INTRODUCTION

Aspects of the present disclosure relate to processes for the preparation of paliperidone palmitate and pharmaceutical compositions comprising paliperidone palmitate.

The drug compound having the adopted name "paliperidone palmitate" can be represented by structural formula (I) and is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives.

Paliperidone palmitate is a racemic mixture of (+)- and (-)-paliperidone palmitate. Paliperidone palmitate is a hexadecanoic acid ester of paliperidone and according to the information on metabolism of paliperidone palmitate available in product prescribing information, paliperidone palmitate is converted to paliperidone when administered.

A chemical name for paliperidone palmitate is (9RS)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-yl hexadecanoate, and it is the active ingredient in a product sold by Janssen, Division of Ortho-McNeil-Janssen Pharmaceuticals, Inc. as Invega® Sustenna® for injection, indicated for the acute and maintenance treatment of schizophrenia in adults.

U.S. Patent No. 5,254,556 discloses paliperidone palmitate, pharmaceutical compositions thereof, and use in the treatment of psychotic diseases. It also discloses several methods for the preparation of paliperidone palmitate. One of the processes for the preparation of paliperidone palmitate involves N-alkylation of a compound of formula (II) with a compound of formula (III), as shown below in Scheme 1.

Scheme 1 U.S. Patent No. 5,254,556 also discloses a process for the preparation paliperidone palmitate, by O-acylation of paliperidone with suitable acylating agents like carboxylic acid, acyl halides, symmetric or mixed anhydrides, or ester, amide, or acyl azides, as shown below in Scheme 2.

Scheme 2

U.S. Patent Nos. 6,077,843 and 6,555,544 describe the preparation of paliperidone palmitate, wherein paliperidone is reacted with hexadecanoic acid in the presence of N,N'-dicyclohexylcarbodiimide and 4-pyrrolidinopyridine, in dichloromethane. Paliperidone palmitate is obtained as crystals with 80.4% yield.

U.S. Patent Application Publication No. 2008/0214808 A1 discloses an aseptic process for the preparation of crystalline paliperidone palmitate substantially free of three impurities with given structures, and having average particle sizes ranging from 20-150 urn.

U.S. Patent Application Publication No. 2009/0209757 A1 discloses a process for the preparation of paliperidone palmitate, a process for purifying palmitic acid, and a process for purifying paliperidone palmitate.

IP.com Journal 2008, 8(11B), 21; IP.com Journal 2008, 8(6B), 5; and IP.com Journal 2008, 8(7A), 27; disclose powder X-ray diffraction (PXRD) patterns of crystalline forms of paliperidone palmitate and processes for their preparation.

Smith et al. disclose the methods for the purification of palmitic acid in ethanol or benzene or purification of palmitic acid through an esterification, followed by saponification, in J. Chem. Soc. 1931, 802 and J. Chem. Soc. 1939, 615.

A need remains for short, industrially scalable, cost-effective, and environmentally-friendly processes for the preparation of paliperidone palmitate having a having a stable polymorphic form and a chemical purity suitable for use in the preparation of pharmaceutical compositions. There is a need for methods of purifying palmitic acid. There is also a need for the methods of purifying paliperidone palmitate.

SUMMARY

In an aspect, this disclosure provides processes for purifying palmitic acid, embodiments comprising:
(i) providing a solution of palmitic acid in a solvent;
(ii) optionally, filtering the solution obtained in step (i); and
(iii) isolating a precipitated palmitic acid.

In an aspect, this disclosure provides processes for preparing paliperidone palmitate, embodiments comprising:
(i) reacting paliperidone with palmitic acid, palmitic anhydride, or palmitoyl
chloride in a solvent, optionally in the presence of a dehydrating agent and/or a base;
(ii) isolating a precipitated paliperidone palmitate; and
(iii) optionally, purifying paliperidone palmitate obtained in (iii).

In an aspect, this disclosure provides processes for purifying paliperidone palmitate, embodiments comprising:
(i) providing a solution of paliperidone palmitate in a solvent;
(ii) optionally, filtering the solution obtained in (i); and
(iii) isolating a precipitated paliperidone palmitate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts a PXRD pattern of paliperidone palmitate obtained by the
procedure of Example 7.

