IMPROVED PROCESS FOR PREPARING PALIPERIDONE, NOVEL POLYMORPHIC FORMS OF THE SAME AND PROCESS THEREOF

Field of the Invention This invention, in general relates to a process for preparing paliperidone. More particularly, the present invention provides an improved process for preparing paliperidone, its novel polymorphic forms and process thereof.

Background of the Invention

Paliperidone, the primary active metabolite of the existing antipsychotic risperidone is 9-hydroxyrisperidone, i.e., risperidone with an extra hydroxyl group.

Paliperidone, chemically known as 3-[2-[4-(6-fluoro-l, 2-benzisoxozol-3-yl)-l- piperidinyl]-ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H -pyrido[l,2-a] pyrimidin-

4-one, is represented by Formula-A:

Formula-A

Paliperidone (Invega), known as second generation antipsychotic drug developed by Janssen Pharmaceuticals is an extended release formulation of paliperidone that employs an oral osmotic extended release delivery system for once- daily dosing. Paliperidone was approved by FDA for the treatment of schizophrenia on December 20, 2006. It was initially marketed for the treatment of schizophrenia and then for bipolar mania.

US 5,158,952 discloses paliperidone and a process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9- (phenylmethoxy)-4H-pyrido[1.2-a] pyrimidin-4-one is hydrogenated to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one which is subsequently condensed with 6- fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride in presence of a base in a solvent, preferably methanol to obtain paliperidone. Following alkylation reaction, methanol is removed by reduced pressure to give oily residue followed by dissolving the residue in chloroform and washing with water. The organic layer is dried, concentrated under reduced pressure to obtain residue, subjected to column

chromatographic purification using a mixture of chloroform and methanol, followed by evaporation of eluents to give residue. The residue so obtained is subjected to repeated crystallizations in different solvents like acetone and isopropyl alcohol to give paliperidone having the melting point 179.8° C. According to the prior art process, the step of hydrogenation of 3-(2- chloroethyl)-2-methyl-9-(phenylmethoxy)-4H-pyrido[l,2-a] pyrimidin-4-one in the presence of 10% Palladium on charcoal catalyst in methanol under hydrogen pressure to obtain 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[l ,2-a] pyrimidin-4- one results in formation of large amount of side products and low yield of around 50% of the desired product. In addition, due to formation of large amount of side products, the isolation of desired product is very difficult and requires purification techniques like column chromatography and repeated crystallization in different solvents.

Moreover, the impurities formed in the hydrogenation reaction are carried forward as such and interfere with the condensation step thereby resulting in the formation of corresponding impurities. The formation of these impurities in the reaction mass makes it very difficult to isolate the final product without subjecting the reaction mass to column purifications and repeated crystallization steps. A number of purification and crystallization steps increase the operational cost of the entire process, thereby making it uneconomical for large-scale production. To overcome the drawback associated with the prior art processes, it is desirable to provide an improved process for the preparation of paliperidone with high purity and yield. Further, the process requires fewer purification steps to obtain the desired product, thereby making the process economical for industrial use.

Object and Summary of the Invention

It is an object of the present invention is to provide an improved process for the preparation of paliperidone.

It is another object of the present invention to provide an economical method for large scale production of paliperidone.

It is yet another object of the present invention to provide an improved process for the preparation of paliperidone, wherein the process results in formation of less impurity, thereby requiring fewer purification steps to obtain the desired product.

It is still another object of the present invention to provide novel polymorphic forms VI and VII of paliperidone and process for producing the same thereof.

It is yet another object of the present invention to provide a process for producing crystalline polymorphic forms of paliperidone i.e. Form I, Form II, Form III, Form IV, Form V, Form VI, and Form VII.

It is still another object of the present invention to provide a process for the preparation of the amorphous paliperidone.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However, the scope of the invention is not restricted to the described embodiments herein after.

