POLYMORPHIC: FORM OF DULOXETINE HYDROCHLORIDE
Field of the invention
The present invention relates lo a polymorphic form of duloxetine hydrochloride and processes for ils preparation. The polymorphic form of the current invention is
;
designated Form I. The present invention also relates lo a process for preparing duloxevine hydrochloride from duloxetine maleate.
Background of the invention
Duloxetttie hydrochloride is a selective serotonin and norepinephrine,reuptake inhibitor (SSNRI) for oral administration. It is chemically (+)-(S)-N-methyi-y-( 1-riaphthyloxy)2-ihiophenepropylanune hydrochloride as represented by Formula I:
(Formula Removed) FORMULA I
U.S. Patent No 5,023,269 provides a process for the preparation of racemic dubxetine oxakle and it discloses maleaie and oxalate salts of S-(+)-duloxetine. However, me '269 patent;does noi provide any method to separate specific enantiomare of duloxetine. US Paient No 5,491,243 provides a similar process for preparing for duloxetine, whprein the final compound of duloxetine is isolated as a hydrqchloride salt using ethyl acetate as a solvent and seeding. The '243 patent says that the desired product is prepared in yields in the range of 95% with very little racemization and that previous procedures gave a product of inferioi purity.
PCT application WO 05/019199 provides processes for preparing amorphous duloxetinc hydriochloride by vacuum drying methods. WO 05/108380 provides processes fur preparing Forms A, R and C of tree base of duloxetine.
Various processes for the preparation of duloxetirie and its intermediates are also provided in EP 0,457,559 A3, US 5,362.886, WO 03/062219, WO 03/07072Q, BP 1,506,965, WO 04/005307, US 2004/0181058, WO 04/056795, WO 04/0653176, 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 Al, WO 04/020389, WO 04/024708, WO 04/031168, EP 1411045 Al, DE 10248479 Al, DE 10248480 Al, 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 2(104/023.148, US 2004/023344, US 6,924,386. DE 10237272 Al, US 2004/181058.
Brief Description of the Figures
Figure 1 is anX-tray powder diffractogram (XRPD) pattern of Form I of dulqxetine hydrochloride.
Figure 2 is a Fourier-Transform Infra-red (FT1R) spectrum of Form I of duloxetine
hydiochloridc.
Summary of the Invention
The present invention provides duloxeiine hydrochloride Form i, which is suitable for preparing pharmaceutics I dosage forms. The present invention further provides a process for preparing Form I of duloxetine hydrochloride. The present inventors have also developed a simple and efficient process for preparing duloxeiine hydrochloride from
liuioxerine indicate
Detailed Description of the Invention
In one aspect, Form I of duloxeiine hydrochloride is provided, having, for example, XRPD pattern substantially as provided, for example, in Figure 1. The XRPD pattern of Form 1 of duloxetine hydrochloride can be characterized by peaks at 20 values 9.74. 14.02, 18.20, 1 S.86, 19.02. 21.00, 22.28, 23.28, 23.48 and 24.64+0.2. It is further dharacterized by additional peaks at 26 values at 14.62, 16.14, 19.36, 19.64. 20.16, 21.46,21.72, 22.74, 25 72. 26. i 6, 26.58, 27.52, 28.08, 29 1. 29.36 and 30.5+0.2. A representative FTIR spectrum of Form I of duloxetine hydrochloride is provided in Figure 2.
In another aspect, a process for the direct preparation of duloxetine hydrochloride from duloxetine maleale without ihe need for seeding is provided, wherein the process cum prises,
a) treating duloxetine maleate with a base to obtain free base of duloxetine,
b) contacting the free base of duloxetine with hydrochloric acid, and
c) isolating duloxetine hydrochloride from the reaction mixture.
The dui&xetine maleate can be prepared, for example, according to flie method provided in Tetrahedron Utters 1990. 31(49), 7 LO1-7104. The maleate salt of duloxetine is Treated with a base in the presence of water or water miscible organic solvent, or a mixture thereof. An alkali metal hydroxide is preferably used as the base, foe liberated tree base of duioxtiiine is extracted with a water immiscible organic solvent. The water immiscible organic solvent is preferably an aromatic hydrocarbon. According to the processes described herein, the tree base of duloxetine is not required to b& isolated from the organic solvent, and it is contacted with hydrochloric acid after partially concentrating ihe solution. Hydrochloric acid may be used as a gas or as a solution in wafer or organic solvents. The duloxeline hydrochloride may be isolated from the reaction mixture by solvent precipitation, concentration, distillation and other such conventional techniques.
In yet another aspect, a process for the preparation of Form J. of dufrxetme hydrochloride is provided, wherein the process comprises, si) dissolving duloxetine hydrochloride in a solvent, b) treating the solution obtained in step > ?1 '
30aC for 2 h iijflMThec at 5°-10°C for 2 h. The solid was filtered, washed Tith a mixture
of absolu .7.5 rnL) and diisopropyl ether (7.5 mL) at about 25°C a^d dried under
vacuum pi 8 to 10 h to obtain the title compound having XRPl and FTIR

pattems -and pt|ted in Figures 1 and 2 respectively.

WE CLAIM:
1. A ■ process for the preparation of Form I of duloxetine hydrochloride,
comprising:
a) dissolving duloxetine hydrochloride in a solvent; b) treating the solution obtained in step (a) with an anti-solvent; and c) isolating Form I of duloxetine hydrochloride from the reaction mixture.
2. A process according to claim 1, wherein the solvent is at least one of a C1-3 alkanol, acetonitrile, acetone, dioxane, dimethyl formamide or tetrahydrofuran.
3. A process-according to claim 2, wherein the solvent is absolute etrtanol.
4. A process according to claim 1, wherein the anti-solvent is at least one of an aliphatic ether, aliphatic hydrocarbon, aromatic hydrocarbon or aliphatic ester.
5. A process for the preparation of duloxetine hydrochloride, comprising:

a) treating duloxetine maleate with a base to obtain free base of dulo|etine;
b) contacting the free base of duloxetine with hydrochloric, acid; and
c) isolating duloxetine hydrochloride from the reaction mixture.

6. A process according to claim 5. wherein step c) is carried out without using any seed.
7. A process according to claim 5, wherein the base is an alkali metal hydroxide.
8. A process according to claim 5, wherein step a) is carried out in the presence of water or water miscible organic solvent, or a mixture thereof.
9. A process according to claim 7, wherein step a) further comprises extracting the free base of duloxetine with a water immiscible organic solvent.