Fig. 2 depicts a differential scanning calorimetry (DSC) curve of paliperidone
palmitate obtained by the procedure of Example 7.

DETAILED DESCRIPTION

In an aspect, this disclosure provides processes for purifying palmitic acid, embodiments comprising:
(i) providing a solution of palmitic acid in a solvent;
(ii) optionally, filtering the solution obtained in (i); and
(iii) isolating a precipitated palmitic acid.

In embodiments of step (i), palmitic acid can be dissolved in any suitable inert solvent. Suitable inert solvent can be any solvent which has no adverse effect on the reaction and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to, saturated or unsaturated, linear or branched, cyclic or acyclic, halogentated or non-halogenated C1 to C8 hydrocarbons, C6 to C12 halogentated or non-halogenated aromatic hydrocarbons, C3 to C7 ketones, C2 to C6 esters, C2 to C6 nitriles, C2 to C6 ethers, C1 to C6 alcohols, aprotic polar solvents, and any of their combinations in various proportions. In embodiments, xylene or p-chlorotoluene is used as a solvent.

In embodiments of step (i), to dissolve palmitic acid in any suitable inert solvent, the temperature of the mass can be increased from room temperature to reflux temperature of the solvent used. The term "room temperature" refers to a temperature of about 20°C to about 35°C. Generally, complete dissolution is obtained at or below the reflux temperature of the solvent.

In embodiments of step (ii), any unwanted solid particles can optionally be removed from the solution using any suitable technique, such as decantation, centrifugation, filtration, etc.

In embodiments of step (iii), palmitic acid can be isolated from the mass by using techniques such as decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing the solid with a solvent. In embodiments, the solution of palmitic acid is cooled to facilitate crystallization of palmitic acid. For example, the solution may be cooled to room temperature or below. Maintaining the solution at reduced temperatures for length of time sufficient to obtain crystalline palmitic acid in a desired yield may be for about 1 hour to about 24 hours, or longer.

In embodiments of step (iii), palmitic acid may be further re-crystallized, as described above, in order to remove impurities or further enhance the purity of the Palmitic acid. Any of the solvents listed for step (i) can be used for the purification of palmitic acid.

In embodiments of step (iii), palmitic acid that is isolated can be dried at suitable temperatures, such as about 30-45°C and suitable pressures, using drying equipment known in the art, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Any drying temperatures and times sufficient to achieve desired product purity can be used.

In embodiments of step (iii), palmitic acid obtained has less than about 0.1% by GC of any other ester with a fatty acid, and the total impurity content is less than about 0.5% by GC. In embodiments, palmitic acid obtained has less than about 0.05% by GC of any other ester with a fatty acid, and the total impurity content is less than about 0.1% by GC. The term "any other ester with a fatty acid" refers to any ester of an aliphatic carboxilic acid, other than palmitic acid, having a C4 to C28 carbon atom chain.

In an aspect, the disclosure provides processes for preparing paliperidone palmitate, embodiments comprising:
(i) reacting paliperidone with palmitic acid, palmitic anhydride, or palmitoyl chloride in a solvent, optionally in the presence of a dehydrating agent and/or a base;
(ii) isolating a precipitated paliperidone palmitate; and
(iii) optionally, purifying paliperidone palmitate obtained in (iii).

In embodiments of step (i), paliperidone which is used as the starting material for the preparation of paliperidone palmitate can be prepared by any method known in the art and, optionally, can be purified by any method to improve its purity.

In embodiments of step (i), the reaction can be carried out in any suitable inert solvent. Suitable inert solvent can be any solvent which has no adverse effect on the reaction and it can dissolve the starting material to some extent. Examples of such solvents include, but are not limited to, saturated or unsaturated, linear or branched, cyclic or acyclic, halogentated or non-halogenated C1 to C8 hydrocarbons, C6 to C12 halogentated or non-halogenated aromatic hydrocarbons, C3 to C7 ketones, C2 to C6 esters, C2 to C6 nitriles, C2 to C6 ethers, C1 to C6 alcohols, aprotic polar solvents, and any of their combinations in various proportions. In embodiments, dichloromethane is used as a solvent.

