FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003 (SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
"SUBTANTIALLY PURE ROPINIROLE HYDROCHLORIDE AND PROCESS FOR THE PREPARATION THEREOF"
Glenmark Pharmaceuticals Limited an Indian Company, registered under the Indian company's Act 1957 and
having its registered office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION
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BACKGROUND OF THE INVVENTION 1. Technical Field
The present invention provides substantially pure ropinirole hydrochloride having HPLC
purity equal to or greater than 99.5%.
Preferably, the substantially pure Ropinirole hydrochloride has an HPLC purity equal to or greater than 99.5% and despropyl indolone impurity, N- hydroxy indolone impurity and 5- Ethyl indolone impurity each less than 0.15% wt represented by the following formulae.

N- hydroxy indolone impurity Despropyl indolone impurity 5- Ethyl indolone impurity
The present invention further provides a process for the preparation of substantially pure Ropinirole hydrochloride.
Description of the Related Art
Ropinirole (also known as 4-[2-(dipropylamino) ethyl]-l, 3- dihydro-indole-2-one) of formula (I) generally used as an active constituent drug a hydrochloride salt in the treatment of Parkinson.

The hydrochloride salt of ropinirole is the form commercially sold under the trade name Requip®. Ropinirole hydrochloride is a non-ergoline dopamine agonist with high relative in vivo specificity and full intrinsic activity at the D2 and D3 dopamine receptors subtypes,
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binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole hydrochloride is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). See, e.g., The Merck Index, Thirteenth Edition, 2001, p. 1482-1483, monograph 8338; and Physician's Desk Reference, "Requip," 58th Edition, p. 1604-1608 (2003). Ropinirole is a member of indolone class of potent non-ergot dopamine receptor antagonist marketed as a symptomatic treatment for Parkinson's disease. EP-0113964-B describes the use of such compounds as being useful in cardiovascular therapy.
U.S. Patent No. 4,452,808 ("the '808 Patent"), herein incorporated by reference, discloses ropinirole and its hydrochloride salt. U.S. Patent. No. 4, 997,954 discloses process for the preparation of ropinirole hydrochloride of 97 % HPLC purity which on purification by crystallization or basification and acidification yields pure Ropinirole HC1 having 98-99 % purity. U.S. Patent No. 5,336,781 discloses process for the preparation of off white solids containing isatin impurity which imposes high colour index to the product.
SUMMARY OF THE INVENTION
In accordance with one of the embodiment of the present invention provided substantially pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.5%.
In accordance with the second embodiment of the present invention provided substantially pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.5% and content of impurities like despropyl indolone impurity, N- hydroxy indolone impurity and 5- ethyl indolone impurity less than
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N- hydroxy indolone impurity Despropyl indolone impurity 5- Ethyl indolone impurity
In accordance with the third embodiment of the present invention provided encompasses process for the preparation of substantially pure ropinirole hydrochloride.
The advantages of the process of the present invention include at least:
1) All existing methods for the preparation of ropinirole hydrochloride require extra steps of purification for the removal above specified impurities. This may lead to the higher cost and cause the drastic load on effluent treatment system.
2) The present invention incorporates the use of very economical and environmentally friendly reagents like sodium hydroxide and hydrochloric acid to remove above specified impurities. Such improvements make the process easier and friendlier on a commercial scale.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with one of the embodiment of the present invention provided substantially pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.5%.
In accordance with the second embodiment of the present invention provided substantially pure ropinirole hydrochloride having HPLC purity equal to or greater than 99.5% and content of impurities like despropyl indolone impurity, N-hydroxy indolone impurity and 5- ethyl indolone impurity less than 0.15%.
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N- hydroxy indolone impurity Despropyl indolone impurity 5- Ethyl indolone impurity
In accordance with the third embodiment of the present invention provided encompasses process for the preparation of substantially pure ropinirole hydrochloride comprising: a) providing a solution of ropinirole base having formula II in one or more organic solvents;

b) extracting of solution with base at pH 10-12;
c) extracting the solution containing ropinirole with an acid;
d) removal of solvent;
e) dissolving resulted solid in polar solvents;
f) addition of hydrochloric acid in dry conditions;
g) recovering the pure ropinirole hydrochloride.
The step of providing a solution of ropinirole may include dissolving any form of ropinirole in a suitable solvent or obtaining an existing solution from a previous processing step. The organic solvents include, but are not limited to benzene or alkyl, aryl, halo substituted benzenes, chlorinated olefins such as dichloro methane, dichloro ethane or cyclic and acyclic hydrocarbons such as n- pentane, n-hexane n- octane etc., cyclic and acyclic ethers such as diethyl ether, tetrahydrofuran, dioxane and esters such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate or the mixtures there of.
