FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title "AN IMPROVED PROCESS FOR THE PREPARATION OF ILOPERIDONE"
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road,
Near Dinesh Hall,
Ahmedabad - 380 009,
Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performey.

AN IMPROVED PROCESS FOR THE PREPARATION OF ILOPERIDONE
FIELD OF THE INVENTION:
The present invention relates to an efficient process for the purification of pharmaceutically active piperidine-1-yl-benzisoxazole derivative i.e. l-[4-[3-[4-(6-fluoro-I.2-benzisoxazol-3-yl)-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone i.e. Iloperidone of formula (1) comprising: a) providing a solution of Iloperidone in water; b) acidifying the solution of step a) with an organic or inorganic acid; c) optionally washing the solution of step (a) with water immiscible organic solvent; d) adding an organic solvent to the solution of step (c) or (b); e) adding an appropriate base to the solution as obtained in step (d); and f) isolating pure Iloperidone. The present invention also covers an improved process for the preparation of l-[4~(3-chloropropoxy)-3-methoxyphenyl]ethanone (II).
BACKGROUND OF THE INVENTION:
Iloperidone is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives, which is useful for the acute treatment of adults with schizophrenia. Iloperidone's IUPAC name is l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone, which has the following structural formula (I).

Iloperidone having compound of formula (I) was first disclosed in EP 0402644 filed in 1990 by Hoechst-Roussel Pharmaceutical Inc.
Iloperidone is marketed as Fanapt® in USA. It is available as 1 mg; 2 mg, 4 mg. 6 mg. 8

mg, 10 mg & 12 mg tablets of IIoperidone free base.
According to EP 0402644, Uoperidone may be prepared by the condensation of the compound of formula (111) 6-fluoro-3-(4-piperidinyl)-1.2-benzisoxazole hydrochloride and compound of formula (II) l-[4-(3-chloropropoxy)-3-rnethoxypheny]]ethanone, in the presence of potassium carbonate as a base in dimethylformamide (DMF), followed by treating reaction mixture with water, extracting with organic solvent that is immiscible in water, washing, drying and concentrating the organic solvent to give the moist solid Uoperidone, which was further recrystallized from ethyl alcohol to produce Uoperidone as a beige (i.e. light brown) solid with only 58% yield as shown in Scheme-1.
Scheme-1:

(a) condensation in K2C03 & DMF (b) reaction mixture poured into water and extracted with ethyl acetate, washing, drying and concentrating to get crude moist product (c) recrystallization from ethanol to produce beige Uoperidone.
Drugs of Future 2000, 25(1): 29 discloses the same process as disclosed in above patent reference for the preparation of Uoperidone comprising the condensation of l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (II) with 6-fluoro-3-(4-piperidinyl)-1,2-

benzisoxazole hydrochloride (III) by means of K2C03 in hot DMF , there is no description of yield and Iloperidone is obtained as a beige solid.
Journal of Medicinal Chemistry, 1995, Vol 38, No. 7,1119-1131 discloses general synthesis of pharmaceutically active piperidine-1-yl-benzisoxazole derivative including Iloperidone (HP 873), which is depicted in Scheme-2;
Scheme-2:

Method A: NaH, DMF, rt. Method B: CH3CN, K2C03, reflux. Method C: (CH3)2CO, K2C03, reflux. Method D: DMF, K2C03 70-90 °C. Method E: CH3CN, K2C03, KI, reflux. Method F: DMF, CH3CN, K2C03, 90-100 °C
US 4810713 & US 4366162 disclose a process for the preparation of compound of formula (II) by reacting l-bromo-3-chlropropane (IV) with acetovanillone or l-(4-hydroxy-3-methoxyphenyl) ethanone (V) in organic solvent such as acetone in the presence of base like potassium carbonate, which was heated at reflux temp for almost 20 hours. The

process as disclosed in US 4810713 & US 4366162 is not suitable at plant scale as it requires too long time for the completion of condensation.
Like any other piperidinyl-benzisoxazole derivatives, lloperidone can also contain process impurities, including unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products. It is also known in the art that impurities present in an active pharmaceutical ingredient ("API") may arise from degradation of the API. for example, during storage or during the manufacturing process, including the chemical synthesis.
Impurities produced during the bulk manufacturing processes must be limited to very small amounts, and are preferably substantially absent. According to ICH guideline API manufacturers requires that process impurities be maintained below set limits. The guidance specifies the quality of raw materials, and process parameters, such as temperature, pressure, time, and stoichiometric ratios, including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
IUPAC name of dimer impurity of formula (VI) is l-{4-[3-(4-acetyl-2-methoxyphenoxy)propoxy]-3-ethoxyphenyl} ethanone.
The inventors of the present invention have observed that during the synthesis of l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (II), when l-bromo-3-chlropropane (IV) reacted with acetovanillone or l-(4-hydroxy-3-methoxyphenyl) ethanone (V) produces ~ 2%-10% of dimer impurity having the following structural formula (VI), which is confirmed by MS (Mass spectrography), 'H-NMR & 13C-NMR.


