FORM 2
THE PATENTS ACT 1970 (Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
COMPLETE SPECIFICATION "PROCESS FOR THE PREPARATION OF PALIPERIDONE PALMITATE"
Glenmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered office at
Glenmark House,
HDO - Corporate BIdg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be performed

PRIORITY
[0001] This application claims the benefit to Indian Provisional Application of 2252/MUM/2011 filed on Aug 10, 2011 and 3576/MUM/2011 filed on December 20, 2011, the content of which is incorporated herein by reference. FIELD OF THE INVENTION
[0002] The present invention relates to a novel process for preparation of'paliperidone palmitate. BACKGROUND OF THE INVENTION:
[0003] Paliperidone palmitate is a psychotropic agent belonging to the chemical class of benzisoxazoles. Paliperidone palmitate, which is chemically known as (9RS)-3-(2-(4-(6-fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidin-9-ylhexadecanoate, has the following structure;

[0004] INVEGA SUSTENNA.® is paliperidone palmitate intramuscular ER suspension available in five dose strengths, indicated for treatment of acute and maintenance treatment of schizophrenia in adults.
[0005] United States Patent No. 5,254,556 (US Patent'556) describes a group of benzisoxazole derivatives including paliperidone palmitate, which acts as psychotropic agents. US Patent '556 does not exemplify a process for preparing paliperidone palmitate,

[0006] United States PG Publication No 2009/0209757 (US PGPub 757) discloses a process for preparing paliperidone palmitate by the reaction of paliperidone with a base to form paliperidone alkoxide and the subsequent reaction of the generated paliperidone alkoxide with palmitoyl chloride. The working examples 1 to 4 of US PGPub'757 exemplify a preparation of paliperidone palmitate by reacting paliperidone alkoxide with palmitoyl chloride. However, the examples fail to disclose the purity of the paliperidone palmitate obtained. Other methods disclosed therein involve the use of palmitic acid or palmitic acid anhydride with paliperidone to form the paliperidone palmitate.
[0007] An article in IP.com, which is publication number IPCOM000171313D of June 4, 2008 discloses the reaction of paliperidone with palmitoyl chloride in the presence of sodium hydroxide. The obtained paliperidone palmitate has to be purified by column chromatography.
[0008] The present invention provides a novel process for preparation of paliperidone palmitate, which involves the reaction of paliperidone with palmitic acid or its derivative in the presence of a mixture of an organic base and 'an inorganic base. The present invention provides a process wherein surprisingly only a mixture of organic base and an inorganic base, and neither an organic base or an inorganic base like metal carbonate used singly, advantageously brings the reaction to proceed to completion. The present invention provides a simple process which can be scaled on an industrial level because it does not require chromatographic purification of the product. . Furthermore, the ensuing paliperidone palmitate product is substantially free of other fatty acid esters of paliperidone, like paliperidone myristate, paliperidone pentadecanate, paliperidone stearate, while conforming to ICH grade specification.
[0009] The present invention also provides a novel process for purification of palmitic acid wherein the palmitic acid contains less than 0.2% of other fatty acids.
SUMMARY OF THE INVENTION

[0010] The present invention provides a process for the preparation of paliperidone palmitate comprising reacting paliperidone with palmitic acid or its derivative in the presence of a mixture of an organic base and an inorganic base.
[0011] The present invention provides a process for purifying paliperidone palmitate comprising recrystallizing paliperidone palmitate from acetone.
[0012] The present invention provides a process for the purification of palmitic acid said purification process comprising use of alcoholic solvents.
[0013] The present invention provides a process for the preparation of paliperidone palmitate comprising
a. purifying palmitic acid with an alcoholic solvent;
b. optionally converting the palmitic acid obtained in step a) to a palmitic acid
derivative; and
c. reacting the palmitic acid or its derivative with paliperidone to obtain
paliperidone palmitate.
BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES
[0014] Fig. 1: X-ray powder diffraction pattern of paliperidone palmitate prepared by Example 1. DETAILED DESCRIPTION OF THE INVENTION
[0015] As used herein "any other ester with a fatty acid" refers to any ester of an aliphatic monocarboxylic acid other than palmitic acid, with C4 to C28 carbon atoms.
[0016] The present invention provides a novel process for the preparation of paliperidone palmitate comprising reacting paliperidone with palmitic acid or its derivative in presence of a mixture of an organic base and an inorganic base.

