FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - A NOVEL PROCESS FOR PREPARATION OF
POLYMORPHIC FORM II OF SERTRALINE HYDROCHLORIDE

2. Applicant(s)
(a) NAME :
(b) NATIONALITY
(c) ADDRESS :

LUPIN LIMITED
An Indian Company.
159, CST Road, Kalina, Santacruz (East), Mumbai 400 098, Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION
The following specification Particularly describes the invention and the manner in which it is to be performed:


FIELD OF INVENTION
The present invention relates to a novel process for preparation of polymorphic Form II of the chemical entity (1S, 4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride [CAS No. 79559-97-0], generically known as Sertraline hydrochloride of formula I, free from any other polymorph.

BACKGROUND AND PRIOR ART
Sertraline hydrochloride of formula I is an antidepressant drug useful for the treatment of panic disorder and obsessive compulsive disorder. Sertraline hydrochloride is reported to exist in 16 different crystalline forms (Form I to Form XVI) and in amorphous form as well. The marketed form of sertraline hydrochloride is the Form II. Several methods have been cited for preparation of these various polymorphic forms of sertraline hydrochloride.
US 4,536,518 (the product patent) describes a process for preparation of sertraline hydrochloride without characterizing its crystalline form. However, as per later US Patent No. 5,248, 699 the synthetic process described and exemplified in US '518 produces crystalline sertraline hydrochloride of polymorphic Form II.

US. 5,248,699 describes the formation of Form I, Form III, Form IV, and Form V of sertraline hydrochloride and also Form II by following the process described and exemplified in US. 4,536,518. The use of acetone as well as methyl isobutyl ketone as solvents for the preparation of metastable Form II of sertraline hydrochloride although is not exemplified i.e. no enabling disclosure is made in this patent but their use for the preparation of metastable Form II of sertraline hydrochloride has been mentioned.
US. 6,459,721 describes various methods for preparation of polymorphic Form II of sertraline hydrochloride among which one of the method comprises of; a) preparing solution of sertraline base or sertraline mandelate in an organic solvent to form a solution; b) adding gaseous hydrogen chloride or its solution in an organic solvent to (a); c) heating the solution to a temperature between about room temperature and about reflux for a time sufficient to induce the formation of sertraline hydrochloride form II and; d) isolating sertraline hydrochloride form II.
The organic solvents disclosed and claimed are selected from the group consisting of dimethylformamide, cyclohexanol, acetone and mixtures thereof.
WO 01/32601 A1 describes preparation of polymorphic Form II of sertraline hydrochloride in methyl isobutyl ketone. The process comprises of: a) preparing solution of sertraline base in methyl isobutyl ketone, b) heating to 60°C, c) addition of seed of pure polymorphic Form II at 60°C, d) addition of aqueous hydrochloric acid to get pH <5 and, e) cooling to 20°C followed by filtration of solid (example 12, page 11). The invention requires seeding of the reaction mixture with the pure polymorph II of sertraline hydrochloride.
OBJECTS OF INVENTION
An object of the present invention is to provide a method for producing Form II of (1S, 4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenamine hydrochloride in high yield and purity, without any contamination whatsoever of other polymorphs.

Another object of the present invention is to provide a method for producing Form II of (1S, 4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, which is reproducible, applicable on industrial scale and could be achieved in short time.
SUMMARY OF INVENTION
Thus according to the basic aspect of the present invention there is provided a process for preparing sertraline hydrochloride Form II, free from any other polymorph, comprising the steps of:
(a) dissolution of sertraline base or its mandelate salt in methyl isobutyl ketone (MIBK),
(b) heating the solution to 60-65°C,
(c) addition of hydrogen chloride gas or a solution of hydrogen chloride to the reaction mixture
(d) maintaining the reaction temperature at 60-65°C for 0.5 to 4 hours and
(e) cooling the reaction mixture gradually to 25-30°C in one hour time followed by isolation of solid by filtration.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a new process for making sertraline hydrochloride Form II from sertraline base or sertraline mandelate. Sertraline base may be made by methods known in the prior art, including the method of US'518.
Sertraline hydrochloride exists in various polymorphs (Form I to Form XVI and
amorphous form). Polymorphs are prepared by crystallization from the melt,
crystallization from super saturated solution, and sublimation. The polymorphs of
pharmaceutical solids are normally prepared by crystallization from a
supersaturated solution.
The formation of different polymorphs is generally controlled during crystallization
through

