Title of Invention

PROCESS FOR PREPARATION OF ROPINIROLE HYDROCHLORIDE.

Abstract

The invention discloses an improved process for the purification of ropinirole hydrochloride by dissolving or suspending crude ropinirole base or its pharmaceutically acceptable salt in a suitable solvent, reacting with a nitrogenous base to form an imine derivative, optionally treating the reaction mixture with a base to adjust the pH. and isolating purified ropinirole hydrochloride. The invention also provides for a pharmaceutical composition comprising pure ropinimle hydrochloride as active ingredient.

Full Text

FIELD OF THE INVENTION The present invention relates to a process useful for the purification of ropinirole or its pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION In order to secure marketing approval for a new drug product, a drug manufacturer must submit detailed evidence to the appropriate regulatory authority to show that the product is suitable for release on to the market. The regulatory authority must be satisfied, inter alia, that the active agent is acceptable for administration to humans and that the particular formulation, which is to be marketed, is free from impurities at the time of release. Potential impurities in pharmaceutically active agents and formulations containing them include residual amounts of synthetic precursors to the active agent, by-products which arise during synthesis of the active agent, residual solvent, isomers of the active agent, contaminants which were present in materials used in the synthesis of the active agent or in the preparation of the pharmaceutical formulation, and unidentified adventitious substances. Other impurities which may appear on storage include substances resulting from degradation of the active agent, for instance by oxidation or hydrolysis. Ropinirole hydrochloride, i.e., 4-[2-(dipropylamino)ethyl]-l,3-dihydro-2H-indol-2-one hydrochloride having the formula (I) is used in the treatment of the signs and symptoms of idiopathic Parkinson"s disease. Parkinson"s disease is a debilitating disease characterized by disturbance of voluntary movement in which muscles become stiff and sluggish, movement becomes clumsy and difficult, and uncontrollable rhythmic twitching of groups of muscles produces characteristic shaking or tremor. The condition is believed to be caused by the degeneration of dopaminergic neurons in the nigral striatal system of the brain, leading to inadequate release of the neurotransmitter dopamine. Administration of conventional anti-parkinsonian drugs like L-DOPA and ergot alkaloids relieves certain symptoms of the disease, but are associated with several undesirable side- effects like dyskinesia, psychiatric problems, nausea, vomiting, and abdominal distension. Furthermore, the conventional drugs fail to halt the disease progression. Ropinirole, an indolone derivative, alleviates this deficiency, and has particularly minimum liability to cause dyskinesia. Furthermore, it has additional beneficial effects on the central nervous system, namely anti-depressant and anxiolytic effects, which are considered to be particularly advantageous, considering that patients requiring current therapies often need to take separate anti-depressant medication. Presence of such qualities in a single compound obviates the need for separate therapy. Ropinirole is believed to act by stimulation of post-synaptic dopamine D2-type receptors within the caudate putamen of the brain, leading to an increase in the activity of the neurotransmitter dopamine. Various procedures are known for the synthesis of ropinirole and its pharmaceutically acceptable salts, including hydrochloride in the prior art. However, the literature processes have limitations due to the reaction sequence and the formation of by- products/impurities associated with them. (Hayler, J. D., Howie, S. L. B., Giles, R. G., Negus, A., Oxley, P. W., Walsgrove, T. C, and Whiter, M., Org. Pro. Res. Dev., Vol 2, 1998, pages 3-9). By-product formation has been found even at a level of 40%." Based on our experience, during the synthesis of Ropinirole hydrochloride, a number of impurities are formed, of which 4- (2- (di-propyl amino) ethyl) isatin hydrochloride having the formula (II), is the most significant