FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(Section 10)
Process for the preparation of Sertraline hydrochloride form - II
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT MAHALAXMI
CHAMBERS, 2ND FLOOR, 22, BHULABHAI DESAI ROAD, MUMBAI
400 026, MAHARASHTRA, INDIA
The following specification particularly describes the nature of the invention and the manner in which it is to be performed

Process for the preparation of Sertraline hydrochloride Form-11
The invention relates to a process for the preparation of Form-11 of Cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthalenamine hydrochloride. (Sertraline hydrochloride) .
Background of the invention:
Sertraline hydrochloride acts to block the synaptosomal uptake of serotonin (5-hydroxy-tryptamine) thereby alleviating serotonin abnormalities at central receptor sites. It is useful for the treatment of mental depression, obsessive-compulsive disorder and panic disorder.
U.S. 4,536,518 discloses the synthesis of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone and its conversion to Sertraline. The hydrochloride salt is prepared using free base in a mixture of ether and ethyl acetate by reacting with excess hydrogen chloride gas. The product is characterized by melting point, specific optical rotation & elemental analysis.
U.S. Patent no 5,248,699 discloses the process for the preparation of five polymorphic forms of Sertraline hydrochloride. The characterization data like X-ray powder diffractogram (XRPD), differential scanning calorimetry (DSC) and Infrared (IR) is also disclosed. This patent in Column no.l, under the description of background of invention describes
"U.S. Pat. No. 4536518 does not refer to specific polymorphic crystalline forms of Sertraline hydrochloride. The synthetic procedure described and exemplified in U.S. Pat. No. 4536,518 produces the Sertraline hydrochloride polymorph designated herein as Form II and described below. It does not suggest the existence of different polymorphic forms of Sertraline".
This patent also discloses the general method for the preparation of Form-II by rapid crystallization of Sertraline hydrochloride in solvent such as isopropanol, hexane, acetone, methyl isobutyl ketone, glacial acetic acid and ethylacetate.
WO 0032551A1 describes the preparation of Sertraline hydrochloride from sertraline base by dissolving it in acetone and lowering the pH of the solution by addition of hydrogen chloride solution, such as hydrogen chloride in isopropanol. The patent further describes the recrystallization of Sertraline hydrochloride using dimethyl formamide or cyclohexanol.
US 0132828 discloses the preparation of Sertraline hydrochloride form-II wherein the solution of Sertraline free amine in ketonic solvent is seeded with the crystals of Form-11 at room temperature (RT) to 55-60 °C and hydrogen chloride solution in water or acetone is added.
WO 01/45692 Al describes the process for preparing Sertraline hydrochloride form-11 from Sertraline hydrochloride form-XIV or form -XV or form-XVI.
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WO 03/099761 Al describes the preparation of form-II by dissolving the Sertraline base in 2-propanol and precipitating with 1.25 molar excess of 3M 2-propanol hydrochloric acid and diisopropyl ether. The product is recrystallized using dimethyl formamide.
W.O.02/096859AI disclosed the conversion of Sertraline mandelate in to Sertraline base in ethyl acetate. Ethyl acetate is distilled off and replaced with isopropanol. The solution of Sertraline base in isopropanol is reacted with hydrogen chloride 12 to 14% in ethyl acetate at 40-65 °C using the seed crystals of polymorphic form-II.
WO 03/093217A1 describes the preparation of form-II substantially free of form-I using Sertraline base or Sertraline mandelate in suitable solvents like n-butanol, cyclohexane, ethyl acetate, acetone, hexane, t-butyl methyl ether, DMF and mixture thereof by contacting the solution or the slurry with a flow of gaseous hydrogen chloride at 30 to 60 °C.
Summary of the Invention:
The main objective of the invention is to provide a new method for the preparation of Sertraline hydrochloride Form-II.
It is an another object of the invention is to provide a process for the preparation of Sertraline hydrochloride Form-II using single solvent.
It is yet another object of the invention is to provide a common method of the preparation for Sertraline hydrochloride Form-II from either Sertraline base or Sertraline mandalate
salt.
It is an another object of the invention is to provide a process for the preparation of Sertraline hydrochloride Form-II without the use of seed.
It is yet another object of the invention is to provide X-ray powder diffractogram (XRPD) and Infrared (IR) characterization data for the crystalline Sertraline hydrochloride Form-II of current invention.
Description of figures:
Figure 1 shows the XRPD of Sertraline hydrochloride Form-II prepared using the
process of present invention. Figure 2 shows IR spectrum of Sertraline hydrochloride Form-II prepared using the
process of present invention
Description of the Invention:
Sertraline free base and Sertraline mandelate used in this invention is prepared by the process given in US patent no 4536518.
A) The process for preparing Cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyI)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride (Sertraline hydrochloride) Form-II using Sertraline free base comprises steps,
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(a) Dissolution of Sertraline base in acetonitrile,
(b) Addition of hydrogen chloride gas or a solution prepared in water or suitable solvents like isopropanol, ethylacetate and acetonitrile below 45 C,
(c) Filtration of product, washing with acetonitrile and drying of product.
B) The process for preparing Cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine hydrochloride (Sertraline hydrochloride) Form-II using Sertraline mandelate comprises steps,
(a) Suspension of Sertraline mandelate in acetonitrile,
(b) Optional addition of Sertraline hydrochloride Form-II seed material,
(c) Addition of hydrogen chloride gas or solution prepared in water or suitable solvents like isopropanol, ethylacetate and acetonitrile below 45°C,
(d) Filtration of product, washing with acetonitrile and drying of product.
The XRPD and the IR spectrum of crystalline Sertraline hydrochloride of the present invention matches with the authentic Form-II material and the characterization data on Sertraline hydrochloride Form-II disclosed in US 5248699.
The following non limiting examples illustrates the invention
Example 1: - Preparation of Sertraline hydrochloride polymorph form-II from sertraline base
10 gm Sertraline free base is added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C. 15% hydrogen chloride gas absorbed in acetonitrile (25ml) is gradually added to the reaction mixture and stirred further for 30 mins at 5-10°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get Sertraline hydrochloride polymorph form-II. Yield = 10.5 gms Purity by HPLC= 99.51% Loss on drying = 0.11 %
Example 2: - Preparation of sertraline hydrochloride polymorph form-II from sertraline mandelate
10 gm Sertraline mandelate is added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C and 1 gm Sertraline hydrochloride Form-II seed is added. 15% hydrogen chloride gas absorbed in acetonitrile (25ml) is gradually added to the reaction mixture and stirred further for 1 hr at 0-5°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get Sertraline hydrochloride polymorph form-II. Yield = 6.2 gms Purity by HPLC = 99.67 % Loss on drying = 0.08 %
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Example 3: - Preparation of sertraline hydrochloride polymorph form-II from sertraline base
10 gm Sertraline free base is. added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C. 15% hydrogen chloride gas absorbed in isopropanol (25ml) is gradually added to the reaction mixture and stirred further for 30 min at 0-5°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get Sertraline hydrochloride polymorph form-II. Yield = 10.2 gms Purity by HPLC = 99.72 % Loss on drying = 0.13 %
Example 4: - Preparation of sertraline hydrochloride polymorph form-II from sertraline mandelate
10 gm Sertraline mandelate is added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C. 15% hydrogen chloride gas absorbed in isopropanol (25ml) is gradually added to the reaction mixture and stirred further for 30 min hr at 0-5°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get Sertraline hydrochloride polymorph form-II. Yield = 6.35 gms Purity by HPLC = 99.80 % Loss on drying = 0.20 %
Example 5: - Preparation of sertraline hydrochloride polymorph form-II from sertraline base.
10 gm Sertraline free base is added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C and 1 gm Sertraline hydrochloride Form-II seed is added. 35% aqueous hydrochloric acid (5ml) is gradually added to the reaction mixture and stirred further for 30 min at 0-5°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get Sertraline hydrochloride polymorph form-II. Yield = 10.3 gms Purity by HPLC = 99.83 % Loss on drying = 0.08 %
Example 6: - Preparation of sertraline hydrochloride polymorph form-II from sertraline Mandelate.
10 gm Sertraline mandelate is added in 100 ml acetonitrile. The reaction mixture is cooled to 10-15°C and 1 gm Sertraline hydrochloride Form-II seed is added. 35% aqueous hydrochloric acid (5ml) is gradually added to the reaction mixture and stirred further for 30 min at 0-5°C. Product is filtered, washed with 2 x 10 ml acetonitrile and dried at 70-75°C under vacuum to get. Sertraline hydrochloride polymorph form-II. Yield = 6.57 gms Purity by HPLC = 99.47 % Loss on drying = 0.18 %