[0017] The palmitic acid derivative is selected from the group consisting of palmitoyl chloride, symmetric or asymmetric palmitic anhydride and ester or amide of palmitic acid.
[0018] The organic base may be selected from the group consisting of triethylamine,
diisopropylethylamine, N,N-dimethylaniline, pyridine derivatives, 1,5-
diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-
butylamine, N-methylmorpholine and alkali metal alkoxides and the like. Preferably pyridine derivatives are used. The pyridine derivative may be a dialkylamino pyridine. More preferably the pyridine derivative is 4-dimethylamino pyridine.
[0019] The inorganic base may be selected from the group consisting of alkali or alkaline metal hydroxides, metal carbonates, metal bicarbonates and metal hydrides. Preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and the like.
[0020] The ratio of organic base to inorganic base may be in the range of about 1: 9 to 9:1.
[0021] In one embodiment the reaction of paliperidone with palmitic acid or its derivative, in presence of a mixture of an organic base and an inorganic base may be carried out in the presence of an organic solvent.
[0022] The organic solvent may be selected from the group consisting of halogenated hydrocarbons like methylene dichloride, ethylene dichloride; nitriles like acetonitrile, propionitrile; alkyl acetates like ethyl acetate, propyl acetate, ketones like acetone propanone and the like. Preferably halogenated hydrocarbon like methylene dichloride is used.
[0023] The reaction of paliperidone with palmitic acid or its derivative may be carried out at room temperature for a period of about 18 to 24 hours.

[0024] In one embodiment the reaction of paliperidone with palmitic acid or its derivative in presence of a mixture of an organic base and an inorganic base may be carried out in an aqueous medium in presence of a phase transfer catalyst.
[0025] The aqueous medium used may be water or water mixed with a water miscible organic solvent.
[0026] The phase transfer catalyst may be selected from the group consisting of quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands and polyethylene glycols and the like
[0027] In one embodiment, the present invention provides a process for the preparation of paliperidone palmitate comprising reacting paliperidone with palmitoyl chloride in the presence of a mixture of an organic base and an inorganic base.
[0028] The reaction of paliperidone with palmitoyl chloride in presence of a mixture of an organic base and an inorganic base may be carried out in the presence of an organic solvent.
[0029] The organic solvent may be selected from the group consisting of halogenated hydrocarbons like methylene dichloride, ethylene dichloride; nitriles like acetonitrile, propionitrile; alkyl acetates like ethyl acetate, propyl acetate, ketones like acetone propanone and the like. Preferably halogenated hydrocarbon like methylene dichloride is used.
[0030] In one embodiment, the present invention provides a process for the preparation of paliperidone palmitate comprising reacting paliperidone with palmitoyl chloride in the presence of a mixture of 4-dimethylamino pyridine and potassium carbonate in methylene dichloride.
[0031] The amount of palmitoyl chloride used is in the range of about 2 to about 4 moles of the amount of paliperidone used.