Without wishing to be bound by any theory, it is believed that when starting raw material 1-bromo-3-chIorpropane (IV) contains dihalo adduct like 1,3-dibromopropane or 1,3-dichloropropane as an impurity, the probability of formation of dimer impurity is very high. Particularly, in the case of 1,3-dibromopropane, because bromine atom is more reactive and selective than chlorine atom. Further, it has been observed that even highly pure 1 -bromo-3-chlorpropane (IV) also produces ~ 2% - 4% of dimer impurity because during the condensation reaction, the produced l-[4-(3-chloropropoxy)-3-methoxyphenyl) ethanone (II) has some tendency to react with unreacted l-(4-hydroxy-3-methoxyphenyl) ethanone (V) to form dimer impurity of formula (VI). In some cases, chloro group of l-bromo-3-chlorpropane (IV) took part in condensation with I-(4-hydroxy-3-methoxyphenyl) ethanone instead of bromine and produced bromo derivative, which further react with l-(4-hydroxy-3-methoxyphenyl) ethanone (V) to generate dimer impurity. In some instances, it was also observed that dimer impurity increased during the condensation of compound of formula (II) & (III).
This impurity in turn is carried forward in subsequent reaction steps and results in Iloperidone of low purity and yield.
The compound of formula (II) i.e. l-[4-(3-chloropropoxy)-3-methoxyphenyl) ethanone is the key intermediate for the preparation of Iloperidone and hence, Iloperidone prepared by using compound of formula (II) may have dimer impurity of 5%-8%, would not give the final compound of desired yield and purity, specifically the content of dimer impurity.
Further, the removal of dimer impurity (VI) requires special techniques like series of solvent extraction, column chromatography, etc. Employing column chromatography technique is tedious, laborious and also involves use of large quantities of solvents, and hence is not suitable for industrial scale operations.
Accordingly, there remains a need for efficient process for the purification of Iloperidone, which is substantially free of dimer impurity. Extensive experimentation was carried out by the present inventors to reduce the level of the dimer impurity by introducing acid-base purification in final step.'

Inventors of the present invention have surprisingly found an improved process for the purification of Iloperidone to remove dimer impurity efficiently, which is simple, fast, cost effective and commercially viable.
Inventors of the present invention have also found an improved process for the preparation of compound of formula (II) which comprises the reaction of a l-bromo-3-chlropropane (IV) with l-(4-hydroxy-3-methoxyphenyl) ethanone (V) in the presence of a base and a phase transfer catalyst in a suitable organic solvent at reflux temperature, which is simple, fast, cost effective and commercially viable.
SUMMARY OF THE INVENTION:
The first aspect of the present invention is to provide a process for the purification of Iloperidone of formula (I) comprising:
a) providing a solution of Iloperidone in water;
b) acidifying the solution of step a) with an organic or inorganic acid;
c) optionally washing the solution of step (a) with water immiscible organic solvent;
d) adding an organic solvent to the solution of step (c) or (b);
e) adding an appropriate base to the solution as obtained in step (d); and
f) isolating pure Iloperidone.
In another embodiment, the present invention provides highly pure Iloperidone prepared according to the present invention having dimer impurity of formula (VI) in amount less than 1%, more preferably less than 0.8%, more preferably less than 0.5%, more preferably less than 0.3%, more preferably less than 0.2% (area as measured by HPLC).
In another embodiment the present invention provides a pharmaceutical composition of highly pure Iloperidone prepared according to the present invention having dimer impurity of formula (VI) in amount less than 1%, more preferably less than 0.8%, more preferably less than 0.5%, more preferably less than 0.3%, more preferably less than 0.2% (area as measured by HPLC).

In another embodiment the present invention provides an improved process for the preparation of compound of formula (II)

compiling-.
i) reacting a l-bromo-3-chlropropane (IV) with l-(4-hydroxy-3-methoxyphenyl) ethanone (V) in the presence of abase and a phase transfer catalyst in a suitable organic solvent at reflux temperature;
ii) isolating compound of formula (II).
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

As used herein, the term "Iloperidone" refers to the l-[4-[3-[4-(6-fIuoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] propoxy]-3-methoxyphenyl]ethanone i.e. compound of formula (I).
As used herein, the term "dimer impurity" refers the compound of formula (VI) having the following structure.

