INTRODUCTION

Aspects of the present invention relate to polymorphic forms and solvates of paliperidone, processes for the preparation of paliperidone polymorphic forms and solvates thereof, and pharmaceutical compositions comprising paliperidone polymorphic forms and solvates thereof.

Paliperidone has a chemical name (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The structural formula of paliperidone can be represented as:

The drug was approved by U.S. Food and Drug Administration in December 2006 for the treatment of schizophrenia. INVEGA® is the brand name of paliperidone products marketed by Ortho-McNeil-Janssen Pharmaceuticals, Inc.. Paliperidone is an active metabolite of risperidone.

U.S. Patent No. 5,158,952 discloses paliperidone, processes for the preparation of paliperidone, pharmaceutical compositions containing paliperidone and a method of treating warm-blooded animals suffering from psychotic diseases with an antipsychotic effective amount of paliperidone. Crude paliperidone obtained from the reaction is purified by twice by the column chromatography and the resulting residue is crystallized from acetone and recrystalized from 2-propanol.

U.S. Patent Application Publication No. 2008/0177067 A1 discloses crystalline polymorphic Forms l-VI of paliperidone and mixtures thereof. It also discloses an amorphous form of paliperidone. The forms are characterized by powder XRD and solid state 13C NMR techniques. The forms are prepared by different processes, such as crystallization, slurrying, or solvent-anti-solvent techniques with different solvent(s) under varying conditions of paliperidone to solvent ratios, heating temperatures or heating rates, maintenance times, cooling temperatures or cooling rates, and drying conditions or techniques.

U.S. Patent Application Publication No. 2009/0270620 A1 discloses a crystalline polymorphic Form II of paliperidone containing isopropyl alcohol, and processes for the preparation of the solvate.

U.S. Patent Application Publication No. 2009/0061005 A1 discloses crystalline polymorphic Forms A2, A3, and A4 of paliperidone, and processes for the preparation of the polymorphic forms.

International Application Publication No. WO 2009/016653 A1 discloses crystalline polymorphic Form a of paliperidone, and processes for the preparation of the form.

International Application Publication No. WO 2009/044413 A1 discloses crystalline polymorphic Forms VI and VII of paliperidone and processes for the preparation of the polymorphic forms. It also discloses processes for the preparation of Form I of paliperidone from Form VI or Form VII.

The occurrence of different crystal forms, i.e., polymorphism, is a property of some compounds. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like X-ray diffraction (XRD) patterns, infrared (IR) spectra, melting points (MP), thermogravimetric analysis (TGA) curves, differential scanning calorimetry (DSC) curves, and solubilities.

Polymorphs are different solids sharing the same molecular formula, yet having distinct physical properties when compared to other polymorphs of the same formula. The discovery of new polymorphs and solvates of a pharmaceutically useful composition provides an opportunity to improve the performance of a drug product in terms of its bioavailability or release profile in vivo or it may have improved stability or advantageous handling properties. Therefore, there remains a need for additional polymorphic forms of paliperidone and for processes to prepare polymorphic forms in more environmentally-friendly, cost-effective, and industrially applicable manners.

SUMMARY

In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline "Form A" which is characterized by a powder X-ray diffraction (PXRD) pattern substantially as depicted in Figure 1. In an aspect, Form A has a powder X-ray diffraction (PXRD) pattern with characteristic peaks located at about 5.28, 10.1, 12.6, 15.9, 16.4, 19.0, 19.3, 20.3, 23.1, 24.3, 25.0, 26.5, and 29.6, ± 0.2 degrees 2-theta.

In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline "Form B" which is characterized by a PXRD pattern substantially as depicted in Figure 3. In an aspect, Form B has a PXRD pattern with characteristic peaks located at about 5.6, 10.0, 10.8, 11.8, 12.7, 14.1, 16.4, 17.2, 19.2, 20.0, 20.8, 21.9, 25.8, 27.2, and 29.2, ± 0.2 degrees 2-theta.

In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline "Form C" which is characterized by a PXRD pattern substantially as depicted in Figure 5. In an aspect, Form C has a PXRD pattern with characteristic peaks at about 5.6, 9.8, 10.8, 12.0, 12.4, 14.0, 15.9, 16.7, 19.2, 21.0, 22.5, 25.8, and 28.9, ± 0.2 degrees 2-theta.