(a) solvent selection, i.e., polarity of the solvent system,
(b) temperature
(c) the degree of super-saturation of the solution
(d) cooling rate
(e) nucleation or seeding
(Joel Bernstein, "Polymorphism in molecular crystals", Oxford Science Publication, 2002")
In their endeavor to look for a process for preparing commercially valuable sertraline hydrochloride form II the inventors of the present invention developed the following process for crystallization, which leads to the desired product in high yield and purity, i.e. free from any other polymorph:
• Solvent is anhydrous Methyl isobutyl ketone (MIBK)
• The solution is heated to 60-65 °C and hydrogen chloride gas or a solution of dry HCI in MIBK is added to the reaction system
• The reaction mixture is maintained at 60-65 °C and stirred up to 4 hours.
• Cooling the reaction mixture gradually to 25-30 °C in one-hour time followed by isolation of solid by filtration.
One of the parameters to control the formation of the polymorph is the selection of the solvent systems i.e. polarity of the solvent. The prior art (WO 01/32601, Example 12, Page 11) teaches a process for preparing form II of sertraline hydrochloride wherein sertraline base is dissolved in MIBK and heated to 60 °C followed by addition of seeds of form II, which in turn, is followed by addition of aqueous solution of hydrogen chloride to the reaction mixture. The reaction mixture is cooled to 20 °C and the product is filtered and vacuum dried. As it is clear from the example that the reaction system is not anhydrous but aqueous in nature, consisting of MIBK and water. Naturally the polarity of the solvent system is different from that of the anhydrous MIBK. For instance, besides change in the dielectric constant, the former contains a proton source and the latter lacks it. One

of the other factors contributing to the formation of a polymorph is the ability of the solute to form intramolecular or intermolecular hydrogen bonding. Naturally a proton source could contribute in changing the nature of the polymorph i.e. crystal packing. The formation of the polymorphs, as discussed herein above, greatly depends upon the polarity of the solvent system and on nucleation of the system with a particular polymorph.
Further, the claims 20-25 of the WO 01/32601direct towards the process for the preparation of the form II of sertraline hydrochloride wherein MIBK and aqueous HCI is used i.e. crystallization from aqueous MIBK and seeding of the reaction system is claimed.
Although the above-mentioned WO 01/32601 claims for the process for sertraline II as defined above but it lacks in enabling disclosure like reaction time and cooling conditions (whether it is a gradual cooling for fast cooling of the reaction system).
The 'seeds' of the pure polymorphic form II are required for the crystallization of the invention described in the WO 01/32601 presumably because the kinetic and free energy of formation of both form I and form II crystals are almost equal, and both have similar probability to crystallize and precipitate from the solution. To avoid getting a mixture of polymorph and to obtain the specified polymorph, it's 'seeds' are added to the reaction systems which acts as nucleus for the precipitating crystals and thereby avoids crystallization of the another form.
The distinguishing feature of the present invention from the prior art is the use of anhydrous reaction system without seeding with polymorph II of sertraline hydrochloride. The polarity of the reaction solvent of the present invention is such that it only facilitates the crystallization of the from II and impedes the crystallization of another form.
Another critical parameter for the formation of the polymorph is the temperature. The inventors have observed that if the reaction is carried at 60-65°C up to 4 hours form II of sertraline hydrochloride is obtained, free from any other polymorph, whereas if the reaction mass is further stirred for a longer duration, maintaining the reaction temperature at 60-65 °C, thermodynamically more stable polymorphic form

