FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENTS RULE 2003
COMPLETE SPECIFICATION
(Section 10 and rule 13)
"MODIFIED RELEASE PHARMACEUTICAL COMPOSITION COMPRISING O, DESMETHYLVENLAFAXINE SUCCINATE"
Glerirnark Generics Limited
an Indian Company, registered under the Indian company's Act 1957
having office at
Glenmark House,
HDO-Corporate Bidg,
Wing -A, B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai - 400 099, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF INVENTION
[0001] The present invention relates to modified release pharmaceutical composition comprising O-desmethyl venlafaxine Succinate (ODVS), and a process for preparing the same,
BACKGROUND OF THE INVENTION
[0002] Desvenlafaxine. also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor ("SNRIs") class. Antidepressants are useful in treating depression and related disorders such as anxiety and compulsive disorders. A genus of antidepressants that have been used in the treatment of depression and mental disorders are known as serotonin selective reuptake inhibitors ("SSRIs"). SSRIs are believed to prevent the reuptake of the neurotransmitter serotonin.
(0003] Although the use of SSRIs has proven effective for some patients, a group of antidepressants that prevent the reuptake of both serotonin and norepinephrine are gaining acceptance. The dual reuptake inhibitors are sometimes referred to as SENRIs or SNRIs." Examples of some SSNRIs currently in use are venlafaxine, desmethylvenlafaxine. sibutramine, nefazodone, milnacipran, desipramine; duloxetine and bicifadine.
[0004] O-desmethylveniafaxine or desmethylvenlafaxine is the major metabolite of venlafaxine and it inhibits noradrenaline and serotonin uptake. US 7291347 describes Succinate salt of O-desmethyl-venlafaxine, its various polymorphs and matrix hydrogel tablet comprising from about 30 to about 50% by weight of ODVS.
SUMMARY OF INVENTION
[0005] One aspect of the present invention provides a modified release pharmaceutical composition comprising ODVS in an amount less than 27 % by weight of the composition.

[0006] In one of the preferred embodiment the modified release pharmaceutical composition comprises ODVS in an amount less than 27% by weight of the composition wherein ODVS is in amorphous form.
[0007] In another preferred embodiment of the invention, the modified release pharmaceutical composition comprises an ODVS in an amount less than 27 % by weight of the composition and release rate retarding polymer, wherein release rate retarding polymer consists of hydroxypropyf methylcellulose of different viscosities.
(0008] In yet another preferred embodiment of the invention, the modified rpiease pharmaceutical composition comprises an ODVS in an amount less than 27 % by weight of the composition wherein ODVS is in amorphous form and release rate retarding polymer, wherein release rate retarding polymer consists of hydroxypropyl methylcellulose of different viscosities.
[0009] In yet another preferred embodiment of the invention, the modified release pharmaceutical composition comprises an ODVS in an amount less than 27 % by weight of the composition wherein the crystalline or semicrystalline forms of ODVS is converted into amorphous ODVS, before or during the process of preparation of composition
[0010] Another aspect of the present invention relates to a process for preparing a modified release pharmaceutical composition comprising ODVS in an amount less than 27 % by weight of the composition.
DETAILED DESCRIPTION OF INVENTION
[0011] The phrase "modified release pharmaceutical composition" as used herein, includes any pharmaceutical composition that achieves slow release of ODVS over an extended period of time.

[0012] "Pharmaceutically acceptable additives as used herein includes one or more of binders,. diluents, surfactants, antioxidants, Iubricants/glidants, coloring agents, coating materials and the like.
[0013] "Release rate retarding polymer" used herein means a polymer which retards or prolongs release of the ODVS by forming a polymeric matrix around ODVS.
[0014] The term "amorphous ODVS" used in the present invention indicates that the said ODVS consists of not more than 10% of crystalline ODVS.
[0015] The term "about" is used herein to mean within 15% preferably within 10% and more preferable within 5% of a given value or range.
[0016] In a preferred embodiment, the present invention provides the modified release pharmaceutical composition comprising. ODVS in an amount less than 27 % by weight of the composition.
[0017] The modified release tablet of present invention comprises 152 mg of ODVS (equivalent to 100 mg ODV). at least one hydrophilic polymer wherein a total weight of tablet is above 563 mg.
[0018] In a preferred embodiment of the invention, the modified release tablet of present invention comprises 152 mg of ODVS (equivalent to 100 mg ODV), at least one hydrophilic polymer wherein a total weight of tablet is 661.44 mg.
[0019] For the purpose of this invention ODVS can be a crystalline, semicrystalline, amorphous,
solvate or hydrate. Though it is not essential for the success of the invention, however for
i the purpose of present invention, ODVS in an amorphous form is preferred.
Alternatively, the present invention also covers a pharmaceutical composition of ODVS,