As used herein, the "highly pure" or 'high purity" means purity greater than 94% preferably more than 97% and more preferably more than 99%.
The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
In general, the present invention provides a process for the purification of Iloperidone of formula (I) comprising:
a) providing a solution of Iloperidone in water;
b) acidifying the solution of step a) with an organic or inorganic acid;
c) optionally washing the solution of step (a) with water immiscible organic solvent;
d) adding an organic solvent to the solution of step (c) or (b);
e) adding an appropriate base to the solution as obtained in step (d); and
f) isolating pure Iloperidone.
Iloperidone of formula (I) can be prepared by any method known in prior art or it can also be prepared by method as disclosed in our own Indian patent application no.

1980/MUM/2007.
In step (a), the free base of Iloperidone is added in water at room temperature. Amount of water added may be in the range of from 2 to 10 parts by volume based on the weight of lioperidone.
In step (b), an aqueous solution of step (a) is acidified with organic or inorganic acid. One or more inorganic acids can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or mixtures thereof. One or more organic acids are selected from formic acid, acetic acid, succinic acid, maleic acid, malic acid, citric acid, ascorbic acid, mandelic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or mixtures thereof. The concentration of acid may be from 5% to 50%. In the preferred embodiment. 5%-50% aqueous solution of acetic acid is added at the room temperature to the solution of step (a). After acidifying the solution of step (a), it is stirred to obtain the clear solution at the room temperature.
In step (c), the solution obtained in step (b) is optionally washed with water immiscible organic solvent, wherein water immiscible organic solvent is selected from hexane, cyclohexane, methylcyclohexane, ethylcyclohexane, heptane, methylene chloride, ethyl acetate, tert-butyl methyl ether, carbon disulfide, benzene, toluene, xylene, chlorobenzene, diethylbenzene and tetralin. Preferably, the water immiscible organic solvent is selected from hexane, cyclohexane, heptane or methylene chloride, generally 1 to 10 parts by volume of water immiscible organic solvent based on weight of Iloperidone is added. After adding water immiscible organic solvent to the solution obtained in step (b), it is stirred at room temperature and layers are separated. The separated aqueous layer is carry forward for further treatment. The obtained aqueous layer can be optionally purified by adding charcoal to it and filtered through hyflow bed, it can be optionally washed with water.
In step (d), the solution obtained in step (b) or (c) is further added with organic solvent. The organic solvent is selected from alcohols (methanol, ethanol, isopropanol, butanol, etc.), ketones ( acetone, methyl isopropyl ketone, etc.), aliphatic ethers (diethyl ether, di tert.

butyl ether, etc.), cyclic ethers ( tetrahydrofuran. dioxane, etc.), aliphatic esters (ethyl acetate, etc.), hydrocarbons (toluene, heptane, hexane, etc,), chlorinated solvent (chloroform, dichloromethane, etc.), acetonitrile, polar aprotic solvents (DMF, DMAc, etc.) or mixtures thereof. Preferably, the organic solvent is alcohol and more preferred is methanol and 4-12 parts by volume of organic solvent based on weight of lloperidone can be added.
In step (e), the solution obtained in step (d) is added with base, wherein base is selected from liquid ammonia, ammonium hydroxide, alkali metal hydroxides, alkali metal methoxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal methoxides, alkaline earth metal carbonates, and mixtures thereof. The base can be added in form of aqueous solution or solution with other suitable solvent can be added, more preferred base is liquid ammonia, wherein liquid ammonia range in concentration from 10 to 20 weight percent ammonia can be used. The reaction mixture is basified by adding base, preferably, to a pH of about 8 to about 13 and more preferably, to a pH of about 8 to about 11 at the temperature of about 0°C-10°C. After basifying the reaction mixture, it is stirred until the precipitation is completed, it is generally completed within 0.5 hours to 3 hours.
In step (f), lloperidone may be isolated by any method known in the art, such as filtering, washing, preferably washing with the solvent like water and alcohol and drying. Drying is carried out at a temperature of about 45°C to about 55°C in hot air oven or under vacuum or air tray dryer.
In another embodiment the present invention provides an improved process for the preparation of compound of formula (TI),


