FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"AMORPHOUS FORM OF PALIPERIDONE PALMITATE"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17th Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India, Pin Code: 4007Q5
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AMORPHOUS FORM OF PALIPERIDONE PALMITATE
FILED OF THE INVENTIONS:
The present invention relates to amorphous form of Paliperidone palmitate. The present invention further relates to processes of preparing amorphous form of Paliperidone palmitate and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Paliperidone palmitate is chemically (9RS)-3-[2-[4(6-Fluoro-l,2-benzisoxazol-3-yl)piperidin-l-yl]ethyl]-2-methyl4-oxo-6,7,8,9-tetrahydro-4Hpyrido[l,2-α]pyrimadin-9-yl hexadecanoate and it is belonging to the chemical class of benzisoxazole derivatives and having the following compound of structural formula I:

Paliperidone palmitate is approved in USA as intramuscular extended release suspension and it has been marketed under the name INVEGA® SUSTENNA® by Janssen Pharms. Paliperidone palmitate is an atypical antipsychotic agent and approved in USA for the treatment of schizophrenia,
Paliperidone palmitate compound is known from U.S. Patent No. 5,254,556 wherein crystalline form of Paliperidone palmitate is described.

U.S. Patent No. 6,077,843 described recrystallization of Paliperidone palmitate in isopropanol and resulting Paliperidone palmitate is in crystalline form.
U.S. Patent publication No. 2009/0209757 described purification of Paliperidone palmitate with ethanol solvent wherein resulting Paliperidone palmitate is obtained in crystalline form.
IP.com Journal (2008), 8(1 IB), 21 (IPCOM000172062D) and IP.com Journal (2008), 8(7A), 27 (IPCOM000171313D) described crystalline form 1 of Paliperidone palmitate.
IP. com Journal (2008), 8(6B), 5 (IPCOM000176267D) described crystalline form II of Paliperidone palmitate. The crystalline form II is characterized by data selected from a group consisting of: a powder XRD pattern having peaks at about 3.1, 10.0, 13.4, 15.1, 19.2,20.0, 21.1, 23.1 and 24.3 ±0.2 degrees 2-theta.
The International Center for Diffraction Data provided physical properties of crystalline monoclinic form of Paliperidone palmitate as follows;
Powder X-ray diffraction data; Monoclinic P21/cα- 34.439, b= 10.101, c= 10.913, α= 90.00, β= 94.383, γ=90.00 and V= 3785.3 and density 1,167.
U. S. Patent Publication No. 2008/214808 described double objective of developing an aseptic production process for Paliperidone palmitate compound of formula I while managing its particle size distribution is achieved and provides a process for preparing aseptic crystalline Paliperidone palmitate compound of formula (I) substantially free of compound of formula II, compound of formula III and compound of formula IV, having an average particle size ranging from 20 to 150 μm ccomprising the steps of;
a) heating Paliperidone palmitate and ethanol parenteral grade to 72°C to 78°C;
b) filtering the solution of step a) over a sterile 0.22 μm filter into a sterile crystallization reactor;
c) allowing Paliperidone palmitate to crystallize while cooling; and either
d) filtering off thus obtained crystals; or

e) reheating thus obtained suspension again to 72°C to 78°C;
f) allowing Paliperidone palmitate to crystallize while cooling and
g) filtering off thus obtained crystals.

The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It also affect on its rate of dissolution in aqueous fluid. The rate of dissolution is also a consideration in formulating liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
U.S. Patent No. 6,555,544 described pharmaceutical composition suitable as a depot formulation for administration by intramuscular or subcutaneous injection, comprising a dispersion of particles consisting essentially of a therapeutically effective amount of a crystalline Paliperidone palmitate.
Accordingly there is a need in the art to develop new form of Paliperidone palmitate and process of preparing same.

SUMMARY OF THE INVENTION:
First aspect of the present invention is to provide amorphous form of Paliperidone palmitate.
According to another aspect, the present invention relates to provide process for the preparation of amorphous form of Paliperidone palmitate.
According to another aspect, the present invention relates to provide a process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a. preparing a solution of crystalline form of Paliperidone palmitate in an organic solvent
and
b. recovering Paliperidone palmitate in an amorphous form from the solution thereof by the
removal of the solvent by techniques selected from the group comprising of spray-drying
or freeze-drying.
According to another aspect, the present invention is to provide a process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a) preparing a solution of crystalline form of Paliperidone palmitate in an organic solvent,
b) removing the solvent from the solution obtained in step a) by agitated thin film drying, and
c) recovering Paliperidone palmitate in an amorphous form from the agitated thin film dryer.
According to another aspect, the present invention is to provide a process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a. preparing a solution of crystalline form of Paliperidone palmitate in an organic solvent
and
b. isolating an amorphous form of Paliperidone palmitate thereof by the method of slow
precipitation.