wherein the crystalline or semiprystallinp forms of ODVS are converted into an amorphous form before or during the process of preparation of composition.
[0020] The present invention provides the modified release pharmaceutical composition comprising, ODVS in an amount less than 27 % by weight of the composition, wherein ODVS is in amorphous form.
[0021] Due to good solubility of ODVS in water, it is difficult to prepare a modified release formulation that will give desired release. While achieving the goal, it is important to strike an appropriate balance between the amount of rate controlling polymer, the viscosity of rate controlling polymer, mass of the tablets, the amount of excipicnts and patient compliance. An appropriate choice of polymer, or combination of polymers or combination of polymers having different viscosities along with other excipients used in pharmaceutical dosage forms will contribute in achieving desired dissolution profile.
[0022] The present invention provides the modified release pharmaceutical composition comprising ODVS in an amount less than 27 % by weight of the composition, and release rate retarding polymers.
|0023] The release rate controlling polymers according to present invention, includes but are not limited to Alkyl celluloses such as methyl cellulose: ethyl cellulose, hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; carboxyalkyl cellulose esters: other natural, semi-synthetic, or synthetic di-. oligo-, and polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; methacrylate copolymers; polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene

oxide and propylene oxide or combination thereof. However hydroxypropyl methyl cellulose is preferred as release rate retarding polymer.
[0024] In preferred embodiment, the modified release pharmaceutical composition of present invention comprises ODVS in an amount less than 27 % by weight of the composition, and release rate retarding polymers consisting of high viscosity HPMC and low viscosity HPMC.
[0025] The present invention provides a modified release tablet formulation which comprises high and low viscosity hydroxypropyl methylcellulose and at least one pharmaceutically acceptable carrier. Above mentioned "High viscosity HPMCs" refers HPMCs having at (22°C) a nominal viscosity above 10,000, and preferably of about 15,000 mPas when dissolved (about 2% by weight) in water. "Low viscosity HPMCs" refers to HPMCs having at room temperature a nominal viscosity below 10,000 and preferably of about 4,000 mPas when dissolved (about 2% by weight) in water.
|0026] Few commercial grades such as METHOCEL®K4Ms METHGCEL®KISM, METHOCEL®K100M, METHOCEI ® E4M and METHOCEL® E10M manufactured by Dow Chemical Company are particularly suitable for the purpose of present invention.
[0027] In addition, when using a combination of polymers, the ratio of polymers also influences the release profile of the preparation. A combination of different polymers, combination of different viscosities of same polymer offers the possibility of combining different mechanisms by which ODVS is released from the matrix. Such combination provides desired control of the pharmacokinetic release profile of the preparation.
[0028] In preferred embodiments, the modified release pharmaceutical composition comprises less 27 % by weight of ODVS and from 17 to 23% of release rate retarding polymer, most preferably 19 to 21% of release rate retarding polymer.

[0029] Particularly preferred brands of release rate retarding polymers are METHOCEL®K15M having a nominal viscosity of about 15,000 mPas and METHOCEL K4M has a nominal viscosity of about 4,000 mPas. The weight ratios of METHOCEL®K15M and K4M used in the compositions described herein can be in the range of about 5:1 to about 1:5, and are preferably in the range of about 2:1 to about 1:2 and are even more preferably in about 1:1.
[0030] The present invention provides the modified release pharmaceutical composition
comprisingODVS in an amount less than 27 % by weight of the composition, and release rate retarding polymers consisting of high viscosity HPMC and low viscosity HPMC in 1:1 ratio.
[0031] The present invention provides the modified release pharmaceutical composition comprising.
a) 152mgofODVS;
b) 56-76mgofHPMCK15MCR,
c) 56^76 mg of HPMC K4M and
d) 357-397 mg of other pharmaceutically acceptable additives wherein weight of tablet is above 563 mg
[0032] In a preferred embodiment, the present invention provides the modified release pharmaceutical composition comprising,
a) 152mgofODVS,
b) 65mgofHPMCK15MCR,
c) 65mgofHPMCK4Mand
d) 379.44 mg of other pharmaceutical acceptable additives wherein weight of tablet is 661.44 mg.