[0032] The palmitoyl chloride may be added directly to the reaction mixture or may be dissolved in the organic solvent,
[0033] In one embodiment, the palmitoyl chloride in methylene dichloride is added slowly in portions to the reaction mixture containing paliperidone, methylene dichloride potassium carbonate and 4-dimethylamino pyridine. After addition of the first portion of palmitoyl chloride in methylene dichloride, the reaction mixture is stirred at room temperature for about 2 to 3 hours followed by addition of the next portion of palmitoyl chloride in methylene dichloride and stirring for a period of about 10 to 15 hours.
[0034] After completion of the reaction, the product may be isolated from the reaction mixture by standard techniques.
[0035] In one embodiment, the present invention provides a process for purifying paliperidone palmitate comprising recrystallizing paliperidone palmitate from acetone.
[0036] The recrystallization of paliperidone palmitate from acetone may be carried out by dissolving the paliperidone palmitate in acetone and refluxing the reaction mixture. Then, this is followed by cooling with stirring to obtain purified paliperidone palmitate, which can be isolated by filtration. In one embodiment of the present invention, the refluxing may be carried for a period of about 20 minutes to about 2 hours, preferably for 30 minutes followed by cooling at about 45°C to about 50°C for a period of about 10-20 minutes, followed by cooling to about 25 °C to about 30°C for about 1-3 hours preferably about 1.5 hours to obtain purified paliperidone palmitate.
[0037] In one embodiment the present invention provides a process for controlling the particle size of paliperidone palmitate depending on the rate of stirring during cooling of the reaction mixture.

[0038] In one embodiment, when the mixture in the process directly described above, is stirred continuously, paliperidone palmitate with D90 less than about 30 u.m is obtained.
[0039] In one embodiment of the present invention, the paliperidone palmitate has DI0 of about 5 µm, D50 about 12 µm, and D90 about 25 u.m.
[0040] In one embodiment when the mixture in the process directly described above is not stirred D90 more than about 40µrn is obtained.
[0041] In one embodiment, the present invention provides a process for the purification of palmitic acid comprising use of alcohols as solvents.
[0042] Various alcohols may be used for the above process. Preferably C1-C5 alcohols may be used. The C1-C5 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol and the like; preferably methanol.
[0043] The process involves addition of palmitic acid to an alcoholic solvent followed by precipitation of the palmitic acid. Preferably such process includes dissolving the palmitic acid in alcohol at higher temperatures followed by cooling to room temperature to precipitate the purified palmitic acid. The procedures for isolation of palmitic acid are well known to a person of skill in the art which include filtration, or evaporation of the solvent.
[0044] In one embodiment, the present invention provides a process for purification of palmitic acid comprising dissolution of palmitic acid in an alcoholic solvent followed by addition of an antisolvent to precipitate the product. Preferably Cl-C5 alcohols may be used. The C1-C5 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol and the like; preferably methanol.
[0045] In one embodiment, the process involves addition of methanol to palmitic acid. The reaction mixture obtained is heated, preferably at a temperature in the range

of 60 - 70 °C. The heating.may be carried out for a period of about 10 minutes to 1 hour; preferably for 30 minutes. The amount of methanol used may be approximately 2-3 times the amount of palmitic acid used. The reaction mixture obtained may be cooled with stirring for a period of about 1 hour to 2 hours at a temperature in the range of about 25 - 30 °C to precipitate the palmitic acid. The precipitated palmitic acid may be separated from the reaction mixture by filtration or by any other method known in the art. If required the obtained palmitic acid is purified by repeating the above procedure.
[0046] The process of purification of palmitic acid as described above provides palmitic acid containing less than 0.2% of other fatty acids as measured by GC.
[0047] In one embodiment, the present invention provides a process for the preparation of paliperidone palmitate comprising
a. purifying palmitic acid with an alcoholic solvent;
b. optionally converting the palmitic acid obtained in step a) to a palmitic acid
derivative; and
c. reacting the palmitic acid or its derivative with paliperidone to obtain
paliperidone palmitate
[0048] In one embodiment, the present invention provides a process for preparation of paliperidone palmitate comprising purification of palmitic acid by dissolution of palmitic acid in an alcoholic solvent at higher temperatures followed by cooling to room temperature. Preferably C1-C5 alcohols may be used. The C1-C5 alcohol may be selected from the group consisting of methanol, ethanol, propanol, isopropanol and the like; preferably methanol.
[0049] In one embodiment, the present invention involves purification of palmitic acid with an alcoholic solvent optionally followed by converting the palmitic acid so obtained to a palmitic acid derivative. Preferably the palmitic acid derivative may be palmitoyl chloride or palmitic anhydride.

