FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification [See Sections 10 and rule 13]
Title: O-Desmethylvenlafaxine Succinate Polymorph & Process for Preparing thereof
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd 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 Desvenlafaxine succinate.
BACKGROUND OF THE INVENTION
Desvenlafaxine succinate, also known as O-desmethyl venlafaxine (ODV) succinate is a succinate salt of ODV. ODV is a major metabolite of venlafaxine, and has been shown to inhibit norepinephrine and serotonin uptake. Synthesis of venlafaxine, its derivatives and its various salts have been disclosed in several publications (U.S. Pat. No. 4,535,186, WO 00/76955, U.S. Pat. Nos. 6,197,828, 6,689,912, 6,673,838 and 7,026,508).
U.S. Pat. No. 6,673,838 discloses five polymorphs of ODV succinate (four crystalline polymorphs and one amorphous polymorph) and processes for their preparation. Out of the five disclosed forms, form I and II are crystalline monohydrate, form III is crystalline hydrate (with water content between hemi and monohydrate), form IV is crystalline anhydrous form and an amorphous form.
Several other polymorphs are reported in various prior arts such as WO2009010990 (from A & B), WO2009009665 (Form V and form VI), WO2008017886 (hydrate), WO2009118758 (Form V, VI, VII), WO2009010990, US200818856 (Form F), WO2008110338 (Form V),
New crystalline polymorph of a drug substance may have different physical and chemical properties such as melting point, hygroscopicity, stability, solubility

and/or dissolution rate, crystallinity, crystal habits, bioavailability, chemical reactivity 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.
Accordingly, there is an ongoing need to search new polymorphic forms of ODV succinate that have good thermal stability and material flow character, lower water contents, and offer advantages for preparing reproducible pharmaceutical formulations. The new polymorphic form of ODV succinate of the present invention helps fulfill this and other needs.
OBJECTS OF THE INVENTION
The main object of the present invention is to provide a novel crystalline polymorphic form of O-desmethylvenlafaxine succinate
Another object of the present invention is to provide a process for preparing a novel crystalline polymorphic form of O- desmethylvenlafaxine succinate.
SUMMARY OF THE INVENTION
The present invention provides a crystalline form Z of O-desmethylvenlafaxine succinate, which is characterized by an X-ray diffraction pattern comprising 2 theta values at 20.02, 26.12 and 31.45 ± 0.2 degrees. The crystalline polymorph of O-desmethylvenlafaxine succinate of the present invention is further characterized

by an X-ray diffraction pattern with 2 theta values at 13.27, 15.95 and 20.51 ± 0.2 degrees.
The present invention provides a process for preparing crystalline form Z comprising the steps of
(a) forming a suspension of O-desmethylvenlafaxine and succinic acid, in a mixture of methylene dichloride, water and hexane or cyclohexane
(b) heating the suspension;
(c) cooling the suspension; of step b to obtain crystalline form Z of O-desmethylvenlafaxine
Brief description of the drawing
Figure 1 shows X-ray diffraction pattern corresponding to form Z of O-desmethylvenlafaxine.
DETAILED DESCRIPTION
The crystalline form Z of O-desmethylvenlafaxine succinate of the present invention is characterized by an X-ray diffraction pattern comprising 2 theta values at 20.02, 26.12 and 31.45 ± 0.2 degrees; wherein the peak at 2 theta value 31.45 ± 0.2 degrees is at medium relative intensity.
In one embodiment the crystalline form Z of O- desmethylvenlafaxine succinate has an X-ray diffraction pattern substantially identical to that shown in figure 1. Peak locations and intensities for the X-ray diffraction pattern in figure 1 are provided in table 1 below.

Table 1

Degrees 29 (±29) Relative intensity %
12.15 13.9
13.27 29.2
15.95 55.4
20.02 100
20.45 47.8
26.12 36.8
31.45 30.7
The crystalline polymorph of O-desmethylvenlafaxine succinate, of the present invention is further characterized by an X-ray diffraction pattern with 2 theta values at 13.27, 15.95 and 20.51 • 0.2 degrees. The water content of the form Z can be between 0 to 0.25 mole %.
In another embodiment the crystalline form Z of O-desmethylvenlafaxine succinate of the present invention has water content of about 0.05%-0.25 mole %. The crystalline form Z of O-desmethylvenlafaxine is a stable form and retains its X-ray diffraction characteristics for at least six months.
According to another aspect, the novel crystalline polymorph of the present invention is prepared in a non-polar solvent system comprising of a mixture of methylene dichloride (MDC)-Hexane-water or methylene dichloride-Cyclohexane-water.
In an embodiment the process to prepare crystalline form Z of present application comprises

