The present invention relates to a process for the preparation of doxepin hydrochloride of Formula-I
^N .HC1
Formula I
The present invention further provides a crystalline form of doxepin hydrochloride and a pharmaceutical composition comprising said crystalline form of doxepin hydrochloride along with at least one pharmaceutical acceptable excipients.
Moreover, present invention provides crystalline form of ll-(3-
(dimethylamino)propyl)-6,l l-dihydrodibenzo[b,e]oxepin-l l-ol (doxepin
hydroxide) of Formula IV and use of said crystalline form of doxepin hydroxide in preparation of doxepin hydrochloride

Formula IV
BACKGROUND OF THE INVENTION
Doxepin, chemically known as (E/Z)-3-(dibenzo[b,e]oxepin-l l(6H)-ylidene)-N,N-dimethylpropan-1 -amine is a tricyclic antidepressant (TCA) used as a pill to treat major depressive disorder, anxiety disorders, chronic hives, and for treating short-term help with trouble remaining asleep after going to bed. It is a reuptake inhibitor of serotonin and norepinephrine, or a serotonin-norepinephrine reuptake inhibitor

(SNRI), and has additional antiadrenergic, antihistamine, antiserotonergic, and anticholinergic activities.
Doxepin was first disclosed in Pfizer's patent US 3,420,851. US'851 discloses a process of preparation of doxepin by treating freshly distilled 3-dimethyl amino propyl chloride with magnesium turnings, crystal of iodine and methyl iodide in dry ether followed by refluxing the solution. To the refluxed ethereal solution so obtained was then added an ethereal solution of 6, ll-dihydrodibenz-[b,e]-oxepin-11-one. Isolated the free base of doxepin followed by treating the free base so obtained with IN HC1 and base to purify doxepin. US'851 further discloses the process of preparation of hydrochloride salt of doxepin wherein said hydrochloride salt is prepared by treating acetone solution of doxepin free base with aqueous solution of hydrochloric acid. Moreover, doxepin hydrochloride so obtained is recrystallized in ether and ethanol.
IN 287428 discloses process for the preparation of doxepin by reacting
tetrahydrofuran solution of 3-dimethylamino propyl magnesium chloride and
reacting it with toluene solution of dibenzo[b,e]oxepin-l l(6H)-one (doxepinone) to
get hydroxyl intermediate; ll-(3-(dimethylamino)propyl)-6,ll-
dihydrodibenzo[b,e]oxepin-ll-ol. The hydroxyl intermediate is treated with hydrochloric acid at a temperature ranging of 0 to 10°C followed by isolation of free base of doxepin which is then converted to its hydrochloride salt.
Although there are several processes known in the literature for the preparation of doxepin hydrochloride, however these processes suffer from a disadvantage such as multiple step process involving isolation of doxepin free base followed by conversion of said free base to hydrochloride salt. Isolation of doxepin free base requires the steps like extraction and acid base treatment resulting into formation of side products which are required to be removed either by purification of doxepin free base or during conversion of said free base to hydrochloride salt. Purification of doxepin free base is a tedious process and hence it is generally preferred to

convert impure doxepin free base to hydrochloride salt as purification of hydrochloride salt is much easier. However, such an approach suffers from a drawback of low yields of doxepin hydrochloride ultimately making the overall process uneconomical.
Therefore, based on the drawbacks of prior art processes, there is an unmet requirement of the development of a process that can reduce the number of impurities and results into isolation of doxepin hydrochloride in high yields.
OBJECT OF THE INVENTION
Main object of the present invention is to provide an improved process for the preparation of doxepin hydrochloride.
In another object, the present invention provides a low cost, reproducible and high yielding process for the preparation of doxepin hydrochloride.
Another object of the present invention is to provide a crystalline form of doxepin hydrochloride.
Another object of the present invention is to provide a crystalline form of doxepin hydroxide and use of said crystalline doxepin hydroxide in preparation of doxepin hydrochloride.
SUMMARY OF THE INVENTION
The present invention is focussed towards the development of a process for the preparation of doxepin hydrochloride wherein said process results into isolation of pure doxepin hydrochloride with high yield.
Accordingly, in main aspect, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I,

Formula I
wherein said process comprising the steps of:
i) reacting doxepinone of Formula III with 3-dimethylamino propyl chloride of Formula II in presence of ethereal solution of magnesium turning and catalyst in a suitable solvent,
-o.
■f
Formula II Formula III
to give ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV,
-o.