[0050] In one embodiment, the present invention provides a process for preparation of a palmitoyl chloride comprising purification of palmitic acid using alcoholic solvents followed by conversion of the so purified palmitic acid to the palmitoyl chloride.
[0051] In one embodiment, the process involves dissolution of palmitic acid in C1-C5 alcohols, preferably methanol, followed by cooling to room temperature to obtain purified palmitic acid which is converted to palmitoyl chloride.
[0052] In one embodiment, the present invention provides a process for preparation of palmitoyl chloride comprising converting the purified palmitic acid to palmitoyl chloride using chlorinating agents such as phosphorous trichloride, phosphorous pentachloride, thionyl chloride, oxalyl chloride and the like. Preferably the chlorinating agent may be thionyl chloride. The reaction may optionally be carried out in the presence of catalysts such as dimethylformamide.
[0053] In a preferred embodiment, the present invention provides process for preparation of palmitoyl chloride comprising chlorination of the purified palmitic acid with thionyl chloride in DMF. The palmitoyl chloride obtained may be isolated from the mixture by fractionation under reduced pressure.
[0054] The process described above provides palmitoyl chloride containing less than 0.15% of other fatty acid chlorides.
[0055] In one embodiment, the present invention provides a process for the purification of palmitoyl chloride comprising high vacuum distillation of palmitoyl chloride.
[0056] In one embodiment, the present invention provides a process for the preparation of paliperidone palmitate comprising
a. purifying palmitic acid using an alcoholic solvent;
b. converting the palmitic acid obtained in step a) to a palmitoyl chloride;
c. reacting the palmitoyl chloride with paliperidone in the presence of a mixture
of bases to obtain paliperidone palmitate; and

d. recrystallizing paliperidone palmitate.
[0057] In a preferred embodiment, the present invention provides a process for preparation of paliperidone palmitate comprising
a. purifying palmitic acid in methanol;
b. converting the palmitic acid obtained in step a) to a palmitoyl chloride by
treating with thionyl chloride in DMF as solvent;
c. reacting the palmitoyl chloride with paliperidone in the presence of a mixture
of 4-dimethylamino pyridine and potassium carbonate in methylene dichloride
to obtain paliperidone palmitate; and
d. recrystallization of paliperidone palmitate from acetone
[0058] In one embodiment, the present invention provides paliperidone palmitate having less than about 0.15% of paliperidone as measured by high performance liquid chromatography (HPLC). Preferably less than 0.1% , more preferably absent.
[0059] The paliperidone palmitate so prepared contains less than 0.15% of any other ester with a fatty acid as determined by HPLC.
[0060] In one embodiment, the present invention provides paliperidone palmitate having less than about 0.15% of paliperidone myristate as measured by high performance liquid chromatography (HPLC).
[0061] In one embodiment, the present invention provides paliperidone palmitate having less than about 0.10%) of paliperidone pentadecanate as measured by HPLC.
[0062] In one embodiment, the present invention provides paliperidone palmitate having less than about 0.10% paliperidone stearate as measured by HPLC.
[0063] In one embodiment, the present invention provides paliperidone palmitate having bacterial endotoxin not more than 1 EU/mg.