In accordance with one preferred embodiment of the present invention there is provided an improved process for producing paliperidone, wherein the process comprises of hydrogenating 3-(2-chloroethyl)-2-methyl-9- (hydroxyprotected)-4H- pyrido[l,2-a] pyrimidin-4-one in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-p yrido

[1,2-a] -pyrimidin-4-one and subsequently condensing 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l,2-a]-pyrimidin-4-o ne with 6-fluoro-3-(4- piperidinyl)-l,2-benzisoxazole in presence of a base and a solvent to give said paliperidone.

In accordance with yet another embodiment of the present invention there is provided an improved process for producing crystalline Form VI of paliperidone, wherein the process comprises of dissolving paliperidone in a solvent and isolating said crystalline Form VI of paliperidone.

In accordance with still another embodiment of the present invention there is provided an improved process for producing crystalline form VII of paliperidone, wherein the process comprises of dissolving said paliperidone in a solvent or mixture of solvents followed by cooling an antisolvent, adding said solvent mixture of paliperidone to the anti-solvent and isolating crystalline Form VII of paliperidone.

In accordance with still another embodiment of the present invention there is provided a crystalline Form VI of paliperidone characterized by an X-Ray powder diffraction pattern having peaks at 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42 ± 0.2 2θ values.

In accordance with yet another embodiment of the present invention there is provided a crystalline Form VII of paliperidone characterized by an X-Ray Powder diffraction pattern having peaks at 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43,

15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 2θ values.

In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of dissolving paliperidone in a solvent, preferably ethyl acetate, at reflux temperature followed by cooling and isolating said Form I.

In accordance with yet another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of dissolving paliperidone in a chlorinated solvent or alcohol or mixture thereof followed by isolating resultant solid employing ether, preferably isopropyl ether.

In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form-I of paliperidone, wherein the process comprises of heating Form VI of paliperidone for a time sufficient to induce transformation of Form VI of paliperidone to Form I of paliperidone and isolating Form

I of paliperidone.

In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of subjecting paliperidone Form VI to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form VI of paliperidone to said polymorphic Form I and isolating said polymorphic Form I.

In accordance with still another embodiment of the present invention, there is provided a process for producing polymorphic Form I of paliperidone, wherein the process comprises of subjecting polymorphic Form VII of paliperidone to relative humidity >90% for a time sufficient to induce the transformation of polymorphic Form

VII to said polymorphic Form I and isolating said polymorphic Form I.

Brief Description of the Drawings

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures, wherein:

Figure 1 shows the X-ray powder diffraction pattern of crystalline paliperidone Form I.

Figure 2 shows the X-ray powder diffraction pattern of crystalline paliperidone Form

II.

Figure 3 shows the X-ray powder diffraction pattern of crystalline paliperidone Form III.

Figure 4 shows the X-ray powder diffraction pattern of crystalline paliperidone Form

IV.

Figure 5 shows the Differential Scanning Calorimetry (DSC) thermogram of paliperidone Form IV. Figure 6 shows the Thermo Gravimetric Analysis (TGA) of paliperidone Form IV.

Figure 7 shows the X-ray powder diffraction pattern of crystalline paliperidone Form

V.

Figure 8 shows the DSC thermogram of paliperidone Form V.

Figure 9 shows the X-ray powder diffraction pattern of crystalline paliperidone Form VI.

Figure 10 shows the DSC thermogram of paliperidone Form VI.

Figure 11 shows the TGA of paliperidone Form VI.

Figure 12 shows the X-ray powder diffraction pattern of crystalline paliperidone Form

VII. Figure 13 shows the DSC thermogram of paliperidone Form VII.

Figure 14 shows the TGA of paliperidone Form VII.

Figure 15 shows the X-ray powder diffraction pattern of amorphous paliperidone.

Detailed Description of the Invention

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention discloses an improved high yielding and economical process for the preparation of paliperidone. In addition, the present invention provides crystalline Form VI and Form VII and process for preparing thereof employing the improved process.

In addition, the present invention discloses method for producing polymorphic forms Form I, II, III, IV, V and amorphous form of paliperidone.