single impurity. The impurities, which are formed during the synthesis of ropinirole hydrochloride including the contaminants of the reagents, get carried over till the final step of preparation of ropinirole hydrochloride. In order to get the highly pure Active Pharmaceutical Ingredient (API) of ropinirole, the purification step is very essential. The crude ropinirole has impurities in the level of 0.5 to 0.6 % as single impurity and 1 % as total impurity. The purification by various solvents does not effectively lead to the purified ropinirole to have single impurity content below 0.1%. Coufal, P. , Stuli, K. , Claessens, H. A. , Hardy, M. J. , Webb, M., J. Chromatog., B: Biomedical Sciences and Applications, Vol. 732 (2), 1999, pages 437-444 describes a capillary liquid chromatographic method for the separation and quantification of ropinirole and its related impurities. The separation and quantification of the single impurity requires complex analytical methods, which are expensive and can be carried out only on a very small scale. Prior art do not discloses any efficient chemical process for the purification of ropinirole hydrochloride, wherein the single impurity is below 0.1% and total impurity is below 0.5%. EP0300614A1, US 4997954, EP113964 describe different processes for preparing ropinirole and its pharmaceutically acceptable salts, which reduce the number of steps involved in the process, improving yields, or getting a commercially advantageous process. However none of these describes the process for removing Isatine impurity in the final product. US4997954 describes process for preparing ropinirole wherein 2-phenyl ethanol(III) (commercially available) was reacted with phosphorous trichloride and paraformaldehyde to give the corresponding isochroman (IV). The isochroman (IV) on reaction with bromine gave the corresponding 2- (2"-bromoethyl) benzaldehyde (V) which on reaction with nitromethane in the presence of sodium methoxide, gave2-(2"bromoethyl) betxnitrostyrene (VI).2- (2" bromoethyl) betmitrostyrene (VI) on reaction with acetyl chloride and ferric-chloride gave 4-2"-bromoethyl)-3-chloro-l, 3-dihydro-2H-indole-2- one (VII). 4-(2"-bromoethyl)-3-chloro-l, 3-dihydro- 2H-indole-2-one(VII) was dehydrohalogenated in presence of Palladium on carbon and sodium hypophosphite to give4- (2"-bromoethyl)-l, 3-dihydro-2H-indole-2-one (VIII), which on further reaction with di-n-propyl amine in presence of aqueous acetonitrile and nitrogen gave ropinirole hydrochloride (I). The sequence of the synthetic steps followed is shown in Scheme 1 During this reaction sequence, along with other impurity formation, especially oxidative impurities, possibly the oxidation of indole-2-one moiety to give diketoindole take place to give rise to the process impurity, as shown in Scheme-2 We have further observed that the level of the diketoindole impurity in the API, as well as pharmaceutical compositions containing the API increases upon storage over extended periods irrespective of the pharmaceutical dosage form. Therefore, high initial levels of the diketoindole impurity in the API prepared by prior art processes, can further lead to increase the impurity content over a prolonged period of time. However, none of process disclosed above in the prior art address the problem of amount of impurity level in the final product. Thus, there exists a need for a process of preparing ropinirole and its pharmaceutically acceptable salts, which provides a purification procedure for ropinirole, which is cost- efficient, ecofriendly, less labour intensive, less time consuming as well as can be carried out on an industrial scale so that the content of the diketoindole impurity can be kept within acceptable levels. Present inventors have surprisingly found the simple and cost effective and industrially applicable process for purifying ropinirole. SUMMARY OF THE INVENTION The present invention provides for the preparation of ropinirole hydrochloride having less than 0.1 % of 4- (2- (dipropylamino) ethyl) isatin comprising the steps of: a) dissolving or suspending crude ropinirole base or its hydrochloride salt in a suitable solvent such as herein described, b) adding a nitrogenous base, such as herein described in the solution or