Field of the Invention
The present invention relates to novel polymorph of (±)-O-desmethylvenlafaxine
glutarate. The present invention further relates to the process for preparing crystalline
form of (±)-0 desmethylvenlafaxine glutarate.
Back ground and Prior Art of the Invention
O-desmethyl venlafaxine (chemically known as 1-[2-(dimethylamino)-1-(4-
phenol)ethyl]cyclohexanol) is a major metabolite of venlafaxine and has been shown to
inhibit norepinephrine and serotonin uptake in the U.S. Pat. No. 4,535,186. O-desmethyl
venlafaxine has the chemical structure as depicted herein below:

Salt formation provides a means of altering the physiochemical and resultant biological
characteristics of a drug without modifying its chemical structure. Selection of a salt for a
compound is an unpredictable exercise that would require a chemist to engage in
experimentation to determine which salt would be in fact suitable among the group of
pharmaceutically acceptable salts. The selection of a suitable salt determines stability,
solubility and quantity of the crystalline structure. This is advantageous in dosage form
development.
The discovery of novel solid forms of such salts, including amorphous forms and crystal
forms of pharmaceutically useful compound provides a new opportunity to improve the
performance characteristic of the final pharmaceutical product. It adds value to the
material that a formulation scientist can use the same for designing, for example a

pharmaceutical dosage form of a drug with targeted release profile or other desired
characteristic.
The product patent US patent No. 4,535,186 describes the preparation of venlafaxine
hydrochloride in almost all the examples and the preparation of venlafaxine fumarate in
exampIe-26. Further this patent discloses different acid addition salts of O-
desmethylvenlafaxine such as hydrochloric, hydrobromic, fumaric, maleic, succinic,
sulfuric, phosphoric, tartaric, acetic, citric, oxalic and similar acids in Column 2, lines 35
to 42. The O-desmethyl venlafaxine formate salt is disclosed in the US patent No.
7,001,920. Aspartate and saccharinate are the other acid addition salts of O-desmethyl
venlafaxine disclosed in CN 101074200 and WO 2009017813 respectively.
Summary of the Invention
The primary objective of the present invention is to provide novel polymorph of (±)-O-
desmethylvenlafaxine glutarate and process for preparing the same thereof.
One aspect of the invention to provide a process for preparing crystalline form of (±)-O-
desmethylvenlafaxine glutarate involving the steps of:
i) dissolving O-desmethylvenlafaxine glutarate in suitable solvent or reacting O-
desmethylvenlafaxine with glutaric acid in a suitable solvent;
ii) crystallizing the crystalline form of O-desmethylvenlafaxine glutarate from the
reaction solution in step (i) either by cooling said reaction solution in step (i) or
concentrating said reaction solution in step (i) or adding an antisolvent said
reaction solution in step (i).
Another aspect of the invention to provide a process for preparing crystalline form of (±)-
O-desmethylvenlafaxine glutarate involving the steps of reacting O-
desmethylvenlafaxine with glutaric acid in a suitable solvent.

A further aspect of the present invention is to provide a process for the preparation of O-
desmethylvenlafaxine glutarate addition salt comprising the steps of treating O-
desmethylvenlafaxine with glutaric acid in a suitable solvent.Detailed Description of the
Invention
The present invention relates to novel polymorph of O-desmethylvenlafaxine glutarate.
The glutarate salt of O-desmethylvenlafaxine exist as enantiomers and this invention
includes racemic mixture as well as stereoisomerically pure forms of the same.
Stereoisomerically pure refers to the compounds, which are comprised of a greater
proportion of the desired isomer than of the optical antipode. A stereoisomerically pure
compound is generally made up of at least 90% of the desired isomer based upon 100%
total weight of O-desmethylvenlafaxine glutarate.
The crystalline O-desmethylvenlafaxine glutarate obtained by the process of the present
invention is characterized by Powder X-ray Diffraction (PXRD) (Figure-1); and
Differential Scanning Calorimetry (Figure-2).
Peak locations and intensity for the XRPD pattern in Figure-1 are provided in table-1
below.



The PXRD peaks (expressed in 2θ ± 0.2° 2θ) at 10.04, 10.63, 10.91, 12.97, 13.96, 14.26,
15.12, 18.02, 18.35, 18.47, 19.88, 19.93, 20.62, 21.45, 21.62, 21.94 and 26.15 are
characteristic of a crystalline O-demethylvenlafaxine glutarate. The DSC shows the peak
value at 150.06 °C and the onset value is on 147.13 °C.
Glutarate salts of O-desmethylvenlafaxine may be formed by reacting glutaric acid with
O-desmethylvenlafaxine free base in a suitable solvent or a mixture thereof. A mixture of
glutaric acid and free base is soluble in a suitable solvent or a mixture of solvents at
temperatures ranging from about 40°C to about 100°C.
The present invention also provides a process for preparing crystalline form of (±)-O-
desmethylvenlafaxine glutarate involving the steps of:
i) dissolving O-desmethylvenlafaxine glutarate in suitable solvent or reacting O-
desmethylvenlafaxine with glutaric acid in a suitable solvent;