According to another aspect, the present invention is to provide a process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a, preparing a solution of crystalline form of Paliperidone palmitate in an organic solvent,
b, flash cooling the solution obtained in step a) to about 10°C to -50°C and
c, isolating an amorphous form of Paliperidone palmitate.
According to another aspect, the present invention is to provide a process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a, melting crystalline form of Paliperidone palmitate and
b. recovering Paliperidone palmitate in an amorphous form,
According to another aspect, the present invention is to provide amorphous form of Paliperidone palmitate by vacuum drying or milling the Paliperidone palmitate.
Another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous form of Paliperidone palmitate and pharmaceutical acceptable excipients.
Another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous form of Paliperidone palmitate in the form of injectable suspension.
Another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous form of Paliperidone palmitate and injection vehicle.
Another aspect of the present invention is to provide a pharmaceutical composition comprising amorphous form of Paliperidone palmitate and aqueous or non aqueous solvent along with suitable pharmaceutically acceptable excipients.
Another aspect of the present invention is to provide processes of preparing pharmaceutical composition comprising amorphous form of Paliperidone palmitate.

Another aspect of the present invention is to provide a method of treating schizophrenia comprising administering amorphous form of Paliperidone palmitate as a medicament in human being.
DETAIL DESCRIPTION OF THE INVETION:
An amorphous form of Paliperidone palmitate may be characterized by X-ray diffraction pattern as depicted in figure 1.
In another aspect the present invention relates to process for the preparation of amorphous form of Paliperidone palmitate.
A crystalline Paliperidone palmitate used for the present invention may be prepared by methods known in the art such as those described in U.S. Patent No. 5,254,556, 6,077,843 and IP.com Journal (2008), 8(6B), 5 (IPCOM000176267D) which are incorporated herein by reference only.
A solution of crystalline form of Paliperidone palmitate in an organic solvent may be prepared by dissolving crystalline form of Paliperidone palmitate in an organic solvent at a temperature in therange of 25°C to 80°C.
Alternatively, such a solution may be obtained directly from a reaction in which Paliperidone palmitate is formed.
Organic solvent according to the present invention can be selected from the group comprising, but not limited to, ketones, alcohols, esters, nitriles, ethers, hydrocarbons such as halogenated aliphatic hydrocarbon solvents, or the like or mixtures thereof.
The ketone solvent can be selected from the group comprising, but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.

The alcohol solvent can be selected from the group comprising, but not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ester solvent can be selected from the group comprising, but not limited to, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s)
thereof.
The nitrile solvent can be selected from the group comprising, but not limited to, acetonitrile, propionitrile or mixture(s) thereof.
The ether solvent can be selected from the group comprising, but not limited to, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvent can be selected from the group comprising, but not limited to, dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The solvent may be removed from the solution by a technique which includes, for example, spray drying or freeze drying.
In one aspect of the present invention, Paliperidone palmitate amorphous form may be recovered from the solution using a spray drying technique. A Mini-Spray Dryer (Model: Buchi 190, Switzerland) can be used. The Buchi 190 Mini-Spray Dryer operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or inert, gases such as nitrogen, argon and carbon dioxide.
In another aspect, Paliperidone palmitate amorphous form may be recovered from the solution using a freeze drying technique. A freeze dryer (Model; Virtis Genesis SQ Freeze Dryer) can be

used in this technique. The Virtis Genesis SQ Freeze Dryer operates on the principle of lyophilization, i.e., a process of stabilizing initially wet materials (aqueous solution or suspensions) by freezing them, then subliming the ice while simultaneously desorbing some of the bound moisture (primary drying). Following removal of the ice, desorption may be continued (secondary drying). This process may be carried out under vacuum.
The spray drying may be accomplished using a spray dryer which operates on the principle of nozzle spraying in a parallel flow, i.e., the sprayed product and the drying gas flow in the same direction. The drying gas can be air or one or more inert gases such as nitrogen, argon, and carbon dioxide. Moreover, the product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be further or additionally dried in a tray drier, dried under vacuum and/or in a Fluid Bed Dryer
The solution of crystalline form of Paliperidone palmitate may be optionally treated with activated charcoal and the resulting solution is filtered through hyflo bed to get filtrate.
The resulting filtrate is fed into an agitated thin film dryer (ATFD). The solvent is subsequently removed from the solution by agitated thin film drying.
The agitated thin film drying process may be accompanied by heating at a temperature in the range of 30°C to 60°C under reduced pressure.
The feeding rate of the solution may be controlled in such a way to facilitate the thin film formation and the evaporation rate. The rotor and vapor duct can have a sealing system so that the drying can preferably be carried under vacuum. Vacuum operation also facilitates amorphous form of Paliperidone palmitate to be obtained without degradation.
The term "recovering Paliperidone palmitate in an amorphous form" according to the present invention includes unloading, amassing, gathering, scaling and/or piling amorphous form of Paliperidone palmitate.