The present invention in general relates to an improved process for the preparation of paliperidone, wherein 3-(2-chloroethyl)-2-methyl-9-( hydroxyprotected)- 4H-pyrido[l,2-a] pyrimidin-4-one of Formula (I) is subjected to hydrogenation reaction in presence of an acid and a catalyst under hydrogen pressure to give 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[l ,2-a] -pyrimidin-4-one of Formula (II) which is further condensed with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula (III) followed by workup to give Paliperidone with improved yield as depicted in Scheme-I. '

(i) (H)

R = Benzyl Methyl

Formula-(II)

Formula-(III)

Condensation

Scheme I

According to an embodiment of the present invention, the hydroxyprotected group of 3-(2-chloroethyl)-2-methyl-9-(hydroxyprotected)-4H-pyrido[l ,2-a]-pyrimidin- 4-one of Formula (I) is selected from benzyl or methyl.

According to a preferred embodiment of the present invention, hydrogenation reaction is carried out in the presence of catalyst selected from noble metal catalyst such as Palladium, Rhodium and Ruthenium; or Raney nickel, under hydrogen pressure.

According to an alternate embodiment of the invention, the hydrogenation reaction is carried out in presence of a solvent selected from methanol, ethanol or isopropyl alcohol. The hydrogenation reaction carried out in the presence of the acid results in formation of fewer impurities compared to prior art process. The yield of desired product is more than 90%. Due to formation of minimal impurities during the hydrogenation step, isolation of desired product is simple and does not require column purification and crystallization in different solvents, thereby leading to improvement in yield.

According to the present invention, the acid employed in the hydrogenation reaction is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, para-toluene sulphonic acid or methane sulphonic acid or mixtures thereof. According to an exemplary embodiment of the present invention, after completion of the hydrogenation, the reaction mass was filtered and concentrated under reduced pressure to give residue. The residue was isolated in distilled mineral (DM) water to yield 3-(2-chloroethyl)-6,7,8,9,-tetrahydro-9-hydroxy-2-methyl-4Hp yrido[l,2- a]-pyrimidin-4-one of formula (H). According to the present invention, the 3-(2-chloroethyl)-6,7,8,9, -tetrahydro-9- hydroxy-2-methyl-4Hpyrido[l,2-a]-pyrimidin-4-one is condensed with 6-fluoro-3-(4- piperidinyl)-l-benzisoxazole in the presence of a base and solvent to give paliperidone. The base is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, preferably sodium carbonate.

The solvent employed in the condensation step is selected from alcohol, ketone, nitrile, ester or ether. The alcohol solvent is selected form methanol, ethanol, isopropyl alcohol and n-butanol. The ketone solvent is selected form acetone, methyl ethyl ketone

and the nitrile solvent is acetonitrile. The ester solvent is ethyl acetate and the ether used is preferably tetrahydrofuran.

According to the present invention, after completion of the condensation reaction, the reaction mass is cooled to low temperature, separated solid filtered and washed with solvent such as alcohol, water or mixture thereof to give paliperidone.

Powder X-ray Diffraction (PXRD)

The said polymorphs of the present invention are characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said polymorphs of the invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of θ/θ configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 4OkV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time. Differential Scanning Calorimetry (DSC)

The DSC measurements were carried out on Mettler Toledo 822 star ^e and TA QlOOO of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 50ml/min. Standard aluminum crucibles covered by lids with three pin holes were used.

Thermo Gravimetric Analysis (TGA)

TGA was recorded on out using the instrument Mettler Toledo TGA/SDTA 85 l ^e and TGA Q5000 of TA instruments. The experiments were performed at a heating rate of 10.0 °C/min over a temperature range of 30°C-300°C purging with nitrogen at a flow rate of 25 ml/min.

Another alternate embodiment of the present invention relates to a process for producing polymorphic forms of paliperidone. Paliperidone is subjected to

J crystallization in different solvents and applying different cooling patterns to yield various polymorphic forms, designated as paliperidone crystalline Forms I, II, III, IV, V, VI, VII and an amorphous form.

According to an embodiment of the present invention the crystalline paliperidone polymorphic Form I is having a substantially similar powder X-ray diffraction pattern shown in Fig. 1 with peaks at about 14.58, 22.04 , 24.65 and 25.05 ° (±) 0.2θ.