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We Claim: -
1. Process for making Sertraline hydrochloride Form-11 using Sertraline base comprising-
steps,
(a) Dissolution of Sertraline base in acetonitrile,
(b) Addition of hydrogen chloride gas or a solution prepared in water or suitable solvents like isopropanol, ethylacetate and acetonitrile below 45 C,
( c) Filtration of product, washing with acetonitrile and drying of product.
2. Process for making Sertraline hydrochloride Form-11 using Sertraline mandelate
comprising steps,
(a) Suspension of Sertraline mandelate in acetonitrile,
(b) Addition of Sertraline hydrochloride Form-II seed material
(c) Addition of hydrogen chloride gas or a solution prepared in water or suitable solvents like isopropanol, ethylacetate and acetonitrile below 45°C,
(d) Filtration of product, washing with acetonitrile and drying of product.

3. Process for making Sertraline hydrochloride Form-II, as claimed in claim no. 1 and 2, wherein the temperature during addition of hydrogen chloride is 10 - 20°C.
4. Process for making Sertraline hydrochloride Form-II, as claimed in claim no. 2, wherein the quantity of seed is 0 - 25 % w/w. More preferably between 2 to 10 % w/w.
5. Process for making Sertraline hydrochloride Form-II, as claimed in claim no. 1 and 2, wherein the quantity of acetonitrile used is 5 to 25 times v/v based on Sertraline base/mandelate input. More preferably between 10-15 times v/v.
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ABSTRACT
Process for the preparation of Sertraline hydrochloride form-II:
Formula-I
The present invention discloses a process for the preparation of Sertraline hydrochloride form-11. The form-II of Sertraline hydrochloride, which is cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-! ,2,3,4-tetrahydro-l-naphthalenamine hydrochloride (Formula-I)

1 5 FEB 2005