The present invention relates to a novel polymorphic form of duloxetine hydrochloride and its preparation. The novel polymorphic form is designated as Form I of duloxetine hydrochloride. The present invention further relates to duloxetine hydrochloride having enantiomeric purity of about 98% or above. The present invention also relates to a novel process for the preparation of duloxetine hydrochloride.
Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. It is chemically (+)-(S)-N-methyl-y-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride as represented by Formula I:
(Formula Removed)
FORMULA I
The processes for the preparation of duloxetine and its intermediates are provided in EP 0,457,559 A3, US 5,362,886, WO 03/062219, WO 03/070720, EP 1,506,965, WO 04/005307, US 2004/0181058, WO 04/056795, WO 04/065376, WO 04/055194, WO 03/018572, JP 2003-192681 A2, US 2003/225153, US 2005/107621, WO 04/005220, WO 04/005239, WO 04/011452, WO 04/013123, WO 04/016603, DE 10237272 A1, WO 04/020389, WO 04/024708, WO 04/031168, EP 1411045 A1, DE 10248479 A1, DE 10248480 A1, WO 04/090094, WO 04/103990, WO 05/021527, WO 05/033094, WO 05/073215, WO 05/080370, US 2003/225274, US 2003/225153, US 2004/023348, US 2004/023344, US 6,924,386, DE 10237272 A1, US 2004/181058.
US Patent No 5,023,269 provides a process for the preparation of racemic duloxetine oxalate and it discloses maleate and oxalate salts of S-(+)-duloxetine. However, the '269 patent does not suggest or provide any method to arrive specific isomers of duloxetine and its salts. US Patent No 5,491,243 provides a similar

process for preparing for duloxetine, wherein the final compound of duloxetine is isolated as a hydrochloride salt. Further, the '243 patent quotes that the desired product is prepared in yields in the range of 95% with very little racemization and it also quotes that previous procedures gave product of inferior purity.
WO 05/019199 provides processes for preparing amorphous duloxetine hydrochloride by vacuum drying methods. WO 05/108386 provides processes for preparing Forms A, B and C of free base of duloxetine.
The present inventors have observed, while the prior art provides various methods to prepare maleate or oxalate salts of duloxetine, there is no efficient method to obtain duloxetine hydrochloride with higher enantiomeric purity. Therefore, the present inventors have developed a simple process and efficient process for preparing duloxetine hydrochloride wjth enantiomeric purity of about 98% or more. The present invention also provides a novel process for preparing duloxetine hydrochloride from duloxetine maleate, thereby improving the purity and yield of the final duloxetine hydrochloride. The present invention also provides a novel polymorphic form of duloxetine hydrochloride designated as Form I and its preparation.
A first aspect of the present invention provides duloxetine hydrochloride having enantiomeric purity of about 98% or above, preferably of about 99.5% or above, more preferably of about 99.9% or above.
A second aspect of the present invention provides Form I of duloxetine hydrochloride having an XRPD pattern as depicted in Figure 1. The Form I of duloxetine hydrochloride is characterized by an XRPD pattern comprising 29 values at 9.74, 14.02, 18.20, 18.86, 19.02, 21.00, 22.28, 23.28; 23.48 and 24.64±0.2. The Form I of duloxetine hydrochloride is further characterized by an XRPD pattern comprising 20 values at 9.74, 14.02, 14.62, 16.14, 18.20, 18.86, 19.02, 19.36, 19.64, 20.16, 21.00, 21.46, 21.72, 22.28, 22.74', 23.28, 23.48, 24.64, 25.72, 26.16, 26.58, 27.52, 28.08, 29.1, 29.36 and 30.5±0.2. Form I of duloxetine hydrochloride having an FTIR spectrum as depicted in Figure 2.

A third aspect of the present invention provides a process for the preparation of duloxetine hydrochloride, wherein the said process comprises,
a) treating duloxetine maleate with a base to obtain free base of duloxetine,
b) treating the free base of duloxetine with hydrochloric acid,
c) isolating duloxetine hydrochloride from the reaction mixture thereof.
The starting duloxetine maleate can be prepared according to the method provided in Tetrahedron Letters, 31(49), 1990, 7101-7104. The maleate salt of duloxetine is treated with a base in the presence of water, water miscible organic solvents or mixtures thereof. An alkali metal hydroxide is preferably used as a base. The liberated free base of duloxetine is not required to be isolated from the reaction mixture and it is directly treated with hydrochloric acid. Hydrochloric acid is used in concentrated form or as a solution of aqueous or organic solvents. The duloxetine hydrochloride is isolated from the reaction mixture by conventional methods such as solvent precipitation, concentration, distillation and the like.
A fourth aspect of the present invention provides a process for the preparation of Form I of duloxetine hydrochloride, wherein the said process comprises,
a) dissolving duloxetine hydrochloride in a solvent,
b) treating the solution obtained in step a) with an antisolvent,
c) isolating Form I of duloxetine hydrochloride from the reaction mixture thereof.
Duloxetine hydrochloride prepared by any method known to the skilled artisan, existing in any crystalline form can be used as a starting material. The duloxetine hydrochloride is dissolved in an organic or aqueous solvent. The organic solvent is selected from a group comprising of C1-3 alkanol, acetonitrile, acetone, dioxane, dimethyl formamide and tetrahydrofuran. The organic solvent can also be a mixture with water. Duloxetine hydrochloride can be dissolved by heating the mixture from about 40°C to about 80°C. An antisolvent is added to the solution so obtained. The antisolvent is selected from group comprising of ethers, aliphatic hydrocarbon, aromatic hydrocarbons, aliphatic esters and petroleum ether. The reaction mixture is heated to a temperature of about 50°C or more, and subsequently cooled to a temperature of about 35°C or less to obtain Form I of duloxetine hydrochloride.