suspension of step (a) to form an imine derivative, c) optionally treating the reaction mixture of step (b) with a suitable base such as herein described to adjust the pH between 9 to 14, d) isolating purified ropinirole hydrochloride of formula (I). Further, the present invention also encompasses crystals of ropinirole hydrochloride, wherein, at least 80% of the crystals have a particle size of less than about 95 microns. The present invention is also directed towards a process for the preparation of highly pure ropinirole hydrochloride, having a single impurity content of less than 0.1 %. The present invention also relates to a crystalline form of ropinirole hydrochloride, designated Form I. The present invention further relates to pharmaceutical compositions comprising ropinirole hydrochloride as active ingredient. BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS Fig 1 depicts an X-ray diffraction pattern of ropinirole hydrochloride Form I DETAILED DESCRIPTION OF THE INVENTION The present invention provides a practicable, economic process for purifying ropinirole hydrochloride on an industrial scale. We have now found an improved process for purifying ropinirole hydrochloride. The principle underlying the process for purification of the crude API (Active Pharmaceutical Ingredient), ropinirole hydrochloride, is the reaction of the crude API with a reagent, which can easily form a water-soluble compound of that impurity and can get washed away with water during the work-up. Thus, the impurities react and form a complex with said reagent and gets eliminated. Further work up gives the purified ropinirole, wherein the purity is found to be less than 0.1% for single impurity, 4-(2-(dipropylamino)ethyl) isatin hydrochloride of formula (II). The process of purification of ropinirole hydrochloride comprises the steps of: a) dissolving or suspending crude ropinirole base or ropinirole hydrochloride in a suitable solvent, b) reacting the solution or suspension of step (a) with a nitrogenous base to form an imine derivative, c) optionally treating the reaction mixture of step (b) with a suitable base to adjust the pH between 9 to 14, d) isolating purified ropinirole hydrochloride of formula (I). The solvent used in step (a) is selected from 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, chlorohydrocarbons, ethers or mixtures thereof. The alcohols that can be used as solvent are methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, isobutyl alcohol or mixtures thereof. In a preferred embodiment, the preferred alcohols are n-propyl alcohol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol. In a more preferred embodiment, the alcohol is isopropyl alcohol. The esters that can be used as solvent are methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof. The aromatic hydrocarbons that can be used as solvent are toluene, o-xylene, m-xylene, and p- xylene. The ketones that can be used as solvent are acetone, methyl ethyl ketone, methylisobutyl ketone or mixtures thereof. The ethers that can be used as solvent are linear ethers such as diisopropyl ether, tert. butyl methyl ether, cyclic ethers such as tetrahydrofuran, dioxane or mixtures thereof. In another preferred embodiment, the protic solvent used is water. The nitrogenous base used in step (b) is selected from the base, which can react with a ketonic group and form an imine derivative. The bases are selected from the group comprising of hydroxylamine hydrochloride, hydrazine hydrate, phenyl hydrazine and the like. In a preferred embodiment of the invention, the base used is hydrazine hydrate. In another preferred embodiment of the invention, the base used is hydroxylamine hydrochloride. In another aspect of the invention, pH adjustment when required is done with a suitable base selected from the group comprising of aqueous alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, aqueous alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, aqueous alkali or alkaline earth metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. 