Indian Patents. 250027:PRODUCTION OF (+) DULOXETINE HYDROCHLORIDE, SUBSTANTIALLY OR COMPLETELY FREE FROM α -NAPHTHOL

Title of Invention	PRODUCTION OF (+) DULOXETINE HYDROCHLORIDE, SUBSTANTIALLY OR COMPLETELY FREE FROM α -NAPHTHOL
Abstract	The present invention relates to a process for preparing duloxetine hydrochloride of formula (I), substantially free from α-naphthol of formula (III), which comprises treating duloxetine of formula (II) with substantially anhydrous hydrochloric acid in solvent.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) 85 The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) TITLE OF THE INVENTION "PRODUCTION OF (+) DULOXETINE HYDROCHLORIDE, SUBSTANTIALLY OR COMPLETELY FREE FROM ct-NAPHTHOL" We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India. The following specification describes the invention: Fief3 of the invention The present invention relates to (+) Duloxetine hydrochloride, which is substantially or completely free from a-Napthol, an acid degradation product of (+) Duloxetine hydrochloride, The invention also discloses a process for preparation of (+) Duloxetine Hydrochloride, which is substantially or completely free from ot-naphthol. Background of the invention: Duloxetine, N-methyl-3-(l-napthalenyloxy)-3-(2-thienyl) propanamine, is a dual serotonin and norepinephrine reuptake inhibitor. (+) Duloxetine hydrochloride has particular therapeutic utility in treatment of major depressive disorder, stress urinary incontinence in women and painful dialectic peripheral neuropathy. The chemical structure of Duloxetine Hydrochloride {(S)-(+)-N-methyl-3 -(1 -naphhalenyloxy)-3 -(2-thienyl)-propanamine, hydrochloride salt} is shown in figure (I). US Patents Nos. 5023269 and US 4956388 discuss 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine, and methods of preparing them. H • HC1 (I) The preparation of Duloxetine is described in Tetrahedron Letters, 31, (49), 7101-04, 1990. Seven different routes of synthesis have also been reported in Drugs of the Future 2000, 25(9) 907-916. These synthesis have involved either a resolution of a key intermediate or a stereospecific reduction of a keto group to the alcohol. WO 2004/056795 discloses a process for preparing (+) Duloxetine by resolving Racemic Duloxetine with chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine. This publication also discloses the process for preparing the acid addition salts of (+) Duloxetine. 2 (+) Duloxetine hydrochloride is acid labile, and acid hydrolysis of the ether linkage produces a-Naphthol. a-Naphthol is extremely toxic and produces cramping, abdominal pain, nausea, and vomiting. Severe systemic effects include nephritis, cystitis, liver damage, convulsions, and acute intravascular hemolysis in individuals with RBC glucose 6-phosphaste deficiency1. In addition, literature retrieved from toxnet is indicative that that Lens opacities & retinal changes have been described for a-Naphthol. In addition a-isomer of Naphthol is said to be even more toxic than P-naphthol In animal toxicity studies a-Naphthol was shown to be highly toxic. Poole et al' have reported investigation of toxicological potential of a-Naphthol. The group investigated oral toxicity of a-naphthol in Charles River CD1 mice in single (2, 1 and 0.5 g/kg body weight) and 30-day repeat dosing (200, 100 and 50 mg/kg body weight) studies. In the single-dose study, animals dosed by oral gavage at 2 g/kg body weight either died or were killed in extremis between 15 and 90 min after dosing. Acute dosing was associated with histopathological lesions seen in the kidneys and stomachs of mice from all treatment groups. The kidney lesions consisted of degeneration of the distal tubule epithelium, papillary necrosis and tubular dilatation. Gastric changes characterized by splitting of the epithelium of the fore stomach and sloughing of the superficial epithelium of the glandular mucosa were generally accompanied by vascular congestion and acute inflammatory cell infiltration. In addition, a search on toxnet2 reveals that a-Naphthol is reported to be toxic in various animal species. An overview of toxicological evaluation is presented below: 1. a-Naphthol (CAS # 90-15-3) was evaluated for acute oral toxicity. The test substance was administered by stomach intubation to non-fasted male albino Harlan-Wistar rats. The observed LD50 was 2.38 (1.56 to 3.65) g/kg, and 1.87 (1.27 to 2.76) g/kg for young and older adult rats, respectively. No further information was submitted. 2. a-Naphthol (CAS # 90-15-3) was evaluated for acute oral toxicity. The test substance was administered as a 50% solution in peanut oil. Rats receiving lethal doses suffered from diarrhea and died within 18 hours after treatment. Pathological examination indicated congestion and edema of the lungs; albumin in the kidney tubules; and superficial necrosis of the stomach. The approximate lethal dose (ALD) was calculated to be 1000 mg/kg. 3. a-Naphthol (CAS # 90-15-3) was evaluated for primary dermal irritation. The test substance was administered at a dosage of 500 mg to the intact and abraded skin of 6 3 albino rabbits. Moderate to severe erythema and edema was noted after 72 hours (irritation score of 7.09/8.00). 