Formula IV

and

ii) converting the compound of Formula IV to doxepin hydrochloride of Formula I.
In another aspect, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I by dehydrating 1 l-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV in presence of acid without converting to doxepin free base,


Formula IV
In another aspect, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I, O.

Formula I
wherein said process comprising the steps of:
i) preparing a solution of 3-dimethylamino propyl chloride of Formula II in a
solvent;

CI'

I

Formula II
ii) adding magnesium turnings to an ethereal solvent in presence of catalyst followed by addition of solution of 3-dimethylamino propyl chloride of Formula II of step i) to get a reaction solution;
iii) preparing a solution of doxepinone of Formula III in a solvent and reacting with the reaction solution of step ii) to get 11-(3-(dimethylamino)propyl)-6,11-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV;

Formula III
Formula IV
-o.

iv) acidifying the ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-11 -ol of Formula IV at a temperature of 15°C or above to get doxepin hydrochloride of Formula I without converting into doxepin free base; and v) optionally recrystallizing to get pure doxepin hydrochloride of Formula I.
In another aspect, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I, wherein said process comprising of conversion of compound of Formula IV directly to doxepin hydrochloride without converting into doxepin free base.
In another aspect, the present invention provides crystalline ll-(3-
(dimethylamino)propyl)-6,l l-dihydrodibenzo[b,e]oxepin-l l-ol (doxepin
hydroxide) of Formula IV characterized by X-Ray power diffraction pattern comprising peaks at about 6.48, 12.94, 18.09, 26.02±0.2°29.
In one another aspect, the present invention provides a crystalline form of doxepin hydrochloride characterized by X-Ray powder diffraction pattern comprising peaks at about 11.80, 16.9, 18.70, 21.19, 23.44 ±O.2°20.
In one another aspect, the present invention provides a process of preparing
crystalline form of doxepin hydrochloride, wherein said process comprising the
steps of:
i) treating doxepin hydrochloride with a suitable solvent;
ii) stirring at a temperature in the range from 0°C to ambient temperature; and
iii) filtering and drying crystalline form of doxepin hydrochloride.
DETAILED DESCRIPTION
Brief Description of Drawings
Fig. 1 depicts X-Ray Powder Diffraction (XRPD) of doxepin hydroxide of Formula
IV.
Fig. 2 depicts X-Ray Powder Diffraction (XRPD) of doxepin hydrochloride.

Fig. 3 depicts Differential Scanning Colorimetry (DSC) of doxepin hydrochloride.

In main embodiment, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I,
-o.

HC1
I
Formula I
wherein said process comprising the steps of:
i) reacting doxepinone of Formula III with 3-dimethylamino propyl chloride of Formula II in presence of ethereal solution of magnesium turning and catalyst in a suitable solvent,
-o.
Formula II Formula III
to give ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV,
-o.


Formula IV

and

ii) converting the compound of Formula IV to doxepin hydrochloride of Formula I.
In another embodiment of the present invention, the ethereal solvent is selected from the group comprising of tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, dioxane, diethyl ether, dimethoxy ethane, diisopropyl ether. Preferably tetrahydrofuran is used as an ethereal solvent in above said step (i).