ii) crystallizing the crystalline form of O-desmethylvenlafaxine glutarate from the
reaction solution in step (i) either by cooling said reaction solution in step (i) or
concentrating said reaction solution in step (i) or adding an antisolvent said
reaction solution in step (i).
Preferred embodiment of the present invention is a process for preparing crystalline
form of (±)-O-desmetnylvenlafaxine glutarate involving the steps of:
(i) reacting O-desmethylvenlafaxine with glutaric acid in a suitable solvent;
(ii) crystallizing the crystalline form of O-desmethylvenlafaxine glutarate from the
reaction solution in step by cooling said reaction solution.
Said suitable solvent is selected from the group comprising of water, esters, ketones,
phenols, alcohols, ethers, aromatic hydrocarbons, amides, sulfoxides, hydrocarbons,
nitrites, halogenated hydrocarbons, pyridines or a mixtures thereof.
The method of the "crystallization from the solution" include, for example, a
concentration method, a slow cooling method, a reaction method (diffusion method,
electrolysis method), a hydrothermal growth method, a fusing agent method, and so forth.
The solvents to be used include, for example, aromatic hydrocarbons (e.g., benzene,
toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,
etc.), saturated hydrocarbons (e.g., hexane, heptane, cyclohexane, etc.), ethers (e.g.,
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), nitriles (e.g., acetonitrile,
etc.), ketones (e.g., acetone, etc.), sulfoxides (e.g., dimethylsulfoxide, etc.), acid amides
(e.g., N,N-dimethylformamide, etc.), esters (e.g., ethyl acetate, etc.), alcohols (e.g.,
methanol, ethanol, isopropyl alcohol, etc.), water, and so forth. These solvents may be
used singly or in a mixture of two or more kinds at appropriate ratios (e.g., 1:1 to 1:100).
Preferably, crystallization may be achieved either by the step of cooling the solution or
by the step of concentrating or by the step of adding an antisolvent or any combinations
of these steps thereof in any order. Crystallization may be also facilitated by seeding with
O-desmethylvenlafaxine glutarate crystals.

The "esters" include, for example, methyl acetate, ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, isobutyl acetate, ethyl formate and the like. The "ketones" include,
for example, acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl butyl ketone,
methyl isobutyl ketone and the like. The "phenols" include, for example, anisole and the
like. The "alcohols" include, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-
butanol, 2-butanol, 2-methy1-1-propanol, pentanol, 3-methy1-1-butanol, 2-
methoxyethanol, 2-ethoxyethanol, ethylene glycol and the like. The "ethers" include, for
example, t-butyl methyl ether, diethyl ether, 1,1-diethoxypropane, 1,1-dimethoxypropane,
2,2-dimethoxypropane, isopropyl ether, tetrahydrofuran, methyltetrahydrofuran and the
like. The "aromatic hydrocarbons" include, for example, chlorobenzene, toluene, xylene,
cumene and the like. The "amides" include, for example, formamide, N,N-
dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone and the like.The
"sulfoxides" include, for example, dimethylsulfoxide and the like.The "hydrocarbons"
include, for example, propane, hexane, pentane, octane, isooctane and the like.The
"nitriles" include, for example, acetonitrile and the like. The "halogenated hydrocarbons"
include, for example, chloroform, dichloromethane, dichloroethene, trichloroethene and
the like. The "pyridines" include, for example, pyridine and the like.
The following examples are provided for purposes of illustration only and should not be
understood as definition of the limits of the invention.Example-1
Preparation of crystalline O-desmethyl venlafaxine glutarate
150 ml of ethanol, 20 grams of O-desmethylvenlafaxine and 10.5 grams of glutaric acid
were mixed by stirring at a temperature of 65 °C for 20 minutes. The reaction mixture was
filtered through 0.2-micron filter paper and the filtrate was slowly cooled to 25-27°C and
stirred for 18-20 hours at the same temperature. The crystallized solid was filtered,
washed with ethanol and dried at 40-45°C under vacuum for 20-24 hours.

WE CLAIM:
(1) A crystalline form of O-desmethylvenlafaxine gluatarate, wherein said crystalline
form exhibits PXRD peaks at 10.04, 10.63, 10.91, 12.97, 13.96, 14.26, 15.12,
18.02, 18.35, 18.47, 19.88, 19.93, 20.62, 21.45, 21.62, 21.94 and 26.15 in 20 ±
0.2° 29.
(2) A crystalline form of O-desmethylvenlafaxine gluatarate, wherein said crystalline
form exhibits the peak value at 150.06 °C and the onset value is on 147.13 °C.
(3) A process for preparing crystalline form of O-desmethylvenlafaxine gluatarate
comprising the steps of:
(i) dissolving the O-desmethylvenlafaxine in suitable solvent or reacting O-
desmethylvenlafaxine with glutaric acid in suitable solvent;
(ii) crystallizing the crystalline form of O-desmethylvenlafaxine glutarate from
the solution obtained in step (i) either by cooling said solution, or
concentrating said solution or adding an antisolvent in said solution,
wherein said crystalline form exhibits PXRD peaks at 10.04, 10.63, 10.91, 12.97,
13.96, 14.26, 15.12, 18.02, 18.35, 18.47, 19.88, 19.93, 20.62, 21.45, 21.62, 21.94 and
26.15 in 2θ ±0.2° 29.
The present invention relates to a novel polymorph of O-desmethylvenlafaxine glutarate
and process for preparing the same thereof.