FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
A PROCESS FOR PREPARING SERTRALINE HYDROCHLORIDE POLYMORPH-V;
AMOLI ORGANICS LTD., A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 407, DALAMAL HOUSE, J. BAJAJ ROAD, NARIMAN POINT, MUMBAI 400 021, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION
PARTICULARLY DESCRIBES THE
INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.
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A PROCESS FOR PREPARING SERTRALINE HYDROCHLORIDE
POLYMORPH - V
FIELD OF INVENTION
The present invention relates to a process for manufacturing polymorph of sertraline salt and preferably to the sertraline hydrochloride polymorph - V.
BACKGROUND OF THE INVENTION
Sertraline Hydrochloride belongs to a class of drugs called selective serotonin reuptake inhibitor (SSRI). The chemical name of Sertraline Hydrochloride is (1S-cis)- 4 - (3, 4 - dichlorophenyl)-1,2, 3, 4-tetrahydro-N-methyl-1- naphthalenamine hydrochloride. The empirical formula C17H17NCI2 -HCI is represented by the following structural formula:

Sertraline is a well known anti depressant drug. Its pharmacological effect is based on its ability to be a cogent and selective brain serotonin reuptake inhibitor. Sertraline is used to treat depression, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), bipolar disorder and social anxiety disorder, also known as social phobia.
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WO 00/32551 A1 discloses a process for the synthesis of sertraline hydrochloride polymorph V. In the reaction disclosed by this patent application, sertraline base is produced by dissolving sertraline mandelate in ethyl acetate followed by neutralization of sertraline mandelate with aqueous sodium hydroxide. The organic phase is separated from the aqueous phase and dried using magnesium sulphate. The solvent is removed under pressure to produce sertraline base as oil. Sertraline base is then dissolved in a solvent selected from group I consisting of methanol, ethanol, water, or mixtures of methanol, ethanol, isopropyl, alcohol, hexane, and ethyl acetate with each other or with water. This is further treated with hydrogen chloride gas to make sertraline hydrochloride polymorph V and sertraline hydrochloride polymorph V is isolated by allowing precipitation to occur from about 0-60 deg C. This method requires multiple solvents e.g. ethyl acetate for the preparation of sertraline base and another solvent selected from group I for the formation of sertraline hydrochloride polymorph V.
US patent Application 20050032907 describes a process for the preparation of Form V of sertraline hydrochloride. The process involves preparation of sertraline base by hydrolysis of sertraline mandelate with sodium hydroxide in toluene, followed by water work up and phase separation. The solvent of the resulting solution may be removed completely by distillation. Sertraline base is then dissolved in a suitable solvent and treated with an amine hydrochloride to form sertraline hydrochloride Form V. The solvent selected for the formation of sertraline hydrochloride Form V is from the group consisting of water: ethanol, propanol. The methods disclosed in the WO00/32551 A1, US 20050032907 patent applications and the prior art methods for the preparation of Form V of sertraline hydrochloride include at least two solvents and/or mixtures of solvents. Further these methods are indirect methods that include separation of the sertraline base formed in the intermediate process by distillation or evaporation of solvent, thereby increasing the manufacturing cost and lengthening the procedure to manufacture Form V of sertraline hydrochloride.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a simple process for the formation of polymorph V of sertraline hydrochloride.
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Another object of the present invention is to provide a direct process for the formation of polymorph V of sertraline hydrochloride from the salts of sertraline such as sertraline mandelate.
Further object of the present invention is to provide an economically viable process for manufacturing polymorph V of sertraline hydrochloride.
According to one of the embodiments of the present invention, a process for
manufacturing polymorph V of sertraline hydrochloride comprises steps of
suspending salt of sertraline in a halocarbon solvent; adding a base to the
suspension resulting in the formation of an organic phase and an aqueous
phase; treating the organic phase with hydrochloric acid; and isolating sertraline
hydrochloride polymorph V. The organic phase can be separated from aqueous
phase.
According to the present invention, the solvent is selected from a halocarbon
group. Preferably the solvent is dichloromethane, carbon tetrachloride, ethylene
dichloride and chloroform or mixture of halocarbon solvent with water. Most
preferably the solvent is dichloromethane.
The salt of sertraline used in the present invention to carry out the reaction is
selected from mandelate, acetate, citrate or hydrochloric acid salt of sertraline.
Preferable salt used to carry out the reaction is mandelate salt of sertraline.
The base used in the present invention to carry out the reaction is selected from
the group of sodium hydroxide, potassium hydroxide, ammonia, sodium
carbonate, sodium bicarbonate and the likes thereof.
In another embodiment of the present invention sertraline base is dissolved in
halocarbon solvent and treated with hydrochloric acid to form polymorph V of
sertraline hydrochloride. The solvent used for dissolving sertraline base is
halocarbon selected from the group of dichloromethane, carbon tetrachloride,
ethylene dichloride, chloroform or mixture of halocarbon solvent with water,
preferably the solvent is dichloromethane.
The process for preparing polymorph V of sertraline hydrochloride as mentioned
in the present invention provides an economically viable process with a yield of
82-83 % and 99.9 % HPLC purity. Use of a single solvent and lessening the
number of the manufacturing steps of the process thereby reduce the cost of
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manufacture of polymorph V of sertraline hydrochloride relative to the prior art processes.
DETAILED DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic Powder X-ray diffraction pattern of Sertraline hydrochloride polymorph V.
Figure 2 is a characteristic IR spectrum of Sertraline hydrochloride polymorph V.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is addressed towards a process to prepare 1S-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride polymorph V (Sertraline hydrochloride polymorph V).
Following is the general scheme of the reaction for the preparation of Sertraline hydrochloride polymorph V by the present invention from sertraline salt:

1= Sertraline salt, wherein
X= Mandelic, acetic, citric or hydrochloric acid
11= Sertraline hydrochloride polymorph V
As depicted in the general scheme of the reaction, the process for manufacturing Sertraline hydrochloride polymorph V according to the present invention includes steps of:
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a. Suspension of a salt I of (1S-cis)-4-(3,4-dichlorophenyl)- 1,2,3,4-
tetrahydro-N-methyl-1-naphthalenamine in a solvent;
b. Basification of the salt by adding a base in the suspension;
c. addition of hydrochloric acid in the solution to obtain II i.e. the desired
polymorph V of sertraline hydrochloride; and
d. isolation of the sertraline hydrochloride polymorph V in crystalline form.
In one of the embodiments of the present invention sertraline salt such as sertraline mandelate, sertraline hydrochloride is suspended in a halocarbon solvent to form a suspension. Other salts of sertraline like sertraline acetate or sertraline citrate can be used in the reaction. The solvent used to suspend either is selected from group of halocarbons such as dichloromethane, carbon tetrachloride, ethylene dichloride, chloroform, or mixture of halocarbon solvent with water. The preferable halocarbon used to carry out the reaction is dichloromethane. Base is added to the suspension for carrying out the basification of the sertraline salt. The base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate or ammonia and the likes thereof. Two phases i.e. an organic phase and an aqueous phase are formed. Sertraline base formed dissolves in the organic phase i.e. in halocarbon solvent. The organic layer is separated and washed with water to remove unwanted salts. Hydrochloric acid is gradually added to the organic phase to attain a pH of 1-2. The solution is refluxed for about 4 hours at a temperature of about 40-50 deg C to yield II i.e. Sertraline hydrochloride polymorph V. Sertraline hydrochloride polymorph V is isolated in crystalline form by cooling the mass to ambient temperature at about 25-30 deg C and then to 5 - 10 deg C for crystallization followed by filtration and drying of the precipitate. The dried sertraline hydrochloride polymorph V has 99.9 % HPLC purity and molar yield is of 82-83%.
In yet another embodiment of the present invention sertraline base is dissolved in a halocarbon solvent selected from the group of dichloromethane, carbon tetrachloride, ethylene dichloride, chloroform or mixture of halocarbon solvent with water. The preferable solvent used to carry out the reaction is dichloromethane. The solution is treated with HCI. The solution is refluxed for about 4 hours at a temperature of about 40-50 deg C to yield II i.e. Sertraline
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hydrochloride polymorph V. Sertraline hydrochloride polymorph V is isolated in crystalline form by cooling the mass to ambient temperature at about 25-30 deg C and then to 5 - 10 deg C for crystallization followed by filtration and drying of the precipitate. The dried sertraline hydrochloride polymorph V has 99.9 % HPLC purity and molar yield is of 82-83%.
The sertraline hydrochloride Form V that results from practicing the invention as exemplified herein is characterized by its Powder X-ray diffraction pattern. Figure 1 is a representative pattern of sertraline hydrochloride Form V. The peaks observed in terms of angles (26, degrees) are listed below:

28 (+0.2) d-space (+0.2)A Relative intensity%
4.05 21.78 100.00
5.11 17.28 24.22
10.31 8.57 29.85
10.87 8.13 82.57
14.11 6.27 36.15
15.54 5.70 5.17
16.26 5.44 26.79
17.07 5.19 22.80
18.32 4.84 31.77
18.54 4.78 13.30
18.92 4.68 54.56
19.23 4.61 29.74
19.62 4.52 48.20
19.93 4.45 9.74
20.80 4.26 26.55
21.16 4.19 4.92
21.92 4.05 26.49
22.97 3.87 29.38
23.47 3.78 37.05
25.16 3.53 64.31
25.32 3.51 91.72