[0033] In an another preferred embodiment of the invention, the modified release pharmacoutical composition comprises ODVS in an amount less than 27 % by weight of the composition, wherein ODVS is in amorphous form and release rate retarding polymers consisting of high viscosity HPMC and low viscosity HPMC.
|00341 Conversion of crystalline or semierystailine forms of ODVS to amorphous ODVS can be done by using techniques known to those skilled in the art, e.g. solid dispersion, spray drying, precipitation, evaporation etc
[0035] In the preferred embodiment, the present invention provides process of preparation of an amorphous ODVS. Amorphous ODVS can be obtained by any of the above said method. However for the purpose of present invention, crystalline or semierystailine ODVS was dispersed in suitable solvent along with one or more pharmaceutically acceptable carrier. Solvent from this dispersion was removed to obtain a solid precipitate which is hereinafter referred as "amorphous granulate of ODVS". The pharmaceutically acceptable carries used to prepare amorphous granulate of ODVS includes but are not limited to HPMC, Polyethylene glycols, Polyethylene oxides, sugars, polyvinyl pyrrolidones (PVP) etc. Polyvinyl pyrrolidone is the preferred one, more preferably PVP K-30. Ratio of these pharmaceutically acceptable carriers to crystalline or semi crystalline ODVS is also an important part of the process.
|0036| fn one embodiment, ratio of crystalline ODVS to PVP K-3G is from about 1:0.5 to 1:1,5, most preferably 1:1.
[0037] The present invention provides the modified release pharmaceutical composition comprising, ODVS in an amount less than 27 % by weight of the composition wherein ODVS is in amorphous form and release rate retarding polymers consisting of high viscosity HPMC and low viscosity HPMC in 1:1 ratio.

[0038] The present invention provides the. modified release pharmaceutical composition comprising,
a) 152 mg of ODVS in amorphous form,
b) 56-76mgofHPMCK15MCR,
c) 56-76 mg of HPMC K4M and
d) 357-397 mg of other pharmaceutioally acceptable additives wherein weight of tablet is above 563 mg
[0039] In a preferred embodiment, the present invention provides the modified release pharmaceutical composition comprising,
a) 152 mg of ODVS in amorphous form,
b) 65 mg of HPMCK15MCR,
c) 65mgofHPMCK4Mand
d) 379.44 mg of other pharmaceutioally acceptable additives wherein weight of tablet is 661.44 mg.
[0040J Beside QDVS and the rate controlling polymer(s), the formulation pf the present invention may also optionally comprise further excipients, i.e., pharmaceutically acceptable formulating agents, in order to promote the manufacture, compressibility, appearance, and taste of the preparation. These formulating agents comprise, for example, diluents or fillers, binding agents, glidants, anti-caking agents, antioxidants, lubricants, flavors, dyes, and preservatives. Other conventional excipients known in the art can also be included.
[0041] The filler may be selected from soluble fillers, for example, sucrose, and lactose, in particular lactose monohydratc, trehalose, maltose, mannitol and sorbitol. Different grades of lactose can be used. In case of a water'soluble active ingredient, like the one described in this invention, more preferably water insoluble fillers, such as strach microcrystalline cellulose, dibasic calcium phosphate dihydrate, and anhydrous dibasic