In another embodiment, the catalyst used in preparation of Grignard reagent used for preparing doxepin hydrochloride in step (i) is selected from dibromoethane, iodine, methyl iodide, ethyl iodide.
In another embodiment, the suitable solvent used for preparing doxepin hydrochloride is selected from, but not limited to, alcohols, ethers, acetates, ketones, hydrocarbons halogenated solvents, such as benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, cyclohexane, n-heptane, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methanol, ethanol, butanol, t-butanol, isopropanol, or mixture thereof.
In another embodiment, the compound of Formula IV can be converted to doxepin hydrochloride by the process of the present invention or by any known conventional methods.
In another embodiment, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I by dehydrating ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula rV in presence of acid without converting to doxepin free base,


Formula IV
In one another embodiment, the present provides a process for the preparation of doxepin hydrochloride of Formula I, O.

Formula I
wherein said process comprising the steps of:
i) preparing a solution of 3-dimethylamino propyl chloride of Formula II in a
solvent;

CI'

I

Formula II
ii) adding magnesium turnings to an ethereal solvent in presence of catalyst followed by addition of solution of 3-dimethylamino propyl chloride of Formula II of step i) to get a reaction solution;
iii) preparing a solution of doxepinone of Formula III in a solvent and reacting with the reaction solution of step ii) to get compound of Formula IV;

-o.


Formula III

Formula IV

iv) acidifying compound of Formula IV at a temperature of 15°C or above to get doxepin hydrochloride of Formula I without preparing doxepin free base; and v) optionally recrystallizing to get pure doxepin hydrochloride of Formula I.
In another embodiment, the acid used for dehydrating compound of Formula IV is acid is selected from, but not limited to, the group comprising of hydrochloric acid, sulfuric acid, mixture of sulfuric and nitric acid, bromic acid and phosphoric acid.
In other embodiment of the present invention, the solvent used for preparing doxepin hydrochloride in step (i) and (iii) is selected from the group comprising of toluene, o/m/p-xylene, diethyl ether, diisopropyl ether, methyl tert-butyl ether, cyclohexane and heptane and mixture thereof. Preferably the solvent used in step (i) and (iii) is toluene.
In another embodiment of the present invention, the ethereal solvent is selected from the group comprising of tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, dioxane, diethyl ether, dimethoxy ethane, diisopropyl ether. Preferably tetrahydrofuran is used as an ethereal solvent in above said step (ii).
In another embodiment, the catalyst used in preparation of Grignard reagent used for preparing doxepin hydrochloride in step (ii) is selected from dibromoethane, iodine, methyl iodide, ethyl iodide.
In another embodiment, 11 -(3 -(dimethyl amino)propyl)-6,11-
dihydrodibenzo[b,e]oxepin-l l-ol of Formula IV is isolated with purity of 98% and above.
In another embodiment, 11 -(3 -(dimethyl amino)propyl)-6,11-
dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV is crystalline in nature and is characterized by X-Ray power diffraction pattern comprising peaks at 6.48, 12.94, 18.09, 26.02±0.2°29.

In another embodiment, 11-(3 -(dimethyl amino)propyl)-6,11-
dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV as obtained in step (iii) is characterized by X-Ray power diffraction pattern as represented in Fig. 1.
In one another embodiment, the acidification of compound of Formula rV performed in step iv) can also be carried out by using alcoholic hydrochloric acid such as methanolic hydrochloric acid, ethanolic hydrochloric acid, isopropanolic hydrochloric acid or mixture thereof.
In a preferred embodiment, acidification of compound of Formula IV is carried out by using methanolic hydrochloric acid or isopropanolic hydrochloric acid.
Moreover, the acidification of compound of Formula IV is carried out a temperature of 15°C or above, preferably at 20-40°C followed by heating at elevated temperature of65-85°C.
In one another embodiment, the recrystallization of doxepin hydrochloride of Formula I can be carried out in a solvent selected from hydrocarbons, ethers, esters, ketones, halogenated solvents, alcohols, water and mixture thereof.
Preferably the solvent is selected from hexane, heptane, cyclohexane, nitromethane, tetrahydrofuran, dioxane, methyl tetrahydrofuran, methyl ethyl ether, diethyl ether, ethyl acetate, methyl acetate, butyl acetate, n-propyl acetate, isopropyl acetate, t-butyl acetate, acetone, methyl tert-butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, chloroform, dichloromethane, tetrachloro carbon, dichloroethane, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol, pentanone, water and mixture thereof. Most preferably, the solvent used for recrystallization of doxepin hydrochloride is selected from ketones such as methyl isobutyl ketone, methyl ethyl ketone, acetone or mixture thereof.