[0064] In one embodiment, the present invention provides characterization of paliperidone palmitate via X-ray powder diffraction pattern, which is substantially in accordance with Figure 1. The X-Ray powder diffraction can be measured by an X-ray powder diffractometer and was performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Kal=1.54060A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded at start angle from 2° to 50° 20, a step size 0.0167° with a time per step of 1000 seconds.
[0065] The present invention provides paliperidone palmitate prepared by the process directly herein described, having purity greater than about 97.5% area, as measured by HPLC.
[0066] The present invention provides paliperidone palmitate prepared by the process directly herein described, having a purity greater than about 98 % area, as measured by HPLC, preferably greater than 99% more preferably about 99.5% area as measured by HPLC.
[0067] The purity by high performance liquid chromatography ("HPLC") was carried out as described below: Reagents, Solvents and Standards:
Water (Milli Q or equivalent) Acetonitrile (HPLC grade) Methanol (HPLC grade) 70% Perchloric acid (GR Grade)
[0068] Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with
quaternary gradient pumps, variable wavelength UV detector attached with data
recorder and integrator software.
Column: Inertsil C8-3, 250 x 4.6mm, 5µ [Part No.: C/N-5020-01901]
Column temperature: 30°C
Mobile Phase:

Mobile Phase A = Buffer
Buffer : Adjust pH of water to 2.2 with diluted Perchloric acid (10% in water). Mobile Phase B = Acetonitrile. Diluent: Methanol Flow Rate: 1.0 mL/minute Detection: UV 280nm Injection Volume: 20 uL [0069] In one embodiment, the present invention provides a process for preparing aseptic crystalline paliperidone palmitate, said process comprising
(a) heating paliperidone palmitate in a solvent system
(b) filtering the solution over a sterile filter into a sterile vessel;

(c) cooling the solution to precipitate paliperidone palmitate; and
(d) isolating the paliperidone palmitate by filtration.
[0064] The solvent system may be selected from the group consisting of alcohols, glycols,
nitriles, ketones, esters, ethers, hydrocarbons, halogenated hydrocarbons and water
or mixtures thereof. [0065] The alcohol may be selected from the group consisting of methanol, ethanol,
propanol, isopropanol, butanol, 2-butanol, isobutanol, pentanol and the like or
mixtures thereof. Preferably high purity grade alcohol may be used. [0066] The glycols may be selected from polyalkylene glycols and mixtures thereof
wherein the polyalkylene glycols have a molecular weight of 200, 400, 800, 900,
1000, 1200, 2000 and 4000, for example polyethylene glycol. [0067] The nitriles may be selected from the group consisting of acetonitrile, propionitrile
and the like [0068] The ketone may be selected from the group consisting of acetone, propanone and
the like. [0069] The esters may be selected from the group consisting of ethylacetate, butyl acetate
and the like. [0070] The ethers may be selected from the group consisting of diethyl ether,
teterhydrofuran, tetrahydropyran and the like.

[0071] The hydrocarbon may be selected from the group consisting of hexane, heptane,
toluene, benzene and the like. [0072] The halogenated hydrocarbon may be selected from the group consisting of
methylene dichloride, ethylene dichloride and the like. [0073] Preferably the solvent system is selected from class 3 solvents as listed in ICH
guidelines like acetone, methyl isobutyl ketone, 2-butanol, ethanol, ethyl acetate,
isopropanol, propanol. [0074] In one embodiment ethanol is used as a solvent. [0075] In one embodiment parenteral grade ethanol is used as a solvent. [0076] In one embodiment a mixture of isopropanol and water is used as solvent. [0077] In one embodiment acetone is used as solvent. [0078] The paliperidone palmitate in solvent system is heated to the refluxing temperature
of solvent to obtain solution of paliperidone palmitate. [0079] The hot solution of paliperidone palmitate in solvent is filtered over a sterile filter
having pore size of 0.22 \i or less and cooled to room temperature or below to
precipitate paliperidone palmitate which is isolated from the solvent by filtration.
The paliperidone palmitate thus obtained is dried in vacuum to obtain aseptic
crystalline paliperidone palmitate. [0080] The aseptic crystalline paliperidone palmitate obtained by the process of the
present invention may be used for formulating an injetable suspension of
paliperidone palmitate. [0081] The following examples are provided to enable one skilled in the art to practice the
invention and are merely illustrative of the invention. The examples should not be
read as limiting the scope of the invention as defined in the features and
advantages.