In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline "Form D" which is characterized by a PXRD pattern substantially as depicted in Figure 7. In an aspect, Form D has a PXRD pattern with characteristic peaks at about 5.3, 9.0, 10.6, 11.5, 14.6, 14.9, 15.6, 17.2, 17.9, 18.6, 19.0, 20.7, 21.4, 23.2, 25.2, 26.4, and 28.1, ± 0.2 degrees 2-theta.

In an aspect, the invention provides simple, industrially scalable and cost-effective processes for the preparation of polymorphic forms of paliperidone having purity acceptable for its use in the preparation of pharmaceutical compositions.
In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form A of paliperidone, embodiments comprising:

(i) providing a solution of paliperidone in formamide;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at low temperatures; and
(iv) isolating the formed solid and drying to obtain polymorphic Form A of paliperidone.

In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form B of paliperidone, embodiments comprising:

(i) providing a solution of paliperidone in dichloromethane;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at low temperatures; and
(iv) isolating the formed solid and drying to obtain polymorphic Form B of paliperidone.

In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form C of paliperidone, embodiments comprising:

(i) slurrying paliperidone in N.N-dimethylacetamide at low temperatures;
and
(ii) isolating the solid and drying to obtain polymorphic Form C of
paliperidone. In aspects, the invention provides processes for the preparation of polymorphic crystalline Form D of paliperidone, embodiments comprising:
(i) providing a solution of paliperidone in a solvent;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at a low temperature; and
(iii) isolating the formed solid and drying to obtain polymorphic Form D of
paliperidone.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts a PXRD pattern of paliperidone polymorphic crystalline Form
A, obtained by the procedure of Example 1.

Figure 2 depicts a TGA curve of paliperidone polymorphiccrystalline Form A, obtained by the procedure of Example 1.

Figure 3 depicts a PXRD pattern of paliperidone polymorphic crystalline Form
B, obtained by the procedure of Example 2.

Figure 4 depicts a TGA curve of paliperidone polymorphic crystalline Form B, obtained by the procedure of Example 2.

Figure 5 depicts a PXRD pattern of paliperidone polymorphic crystalline Form
C, obtained by the procedure of Example 3.

Figure 6 depicts a TGA curve of paliperidone polymorphic crystalline Form C, obtained by the procedure of Example 3.

Figure 7 depicts a PXRD pattern of paliperidone polymorphic crystalline Form
D, obtained by the procedure of Example 4.

Figure 8 depicts a TGA curve of paliperidone polymorphic crystalline Form D, obtained by the procedure of Example 4.

DETAILED DESCRIPTION

In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline Form A.

Crystalline Form A can be characterized by a PXRD pattern substantially as depicted in Figure 1. Form A can also be characterized by a PXRD pattern having peaks at about 5.28, 10.1, 12.6, 15.9, 16.4, 19.0, 19.3, 20.3, 23.1, 24.3, 25.0, 26.5, and 29.6, ± 0.2 degrees 2-theta.

Crystalline Form A can be characterized by a TGA curve substantially as depicted in Figure 2. In embodiments, the TGA curve indicates a weight loss of about 10%.
In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline Form B.

Crystalline Form B can be characterized by a PXRD pattern substantially as depicted in Figure 3. Form B can also be characterized by a PXRD pattern having peaks at about 5.6, 10.0, 10.8, 11.8, 12.7, 14.1, 16.4, 17.2, 19.2,20.0,20.8,21.9,
25.8, 27.2, and 29.2, ± 0.2 degrees 2-theta.

Crystalline Form B can be characterized by a TGA curve substantially as depicted in Figure 4. In embodiments, the TGA curve indicates a weight loss of about 14%.
In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline Form C.

Crystalline Form C can be characterized by PXRD pattern substantially as depicted in Figure 5. Form C can also be characterized by a PXRD pattern having peaks at about 5.6, 9.8, 10.8, 12.0, 12.4, 14.0, 15.9, 16.7, 19.2, 21.0, 22.5, 25.8, and
28.9, ± 0.2 degrees 2-theta.