In embodiments of step (i), the organic solvent can be the same as that of the process for preparing paliperidone.

In embodiments of step (i), paliperidone can be reacted with palmitic acid, palmitic anhydride, or palmitoyl chloride wherein any of the reactants can be used in amounts about 0.5 to about 3 moles, per mole of paliperidone. The reactants can be added in a single lot or in multiple portions to a mass containing paliperidone, or vice versa. In embodiments, about 1.5 moles of palmitic acid is reacted with 1 mole of paliperidone.

In embodiments of step (i), the reaction can be carried out in the presence of a dehydrating agent. Suitable dehydrating agents include N,N'-dicyclohexylcarbodiimide, 1 -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-chloro-1 -methyl-pyridinum iodide, phosphorous pentoxide, 1,1'-carbonylbis[1H-imidazole], 1,1'-sulfonylbis[1H-imidazole], and similar reagents. In embodiments, about 1.0 to about 2.0 moles of a dehydrating agent can be used, per mole of paliperidone. In embodiments, about 1.5 moles of N,N'-dicyclohexylcarbodiimide is used, per mole of paliperidone.

In embodiments of step (i), the reaction can be carried out in the presence of a base. Suitable bases include inorganic bases and organic bases. Examples of bases that are useful in the reaction include, but are not limited to: hydrides, hydroxides, carbonates, bicarbonates, oxides, carboxylates, and alkoxides of alkali or alkaline earth metals, such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and primary, secondary, and tertiary amines, such as ammonia, triethylamine, diisopropylamine, N,N-diethyl-ethanamine, 4-ethylmorpholine, pyridine, 4-pyrrolidinopyridine, and 4-dimethylaminopyridine. In embodiments, about 0.1 to about 1.0 moles of a base can be used, per mole of paliperidone. In embodiments, about 0.3-0.4 moles of 4-dimethylaminopyridine is used, per mole of paliperidone.

In embodiments of step (i), the reaction can be carried out at room temperature, up to the reflux temperature of the solvent used. The term "room temperature" refers to a temperature of about 20°C to about 35°C.

In embodiments of step (i), the reaction mixture may require about 30 minutes to about 30 hours, or longer. In embodiments, it requires about 3 hours, or longer.

In embodiments of step (i), any unwanted solid particles may be removed from the solution by any suitable technique such as filtration optionally followed by washing the solid, such as with a solvent discussed above in which step (i) is carried out.

In embodiments of step (ii), recovery may comprise adding water to the reaction mass in an organic solvent, to form a two-phase system. Some of the impurities or unwanted salts formed during the reaction are extracted in the water layer. After the separation of aqueous and organic phases, paliperidone palmitate is isolated from the organic phase using any method, for example, distillation, distillation under vacuum, evaporating the organic phase to dryness, spray drying, or lyophilization. The reaction mass obtained can be brought to room temperature, if desired.

In embodiments of step (ii), a solvent can be charged into the reaction mass obtained. Any of the solvents discussed above in which step (i) is carried out can be used. The reaction mass may be maintained for any suitable time and can also be cooled to lower temperatures, such as from room temperature to about -20°C, to facilitate crystallization of paliperidone palmitate. In a specific embodiment, isopropanol is charged to the reaction mass at room temperature and maintained at this temperature for 2 hours, or longer.

In embodiments of step (ii), paliperidone palmitate may be isolated from the reaction mass using techniques such as decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing the solid with a solvent.

In embodiments of step (iii), paliperidone palmitate may be further re-crystallized or slurried in a solvent, in order to remove impurities. Any of the solvents listed in step (i) can be used for the purification of paliperidone palmitate.

In embodiments of steps (ii) and (iii), paliperidone palmitate that is isolated can be dried at suitable temperatures, such as about 50-100°C and suitable pressures, using any drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity. In embodiments, paliperidone palmitate is dried in an oven at 70°C for 4 hours, under vacuum.