According to the present invention, the process for producing paliperidone polymorphic Form-I includes:

a) condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9-hydroxy-4H-pyrido[l ,2- a] pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazolemonohydro chloride in the presence of organic base such as diisopropyl amine in an alcoholic solvent such as methanol. b) removing the solvent and treating with acetone and c) isolating polymorphic Form I in alcohol such as isopropyl alcohol.

According to an alternate process of the present invention, the polymorphic Form I of paliperidone is prepared by dissolving paliperidone in a solvent such as ethyl acetate at reflux temperature followed by cooling of the resulting solution and isolating the Form I of paliperidone.

According to another alternate process of the present invention the polymorphic

Form I of paliperidone is alternatively prepared by treating the Form VI or the Form

VII or mixtures thereof in a solvent such as isopropyl alcohol, acetonitrile, heptane, methanol or mixtures thereof to form a slurry followed by filtration to yield the Form I of paliperidone.

According to yet another alternate process of the present invention, the paliperidone polymorphic Form I is prepared by dissolving paliperidone in chlorinated solvent or alcohol or mixture thereof and isolating the solid in ethers such as isopropyl ether to give the polymorphic Form-I. According to the present invention, the paliperidone polymorphic Form I is alternatively prepared by heating Form VI for a time sufficient to transform the Form VI to the Form I of paliperidone, at 40-60°C preferably at 45-50°C. According to an exemplary process the Form VI of paliperidone is subjected to heating for at least 6- 1 ldays, preferably about 7-9 days to convert to paliperidone Form I. According to an alternate embodiment of the present invention, the polymorphic

Form I of paliperidone is prepared by exposing Form VI to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VI to Form I. According to an exemplary process the Form VI of paliperidone is exposed to relative humidity >90% for at least 1-4 days, preferably about 2-3 days to convert to paliperidone Form I.

According to the present invention, paliperidone polymorphic Form I is alternatively prepared by exposing Form VII to relative humidity >90%. The reaction is carried out for a time sufficient to convert the Form VII to Form I preferably for 8-12 days, more preferably about 9-10 days to convert to the Form I of paliperidone.

According to another embodiment of the present invention, polymorphic Form II of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 2, with peaks at about 17.02, 18.90 and 26.11 ° (±) 0.2θ.

According to the present invention, the process for producing polymorphic Form II of paliperidone includes condensing 3-(2-chloroethyl)-6,7,8,9-teterahyro-9- hydroxy-4H-pyrido[l,2-a]pyrimidin-4-one with 6-fluoro-3-(4-piperidinyl)-l,2- benzisoxazole monohydrochloride in the presence inorganic base such as sodium carbonate in solvent medium preferably acetonitrile at 60-65° C, subsequently cooling the reaction product to room temperature, filtering the solid and isolating the separated solid using mixture of water and alcoholic solvents preferably isopropyl alcohol to give polymorphic Form II of paliperidone.

According to still another embodiment of the present invention, the crystalline polymorphic Form III of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 3, with peaks at about 9.65, 15.70, 21.04, 21.43 and 25.81° (±) 0.2θ.

According to the present invention, the paliperidone polymorphic Form II is dissolved in an alcoholic solvent such as methanol, ethanol, isopropyl alcohol, n- butanol mixtures thereof, followed by gradual cooling and filtration to give crystalline polymorphic Form III of paliperidone. According to still another embodiment of the present invention, the crystalline polymorphic Form IV of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 4, with peaks at about 10.25, 23.79 and 25.99° (±) 0.2θ. The crystalline polymorphic Form IV of paliperidone is further characterized by differential scanning calorimetry (DSC) as shown in Fig. 5, and thermogravemetric analysis (TGA) as shown in Fig. 6.

According to the present invention, the crystalline polymorphic Form IV of paliperidone contains water around 8.7%, which is equivalent to around 2.0 moles of water with respect to the paliperidone.

According to the present invention, crystalline polymorphic Form IV of paliperidone is prepared by dissolving the crystalline polymorphic Form II in a mixture of water and water miscible organic solvents, subjecting resulting clear solution to cooling, filtering separated solid and washing the solid to give crystalline paliperidone polymorphic Form IV. The water miscible organic solvent used is selected from alcohol or ketone. The alcohol used is selected from methanol, ethanol, isopropyl alcohol or n-

butanol or mixtures thereof and the ketone solvent is selected from acetone or methyl ethyl ketone.