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The dissolution can be carried out at a temperature ranging from about 20°C to about 80°C and preferably at room temperature. The suitable bases include, but not limited to alkali and alkaline earth metal hydroxides preferably Sodium hydroxide, potassium hydroxide, and barium hydroxide. Removal of solvent is accomplished by; for example, substantially complete evaporation of the solvent, concentrating the solution. Alternatively, the solvent may also be removed by evaporation. The polar solvents include, but not limited to, alcohols, esters, nitrile, ethers and polar aprotic solvents like DMF, DMSO, N, N-DMA, and NMP. The hydrochloric acid can be added in substantially anhydrous conditions at temperature 0 to 100°C.Preferably at temperature 0 to 50°C, more preferably at temperature 0 to 30°C .Substantially pure ropinirole hydrochloride can be isolated by filtration, decanting and other isolation techniques known to the skilled in the art.
More particularly according to the present invention the ropinirole base obtained from the reductive cyclization of 2-substituted-o-nitro phenyl acetic acid derivative may be dissolved aromatic solvents A clear solution thus obtained treated with dilute aqueous alkali metal hydroxides having strengths ranging from 2-30%; preferably 15 -20 % at pH 11-12 at temperature ranging from 0-80°C; preferably 20- 30° C. The organic layer containing ropinirole free base may further be treated with dilute aqueous inorganic acids having strengths ranging from 1-10% preferably 0.5-2 % at pH 7-7.5 at temperature ranging from 0-50°C; preferably 20- 30°C. The resulted organic layer containing ropinirole free base may further be concentrated under reduced pressure at temperature ranging from 30-100°C; preferably 30-50°C to obtain ropinirole base. The resulted solid further dissolved in one or more polar solvents such as water, aliphatic alcohols like methanol, ethanol, isopropanol etc., aliphatic ketones such as acetone, ethyl methyl ketone etc., and aliphatic cyanides such as acetonitrile aliphatic acids such as acetic acid, propionic acid etc., esters such as methyl acetate, ethyl acetate, isopropyl acetate or the mixtures thereof of at temperature ranging from 20-150°C. More preferably the solvent used for the dissolution of ropinirole free base is acetonitrile. The solution can further cooled to 0-20°C, which is then followed by addition of hydrochloric acid in gaseous or solution form till pH 1-2 to afford substantially pure ropinirole hydrochloride having high HPLC purity equal to or more than 99.5 %. Generally crude ropinirole hydrochloride may be dissolved in one or more solvents at temperature ranging from 10-70°c preferably 60-65°C. The resulted clear solution of ropinirole hydrochloride further cooled to 0-3 0°C; preferably 0-15°C to afford pure ropinirole
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hydrochloride having HPLC purity more than 99.5%. The substantially pure ropinirole hydrochloride can be recovered after removing the solvent by performing distillation, distillation under vacuum and filtration under vacuum, decantation, and centrifugation. The product obtained may be further or additionally dried to achieve the desired residual solvent values .For example the product may be further or additionally dried in a tray drier, or dried under vacuum and/or in a Fluid Bed Drier.
The solvents include alkanols like methanol, ethanol, isopropanol etc., ketonic solvents comprises Acetone , methyl ethyl ketone, methyl isobutyl ketone, and cyclic and acyclic ethers such as diethyl ether ,tetrahydrofuran, dioxane etc., and esters as ethyl acetate isopropyl acetate, methyl acetate, aromatic solvents such as benzene or alkyl, aryl, halo substituted benzenes, chlorinated olefins such as dichloro methane , dichloro ethane or cyclic and acyclic hydrocarbons such as n- pentane, n-hexane n- octane etc., or the mixtures there of. The more preferred solvent mixture is toluene and methanol.
Efforts are made to prepare pharmaceutical products of a high grade and with a minimum amount of impurities present. The control of impurities requires a study of various options to decide upon the reaction conditions and testing protocols necessary to insure that drugs which are administered to the public are substantially pure. Accordingly, there remains a need for an improved process for preparing ropinirole hydrochloride that eliminates or substantially reduces the impurities in a convenient and cost efficient manner to provide substantially pure of ropinirole hydrochloride.
The term "ropinirole hydrochloride substantially free of despropyl indolone, N-hydroxy indolone and 5- Ethyl indolone" as used herein shall be understood to mean ropinirole hydrochloride formed with little to no content of despropyl indolone, N- hydroxy indolone and 5- Ethyl indolone. In this manner, the amount of despropyl indolone, N-hydroxy indolone and 5- Ethyl indolone, if present, resulting from the process for preparing ropinirole hydrochloride present will be in relatively minor amounts, e.g., less than about 0.15 % weight percent, preferably less than about 0.1 weight percent and most preferably 0 weight percent.