calcium phosphate, preferably microcrystaliine cellulose, can be used in addition or instead -of the water soluble fillers. In preferred embodiment combination of water soluble and water insoluble fillers are used. The total weight percentage of filler ranges between about 18 % and about 38% by weight, preferably from about 25 to about 30%.
[0042] The compositions described herein also can comprise binders, such as povidones (e.g., PVP K-30, PVP K-60, and PVP K-90), cellulose derivatives (e.g., methylcellulose and sodium carboxymeihylcellulose), gelatin, polyethylene glycol, polymethacrylates, hydroxypropylceliulose, pregelatinized starch and sodium alginate, wherein povidones are preferred, and wherein PVP K -30 is particularly preferred. . The total weight percentage of binder ranges between about 0.5 % and about 3% by weight. Most preferred range is about 1.0 %.
[0043] A glidant can be used to improve powder flow properties prior to and during tabletting and to reduce caking. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate. powdered cellulose, talc, tribasic calcium phosphate and the like. Talc is preferably included as a glidant in an amount up to about 4%. preferably about 3% to about 2.0%, by weight of the tablet.
[0044] A lubricant can be used to enhance release of a tablet from apparatus on which it is formed, for example by preventing adherence to the face of an upper punch ("picking") or lower punch ("sticking"). Suitable lubricants include magnesium stearate, calcium stearate; canola oil, glyceryl palmitostearale. hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and the like. In one embodiment, magnesium stearate is included as a lubricant in an amount of about 0.2% to about 2.0%, preferably about 1 %, by weight of the tablet.

[0045] The modified release tablet of the invention may comprise a nonfunctional coaling, A nonfunctional coating can comprise a polymer component, for example HPMC, PVA etc. optionally with other ingredients, for example, one or more plasticizers, colorants, etc. The term "nonfunctional" in the present context means having no substantial effect on release properties of the tablet, and the coating serves another useful purpose.1 For example, such a coating can impart a distinctive appearance to the tablet, provide protection against attrition during packaging and transportation, improve case of swallowing, and/or have other benefits. A nonfunctional coating should be applied in an amount sufficient to provide complete coverage of the tablet. Typically an amount of about 1% to about 10%, more typically an amount of about 2% to about 5%, by weight of the tablet as a whole, is suitable
[0046] In a preferred embodiment Ijiere is provided a process of making the modified release pharmaceutical composition as hereinabove described comprising the steps of tabletling the final mixture by compressing it on a suitable tablet press to produce matrix tablets. i) Forming an amorphous granulate, of ODVS with pharmaceutical!}' acceptable carrier
and; ii) Separately forming a base granules of other excipients except rate retarding polymers, iii) Co sifting the amorphous granulate of ODVS with glidant/Iubricants, iv) Co sifting of base granules of pharmaceutically acceptable additives with rate
retarding polymers and blend of step (iii) followed by blending. v) Further blending this resultant mix with glidant/Iubricants to obtain a blend for
compression, vi) Compressing the final blend to form the solid oral dosage form.
[0047] Other processes can also be applied to the manufacturing of ODVS modified release tablets, like conventional wet granulation and roller compaction. In case of wet granulation preferably ODVS is granulated with suitable fillers, like, e.g., starches, microcryslalline cellulose, lactose monohydrate or anhydrous dibasic calcium phosphate,

and wet bonding agents, like e.g., hydroxypropyl methyl cellulose hydroxypronyl cellulose, povidone, copovidone. and starch paste, leading to a active ingredient concentrate, which after drying and dry screening is mixed with the main fraction of gel forming excipients, like all the above described retarding principles.
[0048] In case of roller compaction, or in other words dry granulation, either a premix of GDVS with part of the excipients used in the direct compression process, or the complete mixture containing all excipients. is processed through a conventional roller compactor to form ribbons, which are thereafter screened down to granules which are finally' mixed with other excipients, like glidants. lubricants and antiadherents.
EXAMPLES
[0049] The following examples describe compositions of the present invention containing ODVS, but they are not to be interpreted as limiting the scope of the claims
EXAMPLE 1; Modified Release Tablet with combination of different viscosities Hydroxypropylmethyl cellulose.