According to another embodiment of the present invention, crystalline polymorphic Form V of paliperidone is having a substantially similar powder X-ray diffraction pattern as shown in Fig. 7, with peaks at about 9.68, 21.09, 21.47 and 25.86°

(±) 0.2θ. The crystalline polymorphic Form V of paliperidone is further characterized by DSC as shown in Fig. 8.

According to the present invention, the crystalline Form V of paliperidone is prepared by suspending crystalline polymorphic Form II in water, followed by slow addition of acid to give clear solution, adjustment of pH of resulting acid solution between 7.0- 10.0 preferably 8.0-9.0 by using a base and subsequent precipitation, filteration and washing with water to give the crystalline paliperidone Form V. The acid used is selected from acetic acid, formic acid, hydrochloric acid, hydrobromic acid or sulfuric acid, preferably hydrochloric acid. The base used is selected from alkali, alkaline earth carbonates, bicarbonates or hydroxides such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide peferably sodium carbonate.

According to another embodiment of the present invention, the crystalline polymorphic Form VI of paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 9, with peaks at about 5.08, 14.28, 16.99, 18.65, 19.04, 19.93 and 21.42° (±) 0.2θ. The crystalline paliperidone polymorphic Form VI is further characterized by DSC as shown in Fig. 10 and TGA as shown in Fig. 11. According to the present invention, crystalline polymorphic Form VI of paliperidone contains moisture content less than 1.0%. According to the present invention, the polymorphic Form VI of paliperidone is prepared by dissolving paliperidone in a solvent selected from chlorinated solvent or mixture thereof followed by removal of the solvent. The chlorinated solvent is selected from chloroform, dichloromethane, dichloroethane or mixture thereof.

According to another embodiment of the present invention, crystalline paliperidone polymorphic Form VII having substantially similar powder X-ray diffraction pattern as shown in Figure-12, with peaks at about 5.48, 6.04, 9.51, 9.88, 12.46, 14.29, 14.93, 15.43, 15.96, 17.39, 18.16, 18.70, 19.63, 20.83, 21.45, 22.15, 22.73, 23.41, 24.87 ± 0.2 0°. The crystalline paliperidone polymorphic Form- VI is further characterized by DSC as shown in Fig. 13 and TGA as shown in Fig. 14.

According to the present invention, process for the preparation of polymorphic Form VII of paliperidone comprises a) dissolving the paliperidone in a solvent or mixture of solvents b) cooling the anti-solvent to -30 to -35°C c) slowly adding solution mixture of step a) to step b); and d) isolating crystalline polymorphic Form VII of paliperidone. Solvent is selected from alcohol such as isopropyl alcohol, chlorinated hydrocarbon such as chloroform or ether such as isopropyl ether. The process includes optionally seeding the solvent mixture with polymorphic Form VII.

According to another embodiment of the present invention, amorphous paliperidone is having substantially similar powder X-ray diffraction pattern as shown in Fig. 15. According to the present invention, process for the preparation of amorphous paliperidone comprises melting the crystalline paliperidone and isolating amorphous paliperidone.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.

Example- 1 Preparation of 3-r2-Chloro-ethvn-9-hvdroxy-2-methyl-6.7.8.9-tetrahvdro-pyri do[1.2- a]pyrimidin-4-one

9-Benzyloxy-3-(2-chloro-ethyl)-2-methyl-pyrido[l,2-a]pyri midin- 4-one, prepared as per US 5,158,952 (100 g,0.305 mole) was added to methanol (500 ml) at

25-35°C. The suspension was maintained for 15 minutes at 25-35°C and acetic acid

(25g, 0.416 moles) was added to the above suspension at 25-35°C followed by drop wise addition of cone.