10 In a preferred embodiment, the bases that can be used are selected from aqueous sodium hydroxide and aqueous potassium hydroxide. In a more preferred embodiment, the base used is aqueous sodium hydroxide. In another aspect of the invention, the isolation of ropinirole hydrochloride in step (d) optionally involves extracting the aqueous layer with an organic solvent. The organic solvent is a water - immiscible solvent selected from the group comprising of esters, acetonitrile, aliphatic hydrocarbons, aromatic hydrocarbons (toluene, xylene (s)), dimethyl sulfoxide (DMSO), N- methyl pyrrolidone, N, N-dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbons, ethers or mixtures thereof. The esters that can be used as solvent for the extraction of ropinirole hydrochloride in step (d) are selected from the group comprising of methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof. In a preferred embodiment, the ester usedfor isolation is ethyl acetate. The aliphatic hydrocarbons that can be used as the extraction solvent are selected from the group comprising of n-hexane, n-heptane or mixtures thereof. The ethers that can be used as the extraction solvent are selected from the group comprising of linear ethers such as diethyl ether, diisopropyl ether, tert. butyl methyl ether, and cyclic ethers such as tetrahydrofuran, dioxane or mixtures thereof. In a preferred embodiment, the ether used for isolation is diethyl ether. In a still further aspect of the invention is provided a process for the preparation of substantially pure ropinirole, containing less than 0.1 % single impurity. The single impurity content can be determined by conventional analytical techniques such as TLC, HPLC etc. In a further aspect of the present invention is provided a crystalline form of ropinirole hydrochloride, designated Form I, obtained by the process of the instant invention. Preferably, the crystalline Form I is characterized by powder X-ray diffraction pattern (Fig 1), expressed in terms of degrees 2 theta as set out in Table 1 given below: 11 The IR spectrum of ropinirole hydrochloride crystalline Form I produced by the present process is characterized by the following bands: 3077 cm"1, 3005 cm"1, 2882 cm"1, 1721 cm"1 and 1611 cm"1. In another aspect of the invention is provided ropinirole hydrochloride crystalline Form I having single impurity content less than 0.1%. In still another aspect of the invention, the isolation of ropinirole hydrochloride in step (d) optionally involves recrystallization from a suitable solvent. The solvents used for the recrystallization to obtain ropinirole hydrochloride crystalline Form I can be selected from the group comprising of protic solvents such as alcohols, water, and aprotic solvents such as esters, acetonitrile, aliphatic hydrocarbons, aromatic hydrocarbons (toluene, xylene (s)), dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), N-methyl pyrrolidone, N, N- dimethylacetamide, sulfolane, nitrobenzene, ketones, chlorohydrocarbons like methylene chloride, ethers or mixtures thereof. The alcohols that can be used for recrystallization are selected from the group comprising of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, isobutyl alcohol, cyclohexanol or mixtures thereof. The esters that can be used for recrystallization are selected from the group comprising of methyl acetate, ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate or mixtures thereof. The aliphatic hydrocarbons that can be used for recrystallization are selected from the group comprising of n-hexane, n-heptane and the like. The aromatic hydrocarbons that can be used for recrystallization are selected from the group comprising of toluene, o-xylene, m-xylene, p-xylene or mixtures thereof. 13 The ketones that can be used for recrystallization are selected from the group comprising of acetone, methyl ethyl ketone, methylisobutyl ketone, cyclohexanone or mixtures thereof. The ethers that can be used for recrystallization are selected from the group consisting of linear ethers such as diethyl ether, diisopropyl ether, tertiary butyl methyl ether, cyclic ethers such as tetrahydrofuran, dioxane or mixtures thereof. As ropinirole hydrochloride is a highly potent drug and is used in doses of 0.25-5 mg, content uniformity of the drug in a dosage form is very critical to achieve a consistent dosage regimen. Generally this can be achieved by reducing the particle size using conventional milling equipment. Particle size reduction by