FORM 2
THE PATENTS ACT. 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
Title: Endoxifcn Citmtc Polymorph And Process for Preparing the Same
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2" Floor. Chinubhai Centre. Ashram Road, Ahmedabad 380009 Gujarat. India
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel crystalline polymorph of Endoxifen citrate and process for the preparation thereof.
BACKGROUND OF THE INVENTION
Endoxifen, chemically named N-desmethyl-4-hydroxytamoxifen is an active metabolite of tamoxifen, a drug used in the treatment of breast cancer.

Methods of synthesizing Endoxifen which is the active metabolite of tamoxifen are disclosed in literature. For example. US 2009/0291124A1 discloses a method of preparing Endoxifen starting from 4-hydroxybromobenzene.
WO 2009/120999A2 discloses the following method of preparing Endoxifen:



WO 2008/070463 discloses the following method of preparing Endoxifen.
Bioorganic & Medical Chemistry Letters (2010) disclosed a method of preparing Endoxifen including separating Z-form Endoxifen by RP-HPLC. is disclosed.
WO 2012/050263A1 disclosed a process for the preparation of Endoxifen citrate by treating Endoxifen with anhydrous citric acid in (he presence of water and isolating the solid obtained. This patent application neither disclosed the polymorph of Endoxifen citrate nor provides any characterization data of the compound obtained.
New crystalline polymorph of a drug substance may display different melting point, hygroscopicity, stability, solubility and/or dissolution rate, crystailinity. crystal habits, bioavailability and formulation handling characteristics, which are among the numerous properties that need to be considered in preparing medicament that can be effectively administered. Therefore, the regulatory agencies require a definitive control of polymorphic form of the active component in solid pharmaceutical dosage forms.

The present inventors have also made their efforts to make an amorphous form of Endoxifen citrate. But during the preparation of an amorphous form of Endoxifen citrate certain practical difficulties were encountered, for instance the product is stucked to walls of test tube or during spray drying process product is slucked and causing problems in isolation. So. the inventors of the present invention explored an alternate form which is free from practical difficulties and industrially feasible.
Accordingly, there is an ongoing need to search new polymorphic forms of Endoxifen citrate that have better thermal stability and material (low character. lower water contents, and offer advantages for preparing reproducible pharmaceutical formulations. The new polymorphic form of Endoxifen citrate of the present invention helps fulfill this and other needs.
Therefore, the present invention provides not only novel polymorph of Endoxifen citrate but aiso provides the characterization data for analysis of this form.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel crystalline polymorphic form of Endoxifen citrate.
Another object of the present invention is to provide a novel crystalline polymorphic form of Endoxifen citrate which is characterized by an XRD pattern comprising 2 theta value at about 10.8 degree two-theta ± 0.2.
Another object of the present invention is to provide a novel crystalline polymorphic form of Endoxifen citrate which is characterized by an XRD pattern

comprising 2 theta values at about 5.4, 10.8. 11.7, 13.6. 14.5, 18.3. 19.4 and 21.8 degree two-theta ± 0.2.
Another object of the present invention is to provide a crystalline form of Endoxifen citrate, which is characterized by X-ray powder diffraction pattern (XRPD) as depicted in figure 1.
Another object of the present invention is to provide a crystalline form of Endoxifen citrate, which is characterized by differential scanning calorimetry (DSC) endotherm al about 129.50°C ± 2.
Another object of the present invention is to provide a process for preparation of crystalline form of Endoxifen citrate.
SUMMARY OF THE INVENTION
The present invention provides a novel crystalline polymorphic form of Endoxifen citrate which is characterized by an XRD pattern comprising 2 theta vaiue at about 10.8 degree two-theta ± 0.2.
The novel crystalline polymorph of Endoxifen citrate of the present invention, further characterized by an XRD pattern comprising 2 theta values at about 5.4. 11.7. 13.6, 14.5. 18.3. 19.4 and 21.8 degree two-thela ± 0.2.
Further the present invention discloses a method for preparing the said polymorph of Endoxifen citrate.

BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is X-ray Diffractogram (XRD) of crystalline form of Endoxifen citrate as per the present invention.
Fig, 2 is Differentia! Scanning Caioritnctry (DSC) of crystalline form of Endoxifen citrate as per the present invention.
DETAILED DESCRIPTION
In an embodiment the present invention provides novel polymorphic form of Endoxifen citrate. In a preferred embodiment of the invention polymorphic form is crystalline form.
In another embodiment of the present invention novel crystalline polymorphic form of Endoxifen citrate which is characterized by an XRD pattern comprising 2 theta value at about 10.8 degree two-iheta ± 0.2,
In another embodiment of the present invention novel crystalline polymorph of Endoxifen citrate., further characterized by an XRD pattern comprising 2 theta values at about 5.4. 11.7, 13.6, 14.5, 18.3, 19.4 and 21.8 degree two-theta ± 0.2.
In another embodiment the present invention discloses novel crystalline polymorph of Endoxifen citrate, which is characterized by an XRD pattern comprising 2 theta values at about 5.4, 10.S. 11-7. 13.6. 14.5, 18.3. 19.4 and 21.8 degree two-theta ± 0.2.

The crystalline form of Endoxifen citrate can be characterized by PXRD pattern as set forth in figure 1.
The XRD main peaks with positions and relative intensities have been extracted from the diffractogram in Figure! are given below.

Angle Degree two-theta (±0.2) d value Angstrom Intensity
%
5.4 16.3 73.8
10.8 8.1 100
11.7 7.5 49.4
13.6 6.4 50.3
14.5 6.0 78.5
18.3 4.8 62.2
19.4 4.5 54.4
21.8 4.0 51.4
The crystalline form of Endoxifen citrate can also be characterized by an endotherm at about 129.50°C ± 2 in a DSC. The DSC thermogram of crystalline form of Endoxifen citrate is as set forth in figure 2.
The crystalline form of Endoxifen citrate can also be characterized by IR spectroscopy at about 3523, 3500, 3483. 3332. 3307. 3142. 3022. 2970. 2931, 2872, 2829, 2735. 2669, 2540, 2492. 2378. 2320, 2096, 2083. 2071. 2019. 1953, 1892, 1734, 1710, 1602, 1573, 1506. 1435. 1402. 1367. 1336. 1309. 1261. 1236,

1174, 1130. 1105. 1076. 1055. 1028, 091. 923. 875. 840. 769. 731. 704. 644. 609, 588.563,518, 486 and 426 cm-1.
Another embodiment of the present invention is to provide a process for (he-preparation of novel crystalline form of Endoxifen citrate by the reaction of Endoxifen base with citric acid to give Endoxifen citrate salt. Endoxifen Citrate obtained can be purified / rccrysiallized from a solvent or mixture thereof.

In the above reaction step (a). Endoxifen base used in the preparation of Endoxifen citrate can be E-isomer or Z-isomer or mixture thereof. Preferably, Endoxifen is mixture of E- and Z-isomers of Endoxifen.
Citric acid used in the above step (a) of the reaction may be either anhydrous or hydrous. Preferably citric acid used is anhydrous.
The above reaction step (a) can be carried out at room temperature or higher temperature. After that, the reaction mixture can be cooled to room temperature or

lower temperature followed by filtration of reaction mass to obtain crude solid Endoxifen citrate, which may be further washed with water and meihanol.
Purification / recrystaliizalion of crude Endoxifen citrate step (b) can be carried out in presence of suitable solvent or mixture thereof, wherein solvent is selected from either organic or an inorganic solvent.
Organic solvent includes but not limited to alcoholic solvents, hydrocarbon solvents, ester solvents or ether solvents. Alcoholic solvent includes but not limited to methanol, ethanol, propanol. butanol, isobutanol pentanol or hexanol. In a preferred embodiment of the present invention, alcoholic solvent is methanol.
The purification step (b) can be carried out at room temperature or higher temperature. Activated charcoal can be added for the above step fb) in order to remove any color impurities. The reaction mixture can be filtered and washed with methanol to give pure crystalline form of Endoxifen citrate.
fn another embodiment of the invention novel crystalline polymorph of (he present invention is prepared by reacting the solution of Endoxifen base ((Z)-4-fl-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-]-en-l-yl)phenol) with a solution of anhydrous citric acid to give Endoxifen citrate salt. The Endoxifen citrate obtained is purified with methanol and charcoal. The reaction can be summarized as below:


The above reaction step (a) can be carried out at room temperature or higher temperature. After that, the reaction mixture can be cooled to room lemperature or lower temperature followed by filtration of reaction mass. The obtained Endoxifen citrate solid can be washed with water and methanol to give crude Endoxifen citrate.
Purification / recrystallization of crude Endoxifen citrate step (b) can be carried out in presence of methanol and activated charcoal at room temperature or higher temperature. The reaction mixture can be filtered and washed with methanol to give pure crystalline form of Endoxifen citrate.
Endoxifen base used in the present invention can be prepared by any of the known prior ail process, for example as disclosed in examples of the present invention.
Experimental part:
Identification of solids obtained by the present invention can be made by methods known in the art, such as X-Ray Diffraction. Differential Scanning Calorimetry

(DSC) and Infrared Spectroscopy (IR). It should be understood that operator, instrument and other similar changes may result in some margin of error with respect to analytical characterization of the solid.
The XRD, DSC and IR methods used for the identification and characterization of crystalline form of Endoxifen citrate are described below:
a) XRPD method: Analytical characterization of the compound of present invention was carried out by using X-ray powder diffraction using DS Advance of Bruker AXS make. The details of the same arc given in Table No 1,
Table No 1

Instrument D8 Advance
Make Bruker AXS
Detector -Lynx-eye
b) DSC method: The DSC (Differential Scanning Calorimelry) analysis of the compound of present invention was recorded at a temperature range from 60°C to 160°C. The details of the same are given in Tabic No 2.
Table No 2

Instrument name TA Q200
Scanning range 6n°C-160°C
c) IR method: The IR (Infrared Spectroscopy) analysis of the compound of present invention was recorded by IR Affinity - 1 of Shimadzu (manufacturer).

The following examples arc intended to illustrate the present invention. It should be understood that the invention is not limited to those specific examples. Numerous changes and modifications may be made to the embodiments of the invention without departing from actual scope of the invention,
Example 1: Preparation of Endoxifen
(A) Preparation of 2-(4-bromophenoxy)tctrahydro-2H-pyran
p-bromo phenol (800 gm) and 3.4-dihydro-2H-pyran (1200 gm) were charged in a RBF. The reaction mixture thus obtained was stirred at room temperature followed by cooling. Sulphuric acid (5ml) were added to the reaction mixture and the temperature of the reaction mixture was raised to room temperature. After completion of the reaction, layers separated. Organic layer was distilled off. obtained residue was washed with isopropanol to give 900 gm of title compound.
(B) Preparation of 1-(4-(2-chloroethoxy)phcnyl)-2-phcnyl-l-|4-((tctrahydro-
2H-pyran-2-yl)oxy)phenyl|butan-l-ol
Freshly prepared Mg turning (20 gm) and THF (175 ml) were charged in a RBF. Reaction mixture thus obtained was heated 1o 60-70°C. Iodine crystals and ethyl bromide (1ml) were charged into reaction mixture. 2-(4-bromophenoxy)tetrahydro-2H-pyran (200 gm) was added to the reaction mixture; followed by cooling to room temperature. A solution of l-(4-(2-ch!oroethoxy)phenyl)-2-phenylbutan-l-one was added to the reaction mixture at room temperature. After completion of the reaction the reaction mixture was heated to 60-75°C and again cooled to room temperature. 300 ml of HO solution was added to reaction mixture and raised temperature to room temperature. After