H ₂ SO ₄ (30g, 0.306mole) at 25-35° C to get a clear solution. The solution was treated with activated carbon 10.0 gm for 1 hr. Reaction mass was then filtered over celite bed and washed with methanol (50.0 ml). The filtrate was charged into autoclave at 25-35°C along with 10% Pd Carbon [10 g (50% wet)] at 25-35°C. Hydrogenation was continued at 4-5 kg/cm ² at 60-65°C until 9-hydroxy-3-(2-chloro- ethyl)-2-methyl-pyrido[l,2-a] pyrimidin- 4-one <1.0%. The reaction mass was further cooled and Pd/C was filtered over celite and washed with methanol. The solution was cooled to 10-15°C, pH adjusted to 8.0 with sodium carbonate at 10-15°C and the solution stirred for 1 hr at 25-35°C. Resulting salts were filtered and washed with methanol (50.0 ml). The solvent was distilled off completely under vacuum at below 40°C. DM Water (150 ml) was charged to the residue at 25-35°C and cooled to 10-

15°C. Contents were stirred for 1 hr at 10-15°C. Resultant solid was filtered, washed with water and dried at 40-45°C to give 50 g of 3-(2-Chloro-ethyl)-9-hydroxy-2- methyl-6,7,8,9-tetrahydro-pyrido [ 1 ,2-a]pyrimidin-4-one.

Example-2 Preparation of Paliperidone

3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l, 2-a]pyrimidin-4-one (60 gm, 0.165 mole) was added to acetonitrile (300 ml) at 25-35°C and stirred for 10 mins at 25-35°C. 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole.HCl (55.9 gm,0.218 mole) and sodium carbonate anhydrous (78.8 gm, 0.743 mole) was added. Resultant mass was stirred for 10 min at 25-35°C. The temperature was slowly raised to 60- 65°Cand maintained at 60-65°C for 30-45 hrs. Subsequently, mass was cooled and maintained at 25-35°C for 1 hr. The solid is filtered and treated with water (600 ml) for 1 hr. The solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of paliperidone. Example-3

Process for the preparation of crystalline Form I of paliperidone 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-p yrido[l,2- a]pyrimidine-4-one (5.0 gm,0.021 moles), 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole mono hydrochloride (4 gm,0.018 molar), diisopropylamine (4 gms,0.039 moles) and methanol (48 ml) were stirred overnight at 60°C. The reaction mass was evaporated and the residue was suspended in dichloromethane (50 ml) and washed with water. The solvent was evaporated and the residue treated with acetone to get paliperidone crude (5.0 gms). The crude paliperidone (4 gm) was charcoalised in isopropyl alcohol at 75- 80° C, the filtrate cooled and stirred for 1 hr. The reaction mass was again cooled to 0- 5°C and stirred for 2 hrs. Slurry was filtered and washed with chilled isopropyl alcohol. The wet cake was dried at 35-40°C under vacuum (3.3 gm) to obtain polymorphic Form I of paliperidone

Example-4

Transformation of Form VI to Form I of paliperidone by Slurry, Relative Humidity (RTO and Heating

Ig of Form VI of paliperidone is subjected to different crystallization processes. The results are tabulated as follows.

Example-5

Transformation of Form VII to Form I of paliperidone by Slurry and Relative Humidity

Ig of paliperidone Form VII was subjected to different crystallization processes. The results are tabulated as follows.

Example-6

Process for the preparation of crystalline polymorphic Form II of paliperidone

3-(2-chloroethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a ]pyrimidin-4-one (60 gm, 0.165 mole) was added to acetonitrile (300 ml) at 25-35 ⁰ C and stirred for 10 mins at 25-35°C. 6-Fluoro-3-piperidin-4-yl-benzo[d]isoxazole.HCl (55.9 gm,0.218 mole) and sodium carbonate anhydrous (78.8 gm, 0.743 mole) was added to the reaction mass. The reaction mass was then stirred for 10 min at 25-35°C and temperature was raised to 60-65°C. The reaction mass was then maintained at 60-65°C for 30-45 hrs, slowly cooled and maintained at 25-35°C for 1 hr. The resultant solid was filtered and treated with water (600 ml) for 1 hr. The solid was again filtered, washed with water and IPA and dried at 40-45°C to give 85 gm of Form II of paliperidone.