conventional milling procedures and uniform particle size distribution are essential for achieving content uniformity of the drug in a dosage form. It has been surprisingly found that the process of the instant invention yields crystals of ropinirole hydrochloride having a small particle size as well as uniform size distribution, thereby avoiding the need for costly milling equipment and simultaneously reduces the number of process steps to achieve the same. Accordingly, the invention is directed in one embodiment to crystals of ropinirole hydrochloride with a particle size of below 95 microns not less than 80 %. In a preferred embodiment, the invention is directed to crystals of ropinirole hydrochloride with a particle size of below 75 microns not less than 80 %. Pharmaceutical Compositions: The pharmaceutical compositions of the present invention comprise as active ingredient ropinirole hydrochloride containing less than 0.1 % of single impurity and having a particle size of below 75 microns not less than 80%, in combination with a pharmaceutically acceptable diluent, carrier or excipient. 14 The pharmaceutical compositions of the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection. The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive, colourings, aroma, preservatives etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilising the solution and filling it in suitable ampoules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc. Definitions : The term "substantially pure ropinirole" as mentioned herein denotes ropinirole having less than 0.1 % of single impurity. The term "isolating" encompasses operations like extraction, drying, concentration of the reaction mixture, optional adjustment of the pH by adding hydrochloric acid and optional recrystallization from a suitable solvent to obtain the final product. The term "room temperature" as mentioned herein denotes a temperature between 25°C-30°C. Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "including" are to 15 be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited. The present invention has been described by way of examples only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention. PREPARATORY EXAMPLES: Example -1 Preparation of Isochroman (IV) Phosphrous trichloride (185 gm, 1.34 mole) was added to a reaction mass of 2-phenyl ethanol (III) (500 gm, 4.09 mole), paraformaldehyde (135 gm) and hydrochloric acid, over a one hr period at 25-30°C. The mix was stirred for 3 hr at 35-40°C. Adjust pH 7 using NaOH solution below 25°C and extracted with ethyl acetate and the aqueous layer was separated. The extraction was repeated twice. The resultant three extracts were combined, dried over sodium sulphate, and then concentrated to give 520.0 gm of clear pale yellow oil of isochroman (IV) (Yield : 94.69%). Example - 2 Preparation of 2-(2"-bromoethyl) benzaldehyde (V) Bromine (592 gm, 3.675 mole) in dichloromethane (400 ml) was added to isochroman (IV) (500 gm, 3.731 mole) in dichloromethane (3000 ml) over 2 hr in the presence of a strong light source at such a rate that the reaction temperature remains about 38°C. The mixture was stirred for further 2 hr in the presence of light source, keeping the temperature of the mixture below 40?C. 16 The mixture was concentrated at atmosphere pressure to give heavy oil. This was then stirred at 80?Gbrlrr. Thecmdeproductwasdissolvedindchloromethane(300Cml)ardwashedwith water (1500 ml). Washed the organic layer with saturated sodium bicarbonate (4400 ml). This layer was again washed with water and then dried over sodium sulphate. Excess solvent was removed under reduced pressure to given a heavy oil of 2-(2"-bromoethyl) benzaldehyde (V) (650.0 gm) (Yield : 84.80%). Purification of 2-(2"-bromoethyl) benzaldehyde (V) Sodium metabisulphite (500 gm) was dissolved in water (500 ml) and to this was added methanol (500 ml). To it, the benzaldehyde (V) was added and stirred for 30 minutes after which dichloromethane (1500 ml) was added. The resulting suspension was filtered to give a white powder. To sodium carbonate solution (270 gm) in water (4400 ml), the white powder was added and to this mixture, dichloromethane (1500 ml) was further added. After shaking the organic layer, the aqueous layer was separated. The extractions were repeated twice. The resultant three extracts were combined, dried over sodium sulphate and then concentrated to give 300 gm of clear pale yellow oil of 2(2"-bromoethyl) benzaldehyde (V) (300.0 gm) (Yield : 40% ). 