25.84 3.44 40.88
26.67 3.34 8.18
27.68 3.22 11.30
28.97 3.08 37.20
30.32 2.94 17.50
30.94 2.89 6.54
31.17 2.86 15.15
32.07 2.79 8.13
32.98 2.71 18.50
33.30 2.69 21.62
33.58 2.66 6.16
34.41 2.60 9.01
35.66 2.51 4.48
36.04 2.49 11.63
37.12 2.42 2.65
37.68 2.38 8.02
38.35 2.34 5.77
39.15 2.30 5.47
39.96 2.25 7.65
40.59 2.22 9.37
42.00 2.15 5.72
42.48 2.12 3.71
42.93 2.10 3.66
43.46 2.08 4.47
44.80 2.02 9.93
45.54 1.99 8.29
47.02 1.93 6.83
47.80 1.90 7.10
48.61 1.87 3.18
The IR spectrum of sertraline hydrochloride Form V produced by the present process is characterized by the bands: 2459 cm-1, 1589.2 cm-1, 1469 cm-1, 1406 cm-1, 1332 cm-1, 1211 cm-1, 1134 cm-1, 1078 cm-1, 1031 cm-1, 958 cm-1, 821 cm-1, 775 cm-1, 740 cm-1 as shown in Figure 2.
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The following examples illustrate the invention, but are not limiting thereof.
EXAMPLE 1
Preparation of sertraline hydrochloride polymorph V
Sertraline mandelate (50 gms) was suspended in 200 ml of dichloromethane and 100 ml water. Liquor ammonia solution (20%, 100 ml), was added at 25-30°C under stirring. After 15 min. at 25-30°C the organic layer was separated. Aqueous layer was extracted with dichloromethane (3 x 50 ml). Organic layers were pooled and washed with water (3 x 50ml). Organic layers were then treated at 25-30°C by gradual addition of. aqueous hydrochloride acid (30%) to attain a pH of about 1-2. Then the whole was heated to reflux. After about 4 hrs. of reflux, cooled to 25-30°C and further stirred, for 14 hrs. Crystals were collected by filtration and dried to constant weight. Yield: 30 gm (molar yield - 82. 0%). Melting range: 242-246°C (Capillary method).
Example 2:
Preparation of sertraline hydrochloride polymorph V
Sertraline mandelate (50 gms) was suspended in 200 ml of ethylene dichloride and 100 ml water. Liquor ammonia solution (20%, 100 ml), was added at 25-30°C under stirring. After 15 mins at 25-30°C the organic layer was separated. Aqueous layer was extracted with ethylene dichloride (3 x 50 ml). Organic layers were pooled and washed with water (3 x 50ml). Organic layers were then treated at 25-30°C by gradual addition of aqueous hydrochloride acid (30%) to attain a pH of about 1-2. Then the whole was heated to reflux. After about 4 hrs of reflux, cooled to 25-30°C and further stirred for 14 hrs. Crystals were collected by filtration and dried to constant weight. Yield: 31 gms (molar yield - 83.0%). Melting range: 242-247°C (Capillary method).
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We Claim:
1. A process for preparing a polymorph V of (1S-cis)-4-(3,4-dichlorophenyl)-
1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride comprising:
a. suspending a salt of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-1-naphthalenamine in a suitable solvent;
b. adding a base to the suspension formed to generate sertraline
base;
c. treating organic layer with HCI.
2. A process as claimed in claim 1, wherein step b further comprises of separating organic phase from the aqueous phase.
3. A process as claimed in claim 1, wherein the solvent is a halocarbon or mixture of halocarbon and water.
4. A process as claimed in claim 3, wherein the solvent is dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, preferably dichloromethane or mixture of the solvent with water.
5. A process as claimed in claim 1, wherein the salt of sertraline is a mandelate, acetate, citrate or hydrochloric acid salt, preferably mandelate salt.

6. A process as claimed in claim 1, wherein the base includes sodium hydroxide, potassium hydroxide, ammonia, sodium carbonate, sodium bicarbonate and the likes thereof.
7. A process for manufacturing polymorph V of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenaminehydrochloride comprising the steps of dissolving
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sertraline base in halocarbon solvent or mixture of halocarbon solvent with water and treating with HCI.
8. A process as claimed in claim 7, wherein the solvent is a halocarbon or mixture of halocarbon and water.
9. A process as claimed in claim 8, wherein the solvent is dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform, preferably dichloromethane or mixture of the solvent with water.
10. A process for the preparation of Sertraline Hydrochloride polymorph V as described in the preceding claims and description.

Dated this 27th Day of March 2006

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Abstract
The present invention provides a process for manufacturing polymorph V of (1S-cis)-4-(3,4-dichlorophenyl)-1t2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride (Sertraline hydrochloride polymorph V) of the formula:

comprising the steps of suspending salt of (1S-cis)-4-(314-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine in a suitable solvent; adding a base to the suspension formed to generate sertraline base and treating the organic layer with hydrochloric acid to yield the product with 99. 9 % HPLC purity and with a yield of 82-83%.
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