EXAMPLES
Example 1: Preparation of paliperidone palmitate
70 g of paliperidone was added to 875ml of methylene dichloride at about 25 °C to about 30°C. Potassium carbonate (45.4 g) was added followed by addition of 4-dimethyl amino pyridine (7.0 g). Stir the reaction mixture was stirred for about 30 minutes. Meanwhile 50 g palmitoyl chloride was diluted in 112 ml of methylene dichloride. The above prepared palmitoyl chloride solution was added over a period of about 2 hours and the stirring was continued at about 25°C to about 30°C for about 3 hours. A solution of 19g palmitoyl chloride in 40.0 ml methylene dichloride was added and the stirring was continued at about 25°C to about 30° C for about 1 hour. A solution of 19g palmitoyl chloride in 40.0 ml methylene dichloride was added and the stirring was continued at about 25 to about 30°C for about 12 hours. 10 g of potassium carbonate was added. A solution of 9g palmitoyl chloride in 20.0 ml methylene dichloride was added and the stirring was continued at about 25°C to about 30° C for about 4 hours. The completion of reaction was monitored by HPLC. The reaction mixture was filtered through Hyflo bed and washed with methylene dichloride (100 ml). The clear filtrate was washed with 10% sodium carbonate solution (2 x 600 ml). The organic layer was concentrated. To the residue, acetone was added and heated to reflux to get a clear solution. The clear solution was charcoalised and stirring was continued. The solution was filtered through a Hyflo bed and the Hyflo bed was washed with acetone (200 ml).The filtrate was cooled under stirring. The solid product was filtered and washed with acetone and dried in a tray drier. Acetone was added to 63 g of the solid obtained. The reaction mixture was heated at a temperature of about 55°C to about 60° C for about 30 minutes to get a clear solution. The solution was cooled with stirring to about 45°C to about 50° C for about 10 minutes and further cooled to about 25°C to about 30° C for about 90 minutes. The solid obtained was filtered and washed with acetone. The solid obtained was dried to obtain 56g of paliperidone palmitate. Purity by HPLC: 99.5% Impurity Profile

Impurity profile:

s.
No. Name of Impurity Area % by HPLC
1 Paliperidone BDL
2 Paliperidone Myristate 0.13%
3 Paliperidone Pentadecanate 0.06%
4 Palipridone Stearate 0,08%
The bacterial endotoxin limit: not more than 1 EU/mg.
Example 2: Purification of palmitic acid
A 5 lit four necked round bottomed flask containing the mechanical stirrer, reflux condenser, thermo pocket with thermometer was charged with 1000 g of palmitic acid (3.9 mol) and 2000 ml methanol. The suspension was stirred and heated to reflux temperature to complete dissolution by maintaining at 60 to 64 °C for 30 min and then was cooled to 25 to 30 °C. The suspension obtained, was stirred for 1 h and filtered off under suction. The wet solid (1100 g) was recrystallized by dissolving again in 2500 ml of methanol at 60 to 64 °C followed by cooling to 25 to 30 °C. The suspension was stirred for 1 h and filtered off under suction. The wet product was dried for 12 h in air oven at 45 to 50°C. The yield obtained was 50% by weight. Purity: 99.93% area by GC, content of other fatty acids was less than 0.1%.
Example-3: Preparation of Palmitoyl chloride.
A 1 lit four necked round bottomed flask containing the mechanical stirrer, reflux condenser, thermo pocket with thermometer was charged with 200 g of Palmitic acid (0.78 mol), 139.23 g of thionyl chloride (1.17 mol) and 4 ml of DMF. The reaction mixture was stirred and heated to reflux for 2 h. The reaction mass was fractionated under reduced pressure, and main fraction was collected at vapor temperature 160 to 165 °C. The obtained yield was 68% (purity: 99.56% area by GC, other fatty acid chlorides mainly myristoyl chloride and stearoyl chloride were less than 0.1%).
Example 4: Preparation of paliperidone palmitate