As per the present invention, doxepin hydrochloride is prepared by method as mentioned under scheme 1, wherein said method involves less number of reaction steps, wherein conversion of 11-(3 -(dimethyl amino)propyl)-6,11-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV to doxepin hydrochloride is performed without isolating doxepin free base, hence, involves minimum loss of solvents and reagents in purification and work ups. Scheme 1


Dimethylamino propyl chloride hydrochloride
Formula II
alcoholic HC1
O Formula III

In further embodiment, the present invention provides a process for the preparation of doxepin hydrochloride of Formula I, wherein said process comprising of conversion of compound of Formula IV directly to doxepin hydrochloride without isolating/preparing doxepin free base.
In one another embodiment, the present invention provides a crystalline form of doxepin hydrochloride which is characterized by X-Ray powder diffraction pattern comprising peaks at about 11.80, 16.90, 18.70, 21.19, 23.44 ±O.2°20.

In further embodiment, the present invention provides crystalline form of doxepin hydrochloride which is characterized by X-Ray powder diffraction pattern comprising peaks at about 11.80, 12.43, 12.92, 13.68, 14.97, 15.91, 16.26, 16.62, 16.90, 17.96, 18.70, 18.98, 19.60, 19.83, 21.19, 21.53, 22.04, 22.75, 23.44, 23.71, 24.00, 24.93, 26.02, 26.85, 27.55, 27.88, 28.42, 28.65, 29.22, 29.57, 30.20, 31.41, 32.06, 32.88, 34.18, 35.66, 36.49, 37.34, 38.71, 39.24 ±O.2°20.
In one another embodiment, the present invention provides a crystalline form of doxepin hydrochloride which is characterized by X-Ray powder diffraction pattern as represented in Fig. 2.
In further embodiment, the present invention provides a crystalline form of doxepin hydrochloride which is characterized by differential scanning colorimetry with endotherm peak at about 190.75°C.
In further embodiment, the present invention provides a crystalline form of doxepin hydrochloride which is characterized by differential scanning colorimetry with onset peak at about 189.24°C.
In another embodiment, the present invention provides a crystalline form of doxepin hydrochloride which is characterized by differential scanning colorimetry as represented in Fig. 3.
In another embodiment, the present invention provides a process for preparing crystalline doxepin hydrochloride, wherein said process comprising the steps of: i) treating doxepin hydrochloride with a suitable solvent; ii) stirring at a temperature in the range from 0°C to ambient temperature; and iii) filtering and drying to get crystalline doxepin hydrochloride.
In one another embodiment, the present invention provides a process of preparing crystalline form of doxepin hydrochloride characterized by X-Ray powder