Another aspect of the present invention is directed to a pharmaceutical composition containing at least ropinirole hydrochloride substantially free of despropyl indolone, N-
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hydroxy indolone and 5- Ethyl indolone, wherein the D50 and D90 particle size of the unformulated ropinirole or pharmaceutically acceptable salt thereof used as starting material is less than about 400 microns, preferably less than about 200 microns, more preferably less than about 150 microns, still more preferably less than about 50 microns and most preferably less than about 15 microns. Any milling, grinding micronizing or other particle size reduction method known in the art can be used to achieve desired particle size range set forth above.
The substantially pure ropinirole or pharmaceutically acceptable salts thereof free of despropyl indolone, N- hydroxy indolone and 5- Ethyl indolone thus obtained may then be formulated into a pharmaceutical composition or dosage form. Such compositions and dosage forms include, for example, compacted tablets, powder suspensions, capsules, and the like. The compositions of the present invention can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramuscular, or subcutaneous), intracistemally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray. For example, the active ingredient of the invention, or salts or solvates thereof can be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, or controlled-release such as sustained-, dual-, or pulsatile delivery applications. The highly purified form of Ropinirole disclosed herein also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, which are administered by other routes. The most preferred route of administration of the Ropinirole of the present invention is oral.
The active ingredient of the invention may also be administered via fast dispersing or fast dissolving dosage forms or in the form of high energy dispersion or as coated particles. Suitable pharmaceutical composition of the invention may be in coated or un-coated form as desired.
Tabletting compositions may have few or many components depending upon the tabletting method used, the release rate desired and other factors. For example, the compositions of the present invention may contain diluents such as cellulose-derived materials like powdered cellulose, microcrystalline cellulose, microfine cellulose, methyl
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cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and other substituted and unsubstituted celluloses; starch; pregelatinized starch; inorganic diluents such calcium carbonate and calcium diphosphate and other diluents known to one of ordinary skill in the art. Yet other suitable diluents include waxes, sugars (e.g. lactose) and sugar alcohols like mannitol and sorbitol, acrylate polymers and copolymers, as well as pectin, dextrin and gelatin.
Other excipients contemplated by the present invention include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.
Capsule dosages will contain the solid composition within a capsule which may be coated with gelatin. Tablets and powders may also be coated with an enteric coating. The enteric-coated powder forms may have coatings comprising phthalic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate, carboxymethylethylcellulose, a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and like materials, and if desired, they may be employed with suitable plasticizers and/or extending agents. A coated tablet may have a coating on the surface of the tablet or may be a tablet comprising a powder or granules with an enteric coating.
Actual dosage levels of the substantially pure ropinirole in the compositions of the invention may be varied to obtain an amount of that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon such factors as, for example, the desired therapeutic effect, the route of administration, the desired duration of treatment, and other factors. The total daily dose of the compounds of this invention administered to a host in single or divided dose and can vary widely depending upon a variety of factors including, for example, the
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body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, the severity of the particular condition being treated, etc. The pharmaceutical compositions herein can formulate in any release form, e.g., immediate release, sustained release, controlled release, etc.
It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
Example 1 Preparation of Pure Ropinirole hydrochloride
Ropinirole base (308.0 gram) was dissolved in 4.5 liter of toluene. This was followed by addition of 7.5 liter of 15-20 % aq. NaOH solution at 20-35°C. The solution was stirred vigorously at 22-25°C. The toluene layer was separated and extracted with 12 lit 10 % aq. NaOH solution at 22-25°C. The toluene layer was extracted twice with 12 liter of 10 % aq. HC1 solution at 22-25°C. The organic layer was then washed twice with 6 liter water. The Toluene layer was concentrated under reduced pressure at 50- 65°C. The resulted gummy solid was dissolved in 1.2 liter of acetonitrile. The clear solution was then slowly cooled to room temperature and then further cooled to 20°C. This was followed by slowly addition of 10-25 % IPA -HC1 solution (308 ml) to the reaction mass at same temperature to get slurry of precipitated ropinirole hydrochloride. The slurry was then stirred at temperature of 15-20°C for 1 hr followed by filtration and washing with 600 ml of acetonitrile. The resulted solid was further dried at 50-60°C under vacuum to afford pure ropinirole hydrochloride (155grams,) HPLC purity 99.86 %
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Example 2 Preparation of substantially pure Ropinirole hydrochloride
A four-neck 500 ml flask equipped with a mechanical stirring condenser and thermometer was charged with 700 ml toluene and 100 gram crude ropinirole hydrochloride. The suspension was slowly heated at 65 to 75°C, followed by slow addition of 350-400 ml of methanol to get clear solution. The solution was then stirred at same temperature for 1 hr followed by filtration to remove insoluble material. The clear filtrate was then slowly cooled to room temperature and then further cooled to 5-15°C and stirred for 1 hr. The resulted solid was filtered and washed with 100ml (toluene - methanol) mixture (8:2) to afford substantially pure ropinirole hydrochloride, which was further dry at 50-60°C. Yield: 88 grams, HPLC purity 99.5%.
Dated this Nineteenth (19th) day of July, 2006