1HNMR (400 MHz, CDC13) d : 10.16 (1H, s), 7.851 - 7.829 (2H, m), 7.595 - 7.554 (1H, m), 7.519 - 7.479 (1H, m), 7.362 - 7.343 (1H, d), 3.651 - 3.563 (4H, m) I.R.( cm-1): 2964, 2861, 1697, 756 Example - 3 Preparation of 2-(2"-bromoethyl) -b-nitrostyrene (VI) Sodium methoxide (111.0 gm, 2.05 mole) was dissolved in methanol (4.25 ltr) and cooled to 0- 5°C. To the above solution, nitromethane (172.9 gm, 2.83 mole) was added. 2-(2"-bromoethyl) benzaldehyde (V) (425 gm, 1.995 mole) was dissolved in methanol (2.1 lit), which had already been basified with small amount of sodium methoxide solution (42.5 gm) and added over 60 minutes at -5-0°C. The resulting clear solution was stirred for 15 minutes at -5-0°C and then quenched into hydrochloric acid (4.2 lit, 6N) at a temperature below 10°C. The resulting yellow 17 solid was filtered, washed with water and dried to give 222.0 gm of 2-(2"-bromoethyl)-b- nitrostyrene (VI). (Yield: 43.46%) m.p. 65-67°C. 1HNMR (400 MHz, CDC13) d : 8.339 - 8.305 (1H, d), 7.565 (2H, m), 7.374 (2H, t), 7.498 (1H, m), 3.571 (2H, m), 3.365 (2H, t) I.R.( cm"1): 3011, 2838, 1508, 1483, 766 Example - 4 Preparation of 4-(2"-bromoethyl)-3-chloro-l,3-dihydro-2H-indole-2-one (VII) To a pre-cooled solution of ferric chloride (260 gm, 1.64 mole) in dichloromethane (1600 ml) at 0-5°C was added acetyl chloride (121.44 gm, 1.547 mole) at such a rate that the reaction temperature did not exceed 5°C. The reaction mixture was stirred at between 0-5°C for 15 minutes. To the mixture was added a pre-dried solution of 2-(2"-bromoethyl) ?-nitrostyrene (100 gm, 0.395 mole) in dichloromethane (1000 ml) at such a rate that the reaction temperature did not exceed 5°C. The reaction mixture was stirred for 1.5 hr at below 5°C. Add water (2.4 lit) and HC1 (240 ml) in reaction mass and stirred for 30 minutes. The dichloromethane layer was isolated and washed further thrice with water. The dichloromethane layer was then distilled under vacuum. After cooling to 20°C, added dichloromethane (83 ml) and petroleum ether (166 ml). Resulting precipitate was stirred at 10°C for 30 minutes. 4-(2"-bromoethyi)-3-chloro-l,3- dihydro-2H-indole-2-one (VII) was collected by filtration. The solid was washed with petroleum ether (50 ml) and dried at 50°C overnight to give 65 gm of the title compound (VII) (Yield : 60%). 1HNMR (400 MHz, DMSO) 5 : 10.80 (1H, s), 7.278 (1H, t), 6.982 - 6.962 (1H, d), 6.791 - 6.772 (1H, d), 5.714 (1H, s), 2.055 (2H, m), 2.060 (2H, m) I.R.( cm-1): 3030, 2915, 1724, 1682, 1616, 786, 756 18 Example - 5 Preparation of 4-(2"-bromoethyl)-l,3-dihydro-2H-indole-2-one (VIII) To a stirred suspension of 10 % palladium on carbon (7.0 gm, 2.8 mole), 4-(2"-bromoethyl)-3- chloro-l,3-dihydro-2H-indole-2-one (VII) (70 gm, 0.255 mole) in ethyl acetate (1500 ml), heated under reflux, was added aqueous sodium hypophosphite in water (78.17 gm in 222 ml, 0.737 mole) over 1 hr. After 1 hr the reaction was complete. The reaction mixture was filtered hot through a hyflow bed and the water layer was removed before the filtrate was concentrated totally in vacuum. The solid residue was stirred as a slurry in water (500 ml) and collected at the pump. The amount of white solid, (4-(2"-bromoethyl)-l,3-dihydro-2H-indole-2-one) (VIII) obtained was 54 gm. (Yield : 88.97%) 1HNMR (400 MHz, DMSO) d : 10.37 (1H, s), 7.130 (1H, t), 6.862 - 6.843 (1H, d), 6.715 - 6.696 (1H, d), 3.511 (2H, s), 3.724 (2H, t), 3.057 (2H, t). I.R.( cm-1): 3015, 2823, 1724, 1672, 1616, 768. Example - 6 Preparation of 4-[2-(Dipropylamino)ethyl]-l,3-dihydro-2H-indole-2-one hydrochloride (I) Water (137.5 ml) and di-n-propyl amine (137.5 ml) were heated at 60-65°C in an atmosphere of nitrogen for 15 minutes. 