In an aspect, the disclosure provides processes for purifying paliperidone palmitate, embodiments comprising:
(i) providing a solution of paliperidone palmitate in a solvent;
(ii) optionally, filtering the solution obtained in (i); and
(iii) isolating a precipitated paliperidone palmitate.

In embodiments of step (i), a solution of paliperidone palmitate can be prepared in any suitable inert solvent. Suitable inert solvents can be any solvents that has no adverse effect on the compound and can dissolve the starting material to a useful extent.

Examples of such solvents include, but are not limited to, saturated or unsaturated, linear or branched, cyclic or acyclic, halogentated or non-halogenated C1 to C8 hydrocarbons, C6 to C12 halogentated or non-halogenated aromatic hydrocarbons, C3 to C7 ketones, C2 to C6 esters, C2 to C6 nitriles, C2 to C6 ethers, C1 to C6 alcohols, aprotic polar solvents, and any of their combinations in various proportions. In embodiments, isopropanol is used as a solvent.

In embodiments of step (i), to dissolve paliperidone palmitate in a suitable inert solvent, the temperature of the reaction mass can be increased from room temperature up to the reflux temperature of the solvent used. The term "room temperature" refers to temperatures about 20°C to about 35°C. Generally, complete dissolution is obtained at or below the reflux temperature of the solvent.

In embodiments of step (i), carbon may be charged into the solution and then removed after some time. The use of carbon improves the colour, odour, and purity of the desired product.

In embodiments of step (ii), any unwanted solid particles may be removed from the solution using any suitable technique such as decantation, filtration, or centrifugation. If carbon is used in step (i) then the mass is typically filtered, such as through a bed of solid material like Hyflow (flux-calcined diatomaceous earth). The bed is optionally washed with the solvent used in step (i). For example, carbon can be added to the solution and the mass is filtered through Hyflow, followed by washing the Hyflow bed with isopropanol.

In embodiments of step (iii), seed crystals of paliperidone palmitate in any desired polymorphic form can be optionally added to the solution.

In embodiments of step (iii), the reaction mass may be maintained for any suitable time and can also be cooled to lower temperatures, such as from room temperature to about -20°C, to faciHtate crystallization of paliperidone palmitate. In a specific embodiment, the reaction mass is maintained at room temperature for 2 hours, or longer.

In embodiments of step (iii), paliperidone palmitate can be isolated using techniques such as decantation, filtration by gravity or suction, centrifugation, evaporation of solvent, and the like, and optionally washing the resulting solid with a solvent.

In embodiments of step (iii), paliperidone palmitate that is isolated can be dried at suitable temperatures, such as about 50-100°C, and suitable pressures, for about 1-15 hours, or longer, using any drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like. Drying temperatures and times will be sufficient to achieve desired product purity. In specific embodiments, paliperidone palmitate is dried in an oven at 70°C for 4 hours, under vacuum.

In embodiments of step (iii), isolated paliperidone palmitate can be in a crystalline, amorphous, anhydrous, hydrated, or solvated form. The said forms can be prepared by the processes for the preparation of paliperidone palmitate described in the present invention or by the processes known in the art.

In embodiments of step (Hi), isolated paliperidone palmitate has a crystalline polymorphic form having a PXRD pattern, using copper Ka radiation, with peaks located at about 5.1, 7.7, 9.0, 12.8, 15.4, 16.2, 17.7, 19.3, 20.6, 21.6, 23.4, 24.0, and 25.4, ± 0.2° 2-theta.

In embodiments of step (iii), isolated paliperidone palmitate has a DSC curve with an endothermic peak at about 117°C.

In embodiments of step (iii), the product obtained can be purified further by any methods, such as recrystallization, reprecipitation, or chromatography, to improve its chemical purity. Paliperidone palmitate can also be purified by different processes, such as crystallization from a solvent, slurrying in a solvent, or solvent-anti-solvent precipitation techniques, with different solvents under varying conditions of paliperidone palmitate-to-solvent ratios, heating temperatures, heating rates, maintenance times, cooling temperatures, cooling rates, and drying conditions or techniques. Any of the solvents listed in step (i) can be used for the purification of paliperidone palmitate.