A fifth aspect of the present invention provides a pharmaceutical composition comprising Form I of duloxetine hydrochloride and optionally containing one or more excipients.
A sixth aspect of the present invention provides a method for inhibiting serotonin uptake in mammals which comprises administering to a mammal requiring increased neurotransmission of serotonin a pharmaceutically effective amount of Form I of duloxetine hydrochloride.
Figure 1 depicts XRPD of Form I of duloxetine hydrochloride Figure 2 depicts FTIR of Form I of duloxetine hydrochloride
Powder XRD of the samples were determined by using X-Ray Difractometer, Rigaku Corporation, RU-H3R, Goniometer CN2155A3, X-Ray tube with Cu target anode, Divergence slits 1 0, Receiving slit 0.15mm, Scatter slit 1°, Power: 40 KV, 100 mA, Scanning speed: 2 deg/min step: 0.02 deg, Wave length: 1.5406 A
FT-IR of the samples were determined by using Instrument: Perkin Elmer, 16 PC, SCAN: 16scans, 4.0 cm"1, according to the USP 25, general test methods page 1920, infrared absorption spectrum by potassium bromide pellet method.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE 1
PREPARATION OF DULOXETINE HYDROCHLORIDE a) Preparation of duloxetine:
A suspension of duloxetine maleate (20 g, 0.0484 mole) in water was basified to the pH of about 12 with 30% sodium hydroxide at about 25°C. The reaction mixture was extracted with toluene (2 x 200 ml). The toluene layer was washed with water to

attain a pH of 7 to 8 and concentrated under reduced pressure to obtain the title compound as an oily mass which was used directly in the following step.
b) Preparation of duloxetine hydrochloride
Ethyl acetate solution of hydrochloric acid [23 ml, Assay ~8% (w/w)] was added to the residue obtained from step a) in ethyl acetate (90 ml) at 5-10°C to attain the pH of 1.5 to 2.0. The reaction mixture was stirred at 5°-10°C for 2 h. The solid was filtered, washed with ethyl acetate (2 x 20 ml) and dried under vacuum at 45°-50°C for 8-10 h to obtain the title compound with 86% yield as an off-white solid. Yield: 14 g
EXAMPLE 2
PREPARATION OF POLYMORPHIC FORM I OF DULOXETINE HYDROCHLORIDE
A mixture of duloxetine hydrochloride obtained from Example 1 (10 g) in absolute ethanol (30 ml) was stirred at 65°-70°C for 15 minutes to obtain a clear solution. Activated charcoal (1.0 g) was added to the solution so obtained and stirred at 65°-70°C for further 30 minutes. The charcoal was filtered and washed with absolute ethanol (3x15 ml) at about 25°C. Diisopropyl ether was added (35 ml) to the combined filtrate and washed at 40°-45°C. The reaction mixture was reheated to 65°-68°C for 15 minutes and cooled to 25°-30°C to obtain a white solid as a precipitate. The mixture was stirred at 25°-30°C for 2 h and further at 5°-10°C for 2 h. The solid was filtered, washed with a mixture of absolute ethanol (7.5 ml) and diisopropyl ether (7.5 ml) at about 25°C and dried in vacuum at 45°-50°C for 8 to 10 h to obtain the title compound having XRPD and FTIR patterns as depicted in Figures 1 and 2.
Yield: 7.5 g
Enantiomeric purity: 99.99%

WE CLAIM:
1. Duloxetine hydrochloride having enantiomeric purity of about 98% or above.
2. Duloxetine hydrochloride having enantiomeric purity of about 99.5% or above.
3. Duloxetine hydrochloride having enantiomeric purity of about 99.9% or above.
4. Form I of duloxetine hydrochloride having an XRPD pattern as depicted in Figure
1.
5. The Form I of duloxetine hydrochloride as claimed in claim 4 having an XRPD
pattern comprising 20 values at 9.74, 14.02, 18.20, 18.86, 19.02, 21.00, 22.28,
23.28, 23.48 and 24.64±0.2.

7. The Form I of duloxetine hydrochloride as claimed in claim 5 having an XRPD
pattern comprising 20 values at 9.74, 14.02, 14.62, 16.14, 18.20, 18.86, 19.02,
19.36, 19.64, 20.16, 21.00, 21.46, 21.72, 22.28, 22.74, 23.28, 23.48, 24.64, 25.72,
26.16, 26.58, 27.52, 28.08, 29.1, 29.36 and 30.5±0.2.
8. Form I of duloxetine hydrochloride having an FTIR spectrum as depicted in Figure
2.
9. A process for the preparation of duloxetine hydrochloride, wherein the said
process comprises,

a) treating duloxetine maleate with a base to obtain free base of duloxetine,
b) treating the free base of duloxetine with hydrochloric acid,
c) isolating duloxetine hydrochloride from the reaction mixture thereof.
10. A process for the preparation of Form I of duloxetine hydrochloride, wherein the
said process comprises,
a) Dissolving duloxetine hydrochloride in a solvent,
b) treating the solution obtained in step a) with an antisolvent,

c) isolating Form I of duloxetine hydrochloride from the reaction mixture thereof.