4-(2"-bromoethyl)-l,3-dihydro-2H-indole-2-one (VI) (25 gm) in acetonitrile (100 ml) was added to the reaction mass in 15 minutes. Stirred vigorously and heated to 65-70°C for 60 minutes. HPLC indicated that all the starting material had been consumed. Added water (100 ml) to the reaction mass and cooled to 35 - 45°C. Separated the layers. Organic layer was washed with water (200 ml) and distilled under vacuum below 60°C. To the dark oil, added aqueous HC1 solution to adjust the pH to 2 and washed four times with dichloromethane (125 ml). Adjusted the pH 12 to 14 using 20% NaOH solution and extracted thrice with hexane (250 ml). Organic layer stirred with aqueous HC1, separated the layers and adjust pH 12 to 14 using 20% NaOH solution and extracted with hexane thrice. Combined the hexane layers, dried over Na2SO4 and distilled under vacuum. To this oil, added isopropyl 19 alcohol (150 ml) and adjusted the pH to 2.0 using HC1 (35%) to obtain a solid light yellow material as precipitate. The precipitate was filtered to obtain crude 4-[2-(dipropylamino)ethyl]- l,3-dihydro-2H-indole-2-onehydrochloride (I) (15.2 gm) (Yield: 50%) Example -7 Purification of 4-[2-(Dipropylamino)ethyI]-l,3-dihydro-2H-indole-2-one hydrochloride (I) Ropinirole hydrochloride (crude)(I) (15.0 gm, 0.051 mole) was dissolved in water (300 ml) and to this was added hydroxylamine hydrochloride (3.75 gm, 0.054 mole). Stirred for 15 minutes. The pH of the above solution was adjusted between 12 to 14 using 20 % NaOH solution. Stirred for 15 to 20 minutes. To it, hexane (360 ml) was added. After shaking the organic layer, the aqueous layers were separated. The extraction was repeated thrice. The organic layer was dried over sodium sulphate and then concentrated to give 14 gm of clear pale yellow oil. To this oil, added isopropyl alcohol (140 ml) and dichloromethane (140 ml) and adjusted the pH above 2 using HC1 (35%). The resulting reaction mass was distilled up to a temperature of 50°-55°C. The solid material was collected by filtration. 13.57 gm of pure ropinirole hydrochloride was obtained. (Yield: 90.46 %) Single Impurity : 0.04 % (by HPLC) 1HNMR (400 MHz, DMSO) d : 10.39 - 10.43 (2H, d), 7.145 (1H, t), 6.85 - 6.87 (1H, d), 6.715 - 6.734 (1H, d), 3.555 (2H, s), 3.25 - 2.9 (8H, m), 1.73 - 1.67 (4H, m), 0.926 (6H, t) I.R- (cm-1): 3077, 3005, 2882, 1721, 1611. Example 8 Preparation of ropinirole hydrochloride crystalline form (I) 20 2.0 g of ropinirole hydrochloride was added to 10 ml of isopropyl alcohol, heated to reflux and maintained at reflux temperature for 30 min. It was subsequently cooled to room temperature, filtered and washed with 5.0 ml of isopropyl alcohol, and further dried at room temperature for 10-12 hr to obtain 1.93 g of crystalline ropinirole hydrochloride Form I. I.R.( cm-1 ): 3077, 3005, 2882, 1721, 1611. XRD (Form I) : 7.39 ± 0.2, 11.45 ± 0.2 , 13.44 ± 0.2, 15.39 ± 0.2, 16.45 ± 0.2, 18.45 ± 0.2, 19.26 ± 0.2, 20.31 ± 0.2, 21.33 ± 0.2, 22.25 ± 0.2, 22.77 + 0.2, 23.73 ± 0.2, 24.68 ± 0.2, 25.26 ± 0.2, 25.98 ± 0.2, 26.80 ± 0.2, 27.07 ± 0.2, 28.67 ± 0.2, 29.81 ± 0.2, 30.92 ± 0.2, 31.84 ± 0.2, 33.16 ± 0.2, 35.41 ± 0.2, 36.30 ± 0.2 degrees two theta Example 9 Preparation of ropinirole hydrochloride crystalline form (I) 2.0 g of ropinirole hydrochloride was added to 10 ml of methanol, heated to reflux and maintained at reflux temperature for 30 min. Added 8 ml of tetrahydrofuran dropwise to the reflux mixture till the formation of a precipitate. 2 ml of methanol was further added dropwise till the reaction mass became clear. The reaction mixture was maintained at the reflux temperature for 30 min, the heating was discontinued and the reaction mixture cooled down to room temperature. It was filtered and washed with 5.0 ml of tetrahydrofuran, and further dried at room temperature for 10-12 hr to obtain 1.54 g of crystalline ropinirole hydrochloride Form I. 21 We Claim: 1 A process for the preparation of ropinirole hydrochloride having less than 0.1 % of 4- (2- (dipropylamino) ethyl) isatin comprising the steps of: a) dissolving or suspending crude ropinirole base or its hydrochloride salt in a suitable solvent such as herein described, b) adding a nitrogenous base, such as herein described in the solution or suspension of step (a) to form an imine derivative, c) optionally treating the reaction mixture of step (b) with a suitable base such as herein described to adjust the pH between 9 to 14, 2. The process as claimed in claim 1, wherein the solvent used in step (a) is selected from the group comprising of protic solvents such as alcohols, water, and aprotic solvents such as esters, acetonitrile, aromatic hydrocarbons, dimethyl sulfoxide, N-methyl pyrrolidone, N, N-dimethylacetamide, nitrobenzene, ketones, chlorohydrocarbons, ethers or mixtures thereof. 