Powder X-ray diffraction patterns described herein were generated using a Bruker AXS D8 Advance powder X-ray diffractometer, with a copper K-alpha radiation source.

Generally, a diffraction angle (2G) in powder X-ray diffractometry may have an error in the range of ±0.2°. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±0.2°. Accordingly, the present disclosure includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±0.2°. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (29 ± 0.2°) of 7.9°" means "having a diffraction peak at a diffraction angle (29) of 7.7° to 8.1°.

Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary somewhat, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument 7variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by plus or minus about 0.2.degrees. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not), and sample preparation techniques.

Differential scanning calorimetric (DSC) analyses reported herein were carried out using a DSC Q1000 model from TA Instruments with a ramp of 10°C/minute from 20°C up to 200°C. DSC peak assignments can vary by about ±1°C.

A specific process for the preparation of paliperidone palmitate by a method of present disclosure can be illustrated as shown below in Scheme 3.

Paliperidone palmitate F Paliperidone palmitate F
Scheme 3 Possible impurities in paliperidone palmitate, in addition to unreacted starting materials (paliperidone and palmitic acid) described in the present application, can have structural formulas as illustrated below.

Chloro compound

Fluoro compound

Keto compound

Paliperidone N-oxide

Paliperidone car

Paliperidone oxazole impurity

Chloro palmitate compound

Paliperidone palmitate N-oxide

Paliperidone palmitate car

Paliperidone palmitate oxazole impurity

Myristic acid, pentadecanoic acid, heptadecanoic acid, and stearic acid are potential impurities in palmitic acid, thus these four compounds and isopropyl palmitate are also possible impurities in paliperidone palmitate. These four compounds can react with paliperidone, chloro compound, paliperidone N-oxide, paliperidone car, and paliperidone oxazole impurities to produce about twenty ester compounds, which are also possible impurities in paliperidone palmitate.

Fluoro compound can also have isomeric impurities wherein the fluoro group is attached to other vacant positions in the benzene ring. These isomeric impurities of fluoro compound are also possible impurities in paliperidone palmitate as well as the impurities described above.

European Pharmacopoeia 5.0 discloses nine possible impurities, including paliperidone, in risperidone. The related impurities with 9-hydroxy group are possible impurities in paliperidone which is chemically 9-hydroxy-risperidone. If the said impurities are present in paliperidone, then they may react with palmitic acid or related fatty acids to produce further impurities which are possible in paliperidone palmitate.

In embodiments, paliperidone palmitate obtained and purified by a method of the present disclosure has less than about 0.1% by HPLC of any of the impurities mentioned above, and a total impurities content less than about 0.5% by HPLC. In embodiments, paliperidone palmitate obtained has less than about 0.05% by HPLC of any of the impurities mentioned above, and a total impurities content less than about 0.25% by HPLC. In embodiments, paliperidone palmitate obtained has less than about

0.02% by HPLC of any of the impurities mentioned above, and a total impurities content less than about 0.15% by HPLC.

Paliperidone palmitate and its impurities can be analyzed using high performance liquid chromatography (HPLC), such as with a liquid chromatograph equipped with variable wavelength UV detector and the parameters described below:
The preparation of mobile phase A is important, as the related compounds will be isolated and identified in the HPLC method at pH values above about 4.5, such as at pH 6.5.

Palmitic acid and its impurities can be analyzed using gas chromatography (GC), the instrument equipped with FID, integrator, and auto sampler, and using the parameters described below:
Paliperidone palmitate obtained according to a process of the present disclosure can be milled or micronized using any processes known in the art, such as ball milling, jet milling, wet milling, etc., to produce a desired particle size distribution. Paliperidone palmitate obtained according to certain processes of the present disclosure has a particle size distribution wherein: d(0.5) is less than about 150 um, or less than about 100 um, or less than about 25 um; and d(0.9) is less than about 200 um, or less than about 100 um, or less than about 50 um. Particle size distributions can be determined using any means, including laser light diffraction equipment (such as those sold by Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom), Coulter counters, microscopic procedures, etc. The term d(x) in a distribution means that a particular fraction has particles with a maximum size being the value given, 0.5 representing 50% of the particles and 0.9 representing 90% of the particles.