Crystalline Form C can be characterized by a TGA curve substantially as depicted in Figure 6. In embodiments, the TGA curve indicates a weight loss of about 17%.
In an aspect, the invention provides a polymorph or solvate of paliperidone designated as crystalline Form D.

Crystalline Form D can be characterized by a PXRD pattern substantially as depicted in Figure 7. Form D can also be characterized by a PXRD pattern having peaks at about 5.3, 9.0, 10.6, 11.5, 14.6, 14.9, 15.6, 17.2, 17.9, 18.6, 19.0, 20.7, 21.4, 23.2, 25.2, 26.4, and 28.1, ± 0.2 degrees 2-theta.

Crystalline Form D can be characterized by a TGA curve substantially as depicted in Figure 8. In embodiments, the TGA curve indicates a weight loss of about 1%.

PXRD patterns described herein are determined using a Bruker AXS D8 Advance powder X-ray diffractometer with a copper K- alpha radiation source of A=1.5406 A. TGA analysis was carried out on a TGA Q500 from TA Instruments. The sample mass was placed in a platinum pan with nitrogen gas purge at a flow rate of 40 mL/minute for balance and 60 mL/minute for sample. The TG analysis was recorded with a ramp rate of 10°C/minute up to 200°C.

In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form A of paliperidone, embodiments comprising:

(i) providing a solution of paliperidone in formamide;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at low temperatures; and
(iv) isolating the formed solid and drying to obtain polymorphic Form A of paliperidone.

In embodiments, step (i) can comprise heating a mixture of paliperidone and formamide, up to the reflux temperature, to prepare a clear solution. In embodiments, the heating is up to 80-90°C until complete dissolution occurs. The hot mass can be filtered to obtain a clear solution of paliperidone in formamide. The solution can be maintained at about 50°C to the reflux temperature for about 10 minutes to 1 hour, or longer. In embodiments, the solution is maintained at 80-90°C for about 15 minutes.

In embodiments, step (ii) can comprise adding a solution of paliperidone in formamide, at temperatures about 50°C to the reflux temperature, to the anti-solvent which has been previously chilled to about 10°C to -50°C. For example, a solution of paliperidone in formamide, maintained at 80-90°C, is added to the anti-solvent. The anti-solvents that may be used for this step include, but are not limited to, water, hexane, heptane, diethyl ether, diisopropyl ether, methyl ethyl ketone, cyclohexane, methyl tert-butyl ether. Preferably, the anti-solvent is n-hexane. In an embodiment, n-hexane is cooled to -30°C before adding a solution of paliperidone in formamide. Alternatively, anti-solvent can be added to a solution of paliperidone.

In embodiments, step (iii) can comprise maintaining the mixture at low temperatures, such as about 10°C to -50°C, for times about 10 minutes to 4 hours, or longer. For example, the mixture is maintained at -30°C for about 30 minutes.

In embodiments, step (iv) can comprise isolating the formed solid using any isolation techniques known in the art such as decantation, filtration, centrifugation, and vacuum filtration.

Drying can be carried out at suitable temperatures for suitable time periods, using any techniques known in the art such as suction drying, vacuum drying, tray drying, and fluidized bed drying. In an embodiment, drying is carried out in a suction dryer for about 3-4 hours, followed by further drying in a tray dryer at 50°C for about 7 hours or longer.
In embodiments, the invention provides processes for the preparation of polymorphic crystalline Form B of paliperidone, embodiments comprising:

(i) providing a solution of paliperidone in dichloromethane;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at low temperatures; and
(iv) isolating the formed solid and drying to obtain polymorphic Form B of paliperidone.

In embodiments, step (i) can comprise heating a mixture of paliperidone and dichloromethane at temperatures up to the reflux temperature, to prepare a clear solution. In embodiments, the heating is done up to 40°C until complete dissolution occurs. The hot mass can be filtered to obtain a clear solution of paliperidone in dichloromethane. The solution can be maintained at about 35°C to the reflux temperature for about 10 minutes to 1 hour, or longer. For example, the solution is maintained at 35°C for about 10 minutes.