Paliperidone palmitate (5.0 g) was dissolved in mixture of isopropyl alcohol (18.0ml) and water (2.0ml) at 80-85°C. The solution was gradually cooled to about 20-25°C in 45.0 min and stirred for 60 min at 20-25°C. The solid was filtered and washed with IPA. The wet product dried at about 50-55°C in air oven. Dry wt: 4.8 g Particle size distribution: d 10: 4.59 urn; d 50: 11.19 fim; d 90: 23.06 ^m
Example 5: Preparation of paliperidone palmitate
Paliperidone palmitate (5.0 g) was dissolved in absolute ethanol (25.0ml) at 78-82°C. The solution was gradually cooled to about 20-25°C in 45.0 min and maintained for 60 min at about 20-25°C under stirring. The solid product was filtered and washed with absolute ethanol (10.0 ml). The wet product was dried at about 50-55°C in air oven. Dry wt: 4.7 g Particle size distribution: d 10: 4.72 µm; d 50: 1 1.44µm; d 90: 23.39µm
Example 6: Preparation of paliperidone palmitate
24.0 g of Paliperidone palmitate residue obtained from example 1, after methylene dichloride removal was dissolved in commercial ethanol (121.0 ml) at about 78-82°C. The solution was gradually cooled to 25-30°C in 60 min and stirred for 60 min at 20-25°C. The solid product was filtered and washed with commercial ethanol (24.0 ml). The wet product dried at 50-55°in air oven for 8 h. Dry wt: 18.84 g d 10: 5.51 µm; d 50: 12.66 urn; d 90: 25.11 urn

s.
No. Name of Impurity Area % by HPLC
1 Paliperidone BDL
2 Paliperidone Myristate 0.07%
3 Paliperidone Pentadecanate 0.09%
4 Palipridone Stearate 0.06%
Example 7: Preparation of paliperidone palmitate
24.0 g of Paliperidone palmitate residue obtained from example 1, after methylene dichloride removal was dissolved in IPA (96.0 ml) at 80-85°C. The solution was gradually cooled to 25-30°C in 60.0 min and stirred for 60 min at about 20-25°C. The

solid product was filtered nd washed with IPA. The wet product was dried at 50-55°in
air oven for 8 h. Dry wt: 19.06 g
d 10: 6.27 µm;d 50: 14.48 um;d 90: 28.20 urn

s.
No. Name of Impurity Area % by HPLC
1 Paliperidone BDL
2 Paliperidone Myristate 0.07%
3 Paliperidone Pentadecanate 0.09%
4 Palipridone Stearate 0.06%
Example 8: Preparation of paliperidone palmitate
Paliperidone palmitate (10.0 g) was dissolved in acetone (200.0 ml) at 55-60°C. The solution was gradually cooled without stirring at about 25-30°C in 3.0 h and stirred for 15 min at about 25-30°C. The solid product was filtered and washed with acetone (10.0 ml). The wet product was dried at 50-55°C in air oven for 8 h. Dry wt: 8.8 g. Particle size distribution: d 10: 6.65 um; d 50: 17.46 urn; d 90: 40.70 urn
Example 9: Preparation of paliperidone palmitate
Paliperidone palmitate (10.0 g) was dissolved in acetone (350.0 ml) at about 55-60°C. The solution was gradually cooled at about 25-30°C in 1.5 h and stirred for 15 min at about 25-30°C. The solid product was filtered and washed with acetone (10.0 ml). The wet product was dried at about 50-55°C in air oven for 8 h. Dry wt: 8.8 g Particle size distribution: d 10: 5.24 um;d 50: 10.33 µmd 90: 19.04 µm
Comparative Examples
Comparative Example 1
Reaction of paliperidone with palmitoyl chloride using 4-dimethyl amino pyridine
2 g of paliperidone in 20 ml of methylene dichloride were placed into a round bottom flask.0.14g of 4-dimethyl amino pyridine was added and the reaction stirred for about 25°C to about 30° C for about 30 minutes, 1.6 ml of palmitoyl chloride was added and stirred at about room temperature. The reaction as monitored by thin layer