In another aspect of the present invention a solution of crystalline form of Paliperidone palmitate in an organic solvent may be flash cooled to quickly decrease the temperature of solution to about 10°C to -50°C.
The resulting solution may be stirred for a period of 30 minutes to 6 hours at a temperature in the range of 10°C to -50°C to get an amorphous form of Paliperidone palmitate.
An amorphous form of Paliperidone palmitate may be isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
The amorphous form of Paliperidone palmitate may be optionally further dried under vacuum at a temperature in the range of 55'C to 75°C for a period of 1 hour to 8 hours to obtain an amorphous form of Paliperidone palmitate with desired residual solvent content.
The crystalline form of Paliperidone palmitate may be melted at a temperature in the range of 110°C to l25°C
The Paliperidone palmitate amorphous form may be recovered by the steps of cooling and milling of melted Paliperidone palmitate. The milling of melted Paliperidone palmitate may be carried out in a mortar and pestle.
The amorphous form of Paliperidone palmitate may be substantially pure.
The term "substantially pure" refers to amorphous form of Paliperidone palmitate having purity more than 99% as detected by HPLC.
In another aspect of the present invention relates to a pharmaceutical composition comprising amorphous form of Paliperidone palmitate and pharmaceutical acceptable excipients.

The pharmaceutical composition of the present invention may be in the form of injection.
The pharmaceutical composition of the present invention may be the extended release injectable suspension.
The extended release injectable suspension is administered by the route of intramuscular deltoid or gluteal injection,
The extended release injectable suspension of the present invention contains amorphous form of a therapeutically effective amount of a Paliperidone palmitate.
The extended release injectable suspension contains amorphous form of a therapeutically effective amount of a Paliperidone palmitate suspended in suitable aqueous or non-aqueous solvent.
The aqueous solvent can be selected from the group comprising, but not limited to, water.
The suitable non-aqueous solvent used may be the water-immiscible or water-miscible solvent.
The water-immiscible solvent can be selected from the group comprising, but not limited to, corn oil, cotton seed oil, Peanut oil, sesame oil, castor oil, olive oil, ethyl oleate, isopropyl myristate or methyl acetamide.
The water-miscible solvent can be selected from the group comprising, but not limited to, ethanol, glycerin, polyglycerin, propylene glycol, n-lactamide, n-methylpyrrolidone, polyalkylene glycols, triacetin, dimethyl acetamide or dimethyl sulfoxide.
The pharmaceutical composition of present invention further comprises one or more suitable excipients such as suspending agents, viscosity imparting agent, wetting agents, preservatives, antioxidants, chelating agent, tonicity agents, buffering agents, pH adjuvant and stabilizers.

The examples of suspending agents can be selected from the group comprising, but not limited to, sodium carboxymethyl cellulose or methyl cellulose.
The examples of viscosity imparting agent can be selected from the group comprising, but not limited to, Polyvinylpyrrolidone [PVP].
The examples of wetting agents can be selected from the group comprising, but not limited to, polysorbate 20, polysorbate 80, sorbitan trioleate (span85), glycerin or propylene glycol.
The examples of preservatives can be selected from the group comprising, but not limited to, benzyl alcohol, methyl paraben, Propyl Paraben or thimerosal.
The examples of antioxidants can be selected from the group comprising, but not limited to, ascorbic acid and its ester, butylated hydroxytoluene [BHT] or tocopherols.
The examples of chelating agents can be selected from the group comprising, but not limited to, ethylene diamine tetra acetic acid salt or citric acid monohydrate.
The examples of tonicity agents can be selected from the group comprising, but not limited to, dextrose, glycerine, mannitol, sodium chloride or potassium chloride.
The examples of buffering agents can be selected from the group comprising, but not limited to, disodium hydrogen phosphate anhydrous or sodium dihydrogen phosphate monohydrate.
The examples of pH Adjutant can be selected from the group comprising, but not limited to, sodium hydroxide.
The examples of stabilizers can be selected from the group comprising, but not limited to, maleic acid or maleate Salt.