In embodiments, step (ii) can comprise adding a solution of paliperidone in dichloromethane, at temperatures about 35°C to the reflux temperature, to the anti-solvent which is previously cooled to about 10°C to -60°C. The anti-solvents that may be used for this step include, but are not limited to, water, hexane, heptane, diethyl ether, diisopropyl ether, methyl ethyl ketone, cyclohexane, methyl tert-butyl ether. Preferably, the anti-solvent is methyl ethyl ketone. In embodiments, a solution of paliperidone in dichloromethane, maintained at 35°C, is added to methyl ethyl ketone. In embodiments, methyl ethyl ketone is cooled to about -55°C before adding a solution of paliperidone in dichloromethane. Alternatively, anti-solvent can be added to a solution of paliperidone.

In embodiments, step (iii) comprises maintaining the mixture at about 10°C to -60°C for about 10 minutes to 4 hours, or longer. For example, the solution is maintained at -55°C for about 15 minutes.

In embodiments, step (iv) comprises isolating the formed solid using any isolation techniques known in the art, such as decantation, filtration, centrifugation, and vacuum filtration.

Drying can be carried out at suitable temperatures for suitable time, using any isolation techniques known in the art such as suction drying, vacuum drying, tray drying, and fluidized bed drying. In an embodiment, suction drying is carried out under a nitrogen atmosphere for 30 minutes or longer.

In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form C of paliperidone, embodiments comprising:

(i) slurrying paliperidone in N,N-dimethylacetamide at low temperatures; and
(ii) isolating the solid and drying to obtain a polymorphic Form C of paliperidone.

In embodiments, step (i) can comprise slurrying paliperidone in N,N-dimethylacetamide at temperatures about 0°C to -40°C. Step (i) can comprise maintaining the solution at about 0°C to -40°C for about 30 minutes to 8 hours, or longer. For example, the solution is maintained at about -30°C for about 5 hours.

In embodiments, step (ii) can comprise isolating the solid by any isolation techniques known in the art, such as decantation, filtration, centrifugation, and vacuum filtration. For example, the solid is isolated using a pressure Nutsche filtration apparatus.

Drying can be carried out at suitable temperatures for suitable times, using any techniques known in the art, such as suction drying, vacuum drying, and tray drying. In an embodiment, suction drying is carried out under a nitrogen atmosphere for about 2 hours or longer.

In an aspect, the invention provides processes for the preparation of polymorphic crystalline Form D of paliperidone, embodiments comprising:

(i) providing a solution of paliperidone in a solvent;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally, maintaining the solution at low temperatures; and
(iv) isolating the formed solid and drying to obtain polymorphic Form D of paliperidone.

In embodiments, step (i) can comprise heating a mixture of paliperidone and a solvent up to the reflux temperature, to prepare a clear solution. Typically, the heating is done until complete dissolution occurs. The hot mass can be filtered to obtain a clear solution of paliperidone in a solvent. The solvents that may be used for this step include, but are not limited to, toluene, acetone, acetonitrile, dimethyl carbonate, methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 1-pentanol, isoamyl alcohol, ethyl acetate, butyl acetate, dichloromethane, dichloroethane, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, dimethylacetamide, formamide, ethoxyethanol, ethylene glycol, propylene glycol, dimethoxyethane. Preferably, the solvent is toluene. The solution can be maintained at about 30°C to the reflux temperature for about 10 minutes to 1 hour, or longer. For example, the solution is maintained at 80°C for 15 minutes with toluene as a solvent.

In embodiments, step (ii) can comprise adding a solution of paliperidone at a temperature of about 10°C to the reflux temperature, to the anti-solvent which has previously been chilled to about 0°C to 20°C. The anti-solvents that may be used for this step include, but are not limited to, water, hexane, heptane, diethyl ether, diisopropyl ether, methyl ethyl ketone, cyclohexane, methyl tert-butyl ether. Preferably, the anti-solvent is cyclohexane. For example, a solution of paliperidone in toluene is cooled to room temperature and is then added to cyclohexane. In embodiments, room temperature can be 30+5° C. In embodiments, cyclohexane is chilled to about 10°C before adding a solution of paliperidone in toluene. Alternatively, anti-solvent can be added to a solution of paliperidone.

