POLYMORPHIC FORM OF DESVENLAFAXINE SUCCINATE
FIELD OF THE INVENTION The present invention provides polymorphic form R of desvenlafaxine succinate and the
process for its preparation. It also provides a pharmaceutical composition comprising the same
and its use for the treatment of major depressive disorder (MDD)
BACKGROUND OF THE INVENTION Pristiq® (desvenlafaxine succinate monohydrate) is a selective serotonin-norepinephrine reuptake inhibitor(SNRI) and is indicated for the treatment of major depressive disorder (MDD). Desvenlafaxine succinate monohydrate is designated as succinate of RS-4-[2-dimethylamino-l-(l-hydroxycyclohexyl) ethyl] phenol. The structural formula (I) of desvenlafaxine succinate monohydrate is shown below.
(Formula Removed)
Formula I US 6,673,838 describes polymorphic Forms-I, II, IV and amorphous form of desvenlafaxine succinate characterized by their XRD, DSC, TGA and Form-Ill by XRD only. It also describes preparation of polymorphic forms I, II, III and IV involving slurrying of Form-1, Form-II, Form-Ill or mixture thereof in an organic solvent at ambient temperature (Form-I), slow/fast evaporation or cooling of a Form-I mixture in water/organic solvent or comprising solvent-antisolvent technique (Form-II), ball milling or cryo-grinding of Form-I (Form-Ill) and slurrying a mixture containing equal amounts of Form-I and Form-II in acetonitrile at 54°C for several days followed by heating at 120°C for several hours (Form-IV).
Various other patent applications describe polymorphic form of desvenlafaxine succinate characterized by their XRD and other analytical details, some of them are incorporated herein for reference, for example, WO 08/017886 (crystalline hydrate of desvenlafaxine succinate), US20080188567 (Form V and F), WO 08/047167 (Form I and II), WO08110338 (crystalline anhydrous Form V), WO2008156748 (crystalline monohydrate of desvenlafaxine succinate), WO2009009665 (crystalline Form-VI) alongwith the processess for their preparation.

The present invention provides stable polymorphic form of desvenlafaxine succinate, designated as Form-R which shows free-flowing properties and has been prepared involving a simple process.
SUMMARY OF THE INVENTION-The present invention provides polymorphic form R of desvenlafaxine succinate and the process for its preparation. It also provides a pharmaceutical composition comprising the same and its use for the treatment of major depressive disorder (MDD).
One aspect of the present invention provides polymorphic form R of desvenlafaxine succinate, having characteristics d-spacing (A0) values at 8.391, 4.483, 4.246, 4.194, 3.710 and
3.355.
Another aspect of the present invention provides a process for the preparation of polymorphic form R of desvenlafaxine succinate the steps comprising of:
(i) heating reaction mixture containing desvenlafaxine succinate in ketonic solvent; (ii) cooling the reaction mixture to about 40°C; and (iii) isolating polymorphic form R.
According to another aspect, the present invention provides a pharmaceutical composition comprising Form-R of desvenlafaxine succinate with one or more pharmaceutically acceptable carriers and/or excipients.
According to yet another aspect, the present invention provides a method for treating a patient suffering from major depressive disorder (MDD) comprising administering to said patient a therapeutically effective amount of Form-R of desvenlafaxine succinate or a pharmaceutical composition comprising the same.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: X-Ray Diffraction (XRD) pattern of polymorphic form R of desvenlafaxine succinate Figure 2: Differential Scanning Calorimetry (DSC) pattern of Form R
DETAILED DESCRIPTION OF THE INVENTION Various embodiments of the present invention are described hereinafter. In one embodiment, polymorphic form R of desvenlafaxine succinate of the present invention has the