BRIEF DESCRIPTION OF THE DRAWING:
Figure 1 depicts X-ray diffraction pattern of amorphous form of Paliperidone palmitate
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 5 was obtained on D 8 -Advance, Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Ka (X= 1.5406 A) radiation with scanning range between 2.00-39.98°29 at scanning speedof2°/min.
EXAMPLES:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of amorphous form of Paliperidone palmitate.
Crystalline Paliperidone palmitate (l0gm) was dissolved in acetone (60ml) at 50-55°C. The clear
solution was subjected to spray drying in a mini spray dryer at an inlet temperature of 80°C and
an outlet temperature of 50°C with a feed rate of 15 ml/minute. Paliperidone palmitate in an
amorphous form was thus isolated.
Yield: 9.5 gm
Purity: 99.7% (By HPLC)
Example 2: Preparation of amorphous form of Paliperidone palmitate.
A solution of Paliperidone palmitate (lOOgm) in methanol (1200ml) was fed into ATFD at a
vacuum of 50-100 mm Hg and a jacket temperature of 45-54°C. The obtained solid was dried
under reduced pressure at a temperature of 70°C for 5 hours to get title compound.
Yield: 82gm
Purity: 99.9% (By HPLC)

Example 3: Preparation of amorphous form of Paliperidone palmitate
Crystalline Paliperidone palmitate (l0gm) was added ethanol (40ml) and the resulting reaction
mixture was then heated to about 70°C to get clear solution. The clear solution was immediately
cooled to about 0°C over 10 minutes to get suspension. The resulting suspension was stirred at
0°C for 30 minutes. The product thus obtained was filtered and washed with ethanol (10ml) and
dried under vacuum at 40-45oC for 8 hours to get title compound.
Yield: 9.2gm
Purity; 99.8% (By HPLC)
Example 4: Preparation of amorphous form of Paliperidone palmitate.
Crystalline Paliperidone palmitate (lOgm) was added isopropanol (40ml) and the resulting reaction mixture was then heated to about 60°C to get clear solution. The clear solution was immediately cooled to about 0°C over 10 minutes to get suspension. The resulting suspension was stirred at 0oC for 30 minutes. The product thus obtained was filtered and washed with isopropanol (10ml) and dried under vacuum at 40-45°C for 6 hours to get title compound. Yield: 9.3gm Purity: 99.9% (By HPLC)
Example 5: Preparation of amorphous form of Paliperidone palmitate.
Crystalline Paliperidone palmitate (10 gm) was placed in to an oven at 120°C for 40 minutes.
The melted Paliperidone palmitate was cooled to 25°C and then it was milled in a mortar and
pestle to get title compound.
Yield: 9.8 gm
Purity: 99.8% (By HPLC)

WE CLAIM:
1. A process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a. preparing a solution of crystalline form of Paliperidone palmitate in an organic
solvent and
b. recovering Paliperidone palmitate in an amorphous form from the solution thereof by
the removal of the solvent by technique selected from the group comprising of spray-
drying, freeze-drying or agitated thin film drying.
2. A process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a. preparing a solution of crystalline form of Paliperidone palmitate in an organic
solvent,
b. flash cooling the solution obtained in step a) to about 10°C to -50'C and
c. isolating an amorphous form of Paliperidone palmitate.
3. The processes according to claim nos. 1 or 3, wherein a solution of Paliperidone palmitate in an organic solvent is prepared by dissolving crystalline form of Paliperidone palmitate in an organic solvent at a temperature in the range of 25°C to 80°C.
4. The processes according to claim nos. 1,2 or 3, wherein organic solvent is selected from the group comprising of ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, .dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof; alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof; nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether, and/or halogenated

aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
5. The process according to claim no. 1, wherein agitated thin film drying process is accompanied by heating at a temperature in the range of 30°C to 60°C under reduced pressure,
6. The process according to claim no. 2, wherein resulting solution obtained from step a) was stirred for a period of 30 minutes to 6 hours at a temperature in the range of 10"C to -50°C.
7. A process of preparing amorphous form of Paliperidone palmitate comprising the steps of:
a, melting crystalline form of Paliperidone palmitate and
b. recovering Paliperidone palmitate in an amorphous form.
8. The process according to claim no. 7, wherein crystalline form of Paliperidone palmitate is
melted at a temperature in the range of 11(TC to 125°C.
9. A pharmaceutical composition comprising amorphous form of Paliperidone palmitate and
pharmaceutical acceptable excipients.