diffraction pattern comprising peaks at about 11.80, 16.9, 18.70, 21.19, 23.44
±0.2°29, wherein said process comprising the steps of:
i) treating doxepin hydrochloride with a suitable solvent selected from esters,
ketones, or mixture thereof;
ii) stirring at a temperature in the range from 0°C to ambient temperature; and
iii) filtering and drying crystalline form of doxepin hydrochloride.
In further embodiment, the suitable solvent used for preparing crystalline form of doxepin hydrochloride is selected from esters, ketones or mixture thereof, wherein said ketone solvent are selected from, but not limited to, acetone, methyl tert-butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, pentanone; wherein said ester solvent are selected from, but not limited to, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, propenyl acetate, butyl acetate, t-butyl acetate; or mixture thereof. Preferably the solvent is selected from methyl isobutyl ketone, methyl ethyl ketone, acetone, ethyl acetate, t-butyl acetate, and mixture thereof.
In another embodiment, the present invention provides a process for preparing crystalline form of doxepin hydrochloride by treating doxepin hydrochloride with ketone and stirring the reaction solution so obtained at a temperature of 0°C to ambient temperature wherein ambient temperature is preferably room temperature.
In further embodiment, the present invention provides a pharmaceutical composition comprising crystalline form of doxepin hydrochloride and at least one pharmaceutically acceptable excipient, wherein said crystalline form is prepared as per the process of the present invention.
In a preferred embodiment, the present invention provides a composition comprising doxepin hydrochloride and at least one pharmaceutically acceptable excipient, wherein said doxepin hydrochloride is prepared as per the process of the present invention.

In further embodiment, the present invention provides an amorphous form of doxepin hydrochloride wherein said amorphous form is substantially free from crystalline form.
In one more embodiment, the present invention provides substantially pure doxepin hydrochloride free from impurity, 11-(3 -(dimethyl amino)propyl)-6,11-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV and other related impurities wherein each impurity is less than about 0.2% w/w.
In further embodiment, the present invention provides doxepin hydrochloride isolated with purity of 98% or above and preferably 95% or above and most preferably 99% or above.
In other embodiment, the crystalline form of doxepin hydrochloride obtained after recrystallization is isolated with purity of 98% or above and preferably, 99% or above, and 99.9% or above.
In another embodiment, the doxepin hydrochloride is characterized by particle size distribution wherein, d90 is 0.1 um to 200um. In preferred embodiment, the doxepin hydrochloride is characterized by particle size distribution wherein, d% is 2.0 um to 150um.
Further, the present invention is illustrated in detail by way of the following examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES
EXAMPLE 1
Preparation of toluene solution of dimethylamino propyl chloride of Formula
II

Charged 126.5g of dimethylamino propyl chloride hydrochloride 60-65% aq. solution (2.5 mol eq w.r.t doxepinone) and added 50% aq. sodium hydroxide solution followed by addition of toluene. Stirred the reaction mixture till completion of reaction. After completion of reaction, separated the layers and dried the toluene layer which is used as such in next step.
EXAMPLE 2
Preparation of ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]
oxepin-11-ol of Formula IV
Charged magnesium turnings in tetrahydrofuran and heated the reaction solution at
65°C. Added catalytic amount 0.5ml of dibromoethane followed by addition of
toluene solution of dimethylamino propyl chloride obtained from example 1, drop
wise maintaining the temperature at 60-65°C. Stirred the reaction mass so obtained
and then cooled to RT. Separately prepared the toluene solution of doxepinone of
Formula III by adding 50g of doxepinone to 200 ml of toluene. Added toluene
solution of doxepinone to the former reaction mass and stirred the reaction mass for
2 h and cooled the reaction mass to 5-10°C. Added water to the reaction mass and
added 10% sulphuric acid aq. solution. Stirred and separated the layers followed by
distillation of organic layer under vacuum at 50-55°C to get white colour crystal of
1 l-(3-(dimethylamino)propyl)-6,l l-dihydrodibenzo[b,e]oxepin-l l-ol. Added
water to the above crystals. Filtered the crystals and dried to get pure 11-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV (64g, yield=90.0%, Purity: 98.0%)
EXAMPLE 3
Preparation of doxepin hydrochloride of Formula I
Added methanol (3V) and -10-15% Methanolic.HCl (1.30 mol. equivalent) to 75g (1.0 mol equivalent) of compound of Formula IV at 20-25°C. Heated the reaction mass to 70-75°C. Stirred the reaction mass for 1.0 h and distilled out the solvent completely under vacuum to get oily mass.