3. The process as claimed in claim 2, wherein the alcohols are selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t- butyl alcohol, isobutyl alcohol or mixtures thereof. 22 4. The process as claimed in claim 3, wherein the alcohol is isopropyl alcohol. 5. The process as claimed in claim 2, wherein the esters are selected from methyl acetate, ethyl acetate, n-butyl acetate, n-propyl acetate or mixtures thereof. 6. The process as claimed in claim 2, wherein the aromatic hydrocarbons are selected from toluene, o-xylene, m-xylene and p-xylene. 7. The process as claimed in claim 2, wherein the ketones are selected from acetone, methyl ethyl ketone, methylisobutyl ketone or mixtures thereof. 8. The process as claimed in claim 2, wherein the ethers are selected from diisopropyl ether, tert. butyl methyl ether, cyclic ethers such as tetrahydrofuran, dioxane or mixtures thereof. 9. The process as claimed in claim 2, wherein the solvent is water. 10. The process as claimed in claim 1, wherein the nitrogenous base used in step (b) is selected from the group comprising of hydroxylamine hydrochloride, hydrazine hydrate, phenyl hydrazine. 11. The process as claimed in claim 10, wherein the nitrogenous base used in step (b) is hydroxylamine hydrochloride. 12. The process as claimed in claim 10, wherein the nitrogenous base used in step (b) is hydrazine hydrate. 13. The process as claimed in claim 1, wherein the base used in step (c) is selected from the group comprising of aqueous alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, aqueous alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, aqueous alkali or alkaline earth metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. 23 14. The process as claimed in claim 13, wherein the base used in step (c) is aqueous sodium hydroxide. 15. The process as claimed in claim 13, wherein the base used in step (c) is aqueous potassium hydroxide. 16. The process as claimed in claim 1, wherein the purified ropinirole hydrochloride of formula (1) as obtained contains less than 0.1% of single impurity. 17. The process as claimed in claim 1, wherein the purified ropinirole hydrochloride of formula (I) as obtained comprises crystals of ropinirole hydrochloride with a particle size of below 75 microns not less than 80 %. 18. The process as claimed in claim 1, wherein the ropinirole hydrochloride as obtained is having less than 0.1 % of 4- (2- (dipropylamino) ethyl) isatin is further characterized by powder X-ray diffraction pattern with peaks at about (two theta values): 7.39 0.2, 11.45 0.2, 13.44 0.2, 15.39 0.2, 16.45 0.2, 18.45 0.2, 19.26 0. 2, 20.31 0. 2,21. 33 0.2, 22.25 0.2, 22.77 0.2, 23.73 0.2, 24.68 0. 2,25. 26 0. 2,25. 98 + 0.2, 26.80 0.2, 27.07 0.2, 28.67 0.2, 29.81 0. 2,30. 92 0. 2,31. 84 0.2, 33.16 0.2, 35.41 0.2 and 36.30 0.2 degrees two theta. 24 The invention discloses a process for the preparation of ropinirole hydrochloride having less than 0.1 % of 4- (2- (dipropylamino) ethyl) isatin comprising the steps of a) dissolving or suspending crude ropinirole base or its hydrochloride salt in a suitable solvent such as herein described; b) adding a nitrogenous base, such as herein described in the solution or suspension of step (a) to form an imine derivative; c) optionally treating the reaction mixture of step (b) with a suitable base such as herein described to adjust the pH between 9 to 14; d) isolating purified ropinirole hydrochloride of formula (I).

Documents:

66-KOL-2004-CORRESPONDENCE_.pdf

66-KOL-2004-FORM 27_.pdf

66-KOL-2004-FORM-27.pdf

66-kol-2004-granted-abstract.pdf

66-kol-2004-granted-assignment.pdf

66-kol-2004-granted-claims.pdf

66-kol-2004-granted-correspondence.pdf

66-kol-2004-granted-description (complete).pdf

66-kol-2004-granted-drawings.pdf

66-kol-2004-granted-form 1.pdf

66-kol-2004-granted-form 18.pdf

66-kol-2004-granted-form 2.pdf

66-kol-2004-granted-form 3.pdf

66-kol-2004-granted-form 5.pdf

66-kol-2004-granted-gpa.pdf

66-kol-2004-granted-letter patent.pdf

66-kol-2004-granted-reply to examination report.pdf

66-kol-2004-granted-specification.pdf