I is produced. The optimum reaction time is from 30 minutes to 4 hours at 60-65°C for getting pure polymorphic form II, which is free from any other form of sertraline hydrochloride. Then the reaction mass is gradually cooled to ambient temperature in one hour time, the solid crystallizes out which is filtered and vacuum dried. The X-ray diffractogram of polymorphic form II of sertraline hydrochloride obtained by this method is shown in Figure 1. The presence of a peak at 20 angle of 5.5 degree is characteristic of polymorphic form II of sertraline hydrochloride.
Moreover, if the same crystallization is carried in any other solvent, specifically in any ketone, other than MIBK, under the same conditions, the desired product is not obtained. It has been observed that solvents other than MIBK give a mixture of various forms of sertraline hydrochloride. For instance when the process was carried out with methylethyl ketone as a solvent for preparation of form II by using the specified parameters of temperature and reaction time, the product obtained was a mixture of various polymorphs of sertraline hydrochloride, and not the expected form II.
The process of present invention for preparation of polymorphic form II of sertraline hydrochloride comprises of:
a) dissolution of sertraline base or its mandelate salt in anhydrous methyl
isobutyl ketone (MIBK),
b) heating solution to 60-65°C,
c) addition of solution of nearly 10% hydrochloric acid in MIBK at 60-65°C or bubbling of dry HCI gas at 60-65°C till pH is less than 1.0,
d) maintaining the reaction temperature at 60-65°C up to 4 hours and
e) cooling the reaction mixture gradually to 25-30°C in one hour time followed by isolation of solid by filtration.
The inventors have also prepared form I of sertraline hydrochloride by carrying out reactions at 60-65°C for longer time usually up to 8-10 hours (Example 9). The X-ray diffrcatogram of polymorphic form I of sertraline hydrochloride obtained by this

method is shown in Figure 2. The presence of a peak at 2 6 angle of 7.1 degree is characteristic of polymorphic form I of sertraline hydrochloride.
Quantification of form I and form II in product is carried out by X-ray diffraction measurements made on solid powder. The X-ray diffraction pattern provides convenient and practical means for quantitative determination of the relative amount of form I and form II in the product. The physical mixtures containing 0.5%, 0.8%, 1.0%, 1.5%, 2%, 2.5% and 5% of form I in form II were prepared and their X-ray diffrcatogram were recorded and characteristic peak at 2 theta angle at 7.1 degree was checked. For the given physical mixtures containing form I up to 0.8% in form II is significantly detectable while for the given physical mixtures containing form I less than 0.8% in form II is undetectable. The X-ray diffrcatogram of polymorphic form II of sertraline hydrochloride obtained by the method of present invention as shown in Figure 1 clearly indicate that the product is free from polymorphic form I of sertraline hydrochloride as the characteristic peak arising from polymorphic form I at 2 8 angle of 7.1 degree is totally absent.
In conclusion the process conditions of the present invention are optimized to furnish pure polymorphic form II of sertraline hydrochloride, free from form I. Also, the process is reproducible, applicable on industrial scale and could be achieved in short time.
BRIEF DESCRIPTION OF FIGURE 1:
XRD of sertraline hydrochloride form II XRD conditions:
Anode: Cu
Wavelength: 1.5406 A
Start position (° 26): 2.000
End position (° 20): 50.000
X-ray (powder) diffraction pattern of sertraline hydrochloride Form II

29 d spacing [A]
5.406 16.33277
10.825 8.16670
13.228 6.68778
14.569 6.07499
16.265 5.44528
17.124 5.17401
17.968 4.93289
18.180 4.87585
18.991 4.66923
20.353 4.35984
22.593 3.93245
23.741 3.74484
24.414 3.64306
24.959 3.56467
25.706 3.46283
26.653 3.34182
27.385 3.25416
27.842 3.20175
28.495 3.12985
29.410 3.03452
30.039 2.97240
30.563 2.92262
32.469 2.75534
32.845 2.72462
35.143 2.55158
36.891 2.43453
37.361 2.40499
37.899 2.37210
39.044 2.30513

43.703 2.06958
44.693 2.02601
BRIEF DESCRIPTION OF FIGURE 2:
XRD of sertraline hydrochloride form I XRD conditions:
Anode: Cu
Wavelength: 1.5406 A
Start position (° 29): 2.000
End position (° 26): 50.000
X-ray (powder) diffraction pattern of sertraline hydrochloride Form I

20 d spacing [A]
7.076 12.48320
12.752 6.93651
13.159 6.72290
14.158 6.25044
15.380 5.75645
15.758 5.61929
16.920 5.23605
17.673 5.01438
18.691 4.74352
20.937 4.23953
21.276 4.17269
22.568 3.93675
23.426 3.79435
24.069 3.69448
25.049 3.55210
25.651 3.47016