TABLE 1
Sr.
No. Ingredient Qty/ tablet (mg)
(A) Amorphous granulate formation
1 Desmethylvenlafaxine Succinate 152
2 Polyvinyl Pyrrolidone (PVP K-30) 152
3 Buthylated Hydroxyanisole (BHA) 0.5
4 Buthylated Hydroxytoluene (BHT) 0.4
5 Talc 7.5
(B) Base Granule Formation
6 Lactose Monohydrate 90.0
7 Microcrystalline Cellulose (Avicel PH 102) 90.0
8 Polyvinyl Pyrrolidone (PVP K-30 ) 7.5
9 Purified water qs
(C) Dry Mixing
10 Hydroxypropylmethyl cellulose (HPMC K4M) 65.00
11 Hydroxypropylmethyl cellulose (HPMC K15M CR) 65.00
12 Talc 6.10
(D) Compression
Total core tablet weight 636.00
(E) Coating
13 PVA based Opadry 25.44
Total coated tablet weight 661.44 ]
The manufacturing process consists of following steps;
(A) Preparation of amorphous granulates of O-desmethylvenlafaxine succinate and PVP K-30:
1. Dissolved ODVS and PVP K-30 in (1:1 ratio) along with BHA and BHT by using methanol as a solvent and making solid content upto 20% w/w.
2. Dried this solution in Rotavapour at 45°C till a dry amorphous powder was obtained.
3. Co sifted this amorphous granulates of ODVS with talc and blended it in blender for 5 minutes.
(B) Preparation of Base granules of excipients except rate retarding polymers:

1. Co sifted lactose monohydrate, microcrystalline cellulose, PVP. K-30 through # 40 sieve and loaded in RMG for granulation.
2. Granulation was done by Purified water.
3. Granulation was followed by drying of base granules in FBD and finally sifting f base granules through # 20 sieve.
(C) Mixing of Step (A) and Step (B) and rate retarding polymers:
1. Co-sifted base granules of step B3 with HPMC K15M CR and HPMC K.M through # 20 sieve.
2. Mixed blend of above step C1 with blend of step A3 and blended it in blender for 10 minutes.
3. Added pre sifted talc to above step C2 and blended for further 5 minutes.
(D) Compression:
1. Compressed the blend of C3 on a suitable compression machine with suitable punches.
(E) Coating:
1. Dissolved PVA based Opadry in Purified water using a overhead stirrer and mixed till solution obtained.
2. Coated tablets of Step Dl with coating solution of Step El till desired weight gain.
EXAMPLE 2: Modified Release Tablet with combination of combination of different viscosities Hydroxypropylmethyl cellulose at 1:3 ratio

TABLE 2
Sr.
No. Ingredient Qty/ tablet
(mg)
(A) Amorphous granulate formation
1 Desmethylvenlafaxine Succinate 152.00
2 Polyvinyl Pyrrolidone (PVP K-30) 152.00
3 Buthylated Hydroxyanisole (BHA) 0.5
4 Buthylated Hydroxytoluene (BHT) 0.4
5 Talc 7.5
(B) Base Granule Formation
6 Lactose Monohydrate 90.00
7 Microcrystalline Cellulose (Avicel PH 102) 90.00
8 Polyvinyl Pyrrolidone (PVP K-30 ) 7.5
9 Purified water qs
(C) Dry Mixing
10 Hydroxypropylmethyl cellulose (HPMC K4M) 32.5
11 Hydroxypropylmethyl cellulose (HPMC K15M CR) 97.5
12 Talc 6.10
(») Compression
Total core tablet weight 636.00
(E) Coating
13 PVA based Opadry 25.44
Total coated tablet weight 661.44 |
The man ufacturing process followed was same as Example 1.
EXAMPLE 3: Modified Release Tablet with combination of different viscosities Hydroxypropylmethyl cellulose (By direct compression)

TABLE 3
Sr. No. Ingredient Qry/tablet (nig)
(A) Amorphous granulate formation
1 Desmethylvenlafaxine Succinate 152
2 Polyvinyl Pyrrolidone (PVP K-30) 152
(B) Mixing
3 Microcrystailine Cellulose 187.5
4 Hydroxypropylmethyl cellulose (HPMC K15 M CR) 65.5
5 Hydroxypropylmethyl cellulose (HPMC K4 M) 65.5
6 Talc 6.0
(C) Lubrication
7 Magnesium Stearate 7.5
(D) Compression
Total core tablet weight 636.00
(E) Coating
8 PVA based Opadry 25.44
Total 661.44
The manufacturing process consists of
(A) Preparation of amorphous granulate of O-desmethylvenlafaxine succinate and PVP K-30:
1. Dissolved ODVS and PVP K-30 in (1:1 ratio) by using methanol as a solvent.
2. Dried this solution in Rotavapour at 45°C till a dry amorphous powder was obtained.
(B) Mixing.of amorphous granulates and other excipienls:
1. Co- sifted amorphous granulate of ODVS with microcrystailine cellulose, hydroxypropyl methyl cellulose (Methocel K15M CR) and hydroxypropyl Methyl Cellulose (Methocel K4 M) through # 40 and mixing in blender for 15 min.
2. Added presifted Talc in step B1 and blended for further 5 minutes.
(C) Lubrication:

1. Finally, presifted Mg-Stearate was added to step B2 and blended foe further 3 minutes.
(D] Compression:
1. Compressed the blend of step CI on a suitable compression machine with suitable punches,
(E) Coating:
1. Dissolved PVA based Opadry in Purified water using a overhead stirrer and mixed till
solution obtained.
2. Coated tablets of Step D1 with coating solution of Step El till desired weight gain.
EXAMPLE 4: Modified Release Tablet with combination of different viscosities
Hydroxypropylmethyl cellulose and Lactose as additional filler (By direct compression)

TABLE 4
Sr.
No. Ingredient Qty/tablet (mg)
(A) Amorphous granulate formation
1 Desmethylvenlafaxine Succinate 152.00
2 Polyvinyl Pyrrolidone (PVP K-30) 152.00
(B) Mixing
Lactose Monohydrate 31.25
4 Mierocrystalline Cellulose. 156.25
5 Hydroxypropylmethyl cellulose (HPMC K15 M CR) 65.5
6 Hydroxypropylmethyl cellulose (HPMC K4 M) 65.5
7 Talc 6.00
(C) Lubrication
8 Magnesium Stearate 7.5
(D) Compression
Total core tablet weight 636.00
(E) Coating
9 PVA based Opadry 25.44
Total 661.44

The manufacturing process consists of
(A) Preparation of amorphous granulate of O-desmethylvenlafaxine succinate and PVP K-30;
1. Dissolved ODVS and PVP K-30 in (1:1 ratio) by using methanol as a solvent.
2. Dried this solution in Rotavapour at 45°C till a dry amorphous powder was obtained.
(B) Mixing of amorphous granulates and other excipients:
1. Co- sifted amorphous granulate of ODVS with microcrystalline cellulose, lactose monohydrate , hydroxypropylmethyl cellulose (Methocel K15M CR) and hydroxypropylmethyl cellulose (Methocel K4 M) through # 40 and. mixing in blender for 15 min.
2. Added presifted Talc in step B1 and blended for further 5 minutes.
(C) Lubrication:
1. Finally, presifted Mg-Stearate was added to step B2 and blended foe further 3 minutes.
(D) Compression:
1. Compressed the blend of step CI on a suitable compression machine with suitable punches.
(E) Coating:
1. Dissolved PVA based Opadry in Purified water using a overhead stirrer and mixed till solution obtained.
2. Coated tablets of Step Dl with coating solution of Step El till desired weight gain.
Claims;
1. Modified release pharmaceutical composition comprising O- desmethylvenlafaxine
succinate wherein 0- desmethylvenlafaxine succinate is in an amount less ihan 27% by weight of the composition.

2. Modified release pharmaceutical composition of claim 1, wherein quantity of O desmethylvenlafaxine succinic is equivalent to lOOmg of 0- desmethylvenlafaxine.
3. Modified release composition of claim 2, further comprising release rale retarding polymer selected from alkyl celluloses, hydroxyalkyl celluloses, carboxyalkyl cellulose esters, other natural, semi-synthetic, or synthetic di-, oligo-, and polysaccharides, polyvinyl alcohol; polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide or combination thereof
4. Modified release composition of claim 3, wherein release rate retarding polymer is comprises hydroxyalkyl celluloses,
5. Modified release composition of claim 4, wherein release rate retarding polymer is hydroxypropyl methylceilulose.
6. Modified release composition of claim 1 or 2, wherein O- desmethylvenlafaxine succinate is in amorphous form.
7. Modified release composition of claim lor 2, wherein the crystalline or semicrystalline forms of 0- desmethylvenlafaxine succinate is converted into
amorphous O- desmethylvenlafaxine succinate . before or during the process of
i
preparation of composition