comprising:
i) reacting a l-bromo-3-chlropropane (IV) with l-(4-hydroxy-3-methoxyphenyl) ethanone (V) in the presence of a base and a phase transfer catalyst in a suitable organic solvent at reflux temperature;
ii) isolating compound of formula (II).
In step (i) reaction of l-bromo-3-chlropropane (IV) with l-(4-hydroxy-3-methoxyphenyI) ethanone (V) is carried out in the presence of a base and a phase transfer catalyst in a suitable organic solvent at reflux temperature. The base used in the present invention can be any suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate. potassium bicarbonate, sodium hydroxide, potassium hydroxide, preferably potassium carbonate. The mole ratio of base with respect to the compound of formula (V) may be 1:1 to 2:1.
The phase transfer catalyst is selected from the group comprising of tetrabutylammonium bromide (TBAB), tetrabutylammonium hydroxide, TEBA, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide, more preferably tetrabutylammonium bromide (TBAB) and amount of phase transfer catalyst may be 1% to 2% w/w with respect to the compound of formula (V).
The organic solvent used in step (i) is selected from alcohols (methanol, ethanol, isopropanol, butanol, etc.), ketones ( acetone, methyl isopropyl ketone, etc.), aliphatic ethers (diethyl ether, di tert. butyl ether, etc.), cyclic ethers (tetrahydrofuran, dioxane. etc.), aliphatic esters (ethyl acetate, etc.), hydrocarbons (toluene, heptane, hexane. etc.), chlorinated solvent (chloroform, dichloromethane, etc), acetonitrile, polar aprotic solvents (DMF, DMAc, etc.) or mixtures thereof, preferable solvent is acetone or acetonitrile. The amount of organic solvent is 5 to 25 parts by volume of compound of formula (V) is added. An amount of the solvent added may be in the range of from 10 to 20 parts by volume with respect to the weight of compound of formula (V).

There is no special sequence of addition of intermediate of formula (IV) & (V) desired, in general practice, a compound of formula (V) is first added in suitable organic solvent followed by the addition of base and phase transfer catalyst at room temperature and compound of formula (IV) is added at last. After the addition is over, reaction mixture is heated at reflux temperature and the condensation is accomplished over a time period of about 0.5 to about 5 hours, it can be confirmed by HPLC analysis.
In step (ii), the compound of formula (II) is isolated by any method known in the art, such as filtering, washing, preferably washing with the solvent used and drying. Generally, the reaction mixture is cooled to room temperature, filtered and washed with solvent as used in step (i). After washing, solvent is distilled out by vacuum distillation to obtain the compound of formxula (II) in residual form, which may be optionally treated with another organic solvent such as alcohol to obtain the solution or else it is directly added with water at room temperature and stirred until the precipitation is completed. The obtain solid is filtered and dried at a temperature of about 45°C to about 55°C in hot air oven or under vacuum or air tray dryer for 10-15 hours.
Iloperidone obtained according to the present invention can be formulated into pharmaceutical composition, preferably in a dosage form suitable for oral or parenteral administration.
Iloperidone obtained according to the present invention can be formulated into pharmaceutical composition either alone or in combination with a pharmaceutically acceptable excipients into solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, solutions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, suspensions, dispersions, and freeze dried compositions. Pharmaceutical composition may be in the form of immediate release, delayed release or modified release. Further, oral immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of

hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The oral compositions may be prepared by direct blending, dry granulation, wet granulation, and melt granulation. The oral composition can also be manufactured using solid dispersion technique or adsorption technique. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Parenteral pharmaceutical composition may be in the form of immediate release or modified release. Modified release parenteral composition may be in the form of depot injection or biodegradable implants such as solution, suspension or emulsion. Modified release parenteral composition can be prepared by techniques including but are not limited to microspheres, microparticles and microcapsules.
The preferred composition according to present invention is tablet as oral and depot injection as parenteral composition. Iloperidone used in pharmaceutical composition can be in a form of free base or in the form of pharmaceutically acceptable salts. Further, Iloperidone, where applicable, may be present either in crystalline or amorphous. Iloperidone API can be used for preparation of composition either in micronized or un-micronized form. The particle size of the Iloperidone used in instant invention is 90 % of the Iloperidone particles are less than 250 microns, preferably 90 % of the Iloperidone particles are less than 100 microns. The preferred method for preparation of Iloperidone tablet in the instant invention is direct compression. In the present case, Iloperidone tablets having dissolution of at least 80 % after 45 minutes are provided.
Compositions of the present invention may further comprise one or more pharmaceuticatly acceptable excipients.
The pharmaceutical composition of the present invention can be in the form of a dosage form prepared using pharmaceutically acceptable adjuvants known in the art such as diluents, binders, wetting agents, disintegrating agents, lubricants, release rate controlling polymers, solvents and the like.
Diluents or fillers include, but are not limited to. lactose, microcrystalline cellulose,