In embodiments, step (iii) comprises maintaining the solution at about 0°C to 20°C for about 10 minutes to 4 hours or longer. For example, the solution is maintained at about 10°C for about 10 minutes.

In embodiments, step (iv) comprises isolating the formed solid using any isolation techniques known in the art such as decantation, filtration, centrifugation, and vacuum filtration.

Drying can be carried out at suitable temperatures for suitable times, using any techniques known in the art, such as suction drying, vacuum drying, tray drying, and fluidized bed drying. For example, drying is carried out in a suction dryer for about 5 minutes, followed by further drying in a vacuum tray dryer at about 70°C for about 4 hours.

The starting material i.e. paliperidone used for the present invention can be made by any of the processes known in the art

The starting material i.e. paliperidone used in the present invention may be purified before its use. The end products of the present invention i.e. paliperidone may be purified before its use.

Purification of paliperidone may be carried out by crystallization in a suitable solvent. The solvents that may be utilized for this step include, but are not limited to, alcohols such as methanol, ethanol, isopropyl alcohol and n-propanol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride; ketones such as acetone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate and t-butyl acetate; ethers such as tetrahydrofuran and 1,4-dioxane; aromatic solvents, e.g., toluene, xylene, chlorobenzene, and methoxybenzene; nitriles such as acetonitrile and propionitrile; dimethylsulfoxide; N,N-dimethylformamide; N,N-dimethylacetamide; pyridine; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone; 1,3-dimethyl-2-imidazolidinone; 1,1,3,3-tetramethylurea; 1-methyl-2-pyrrolidinone; nitrobenzene; and mixtures thereof. Purification of paliperidone may also be carried out by slurrying in a solvent. The solvents that may be utilized for this purification step are the same as the solvents that are discussed in the earlier purification step. Purification of paliperidone may also be carried out by solvent-anti-solvent technique. The solvents that may be utilized for this purification step are the same as the solvents that are discussed in the earlier purification step. The anti-solvents that may be used for this step include, but are not limited to, hydrocarbon solvents such as n-heptane, cyclohexane and n-hexane, water, and mixtures thereof.

Paliperidone obtained by any of the processes of the present invention is substantially pure. As used herein "substantially pure" refers to chemical purity. Paliperidone of the present application contains less than about 1% of total impurities, or less than about 0.5% of total impurities, or less than about 0.1% of total impurities, by weight.
Paliperidone obtained by any of the processes of the present invention has a particle size distribution where D(0.9) is less than about 250 microns, often less than about 150 microns. A desired particle size distribution may be obtained directly from the process of the present invention or may be obtained by using techniques known to persons skilled in the art, such as milling, grinding, sifting spray-drying.

Paliperidone obtained by a process of the invention can be used to prepare pharmaceutical formulations, including tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations. Pharmaceutical formulations containing paliperidone may be prepared with pharmaceutical excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, lubricants, and others. Various modes of administration of the pharmaceutical compositions of paliperidone of the present invention can be used depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
Certain specific aspects and embodiments of the invention are further explained by the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the spirit of the invention, and the scope of the invention is not to be limited by the examples.

EXAMPLES

Example 1: Paliperidone crystalline Form A.
A slurry of paliperidone (2.5 g) and formamide (186 mL) is heated to reflux until complete dissolution, in a round bottom flask. The hot solution is filtered under vacuum. The clear solution is heated to 90°C and then is added to n-hexane (500 mL) that has been previously chilled in a dry ice bath (-30°C). The mass is maintained at -30°C for 30 minutes. The formed solid is isolated by filtration under vacuum and the wet material is suction dried for 3 hours. The material is finally dried in a vacuum tray dryer (VTD) for 7 hours at 50°C. Product weight: 0.8 g; HPLC purity: 98.98%; TGA wt. loss: 10.29%. The PXRD pattern is as shown in Figure 1, and the TGA curve is as shown in Figure 2.

