimed in claim 14, wherein ketones are selected from methylethylketone and methylisobutyl ketone or mixtures thereof. 16. The process as claimed in claim 15, wherein said ketone is methylethylketone. 17. The process as claimed in claim 9, wherein said ethers are linear ethers or cyclic ethers. 18. The process as claimed in claim 17, wherein said linear ethers used are selected from diisopropyl ether and tertiary butylmethyl ether. 19. The process as claimed in claim 17, wherein said linear ethers are selected from isopropyl ether and tertiary butylmethyl ether. 20. The process as claimed in claim 17, wherein said cyclic ethers are selected from tetrahydro furan and dioxane or mixtures thereof. 21. The process as claimed in claim 1, wherein said base used in step 1 (a) and (c) is selected from the group comprising of alkali or alkaline earth metal carbonates, bicarbonates, hydroxides, alkoxides, hydrides and organic bases or combinations thereof. 22. The process as claimed in claim 21, wherein said alkali metal is sodium or potassium. 23. The process as claimed in claim 21, wherein said alkaline earth metal is calcium. 24. The process as claimed in claim 1, wherein the reaction in step (a) is carried out in the temperature range of 10 - 40°C. 25. The process as claimed in claim 24, wherein said temperature range is 20 - 35°C. 26. The process as claimed in claim 1, wherein said solvent used for purification and / or obtaining desired polymorph is selected from the group comprising of alcohols, esters, acetonitrile, aromatic hydrocarbons, dimythyl sulfoxide, N-methyl pyrrolidone, N,N- dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbon and ethers or mixtures thereof. 27. The process as claimed in claim 26, wherein said solvent is selected from the group comprising of butylacetate, isopropylalcohol, dimethylformamide or mixtures thereof. 28. The process as claimed in claim 26, wherein said ester is butylacetate. 29. The process as claimed in claim 26, wherein said solvent used is a mixture of isopropyl alcohol and dimethylformamide in the ratio of 99:1 to 1:99. 30. The process as claimed in claim 29, wherein isopropyl alcohol and dimethylformamide are in the ratio of 60:40 to 99:1. 31. The process as claimed in claim 29, the ratio of isopropyl alcohol and dimethylformamide is 95:5. 32. A process for the production of Risperidone of formula (I), substantially as herein described particularly with reference to the foregoing example. The invention is for an improved process for of production of risperidone of formula (I) which comprises the steps of: (a) reacting a halo compound with an oxime in a solvent and a base at 10-40°C; (b) refluxing the reaction mixture of step (a) for 4- 10 hours; (c) adding base to the cooled refluxed mixture of step (b) while maintaining the temperature at 20-40°C for 10-18 hours; (d) filtering and drying the risperidone thus obtained and (e) optionally purifying risperidone obtained in step (d). The invention also discloses a new polymorphic variety of risperidone namely, risperidone form T1 having its characteristic X-ray diffraction pattern and IR data.

Documents:

507-CAL-2002-CORRESPONDENCE 1.1.pdf

507-CAL-2002-CORRESPONDENCE_.pdf

507-CAL-2002-FORM 27_.pdf

507-CAL-2002-FORM-27.pdf

507-cal-2002-granted-abstract.pdf

507-cal-2002-granted-assignment.pdf

507-cal-2002-granted-claims.pdf

507-cal-2002-granted-correspondence.pdf

507-cal-2002-granted-description (complete).pdf

507-cal-2002-granted-drawings.pdf

507-cal-2002-granted-examination report.pdf

507-cal-2002-granted-form 1.pdf

507-cal-2002-granted-form 18.pdf

507-cal-2002-granted-form 2.pdf

507-cal-2002-granted-form 3.pdf

507-cal-2002-granted-form 5.pdf

507-cal-2002-granted-gpa.pdf

507-cal-2002-granted-reply to examination report.pdf

507-cal-2002-granted-specification.pdf

507-CAL-2002-LETER PATENTS.pdf