(a) forming a suspension of O-desmethyl venlafaxine and succinic acid in a mixture of methylene dichloride, water and hexane or cyclohexane.
(b) heating the suspension to 40°C - 80°C;
(c) cooling the suspension 0°C - 35°C; and
(d) filtering the suspension to isolate the O-desmehtyl venlafaxine form Z
The suspension obtained in step a) is heated at or below the reflux temperature of solvent mixture. Preferably the suspension or reaction mixture is heated at a temperature in range of 40°C - 80°C. More preferably the reaction mixture is heated in the range of 35°C - 45°C. The time of heating may vary from 15 minutes to about 5 hours.
Preferably the reaction mixture is cooled to isolate crystalline form Z of O-desmethylvenlafaxine. The reaction mixture may be cooled to ambient temperature to 0°C, and can be maintained at the same till complete separation of the crystals.
The crystals thus obtained may be separated from the solution by filtration, decantation, centrifugation or any other method known in the art. The crystals thus obtained can be dried at atmospheric pressure or under vacuum.
In one embodiment of the pharmaceutical composition, the composition comprises the crystalline form Z described in the present invention and at least one pharmaceutically acceptable excipient. In another embodiment, the pharmaceutical composition is useful for the treatment of depression.
The crystalline form Z of O-desmethylvenlafaxine succinate disclosed in the present invention can be formulated into the conventional dosage forms for

peroral or parenteral administration. Tablets and capsules are preferred formulation. They can be produced by conventional mixing processes and with the use of conventional pharmaceutical excipients. Pharmaceutically acceptable excipients comprises of binders, disintegrants, flavoring agents and the likes thereof.
Relative intensity is defined as the ratio of the peak intensity to that of the most intense peak. According to the present invention, medium relative intensity is defined as the ratio of the peak intensity to that of the most intense peak, wherein the calculated ratio is in the range of about 10 to about 35%.
X-Ray Powder Diffraction (XRPD)
X-ray powder diffraction (XRD) is a well known method for understanding the various crystalline characteristics of a compound. It is a rapid analytical technique primarily used for phase identification of a crystalline material and can provide information on unit cell dimensions.
Method of performing XRPD
Place the substance being examined on the sample holder; pack and smooth its surface with a polished glass microscope slide and record the diffractogram. Compare the XRPD pattern of sample with XRPD pattern of Desvenlafaxine working standard, similarly determined.
Instrument and Settings

Instrument D-8 Advance
Make Bruker AXS
Detector Lynx eye

X-ray parameter:
X-ray tube Copper KαA
Kβ filter Ni
Wavelength 1.5406 A0
Scan parameter:
Scan type Locked coupled
Scan mode Continuous
Scan axis start 29 20
Scan axis stop 29 500
Scan speed 0.5 sec
Scan step size 0.03°
Motorized slits:
Divergence slit 0.3°
Ant scattering slit Fixed
Rotation On (30rpm)
Generator parameter:
Voltage 40 kV
Current 30 mA
EXAMPLES
The above said invention can be illustrated by but not limited to following example(s).
Example 1:
15.0 g O-desmethyl venlafaxine free base and 6.72 g succinic acid were charged in to the mixture of 45 ml methylene dichloride and 135 ml hexane under stirring. 0.2 ml water was added in to the reaction mixture. The temperature of reaction mixture was raised to 42-45 °C and maintained at the same for 3.0 hours. After that, heating was stopped and reaction mixture was allowed to cool to ambient

temperature, filtered the solid and washed with 30 ml of hexane. The solid was dried at 50-55 °C under vacuum.
Yield - 21.5 g; Assay - 99.5 %
Example 2:
500 g O-desmethylvenlafaxine free base and 224.18 g succinic acid were charged in to the mixture of 1500 ml dichloromethane and 4500 ml cyclohexane under stirring. 6.5 ml water was added in to the reaction mixture. The reaction mixture was heated at 42-45 °C for 3.0 hours. After that, heating was stopped and reaction mixture was allowed to cool to ambient temperature, filtered the solid and washed with 1000 ml of cyclohexane. The solid was dried at 50-55 °C under vacuum.
Yield- 950 g; Assay - 100.7 %

We Claim:
1. A crystalline form Z of O-desmethylvenlafaxine succinate characterized by an X-Ray powder diffraction pattern having characteristic peak of medium relative intensity at 31.45 (± 0.2° 29).
2. Crystalline form Z of O-desmethylvenlafaxine succinate according to claim 1, wherein the crystalline form further exhibits an X-Ray powder diffraction pattern having characteristic peaks at 20.02 and 26.12 (± 0.2° 29).
3. Crystalline form Z of O-desmethylvenlafaxine succinate according to claim 1, wherein the crystalline form further exhibits an X-Ray powder diffraction pattern having characteristic peaks at 13.27, 15.95 and 20.51 (± 0.2° 29).
4. Crystalline form Z of O-desmethylvenlafaxine succinate according to claim 1, wherein said O-desmethylvenlafaxine succinate exhibits an XRPD pattern that substantially corresponds to figure 1.
5. Crystalline form Z of O-desmethylvenlafaxine succinate according to claim 1, wherein the medium relative intensity is in the range of about 10 to about
35%.
6. A process for preparing crystalline form Z of O-desmethylvenlafaxine
succinate comprising steps of
a. forming a suspension of O-desmethyl venlafaxine, succinic acid in a
mixture of methylene dichloride, water and hexane or cyclohexane;
b. heating the suspension to a temperature of 40°C to 80°C;
c. cooling the suspension to a temperature of 0°C to 35°C

7. A pharmaceutical composition comprising the compound of any of the preceding claims and at least one pharmaceutically acceptable excipient.
8. The pharmaceutical composition according to claim 7, wherein the composition is administered for the treatment of depression to a subject in need thereof.