Example 2: Paliperidone crystalline Form B.
A slurry of paliperidone (1.0 g) and dichloromethane (15 mL) is heated to reflux until complete dissolution, in a round bottom flask. The hot solution is filtered under vacuum. The clear solution is maintained at 35°C for 5 minutes and then is added to methyl ethyl ketone (500 mL) that has been previously chilled in a dry ice bath (-45°C). The mass is maintained at -55°C for 10 minutes. The formed solid is isolated by filtration under vacuum, then is suction dried in a nitrogen atmosphere. Product weight: 0.93 g; HPLC purity: 99.40%; TGA wt. loss: 13.61%. The PXRD pattern is as shown in Figure 3, and the TGA curve is as shown in Figure 4.

Example 3: Paliperidone crystalline Form C.
A slurry of paliperidone (2.0 g) and N,N-dimethylacetamide (60 mL) is stirred at -26°C for 5 hours in a round bottom flask. The solid is filtered using a pressure Nutsche filter (PNF) and is suction dried for 2 hours in a nitrogen atmosphere. Product weight: 1.8 g; HPLC purity: 99.45%; TGA wt. loss: 16.94%. The PXRD pattern is as shown in Figure 5, and the TGA curve is as shown in Figure 6.

Example 4: Paliperidone crystalline Form D.
A slurry of paliperidone (0.5 g) and toluene (80 mL) is heated to reflux until complete dissolution in a round bottom flask. The clear solution is then brought to 30°C and is added to cyclohexane (250 mL) that has previously been chilled to 10-12°C. The mass is maintained at 10-12°C for 10 minutes. The formed solid is isolated by filtration and suction dried for 5 minutes. The wet material is finally dried in a VTD for 4 hours at 70°C. Product weight: 0.28 g; HPLC purity: 99.35%; TGA wt. loss: 0.81%. The PXRD pattern is as shown in Figure 7, and the TGA curve is as shown in Figure 8.

CLAIMS:

1. A process for preparing crystalline Form A of paliperidone, comprising:
(i) providing a solution of paliperidone in formamide;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally maintaining the reaction mass for precipitation .
(iv) isolating the crystalline Form A of paliperidone.

2. A process for preparing crystalline Form B of paliperidone, comprising:
(i) providing a solution of paliperidone in dichloromethane;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally maintaining the reaction mass for precipitation .
(iv) isolating the crystalline Form B of paliperidone.

3. A process for preparing crystalline Form C of paliperidone, comprising:
(i) slurrying Paliperidone in N,N-dimethyl acetamide
(ii) isolating the crystalline Form C of paliperidone.

4. A process for preparing crystalline Form D of paliperidone, comprising:
(i) providing a solution of paliperidone in toluene;
(ii) combining the solution with previously chilled anti-solvent;
(iii) optionally maintaining the reaction mass for precipitation .
(iv) isolating the crystalline Form D of paliperidone.

5. A pharmaceutical composition containing paliperidone obtained by any of claims 1-4 and one or more pharmaceutically acceptable excipients.

6. Crystalline Paliperidone Form A, which has characteristic PXRD peaks at about 5.28, 10.1, 12.6, 15.9, 16.4, 19.0, 19.3, 20.3, 23.1, 24.3, 25.0, 26.5, and 29.6, ± 0.2 degrees 2-theta obtained by the process of claim 1.

7. Crystalline Paliperidone Form B, which has characteristic PXRD peaks at about 5.6, 10.0, 10.8, 11.8, 12.7, 14.1, 16.4, 17.2, 19.2, 20.0, 20.8, 21.9, 25.8, 27.2, and 29.2, ± 0.2 degrees 2-theta obtained by the process of claim 2.

8. Crystalline Paliperidone Form C, which has characteristic PXRD peaks at about 5.6, 9.8, 10.8, 12.0, 12.4, 14.0, 15.9, 16.7, 19.2, 21.0, 22.5, 25.8, ± 0.2 degrees 2-theta obtained by the process of claim 3.

9. Crystalline Paliperidone Form B, which has characteristic PXRD peaks at about 5.3, 9.0, 10.6, 11.5, 14.6, 14.9, 15.6, 17.2, 17.9, 18.6, 19.0, 20.7, 21.4, 23.2, 25.2, 26.4, and 28.1, ± 0.2 degrees 2-theta obtained by the process of claim 4.

10. A pharmaceutical composition containing paliperidone of any of claims 6-9 and one or more pharmaceutically acceptable excipients.