26.317 3.38372
27.028 3.29631
28.487 3.13073
29.352 3.04041
29.979 2.97824
30.462 2.93214
33.879 2.64241
34.210 2.61894
35.290 2.54124
35.798 2.50632
37.860 2.37444
39.131 2.30023
40.473 2.22699
43.271 2.08921
46.083 1.96806
EXAMPLES
The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skilled in the art will understand how to vary the exemplified preparations to obtain the desired results.
1) Preparation of Form-I I from Free Sertraline Base:
5 g Sertraline base is dissolved in 50 ml of Methylisobutylketone & heated to
60-65°C. To that dry HCI gas is purged at 60-65°C till pH of reaction
mass<1.
The reaction mass is stirred at 60-65°C for 2-3 hrs. After 2-3 hrs, the
reaction mass is cooled to 25-30°C, stirred for 10 min & filtered. The solids
are dried at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI.
Form-ll
% Yield: 96

2) Preparation of Form-ll from Free Sertraline Base:
5 g Sertraline base is dissolved in 50 ml of Methylisobutylketone & heated to
60-65°C. To that dry HCI gas is purged at 60-65°C till pH of reaction
mass<1.
The reaction mass is cooled to 25-30°C in 1 hr and stirred at this temp for 1-
2 hrs. After 1-2hrs,reaction mass is filtered. The solid is dried at 60-65°C
under vacuum for 10 hrs to give 5.4 g of Sertraline HCI. Form-ll
% Yield: 96
3) Preparation of Form-ll from Sertraline mandelate salt:
10 g of sertraline mandelate salt was suspended in 50 ml of DM water & 50 ml Methylisobutylketone & cooled to 15-20°C. 10% NaOH solution was added slowly to pH = 10. The mixture was stirred for 20-25 min and layers separated. The aqueous layer was extracted with (2x25ml) of Methylisobutylketone. Both Methylisobutylketone layers were mixed, Washed with 25 ml 5% NaOH & with water till pH is neutral. The Methylisobutylketone layer was concentrated under vacuum to a residue. 40 ml of Methylisobutylketone was added to the residue and stirred for 10-15 min. The reaction mass is heated to 60-65°C. To that dry HCI gas is purged at 60-65°C till pH of reaction mass<1.
The reaction mass is stirred at 60-65°C for 2-3 hrs. After 2-3 hrs, reaction mass cooled to 25-30°C, stirred for 10 min & filtered. The solids are dried at 60-65°C under vacuum for 12 hrs to give 6.5 g of Sertraline. HCI Form-ll. % Yield: 87
4) Preparation of Form-ll from Sertraline mandelate salt:
10 g of sertraline mandelate salt was suspended in 50 ml of DM water & 50 ml Methylisobutylketone & cooled to 15-20°C. 10% NaOH solution was added slowly to pH = 10. The mixture was stirred for 20-25 min and layers separated. The aqueous layer was extracted with (2x25ml) of Methylisobutylketone. Both Methylisobutylketone layers were mixed, Washed with 25 ml 5% NaOH & with water till pH is neutral. The

Methylisobutylketone layer was concentrated under vacuum to a residue. 40 ml of Methylisobutylketone was added to the residue and stirred for 10-15 min. The reaction mass is heated to 60-65°C. To that dry HCI gas is purged at 60-65°C till pH of reaction mass<1.
After achieving acidity reaction mass is cooled to 25-30°C in 1 hr and stirred at this temp for 1-2 hrs. After 1-2hrs,reaction mass is filtered. The solids are dried at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI. Form-ll % Yield: 72
5) Preparation of Form-ll from Free Sertraline Base:
5 g Sertraline free base is dissolved in 50 ml of Methylisobutylketone & heated to 60-65°C. 6.5 ml 10% HCI in MIBK is added at 60-65°C in 5-10 min. The reaction mass is stirred at 60-65°C for 2-3 hrs. After 2-3 hrs, the reaction mass is cooled to 25-30°C, stirred for 10 min & filtered. The solids are dried at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI. Form-ll % Yield: 96
6) Preparation of Form-ll from Free Sertraline Base:
5 g Sertraline free base is dissolved in 50 ml of Methylisobutylketone &
heated to 60-65°C. 6.5 ml 10% HCI in MIBK is added at 60-65°C in 5-10
min.
After addition reaction mass is cooled to 25-30°C in 1 hr and stirred at this
temp for 1-2 hrs. After 1-2hrs,reaction mass is filtered. The solids are dried
at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI. Form-ll
% Yield: 96
7) Preparation of Form-ll from Sertraline mandelate salt:
10 g of sertraline mandelate salt was suspended in 50 ml of DM water & 50 ml Methylisobutylketone & cooled to 15-20°C. 10% NaOH solution was added slowly to pH = 10. The mixture was stirred for 20-25 min and layers