Added MIBK (5V) and stirred at 40°-90°C to get precipitate. Filtered the precipitates so obtained at 20°-40°C to get 71g of doxepin hydrochloride of Formula I. (Yield: 90%, Purity: 99.8%)

WE CLAIM:

1. A process for the preparation of doxepin hydrochloride of Formula I,
-o.


Formula I
wherein said process comprising the steps of:
i) reacting doxepinone of Formula III with 3-dimethylamino propyl chloride of Formula II in presence of ethereal solution of magnesium turning and catalyst in a suitable solvent,
O.
T
Formula II Formula III
to give ll-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-ll-ol of Formula IV, -o.


Formula IV

and

ii) converting the compound of Formula IV to doxepin hydrochloride of Formula I.
2. The process as claimed in claim 1, wherein said ethereal solution of magnesium turning is prepared by taking magnesium turnings in ether selected from the group comprising of tetrahydrofuran, methyl tetrahydrofuran, tert-butyl methyl ether, dioxane, diethyl ether, dimethoxy ethane, and diisopropyl ether, and wherein said catalyst is selected from dibromoethane, iodine, methyl iodide, and ethyl iodide.

3. The process as claimed in claim 1, wherein said solvent is selected from the group comprising of benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, cyclohexane, n-heptane, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methanol, ethanol, butanol, t-butanol, isopropanol or mixture thereof.

4. A process for the preparation of doxepin hydrochloride of Formula I by dehydrating 1 l-(3-(dimethylamino)propyl)-6,l l-dihydrodibenzo[b,e]oxepin-l l-ol of Formula IV in presence of acid without converting to doxepin free base,
Formula IV
o.
5. The process as claimed in any of the preceding claim, wherein preparation of doxepin hydrochloride of Formula I,


comprising of:
i) preparing a solution of 3-dimethylamino propyl chloride of Formula II in a
solvent;
CI'^Ss/S'N/
I
Formula II
ii) adding magnesium turnings to an ethereal solvent in presence of catalyst followed by addition of solution of 3-dimethylamino propyl chloride of Formula II of step i) to get a reaction solution;
iii) preparing a solution of doxepinone of Formula III in a solvent and reacting with the reaction solution of step ii) to get compound of Formula IV;
-o.

o
Formula III Formula IV
iv) acidifying compound of Formula IV at a temperature of 15°C or above to get doxepin hydrochloride of Formula I without preparing doxepin free base; and v) optionally recrystallizing to get pure doxepin hydrochloride of Formula I.
6. The process as claimed in claim 4 and 5, wherein said acid is selected from the group comprising of hydrochloric acid, sulfuric acid, mixture of sulfuric and nitric acid, bromic acid and phosphoric acid, methanolic hydrochloric acid, ethanolic hydrochloric acid, isopropanolic hydrochloric acid or mixture thereof.
7. Crystalline 1 l-(3-(dimethylamino)propyl)-6,ll-dihydrodibenzo[b,e]oxepin-l 1-ol of Formula IV characterized by X-Ray power diffraction pattern comprising peaks at about 6.48, 12.94, 18.09, 26.02±0.2°29.
8. A process for preparing crystalline doxepin hydrochloride, wherein said process comprising the steps of:
i) treating doxepin hydrochloride with a suitable solvent;

ii) stirring at a temperature in the range from 0°C to ambient temperature; and iii) filtering and drying to get crystalline doxepin hydrochloride.
9. The process as claimed in claim 8, wherein said crystalline doxepin
hydrochloride is characterized by X-Ray powder diffraction pattern comprising
peaks at about 11.80, 16.9, 18.70, 21.19, 23.44 ±O.2°20.
10. A substantially pure doxepin hydrochloride free from impurity, ll-(3-
(dimethylamino)propyl)-6,l l-dihydrodibenzo[b,e]oxepin-l l-ol of Formula IV and
other related impurities wherein each impurity is less than about 0.2% w/w.