calcium hydrogen phosphate, starch, modified starch, tribasic calcium phosphate, microcelac 100 (spray-dried mixture of lactose monohydrate and microcrystalline cellulose. 75:25), silicified microcrystalline cellulose, calcium carbonate, kaolin, magnesium carbonate, magnesium oxide, sodium chloride, mannitol, spray dried Mannitol (Pearlitol SD 200), glucose, urea, starch, calcium carbonate, kaolin, and silicic acid or combination thereof. The "diluent" or "filler" is present in the composition in the range of 50% to 80% by weight of dosage form.
Binders include, but are not limited to, water, ethanol, polyvinylpyrrolidone, hypromellose, hydroxy propyl cellulose, copolyvidone, shellac, zein, gelatin, polymethacrylates, synthetic resins, eudragits, and the like. The binder may be present in an amount ranging from 0.1 % to 25 % by weight of the composition.
Disintegrating agents include, but are not limited to, pregelatinised starch, corn starch or other starch derivatives, crosspovidone, croscarmellose sodium, croscarmellose calcium, sodium starch glycolate, microcrystalline cellulose, carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose or mixtures thereof. Disintegrant may be added in intragranular or extragranular or both stages. The disintegrant may be present in an amount ranging from 4 % to 8 % by weight of the composition.
Glidant or lubricant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, magnesium trisilicate; or mixtures thereof. The lubricant or glidant may be present in an amount ranging from 0.1 % to 5 % by weight of the composition.
Wetting agents can be selected from the group of surfactants, solubilizers, complexing agents. The preffered wetting agents are surfactants. The surfactant can be selected from hydrophilic surfactants and lipophilic surfactants, mixtures there of. The surfactants may be anionic, nonionic, cationic, zwitterionic or amphiphilic. The relative hydrophilicity and hydrophobicity of surfactants is described by HLB (hydrophilic-Iipophilic balance) value.

Hydrophilic surfactants include surfactants with HLB greater than 10 as well as anionic, cationic, amphophilic or zwitterionic surfactants for which the HLB scale is not generally applicable. Similarly, lipophilic surfactants are surfactants having an HLB value less than 10. The hydrophilic non-ionic surfactants may be, but not limited to, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol fatty acid monoesters, PEG-fatty acid diesters, hydrophilic trans-esterification products of alcohols or polyols with at least one member of the group consisting of natural and/or hydrogenated oils. The most commonly used oils are castor oil or hydrogenated castor oil. or an edible vegetable oil such as corn oil, olive oil, peanut oil. palm kernel oil, almond oil. Preferred polyols include glycerol. propylene glycol, ethylene glycol, polyethylene glycol, sorbitol and pentaerythritol. Preferred hydrophilic surfactants in this class include PEG-35 castor oil, polyoxyethylene-polypropylene copolymer (Lutrol, BASF), and PEG-40 hydrogenated castor oil.
The amphophilic surfactants includes, but are not limited to, d-[alpha]- tocopheryl polyethylene glycol 1000 succinate and d-[alpha]-tocopherol acid salts such as succinate, acetate, etc.
The ionic surfactants may be, but not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, or polypeptides; glyceride derivatives of amino acids, oligopeptides, or polypeptides; lecithins or hydrogenated lecithins; lysolecithins or hydrogenated lysolecithins; phospholipids or derivatives thereof; [ysophospholipids or derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyl lattylates; mono- or di- acetylated tartaric acid esters of mono- or di-glycerides; succinylated mono- or di-glycerides; citric acid esters of mono- or di-glycerides; or mixtures thereof. The lipophilic surfactants may be, but not limited to, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters: like polysorbates; sterols and sterol derivatives; polyoxyethylated sterols or sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- or di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils,

hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; polyethylene glycol (PEG) sorbitan fatty acid esters; PEG glycerol fatty acid esters; polyglycerized fatty acid; polyoxyethylene-polyoxypropylene block copolymers; sorbitan fatty acid esters; or mixtures thereof.
Preferably, the surfactant may be PEG-20-glyceryl stearate (Capmul® by Abitec), PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF), PEG 6 corn oil (Labrafil® by Gattefosse), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse), stearoy! macrogol glyceride (Gelucire 50/13® by Gattefosse), polygtyceryl - 10 mono dioleate (Caprol® PEG 860 by Abitec), propylene glycol oleate (Lutrol OP® by BASF), propylene glycol dioctanoate (Captex® by Abitec), propylene glycol caprylate/caprate (Labrafac® by Gattefosse), glyceryl monooleate (Peceol® by Gattefosse), glycerol monolinoleate (Maisine® by Gattefosse), glycerol memstearate {Captmu® by Abitec), PEG- 20 sorbitan monolaurate (Tween 20® by ICI), PEG - 4 lauryl ether (Brij 30® by ICI), sucrose distearate (Sucroester 7® by Gattefosse), sucrose monopalmitate (Sucroester 15® by Gattefosse), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF), polyethylene glycol 660 hydroxystearate, (Solutol® by BASF), sodium lauryl sulphate, sodium dodecyl sulphate, dioctyl suphosuccinate. L- hydroxypropyl cellulose, hydroxylethylcellulose, hydroxy propylcellulose, propylene glycol alginate, sodium taurocholate. sodium glycocholate, sodium deoxycholate, betains , polyethylene glycol (Carbowax® by DOW), d-[alpha]- tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman), or mixtures thereof.
More preferably, the surfactant may be PEG-40 hydrogenated castor oil (Cremophor RH 40® by BASF - HLB - 1.3), lauryl macrogol - 32 glyceride (Gelucire 44/14® by Gattefosse - HLB - 14) stearoyl macrogol glyceride (Gelucire 50/13® by Gattefosse - HLB - 13), PEG- 20 sorbitan monolaurate (Tween 20® by JCI - HLB - 17), PEG - 4 lauryl ether (Brij 30® by ICI- HLB - 9.7), polyoxyethylene-polyoxypropylene block copolymer (Lutrol® series BASF having different HLB ranging from 15-30), Sodium lauryl sulphate (HLB-40), polyethylene glycol (Carbowax® by DOW), d-[alpha]-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS® by Eastman- HLB - 15), or mixtures thereof. The wetting agent may be added intragranularly or extragranularly or in binder solution. The