chromatography (TLC). The reaction did not initiate (i.e. no reaction occurred) even after
24 hours, as was evident from the absence of a new spot in TLC.
Comparative Example 2
Reaction of paliperidone with palmitoyl chloride using 4-dimethyl amino pyridine
In a round bottom flask, 20 ml of tetrahydrofuran was added to 2 g of paliperidone.0.14g of 4-dimethyl amino pyridine was added and the reaction stirred for about 25°C to about 30°C for about 30 minutes. 1.6 ml of palmitoyl chloride was added and stirred at about room temperature. The reaction was monitored by TLC. The reaction did not initiate even after 24 hours as was evident from the absence of a new spot in TLC.
Comparative Example 3
Reaction of paliperidone with palmitoyl chloride using potassium carbonate
In a round bottom flask, 20 ml of methylene dichloride was added to 2 g of paliperidone. 1.3 g of 10% potassium carbonate solution was added and the reaction stirred for about 25°C to about 30° C for about 30 minutes. 1.6 ml of palmitoyl chloride was added and stirred at about room temperature. The reaction was monitored by TLC. The reaction did not initiate even after 24 hours as was evident from the absence of a new spot in TLC.
Comparative Example 4
Reaction of paliperidone with palmitoyl chloride using potassium carbonate
In a round bottom flask 62.50 ml of tetrahydrofuran was added to 5 g of paliperidone.3.23 g of potassium carbonate was added and the reaction stirred for about
25 to about 30° C for 30 minutes. 3.94 ml of palmitoyl chloride diluted with 8 ml of
tetrahydrofuran was added and stirred at room temperature. The reaction as monitored by
TLC. The reaction did not initiate even after 24 hours as was evident from absence of
new spot in TLC.

We Claim:
1. A process for the preparation of paliperidone palmitate comprising reacting paliperidone with palmitic acid or its derivative in the presence of a mixture of an organic base and an inorganic base.
2. A process as claimed in claim 1 wherein the palmitic acid derivative is selected from the group consisting of palmitoyl chloride, symmetric or asymmetric palmitic anhydride and ester or amide of palmitic acid.
3. A process as claimed in claim 1 wherein the organic base is selected from the group consisting of tri ethyl amine, diisopropylethylamine, N,N-dimethylaniline, pyridine derivatives, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, N-methylmorpholine and alkali metal alkoxides.
4. A process as claimed in claim 1 wherein the inorganic base is selected from the
group consisting of alkali or alkaline metal hydroxides, metal carbonates, metal
bicarbonates and metal hydrides.
5. A process as claimed in claim 1 wherein the organic base is dialkylamino pyridine and the inorganic base is alkali metal carbonate.
6. A process as claimed in claim 1 comprising reacting paliperidone with palmitoyl chloride in presence of a mixture of dimethylamino pyridine and potassium carbonate.
7. A process as claimed in claim 2 wherein the palmitoyl chloride is purified by high vacuum distillation.
8. A process for the purification of paliperidone palmitate comprising recrystallizing paliperidone palmitate from acetone.

9. A process for the purification of palmitic acid said purification process comprising use of alcoholic solvents.
10. A process for the preparation of paliperidone palmitate comprising
a. purifying palmitic acid with an alcoholic solvent;
b. optionally converting the palmitic acid obtained in step a) to a palmitic acid
derivative; and
c. reacting the palmitic acid or its derivative with paliperidone to obtain
paliperidone palmitate.