d-spacing (A0) values at 16.80, 15.26, 9.12, 8.39, 8.27. 7.78, 6.41, 6.07, 5.83, 5.60, 5.30, 5.15, 5.01, 4.93, 4.56, 4.48, 4.25, 4.19, 4.13, 4.08, 4.02, 3.92, 3.89, 3.71, 3.67, 3.57, 3.50, 3.42, 3.35, 3.19, 3.08, 3.03, 2.98, 2.92, 2.89, 2.80, 2.69, 2.62, 2.54, 2.43, 2.38, 2.34, 2.28 and the corresponding 2-theta values at 5.26, 5.79, 9.69, 10.54, 10.69, 11.38, 13.81, 14.58, 15.21, 15.83, 16.72, 17.21, 17.68, 17.99, 19.47, 19.80, 20.92, 21.18, 21.49, 21.76, 22.08, 22.67, 22.87, 23.98, 24.27, 24.91, 25.45, 26.05, 26.56, 27.96, 29.02, 29.48, 29.96, 30.64, 30.94, 32.00, 33.30, 34.20, 35.25, 37.05, 37.85, 38.52, 39.54 ± 0.2.
In one embodiment of the present invention R form of the desvenlafaxine succinate has substantially the same XRD pattern as depicted in Figure 1.
In another embodiment of the present invention R form of the desvenlafaxine succinate has substantially the same DSC pattern as depicted in Figure 2.
In still another embodiment of the present invention R form of the desvenlafaxine succinate has characteristics endotherm peak at 148.69°C
One embodiment of the present invention provides pharmaceutical composition comprising (a) less than 1% to atleast 99% by weight of the polymorph Form-R (b) crystalline Form I, II, III, IV or amorphous form of the desvenlafaxine succinate with pharmaceutically acceptable carriers and/ or excipients..
The present invention provides a process for the preparation of polymorphic form R of desvenlafaxine succinate the steps comprising of:
(i) heating reaction mixture containing desvenlafaxine succinate in ketonic solvent; (ii) cooling the reaction mixture to about 40°C; and (iii) isolating polymorphic form R.
"Reaction mixture" herein include slurry or suspension of desvenlafaxine succinate in ketonic solvent.
"Desvenlafaxine succinate " herein include for example, different polymorphic forms of desvenlafaxine succinate selected from Form-I, II, III or amorphous form as per US 6,673,838.

As used herein, the term "about" when used in reference to defined parameters e.g., temperature and time, indicates inherent variability in. for example, measuring the parameter or achieving the parameter.
According to one of the embodiments of the present invention, examples of ketonic solvents may include but are not limited to acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-hexanone, 2-heptanone, 2-octanone and/or mixtures thereof.
The reaction mixture containing desvenlafaxine succinate in ketonic solvent may be heated to about reflux temperature. "Reflux temperature" herein involves the temperature at which solvent mixture starts boiling.
The refluxing of the above reaction mixture may be carried out for about 150 hours to about 200 hours.
According to another embodiment of the present invention, cooling of the reaction mixture can be done to about 40°C after refluxing. The cooling of the reaction mixture may be carried out in the range of about 25-40°C in about 30 minutes to about 1 hour, cooling rate can be changed accordingly by a person skilled in art.
The solid can be isolated by conventional means known to a person of ordinary skill in art including for example decantation, filtration or centrifugation, preferably under nitrogen atmosphere to avoid contamination with water.
The isolated solid can be dried under vacuum and/or air or by any other drying means known in the prior-art. The drying of the solid can be carried out in air at room temperature for about 15-25 hours. The solid refers to crystalline form-R of the desvenlafaxine succinate characterized by its XRD and DSC spectra.
The Form-R of the desvenlafaxine succinate as obtained above is having moisture content less than 0.05% when measured by Karl Fischer technique
The Form-R of desvenlafaxine succinate can be formulated into pharmaceutical compositions with excipients or carriers. The various dosage forms which include, but are not
limited to tablets, capsules, troches, lozenges, dispersions, suspensions, suppositories, ointments,

cataplasms, pastes, powders, creams, solutions, patches. Preferably the pharmaceutical composition comprises an amount of claimed morph effective to treat the desired indication in an animal, such as a human.
The packaging of the Form-R of desvenlafaxine succinate can be done in self sealing polybags under vacuum after nitrogen flushing, or nitrogen atmosphere, with/or moisture absorbent to improve stability of the material.
In the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLE
The reaction mixture containing desvenlafaxine succinate (50gm) and acetone (1000mL) was refluxed at 56°C in an assembly fitted with Dean-Stark apparatus for 24 hours followed by recovery of acetone (100 mL) and refilling with fresh acetone (100 mL). The reaction mixture was continuously refluxed for 156 hours followed by cooling of the reaction mixture to 40°C in 30 minutes. The solid was filtered in sintered funnel under nitrogen atmosphere, dried under vacuum at room temperature for 20 hours to obtain Form-R having moisture content of about 0.05%. Yield: 82%