Paliperidone palmitate obtained according to certain processes of the present disclosure has a surface area of less than 5 m2/g or about 0.2 m2/g to about 5 m2/g as measured by B.E.T. (Brunauer-Emmett-Teller), preferably from about 0.2 m2/g to about 3 m2/g.

An aspect of the present disclosure provides pharmaceutical compositions containing a therapeutically effective amount of paliperidone palmitate, together with one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions comprising paliperidone palmitate of the disclosure, together with one or more pharmaceutically acceptable excipients, may be formulated as: 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, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze-dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate-controlling substances to form matrix or reservoir systems, or combinations of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated.

Pharmaceutically acceptable excipients that are useful in the present disclosure include, but are not limited to, any one or more of: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starches, and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film-formers, plasticizers, colourants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.

Certain specific aspects and embodiments of the present disclosure will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES Example 1: Purification of palmitic acid.

Xylene (250 ml_) and palmitic acid (100 g) are charged into a round bottom flask at 28°C. The mass is stirred for 30 minutes at 35°C to obtain a clear solution. The solution is cooled to 28°C and stirred for 3 hours at 28°C. The formed solid is filtered, washed with xylene (15 mL), and dried at 40°C for 3 hours. Yield: 55 g. Purity by GC: 99.4%.

Example 2: Purification of palmitic acid.
Xylene (137.5 mL) and palmitic acid (55 g) are charged into a round bottom flask at 28°C. The mass is stirred and heated to 45°C to obtain a clear solution. The solution is cooled to 28°C and stirred for 2 hours at 28°C. The formed solid is filtered, washed with xylene (10 mL), and dried at 40°C for 4 hours. Yield: 31.6 g. Purity by GC: 99.6%.

Example 3: Purification of palmitic acid.
p-Chlorotoluene (60 mL) and palmitic acid (20 g) are charged into a round bottom flask at 29°C. The mass is stirred and heated to 60°C to obtain a clear solution. The solution is cooled to 29°C over 1 hour, 45 minutes and then stirred for 2 hours at 29°C. The formed solid is filtered, washed with p-chlorotoluene (5 mL), and dried at 41 °C for 2 hours, 30 minutes. Yield: 8.3 g. Purity by GC: 99.37%.

Example 4: Purification of palmitic acid.
p-Chlorotoluene (17.5 mL) and palmitic acid (7 g) are charged into a round bottom flask at 28°C. The mass is stirred and heated to 60°C to obtain a clear solution.
The solution is cooled to 28°C over 45 minutes and stirred for 17 hours at 28°C. The formed solid is filtered, washed with p-chlorotoluene (3 mL), and dried at 40°C for 3 hours, 30 minutes. Yield: 4.2 g. Purity by GC: 99.5%.

Example 5: Purification of palmitic acid.
n-Heptane (2450 mL) and palmitic acid (490 g) are charged into a round bottom flask at 26°C. The mass is stirred and heated to 45°C to obtain a clear solution. The solution is cooled to 26°C over 60 minutes and then stirred for 3 hours at 26°C. The formed solid is filtered under vacuum, washed with n-heptane (225 mL), and dried at 45°C for 3 hours. Yield: 361.6 g. Purity by GC: 99.77%.