wetting agent can be used but not limited to direct compression, dry granulation, wet granulation, and melt granulation.
The complexing agent includes cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha- cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin. or their derivatives, such as hydroxypropyl beta cyclodextrins, or mixtures thereof. The complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid.
The solvents include but not limited to water, isopropyl alcohol, ethanol, methanol, acetone halogenated alkanes (e.g. di-chloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethyl acetate, ethyl ether, cyclohexane, benzene, n-hexane and toluene. These solvents may be used alone or in combination.
Tablets can be further coated with commonly known coating materials such as sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coatings, tablets coated with films, double layered tablets, and multi-layered tablets.
When the microspheres are to be processed into an injectable preparation, they are dispersed in an aqueous vehicle together with a dispersing agent (carboxymethylcellulose, sodium alginate) and / or release rate controlling agent, preservative (e.g. methyl-paraben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonicity agent (e.g. sodium chloride, glycerin, sorbitol, glucose, etc.), etc. The vehicle may also be a vegetable oil (e.g. olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol or the like. In this manner, a prolonged release injection can be produced. The prolonged release injection made from said microspheres may be further supplemented with an excipient (e.g. mannitol, sorbitol, lactose, glucose, etc.), redispersed, and then be solidified by freeze-drying or spray-drying, and on extemporaneous addition of a distilled water for injection or suitable vehicle for the reconstitution, such preparation gives a prolonged release injection with greater stability.
When shaping the pharmaceutical composition into an oral solid dosage form, any

commonly known excipient used in the art can be used other than explained above.
Additional ingredients, such as dissolving agents, buffer agents, coloring agents, preservatives, perfumes, seasoning agents, sweetening agents, and other medicines may also be added to the desired formulation.
The amount of Iloperidone contained in a pharmaceutical composition is decided based on requirement sufficient to treat, ameliorate, or reduce the symptoms associated with the disease to be treated.
The invention will now be described by reference to the following examples, which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.
EXAMPLE 1:
l-[4-(3-chloropropoxy)-3-methoxy phenyl] etha none
To a solution of 20 gm of l-(4-hydroxy-3-methoxyphenyI) ethanone in 200 ml of acetone was added 25 gm of K2C03, 0.4 gm of TBAB and 24.6 gm of l-bromo-3-chloro propane at room temperature. The mixture was heated at reflux temperature at 56°C-58° C and maintained for 4 hours. The reaction mixture was followed by thin layer chromatography. At the end of the reaction, reaction mixture was cooled up to room temperature. The mixture was filtered and obtained residue was washed with acetone (2 x 40 ml). The organic solvent was removed by distillation under vacuum at 30°C and obtained residue was added with 200 ml of water and stirred for 60 minutes at 30°C. The separated solid was filtered, washed with water (2 x 20ml) and dried in air tray dryer at 40°C for 10 hours.
Dry weight = 28.1 gm
HPLC purity = 91.44%
Dimer impurity content = 5.68%