Example-7 Process for the preparation of crystalline polymorphic Form III of paliperidone

Paliperidone (7.2 gm) was added to isopropyl alcohol (220 ml) at 25-35°C and stirred for 15 min. Slowly the temperature was raised to reflux temperature to obtain a clear solution. Activated carbon (1.5 gm) was charged to the reaction mass at reflux temperature and maintained at reflux for 60 min. The carbon was then filtered over celite bed at reflux and washed with hot isopropyl alcohol. The filtrate was cooled to 0-

5°C and maintained for 2 hrs. The solid was then filtered, washed with chilled isopropyl alcohol and dried under vacuum below 40-45°C to give 4.5 gm of Form III of paliperidone.

ExampIe-8 Process for the preparation of crystalline polymorphic Form III of Paliperidone

1 gm of polymorphic Form IV of paliperidone was dried in a static dryer and heated at 40-60° C under vacuum to give polymorphic Form III of paliperidone.

Example-9 Process for the preparation of crystalline polymorphic Form IV of paliperidone

Paliperidone (2 gm) was added to ethanol (20 ml) and water (2ml) at 25-35°C and stirred for 15 min. Slowly the temperature was raised to reflux under nitrogen to obtain a clear solution. The solution was slowly cooled to 25-35°C in 1.5hours and further cooled to 0-5 ⁰ C in 30 minutes and maintained for 1.0 hour. Solid was then filtered and washed with chilled ethanol, dried under vacuum below 40-45 ⁰ C to give 1.0 gm of Form IV of paliperidone.

Example-10

Process for the preparation of crystalline polymorphic Form IV of paliperidone

3 gm of Paliperidone was dissolved in 1:1 mixture of acetonitrile and water ( v/v 350 ml), resulting solution was then subjected to freeze drying at -104° C and below 200 Torr vacuum to give polymorphic Form IV of paliperidone.

Example- 11 Process for the preparation of crystalline polymorphic Form V of paliperidone

Paliperidone (1 gm) was added to 0.5N Hydrochloric acid solution (10 ml) at 25-35°C and stirred for 15 min. The solution was then heated to 60-65°C and pH adjusted to 8.0 with sodium carbonate solution at 60-65°C. Further, the suspension was cooled slowly and stirred at 25-35°C for 2 hrs. The solid was filtered and washed with chilled water ( 5 ml), dried under vacuum below 40-45°C to give 0.90 gm of Form V of paliperidone.

Example- 12 Process for the preparation of crystalline polymorphic Form VI of paliperidone

5 gm of Paliperidone was dissloved in 65 ml chloroform under stiring at 55-60° C for 10 minutes. The resulting solution was filtered through celite to remove undissloved particulate. The filtrate was subjected to spray drying at temperature 100- 105°C using nitrogen gas to give crystalline polymorphic Form- VI of paliperidone. Example- 13

Process for the preparation of crystalline polymorphic Form VII of paliperidone

5g of Paliperidone was suspended in 1 : 1 mixture of chloroform and isopropyl alcohol (v/v 80ml) at room temperature and heated to about 4O ⁰ C to obtain a clear solution. The resulting solution was filtered through hyflo bed to remove the particulate and added to isopropyl ether (420 ml) maintained at -3O ⁰ C for 15 min with agitation.

The precipitated solid was then filtered to give Form VII of paliperidone.

Example-14 Process for the preparation of crystalline polymorphic Form VII of Paliperidone

5g of Paliperidone was suspended in 1 :1 mixture of chloroform and isopropyl alcohol (v/v 80ml) at room temperature and heated to about 4O ⁰ C to obtain a clear solution. The resulting solution was filtered through celite bed to remove the particulate and added to isopropyl ether (420 ml) maintained at -3O ⁰ C with seeds of Form VII for 15 min with agitation. The precipitated solid was filtered to give Form VII of paliperidone.

Example- 15

Process for the preparation of amorphous paliperidone

5g of Paliperidone was heated at about 17O ⁰ C and maintained for about 5 minutes to form a melt followed by cooling the melt to obtain amorphous paliperidone.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.