separated. The aqueous layer was extracted with (2x25ml) of Methylisobutylketone. Both Methylisobutylketone layers were mixed, Washed with 25 ml 5% NaOH & with water till pH is neutral. The Methylisobutylketone layer was concentrated under vacuum to a residue. 40 ml of Methylisobutylketone was added to the residue and stirred for 10-15 min. The reaction mass is heated to 60-65°C.8.77 ml 10% HCI in MIBK is added at 60-65°C in 5-10 min.
The reaction mass is stirred at 60-65°C for 2-3 hrs. After 2-3 hrs, reaction mass cooled to 25-30°C, stirred for 10 min & filtered. The solids are dried at 60-65°C under vacuum for 12 hrs to give 6.5 g of Sertraline. HCI Form-ll. % Yield: 87
8) Preparation of Form-ll from Sertraline mandelate salt:
10 g of sertraline mandelate salt was suspended in 50 ml of DM water & 50 ml Methylisobutylketone & cooled to 15-20°C. 10% NaOH solution was added slowly to pH = 10. The mixture was stirred for 20-25 min and layers separated. The aqueous layer was extracted with (2x25ml) of Methylisobutylketone. Both Methylisobutylketone layers were mixed, Washed with 25 ml 5% NaOH & with water till pH is neutral. The Methylisobutylketone layer was concentrated under vacuum to a residue. 40 ml of Methylisobutylketone was added to the residue and stirred for 10-15 min. The reaction mass is heated to 60-65°C.To that 8.77 ml 10% HCI in MIBK is added at 60-65°C in 5-10 min. After addition reaction mass is cooled to 25-30°C in 1 hr and stirred at this temp for 1-2 hrs. After 1-2hrs,reaction mass is filtered. The solids are dried at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI. Form-ll. % Yield: 72
9) Preparation of Form-I from Free Sertraline Base:
5 g Sertraline base is dissolved in 50 ml of Methylisobutylketone & heated to 60-65°C. To that dry HCI gas is purged at 60-65°C till pH of reaction mass<1.

The reaction mass is stirred at 60-65°C for 8-10 hrs. After 8-10 hrs, the
reaction mass is cooled to 25-30°C, stirred for 10 min & filtered. The solids
are dried at 60-65°C under vacuum for 10 hrs to give 5.4 g of Sertraline HCI.
Form-I
% Yield: 96

WE CLAIM
1. A process for making sertraline hydrochloride Form II, free from any other
polymorph, comprising the steps of:
a) dissolution of sertraline base or its mandelate salt in methyl
isobutyl ketone (MIBK),
b) heating the solution to 60-65°C,
c) addition of hydrogen chloride gas or a solution of hydrogen chloride to the reaction mixture
d) maintaining the reaction temperature at 60-65°C for 0.5 to 4 hours and
e) cooling the reaction mixture gradually to 25-
30°C in one hour time followed by isolation of
solid by filtration.
2. Process as claimed in claim 1 wherein the hydrogen chloride is added as gaseous hydrogen chloride.
3. Process as claimed in claim 1 wherein dry hydrogen chloride is added as a solution of hydrogen chloride in MIBK.
4. Process as claimed in claim 3 wherein 10% hydrogen chloride solution in MIBK is used.
5. Process as claimed in claim 1 wherein hydrogen chloride is passed in the solution till the pH <1>.