EXAMPLE 2
l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] propoxy]-3-methoxyphenyl] ethanone i.e. Iloperidone
Stage-1:
In a 1 lit. of clean RBF (round bottom flask), 25 gm of l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (as obtained in Example-1) and 150 ml of water were added at room temperature. The reaction mixture was added with 28.5 gm of potassium carbonate and 26.4 gm of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (II) and reaction mass was heated to about 80° C and maintained for 4.0 hours. The reaction mixture was followed by HPLC. At the end of the reaction, it was slowly cooled to 30° C. filtered and washed with water (2 * 25 ml), and suck dried the product well. The obtained wet cake was added with 125 ml of methanol, heated to 58°C for 30 minutes and then reaction mixture was cooled to room temperature and stirred for 30 minutes at the same temperature. The separated solid was filtered and washed with methanol (2 x 25 ml). Iloperidone wet weight = 40.8 gm Purity = 93.76% Dimer impurity = 5.96%
Stage-2:
A solution of 40.8 gm Iloperidone (as obtained in stage 1) in 150 ml of water was cooled to 5±5°C. The reaction mixture was acidified with acetic acid solution (50%) till the clear solution was obtained. The reaction mass was stirred for 10 minutes at 10±5°C followed by washing with cyclohexane (1* 50 ml). The separated aqueous layer was added with 2.5 gm of activated charcoal and stirred for 15 minutes at 10±5CC. The reaction mass was filtered through hyflow bed and washed with water (2 x 25 ml). Methanol (250 ml) was added to the reaction mass, which was than basified with liquid ammonia (17%-20%) till the pH = 8.5-9 was obtained and stirred for 30 minutes at 5±5°C. The separated solid was filtered, washed with water (2 x 50 ml) and methanol (2 x 50 ml) and dried in vacuum tray drier at 40°Cfor 10 hours.

Iloperidone dry weight = 35.5 gm
Purity = 99.91%
Dimer impurity content= 0.09%
EXAMPLE 3: l-[4-(3-chloropropoxy)-3-methoxyphenyI] ethanone
To a solution of 100.0 gm of l-(4-hydroxy-3-methoxyphenyl) ethanone in 1000 ml of acetone, was added 124.6 gm of K2C03, 2.0 gm of TBAB and 123.2 gm of l-bromo-3-chloro propane at room temperature. The mixture was heated at reflux temperature at 56°C-58° C and maintained for 4 hours. The reaction mixture was followed by thin layer chromatography. At the end of the reaction, reaction mixture was cooled up to room temperature. The mixture was filtered and the obtained residue was washed with acetone (2 x 200 ml). The organic solvent was removed by distillation under vacuum at 40°C. The obtained residue was added with 100 ml of methanol and methanol was distilled out under vacuum at 40°C. The residue was again added with methanol (200 ml) and stirred to dissolve completely at 40°C and cooled to 27°C. Reaction mass was added with 600 ml of water in step wise manner and stirred till the precipitation was completed. The separated solid was filtered and washed with water (2 x 100 ml) and dried the wet cake in air tray drier for 12 hours at 40°C.
Dry weight = 143.5 gm HPLC purity = 94.37% . Dimer impurity content = 2.52%
Example-4:
l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l- piperidinyl] propoxy]-3-methoxyphenyl]
ethanone i.e. Iloperidone
In a 2 lit. of clean RBF (round bottom flask), 125 gm of l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone (as obtained in Example-3) and 750 ml of water were added at room temperature. The reaction mixture was added with 142.3 gm of potassium carbonate

and 132.2 gm of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride and reaction mass was heated to about 80° C and maintained for 4.0 hours. The reaction mixture was followed by HPLC. At the end of the reaction, it was slowly cooled to 65° C and added with 1500 ml of methanol at temperature about of 65°C over a period of 45-60 minutes. The reaction mass stirred at the same temperature for 30 minutes and cooled to room temperature. The separated solid was filtered and washed with water (2 x125 ml) and methanol (2 x 25 ml), suck dried well and taken for further purification. (Wet weight = 208.5 gm)
A solution of 205 gm Iloperidone in 1600 ml of water was acidified with 200 ml of acetic acid solution (50%) to obtain the clear solution. The reaction mass was stirred for 10 minutes at 25±2°C followed by washing with cyclohexane (400 ml). The separated aqueous acidic layer was added with 20 gm of activated charcoal and stirred for 15 minutes at 25±2°C. The reaction mass was filtered through hyflow bed and washed with water (1 x 200 ml). Methanol (250.ml) was added to the reaction mass and cooled to 5±5°C, which was than basified with liquid ammonia (17%-20%) till the pH = 8.5-9 was obtained and stirred for 30 minutes at 5±5°C. The separated solid was filtered, washed with water (2 x 200 ml) and methanol (I x 200 ml) and dried in vacuum tray drier at 40°C for 10 hours.
Dry weight = 190.0 gm
Purity = 99.77%
Dimer impurity content = 0.13%
Example-5:
l-[4-[3-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)-l- piperidinyl] propoxy]-3-methoxyphenyl]
ethanone i.e. iloperidone
In a 2 lit. of clean RBF (round bottom flask), 130 gm of l-[4-(3-chloropropoxy)-3-methoxyphenyl] ethanone and 780 ml of water were added at room temperature. The reaction mixture was added with 148.0 gm of potassium carbonate and 137.5 gm of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride and reaction mass was heated about to 82±2° C and maintained for 4 hours. The reaction mixture was followed by HPLC.

