FORM2
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 FINGOLIMOD HYDROCHLORIDE AND PROCESSES FOR PREPARING SAME"
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: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

AN AMORPHOUS FINGOLIMOD HYDROCHLORIDE AND PROCESSES FOR PREPARING SAME
FIELD OF THE INVENTION:
The present invention relate to an amorphous form of fingolimod hydrochloride. The present invention further relates to processes of preparing an amorphous form of fingolimod hydrochloride and pharmaceutical composition thereof.
BACKGROUND OF THE INVENTION:
Fingolimod hydrochloride is chemically 2-amino-2-[2-(4-octylphenyl) ethyl] propan-1, 3-diol hydrochloride and is known from U.S. Patent No. 5,604,229 and is represented by compound of structural formula I.

Fingolimod hydrochloride has been approved in USA and sold in market under the proprietary name GILENYA. It is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.
U.S. Patent No. 5.604,229 describes recrystallization of fingolimod hydrochloride in ethanol and the resulting fingolimod hydrochloride obtained is crystalline in nature.

U.S. Patent Publication No. 2011/0229501 describes various polymorphic forms of fingolimod hydrochloride designated as Form I (at room temperature), Form II (however at a transition temperature of approximately 40°C) and Form III (however at a transition temperature of approximately 66°C. Further, the patent application also mentions that approximately 107°C, fingolimod hydrochloride forms a phase with lower crystalling order.

PCT Publication No. 2011/009634 describes two polymorphic forms of fingolimod hydrochloride designated as Form E (mixture of Form A and Form B), and Form B. The polymorphic Form E is obtained by evaporating solution of fingolimod in mixture of ethanol and water. The polymorphic Form B is obtained by removal of solvent by spray-drying or freeze-drying technique (rapidly dried).

PCT Publication No. 2012/070059 describes three polymorphic forms of fingolimod hydrochloride designated as Form α, Form β and Form µ. The polymorphic Form α is obtained by crystallization fingolimod hydrochloride in acetic acid.. The polymorphic Form β is obtained by crystallization of fingolimod hydrochloride in mixture of DMF and acetone (as co-solvent). The polymorphic Form µ is obtained by melting fingolimod hydrochloride followed by slowly cooling the melt liquid.
The present applicant of the patent has surprisingly founq fingolimod hydrochloride in an amorphous form, which is obtained by melting fingolimod hydrochloride, removal of solvent by spray-drying or freeze-drying technique and method of slow Precipitation.

SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide an amorphous form of fingolimod hydrochloride.
A second aspect of the present invention is to provide processes of preparing an amorphous form of fingolimod hydrochloride.

A third aspect of the present invention is to provide a process of preparing an amorphous form of fingolimod hydrochloride comprising the steps of:
a. providing a solution of crystalline fmgolimod hydrochloride in an organic solvent and
b. isolating an amorphous form of fmgolimod hydrochloride thereof by the removal of the
solvent by spray-drying or freeze-drying technique or Under reduced pressure.
A fourth aspect of the present invention is to provide a process of preparing an amorphous form of fingolimod hydrochloride comprising the steps of:
a. providing a solution of crystalline fingolimod hydrochloride in an organic solvent and
b. isolating an amorphous form of fingolimod hydrochloride thereof by the method of slow
precipitation.
Another aspect of the present invention is to provide a process of preparing an amorphous form of fingolimod hydrochloride comprising the steps of:
a. melting crystalline fingolimod hydrochloride and
b. isolating fingolimod hydrochloride in an amorphous form.
Another aspect of the present invention is to provide a process of preparing amorphous form of fingolimod hydrochloride comprising the steps of:
a. providing a solution of crystalline fingolimod hydrochloride in an organic solvent,
b. flash cooling the solution obtained in step-a to about 10 to - 50ºC to form suspension, and
c. isolating amorphous form of fingolimod hydrochloride,
Another aspect of the present invention is to provide a pharmaceutical composition comprising an amorphous form of fingolimod hydrochloride and pharmaceutical acceptable excipients.
DETAIL DESCRIPTION OF THE INVENTION:
A crystalline fingolimod hydrochloride used for the present invention may be prepared by methods known in the art such as those described in U.S. Patent No. 5.604,229, U.S. Patent