Example 6: Preparation of paliperidone palmitate.
Paliperidone (35 g), palmitic acid (31.5 g), dicyclohexylcarbodiimide (25.34 g), 4-dimethylaminopyridine (3.8 g), and methylene chloride (350 mL) are charged into a round bottom flask at 27°C. The mass is stirred for 3 hours at the same temperature. The mass is filtered and the solid is washed with methylene chloride (350 mL). Water (350 mL) is added to the filtrate and the mass is stirred for 15 minutes. The layers are separated. The organic layer is distilled completely at 45°C to obtain a residue. Isopropyl alcohol (875 mL) is added to the residue and the mass is heated to 81 °C. The reaction mass is cooled to 27°C over 30 minutes and maintained for 2 hours at the same temperature. The formed solid is filtered, washed with isopropyl alcohol (105 mL), and dried at 62°C for 3 hours. Yield: 52.0 g. HPLC purity: 99.45%.

Example 7: Purification of paliperidone palmitate.
Isopropyl alcohol (1250 mL) and paliperidone palmitate (50 g) are charged into a round bottom flask at 27°C. The mass is stirred and heated to 81 °C to obtain a homogeneous solution. Carbon (2.5 g) is added at 81 °C and the mass is maintained for 30 minutes at the same temperature. The mass is filtered through a Hyflo (flux-calcined diatomaceous earth treated with sodium carbonate) bed and the bed is washed with hot isopropyl alcohol (100 mL). The filtrate is cooled to 28°C and maintained for 1 hour, 30 minutes at the same temperature. The formed solid is filtered, washed with isopropyl alcohol (100 mL), and dried at 74°C for 4 hours, 30 minutes. Yield: 47.6 g. HPLC purity: 99.77%. Particle size distribution: d(0.1): 3.8 urn, d(0.5): 11.5 um, d(0.9): 29.2 um.

Example 8: Preparation of paliperidone palmitate.
Palmitic acid (4.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.8 g), 4-dimethylaminopyridine (0.5 g), paliperidone (5 g) and methylene chloride (50 mL) are charged into a round bottom flask at 27°C. The mass is stirred for 6 hours at the same temperature. Water (50 mL) is added and the mass is stirred for 15 minutes. The organic and aqueous layers are separated. The aqueous layer is extracted with methylene chloride (50 mL). The combined organic layer is distilled completely at 41 °C to produce a residue. Isopropyl alcohol (125 mL) is added to the residue and distilled to a mass temperature of 82°C. The mass is cooled to 27°C over 30 minutes and maintained for 90 minutes at the same temperature. The formed solid is filtered, washed with isopropyl alcohol (15 mL), and then dried at 74°C for 4 hours. Yield: 6.4 g. HPLC purity: 99.70%.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the disclosure described and claimed herein.

While particular embodiments of the present disclosure have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this disclosure.

WE CLAIM:

1. A process for preparing paliperidone palmitate, comprising:
(i) reacting paliperidone with palmitic acid in methylene chloride in the presence of a dehydrating agent and a base;
(ii) isolating a precipitated paliperidone palmitate; and
(iii) optionally, purifying paliperidone palmitate obtained in (ii).

2. The process according to claim-1, wherein said dehydrating agent selected from N, N'-dicyclohexylcarbodiimide and 1-ethyl-3-(dimethylaminopropyl)-carbodiimide.

3. The process according to claim-1, wherein said base is 4-dimethylaminopyridine.

4. A process for purifying paliperidone palmitate, comprising:
(i) providing a solution of paliperidone palmitate in a solvent;
(ii) optionally, filtering the solution obtained in (i); and
(iii) isolating a precipitated paliperidone palmitate.

5. The process according to claim-4, wherein said solvent is isopropanol.

6. Paliperidone palmitate according to any of the preceding claims, which is in crystalline form having the PXRD pattern as in Figure 1.

7. Paliperidone palmitate according to any of the preceding claims, which is having HPLC purity more than 99.5%.

8. A process for the purifying Palmitic acid comprising:
(i) providing a solution of palmitic acid in a solvent selected from xylene, p- chlorotoluene, n-heptane or mixtures thereof;
(ii) optionally filtering the solution obtained in (i); and
(Hi) isolating precipitated palmitic acid.

9. A process for the preparation of paliperidone palmitate comprising the use of Palmitic acid obtained according to claim 8.

10. A pharmaceutical composition comprising paliperidone palmitate prepared according to any of the preceding claims.