At the end of the reaction, it was slowly cooled to 60±2° C and added with 910 ml of acetone at temperature about of 60±2°C. The reaction mass was stirred at the same temperature for 30 minutes and cooled to room temperature. The separated solid was filtered and washed with water (2 x130 ml) and acetone (130 ml), suck dried well and taken for further purification. (Wet weight = 203.0 gm)
1200 ml of acetone and 200 gm of above wet cake were added into round bottom flask and the reaction mass was heated about to 58±2° C to get the clear solution. 1200 ml of water was slowly added to the reaction mass at 58±2° C. The reaction mass was stirred at the same temperature for 30 minutes and cooled to room temperature. The separated solid was filtered and washed with water (2 x 200 ml), suck dried well and taken for further purification. (Wet weight = 217.0 gm)
A solution of 200 gm Tloperidone in 800 ml of water was acidified with 200 ml of acetic acid solution (50%) to obtain the clear solution. The reaction mass was stirred for 20 minutes at 27±3°C. The charcoal slurry (20 g activated charcoal in 200 ml of water) was added to the reaction mass at 27±3°C and was stirred for 30 minutes at the same temperature. The reaction mass was filtered through hyflow bed and washed with 1% acetic acid solution (2x 100 ml). The clear filtrate was charged in round bottom flask at 27±3°C and cooled to 20±3°C. 1400 ml methanol was added to the reaction mass and the reaction mass was cooled at 5±5°C. The pH of the reaction mass was adjusted to 8.5±0.5 by using ammonia solution. The reaction mass was stirred for 1 hour at 5±5°C. The separated solid was filtered and washed with water (2 x 200 ml) and methanol (2 * 100 ml) and dried in vacuum tray drier at 50°C for 12 hours.
Dry weight = 186.0 gm
Purity = 99.99%
Dimer impurity content = Not detected

We claim:
1. A process for the purification of Tloperidone (I) comprising;
(a) providing a solution of Iloperidone in water;
(b) acidifying the solution of step (a) with an organic or inorganic acid;
(c) optionally washing the solution of step (a) with water immiscible organic solvent;
(d) adding an organic solvent to the solution of step (c) or (b);
(e) adding an appropriate base to the solution as obtained in step (d); and
(f) isolating pure Iloperidone,
2. The process according to claim 1, wherein inorganic or organic acid of step (b) is
selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, succinic acid, maleic acid, malic acid, citric acid, ascorbic acid, mandelic acid, oxalic acid, tartaric acid, dibenzoyl tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid or mixtures thereof.
3. The process according to claim 1, wherein water immiscible organic solvent of step (c) is
selected from hexane. cyclohexane, methylcyclohexane, ethylcyctohexane, heptane, methylene chloride, ethyl acetate, tert-butyl methyl ether, carbon disulfide, benzene, toluene, xylene, chlorobenzene, diethylbenzene and tetralin.
4. The process according to claim 1, wherein organic solvent of step (d) is selected from
alcohols, ketones, aliphatic ethers, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated solvent, acetonitrile, polar aprotic solvents or mixtures thereof.
5. The process according to claim 1, wherein base of step (e) is selected from liquid
ammonia, ammonium hydroxide, alkali metal hydroxides, alkali metal methoxides, alkali metal carbonates, alkaline earth metal hydroxides, alkaline earth metal methoxides, alkaline earth metal carbonates, and mixtures thereof.
6. A process for the preparation of compound of formula (II)


comprising:
i) reacting a l-bromo-3-chlropropane (IV) with l-(4-hydroxy-3-methoxyphenyl) ethanone (V) in the presence of a base and a phase transfer catalyst in a suitable organic solvent at reflux temperature;
ii) isolating compound of formula (II).
7. The process according to claim 6, wherein organic solvent is selected from alcohols,
ketones, aliphatic ethers, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated
solvent acetonitrile, polar aprotic solvents or mixtures thereof.
8. The process according to claim 6, wherein base is selected from sodium carbonate,
sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide.
9. The process according to claim 6, wherein phase transfer catalyst is selected from
tetrabutylammonium bromide (TBAB), tetrabutylamrnonium hydroxide, TEBA, tricaprylylrnethylammonium chloride, dodecy' sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributyl phosphonium bromide, or hexadecyl trimethyl ammonium bromide.
10. A process for the preparation of Iloperidone and compound of formula (II) substantially
as herein described, particularly with reference to the foregoing examples.