Publication No. 2011/0229501, PCT Publication Nos. 2011/009634 or 2012/070059, which are incorporated herein by reference only.
A solution of crystalline fingolimod hydrochloride in an organic solvent may be prepared by dissolving crystalline fingolimod hydrochloride in an organic solvent at a temperature in the range of 25°C to80°C.
Alternatively, such a solution may be obtained directly from a reaction in which fingolimod hydrochloride is formed.
Examples of an organic solvent may include ketones, alcohols, esters, nitriies, 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.
A solution of crystalline fingolimod hydrochloride in an organic solvent may be flash cooled to quickly decrease the temperature of solution to about 10 to -50°C to get suspension.
The resulting suspension may be stirred for a period of 30 minutes to 6 hours at a temperature to about 10 to -50°C to get amorphous form of fingolimod hydrochloride.
An amorphous form of fingolimod hydrochloride may be isolated by the steps of filtration,. centrifugation, washing, drying or the combinations thereof.
The amorphous form of fingolimod hydrochloride may be optionally further dried under vacuum at a temperature in the range of 40°C to 60°C for a period of 1 hour to 8 hours to obtain amorphous form of fingolimod hydrochloride with desired residual solvent content.
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 fingolimod hydrochloride.
Crystalline fingolimod hydrochloride (10gm) was added isopropanol (30ml) and the resulting reaction mixture was then heated to about 65°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 isopropanol (10ml) and dried under vacuum at 40-45°C for 8 hours to get title compound. Yield: 9.2gm Purity: 99.9% (By HPLC)

Example 2: Preparation of amorphous form of fingolimod hydrochloride.
Crystalline fingolimod hydrochloride (10gm) was added ethanol (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 0°C for 30 minutes. The product thus obtained was filtered and washed with
ethanol (10ml) and dried under vacuum at 40-45°C for 6 hours to get title compound.
Yield: 9.3gm
Purity: 99.9% (By HPLC)

WE CLAIM:
1. A process of preparing amorphous form of fingolimod hydrochloride comprising the
steps of:
a. providing a solution of crystalline fingolimod hydrochloride in an organic solvent,
b. flash cooling the solution obtained in step-a to about 10 to -50°C to form
suspension, and
c. isolating amorphous form of fingolimod hydrochloride.
2. The process according to claim no. 1 wherein, a solution of crystalline fingolimod hydrochloride in an organic solvent is prepared by dissolving crystalline fingolimod hydrochloride in an organic solvent at a temperature in the range of 25°C to 80°C.
3. The process according to claim nos. 1 and 2 wherein, an organic solvent is selected from the group comprising of ketones, alcohols, esters, nitriles, halogenated aliphatic hydrocarbon solvents, ethers or mixtures thereof.
4. The process according to claim no. 3 wherein, ketone solvent is 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 solvent is selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof: The ester
. solvent is 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 solvent is selected from the group comprising of acetonitrile, propionitrile or mixture(s) thereof; The halogenated aliphatic hydrocarbon solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof; The ether solvent is 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.

5. The process according to claim no. ] wherein, a solution of crystalline fingolimod hydrochloride in an organic solvent is flash cooled to quickly decrease the temperature of solution to about 10 to -50°C to get suspension.
6. The process according to claim no. 5, wherein resulting suspension is stirred for a period of 30 minutes to 6 hours at a temperature to about 10 to -50°C to get amorphous form of fingolimod hydrochloride.
7. The process according to claim no. 1 wherein, an amorphous form of fingolimod hydrochloride is isolated by the steps of filtration, centrifugation, washing, drying or the combinations thereof.
8. The process according to claim no. 7 wherein, an amorphous form of fingolimod hydrochloride is optionally further dried under vacuum at a temperature in the range of 40°C to 60°C for a period of 1 hour to 8 hours to obtain amorphous form of fingolimod hydrochloride with desired residual solvent content.