separation of layers, organic layer was washed with water (400 ml), sodium bicarbonate solution and sodium chloride solution to obtain 300 gin of residue of title compound,
(C) Preparation of (E/Z)-4-(l-(4-(2-chloroetho\y)phcnyl)-2-phenylbut-l-cn-l-yl)phcnol
Residue of l-(4-(2-chioroethoxy)phenyl)-2-phenyl-l-[4-((tetrahyciro-2H-pyran-2 yl)oxy)pheny1]butan-1-ol (300 gm) prepared according to above example 13 and methanol (1200 ml) were charged in a RBF. The obtained reaction mixture was cooled to room temperature, followed by addition of cone. HC1 (300 ml). The reaction mixture was heated at 70-80°C and again cooled to room temperature. Water (300 ml) and methylene chloride (900 ml) were charged to reaction mixture. After separation of layers, the organic layer was distilled off to obtain 250 gm of of title compound.
(0) Preparation of Endoxifen base
(E/Z)-4-(l -(4-(2-chlorocthoxy)phenyl)-2-phenylbut-1 -en-1 -yl)phenol (250 gm) prepared according to above example C and methanol (2 L) were charged in a RBF. Mono methyl amine solution (7.5 L) was added to the reaction mass at room temperature. After completion of the reaction the reaction mass was heated to 60-70°C followed by cooling to room temperature. Di isopropyl ether (4 L) was charged into reaction mass. After separation of layers, the organic layer was filtered off !o give residue (200 gm) Ethyl acetate (400 ml) was charged into residue at room temperature. The reaction mass was filtered and (he obtained solid was washed with ethyl acetate (200 ml) to give Endoxifen base (140 gm).

Endoxifen base (140 gin) and ethyl acetate (150 mi) were charged in a RBF. The reaction mass was filtered and washed with ethyl acetate (150 ml) in give residue of Endoxifen base (SO gm).
Endoxifen base residue (SO gm) and isopropyl alcohol (600 ml) were charged in a RBF. n-heptane (1700 ml) was added to the reaction mass at room temperature. The reaction mass was filtered off to obtain 40 gm of Endoxifen base solid.
Example 2: Purification of Endoxifen base
Endoxifen base (40 gm) prepared from example 1 and chlorobenzenc (250 ml) was charged in a RBF. Thus formed reaction mixture was heated to 60-70°C and then cooled to room temperature. The reaction mixture was filtered to obtain 25 gm of pure Endoxifen base.
Example 3: Preparation of Endoxifen citrate from Endoxifen
Citric acid (75 gm) and water (150 ml) were charged in a RBF. The obtained solution was heated at a temperature of 30-o0°C. followed by addition of Endoxifen (25 gm). After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was filtered to obtain 30 gm of Endoxifen citrate solid.
Example 4: Preparation of crystalline form of Endoxifen citrate
Endoxifen citrate (30 gm) prepared from example 3 and methanol (400 ml) were taken in a RBF. The reaction mixture was heated to 60-70°C followed by cooling

to room temperature. The reaction mixture was filtered: solid thus obtained was dried to give 24 gm of title compound.

We claim:
1. A crystalline form of Endoxifen citrate.
2. The crystalline form of Endoxifen citrate as claimed in claim 1, which is characterized by characteristic peaks at about 5.4. 10.8. 11.7. 13.6. 14.5. 18.3, 19.4 and 21.8 degree two-theta ± 0.2.
3. The crystalline form of Endoxifen citrate as claimed in claim 1. which is characterized by X-ray powder diffraction pattern (XRPD) as depicted in figure 1.
4. A crystalline form of Endoxifen citrate, which is characterized by differential scanning calorimetry (DSC) endotherm at about 129.50°C ± 2,

5. The crystalline form of Endoxifen citrate as claimed in claim 4. which is characterized by differential scanning calorimetry (DSC) as depicted in figure 2.
6. A process for preparation of crystal line form of Endoxifen cilrale comprising:

(a) reaction of Endoxifen with citric acid to give Endoxifen citrate: and
(b) purification of Endoxifen citrate with suitable solvent or mixture thereof.

7. The process as claimed in claim 6, wherein solvent is organic solvent or an inorganic solvent.
8. The process as claimed in claim 7. wherein organic solvent is an alcoholic solvent comprising methanol, ethanol, n-propanof isopropanol. butanof isobulanol and pentanol.

9. The process as claimed in claim 6. wherein charcoal is added in the purification of Endoxifen citrate.