WE CLAIM:
1. Polymorphic form R of desvenlafaxine succinate.
2. Polymorphic form R of desvenlafaxine succinate of claim 1 exhibiting X-ray diffraction
(XRD) d-spacing (A0) values selected from 8.391, 4.483, 4.246, 4.194, 3.710 or 3.355.
3. Polymorphic form R of desvenlafaxine succinate of claim 1 exhibiting X-ray diffraction (XRD) d-spacing (A0) values at 16.80, 15.26, 9.12, 8.39, 8.27, 7.78, 6.41, 6.07, 5.83, 5.60, 5.30, 5.15, 5.01, 4.93, 4.56, 4.48, 4.25, 4.19, 4.13, 4.08, 4.02, 3.92, 3.89, 3.71, 3.67, 3.57, 3.50, 3.42, 3.35, 3.19, 3.08, 3.03, 2.98, 2.92, 2.89, 2.80, 2.69, 2.62, 2.54, 2.43, 2.38, 2.34, 2.28.
4. Polymorphic form R of desvenlafaxine succinate of claim 1 exhibiting characteristics X-ray diffraction (XRD) peaks expressed in degrees 2 theta at 5.26, 5.79, 9.69, 10.54, 10.69, 11.38, 13.81, 14.58, 15.21, 15.83, 16.72, 17.21, 17.68, 17.99, 19.47, 19.80, 20.92, 21.18, 21.49, 21.76, 22.08, 22.67, 22.87, 23.98, 24.27, 24.91, 25.45, 26.05, 26.56, 27.96, 29.02, 29.48, 29.96, 30.64, 30.94, 32.00, 33.30, 34.20, 35.25, 37.05, 37.85, 38.52, 39.54 ±0.2.
5. Polymorphic form R of desvenlafaxine succinate of claim 1 exhibiting a Differential Scanning Calorimetric (DSC) thermogram comprising characteristics endothermic peak at 148.69°C.
6. Polymorphic form R of desvenlafaxine succinate of claim 1 exhibiting a) substantially
the same X-ray diffraction pattern (XRD) as depicted in Figure 1 or b) substantially the
same Differential Scanning Calorimetric (DSC) pattern as depicted in Figure 2.
7. A process for the preparation of polymorphic form R of desvenlafaxine succinate the
steps comprising of:
a) heating reaction mixture containing desvenlafaxine succinate in ketonic solvent;
b) cooling the reaction mixture to about 40°C; and
c) isolating polymorphic form R.
8. The process according to claim 7, wherein ketonic solvent used in step (a) is selected
from the group comprising of acetone, 2-butanone, 2-pentanone, 3-pentanone, 2-
hexanone, 2-heptanone, 2-octanone and/or mixtures thereof.
9. The process according to claim 7, wherein heating of the reaction mixture is carried out
from about 150 hours to about 200 hours.
10. The process according to claim 7, wherein cooling of the reaction mixture in step (b) is
carried out at the temperature in the range from about 25°C to about 40°C.
11. The process according to claim 7, wherein drying of the solid is carried out in air at room temperature for about 15 to about 25 hours.
12. Polymorphic form R of the desvenlafaxine succinate obtained by the process according to claim 7 has moisture content less than 0.05%.
13. A pharmaceutical composition comprising Form-R of desvenlafaxine succinate with one
or more pharmaceutically acceptable carriers and/or excipients.
14. A pharmaceutical composition of claim 13 comprising (a) less than 1% to atleast 99% by weight of the polymorph Form-R (b) crystalline Form I, II, III, IV or amorphous form of the desvenlafaxine succinate with pharmaceutically acceptable carriers and/ or excipients.
15. A method for treating a patient suffering from major depressive disorder (MDD) comprising administering to said patient a therapeutically effective amount of Form-R of desvenlafaxine succinate or a pharmaceutical composition comprising the same