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
"AN AMORPHOUS ILOPER1DONE AND PROCESSES FOR PREPARING SAME."
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN AMORPHOUS ILOPERIDONE AND PROCESSES FOR PREPARING SAME
FIELD OF THE INVENTION:
The present invention relate to an amorphous form of iloperidone. The present invention further relate to processes of preparing amorphous form of iloperidone and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Iloperidone is chemically 4'-[3-[4-(6-Fluoro-1, 2-benzisoxazol-3-yl) piperidino] propoxy]-3'-methoxyacetophenone and is known from U.S. Patent No. RE 39, 198 and is represented by compound of structural formula 1.

Formula I
Iloperidone has been approved in USA and sold in market under the proprietary name FANPAT. It is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults.

U.S. Patent No. RE 39, 198 describe crystallization of iloperidone in ethanol and the resulting iloperidone obtained as beige solid.
U.S. patent publication no. 2010/076196 discloses crystalline form of iloperidone which is being prepared by recrystallization of iloperidone in ethanol solvent.
P.C.T publication no. 2011/032404 describe crystallization of iloperidone in ethyl acetate and the resulting product is crystalline in nature.
"Amorphous" refers to any solid substances which (i) lacks order in three dimensions, or (ii) exhibits order in less than three dimensions, order only over short distances (e.g., less than 10 A), or both. Thus, amorphous substances include partially crystalline materials and crystalline mesophases with, e.g. one- or two-dimensional translational order (liquid crystals), orientational disorder (orientationally disordered crystals), or conformational disorder (conformationally disordered crystals). Amorphous solids may be characterized by known techniques, including X-ray powder diffraction (XRPD) crystallography, solid state nuclear magnet resonance (ssNMR) spectroscopy, differential scanning calorirnetry (DSC), or some combination of these techniques. As illustrated, below, amorphous solids give diffuse XRPD patterns, typically comprised of one or two broad peaks (i.e., peaks having base widths of about 5° 28 or greater).
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide an amorphous form of iloperidone.
A second aspect of the present invention is to provide a process for the preparation of iloperidone amorphous form comprising the steps of:
a. providing a solution of crystalline iloperidone in an organic solvent and
b. recovering iloperidone in the amorphous form from the solution thereof by the
removal of the solvent by spray-drying or freeze-drying technique.

Another aspect of the present invention is to provide substantially pure iloperidone amorphous form.
Another aspect of the present invention is to provide substantially pure iloperidone amorphous form obtained by spray-drying or freeze-drying of a solution of crystalline iloperidone in an organic solvent.
Another aspect of the present invention is to provide a process for the preparation of substantially pure iloperidone amorphous form comprising the steps of:
a. melting crystalline iloperidone and
b. recovering iloperidone in the amorphous form.
Another aspect of the present invention is to provide a pharmaceutical composition comprising substantially pure amorphous form of iloperidone.
DETAIL DESCRIPTION OF THE INVENTION:
An amorphous form of iloperidone may be characterized by X-ray diffraction pattern as depicted in Figure 1.
Crystalline iloperidone used for the present invention may be prepared by methods known in the art such as those described in U.S. Patent No. RE 39, 198; U.S. patent publication no. 2010/076196; P.C.T publication no. 2011/032404 which are incorporated herein by reference only.
A solution of crystalline iloperidone in organic solvents may be prepared by dissolving crystalline iloperidone in an organic solvent at a temperature in the range of 25°C to 30°C.
Alternatively, such a solution may be obtained directly from a reaction in which iloperidone is formed.

Examples of organic solvent may include ketones, alcohols, esters, nitriles, halogenated aliphatic hydrocarbon solvents, ethers or mixtures thereof.
The ketone solvents may be selected from the group comprising of 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 solvents may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ester solvents may be selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
The nitrile solvents may be selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvents may be selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The ether solvents may be selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
The solvent may be removed from the solution by a technique which includes, for example, spray drying and freeze drying.

In one aspect, iloperidone 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, iloperidone 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 crystalline iloperidone may be melted at a temperature in the range of 90°C to 120°C.
The iloperidone amorphous form may be recovered by the steps of cooling and milling of melted iloperidone. The milling of melted iloperidone may be carried out in a clay mortar and pestle.
The cooling of melted iloperidone may be carried out up to the temperature in the range
of 20-30°C.

The substantially pure iloperidone amorphous form obtained by the present invention may be additionally dried at a temperature in the range of 40-60°C for 2 hours to 8 hours.
The term 'substantially pure iloperidone amorphous form' refers to iloperidone amorphous form having purity more than 99% as detected by HPLC.
The pharmaceutical composition comprising substantially pure amorphous form of iloperidone and one or more pharmaceutically acceptable carriers, excipients or diluents.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure \ depicts X-ray diffraction pattern of iloperidone amorphous form.
X-Ray Powder Diffraction (XRPD) pattern of the product of Examples 1 to 2 was obtained on D 8 -Advance. Bruker AXE, Germany, diffractometer equipped with Scintillation detector using Copper Ka (λ= 1.5406 A) radiation with scanning range between 2.00-39.98°2e at scanning speed of 2%min.

EXAMLES.
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 substantially pure amorphous form of iloperidone.
Crystalline iloperidone (10 gm) was placed in to an oven at 118°C for 45 minutes. The
melted iloperidone was cooled to 25°C and then it was milled in a clay mortar and pestle
to get title compound.
Yield: 9.8 gm
Purity: 99.94% (By HPLC)
Example 2: Preparation of substantially pure amorphous form of iloperidone.
Crystalline iloperidone (10 gm) was dissolved in methanol (60 ml) at 25-30°C. The clear
solution was subjected to spray drying in a mini spray dryer at an inlet temperature of
60°C and an outlet temperature of 40°C with a feed rate of 15 ml/minute. Iloperidone in
an amorphous form was thus isolated.
Yield: 9.5 gm
Purity: 99.98% (By HPLC)

WE CLAIM:
1. An amorphous form of iloperidone is characterized by X-ray diffraction pattern as depicted in Figure 1.
2. A process for the preparation of iloperidone amorphous form comprising the steps of:
a. providing a solution of crystalline iloperidone in an organic solvent and
b. recovering iloperidone in the amorphous form from the solution thereof by the
removal of the solvent by spray-drying or freeze-drying technique.
3. The process according to claim no. 2 wherein, a solution of crystalline iloperidone in organic solvents is prepared by dissolving crystalline iloperidone in an organic solvent at a temperature in the range of 25°C to 30°C.
4. The process according to claim nos. 2 and 3 wherein, examples of organic solvent is selected from the group comprising of ketones solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyi 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; halogenated aliphatic hydrocarbon solvents such as dichloromethane. dichloroethane, chloroform, carbon tetrachloride 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 or mixture(s) thereof.
5. The process according to claim no.2 wherein, amorphous iloperidone is recovered from the solution by spray drying or by freeze drying.

6. A substantially pure iloperidone amorphous form obtained by spray-drying or freeze-drying of a solution of crystalline iloperidone in an organic solvent.
7. A process for the preparation of substantially pure iloperidone amorphous form comprising the steps of:
a. melting crystalline iloperidone and
b. recovering iloperidone in the amorphous form.
8. The process according to claim no. 7 wherein, crystalline iloperidone is melted at a temperature in the range of 90°C to 120°C.
9. The process according to claim no. 7 wherein, iloperidone amorphous form is recovered by the steps of cooling and milling of melted iloperidone.
10. A pharmaceutical composition comprising substantially pure amorphous form of iloperidone and one or more pharmaceutically acceptable carriers, excipients or diluents.