4. a-Naphthol (CAS # 90-15-3) was evaluated for primary eye irritation. The test substance was administered at a dosage of 100 mg to 6 albino rabbits. Slight to moderate effects of the cornea, iris, and conjunctivae were noted (irritation score of 61.7/110). a-Naphthol is a potential degradradation product of (+) Duloxetine hydrochloride and is very toxic for human consumption. The inventors of this patent application have disclosed a unique composition of active pharmaceutical ingredient of (+) Duloxetine hydrochloride, which is substantially or completely free from a-Naphthol. The (+) Duloxetine hydrochloride produced by present invention is substantially or completely free from a-Naphthol and has industrial application in preparing pharmaceutical, formulations having a substantially low quantities or completely free of a-Naphthol thereby reducing the total exposure to a-naphthol and thereby reducing the toxicological liabilities associated with exposure of a-Naphthol. Such an Active Pharmaceutical Ingredient (API) composition of of (+) Duloxetine hydrochloridewould be useful for preparing formulations like enteric coated tablets, capsules, beads and other dosage forms for patients/human beings who are in need of (+) Duloxetine hydrochloride treatment. Summary of the invention: The present invention provides: 1. An API composition of (+) Duloxetine hydrochloride, which is substantially free or completely free from a-Napthol content on a weight/weight basis. Substantially pure (+) Duloxetine hydrochloride of this invention include, without limitation, a. (+) Duloxetine hydrochloride preferably containing 0.1% to 0.01% of a- Naphthol with respect to the weight of (+) Duloxetine hydrochloride. b. (+) Duloxetine hydrochloride more preferably containing less than 0.01% of a-Naphthol with respect to the weight of (+) Duloxetine hydrochloride. c. In another preferred mode the (+) Duloxetine produced by the disclosed process is completely free of a-Napthol. 2. Process for preparing (+) Duloxetine Hydrochloride, which is substantially free or completely free from a-naphthol content on a weight-by-weight basis. 4 Present invention is directed to ensure the preparation of (+) Duloxetine Hydrochloride in such a way that a-naphthol content preferably remains in range of 0.1% to 0.01%, in less than 0.01% and most preferably completely free from a-Napthol during normal (25 °C; 60% RH) and accelerated stability conditions (40 °C; 75% RH) as per ICH guidelines. 4. This invention relates to a process for the preparation of (+) Duloxetine Hydrochloride, which is also relatively stable in regard to a-naphthol and other potential impurities and the process with economical aspects and suitable to the plant operations. Disclosure of invention: Racemic (±) Duloxetine is resolved by (-) p-di-tolyl-L-tartaric acid in an organic solvent from linear, branched or cyclic ketonic solvent of Ci to C6 to obtain (^p-di-tolyl-L-tartaric acid salt of (+) Duloxetine. This (-)p-di-tolyl-L-tartaric acid salt of (+) Duloxetine is converted into (+) Duloxetine by reacting with suitable alkali. The (+) Duloxetine is reacted with dry HCl gas in an organic solvent. The (+) Duloxetine Hydrochloride (technical) formed is then purified from suitable organic solvent to obtain pure (+) Duloxetine Hydrochloride, which is substantially free from a-naphthol (Scheme-1). S *DTTA (-)p-di-tolyl-L-tartaric acid (DTTA) NaOH NT . HCl H HCl, gas Scheme -1 5 Hydroxylated and non-hydroxylated solvents are used to decrease or remove a-Naphthol contents from (+) Duloxetine hydrochloride technical (Example-3) to produce (+) duloxetine hydrochloride, which is substantially or completely free from a-Naphthol (Example-4) The present invention will now be described with reference to the following non-limiting examples: Example-1 : Preparation of (-)p-di-tolyl-L-tartaric acid salt of (+) Duloxetine : Charge 924 L of acetone and 77.0 Kg of (±)Duloxetine base in a SS reactor. Charge 100.1 Kg of (-)p-di-tolyl-L-tartaric acid, at 25°C to 35°C. Stir for 90 minutes at 25°C to 35°C. Centrifuge the product and wash with two 77 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford 61.6 Kg of (-)p-di-tolyl-L-tartaric acid salt of (+)Duloxetine. Example-2 : Preparation of (+) Duloxetine base : Charge 956 L of water and 95.6 Kg of (-)p-di-tolyl-L-tartaric acid salt of (+)Duloxetine (obtained from Example-1) in SS reactor. Stir for 10 minutes. Charge 574 L of Methylene chloride. Stir for 10 minutes. Slowly add sodium hydroxide solution (14.34 Kg of sodium hydroxide and 143.4 L process water) upto pH 9.0 to 9.5 at 25°C to 35°C. Stir the contents for 1.0 hour and allow the layers to settle for 15 minutes. Separate Methylene chloride layer from bottom. Wash the organic layer with 143.4 L of process water. Filter Methylene chloride layer through Hyflosupercel bed and wash the Hyflosupercel bed with 47.8 L of Methylene chloride. Distil out Methylene chloride under vacuum below 50°C to afford 40.0 Kg of (+)Duloxetine base. Example-3 : Preparation of (+) Duloxetine Hydrochloride (Technical): Charge 400 L of acetone and 40.0 Kg of (+) Duloxetine base (obtained from Example-2) in SS reactor. Stir to get clear solution at 25°C to 35°C. Filter the solution through fine filter pads. Charge filtrate in GLR. Cool the reaction content to 10°C to 15°C . Purge dry HC1 gas at 10°C to 15°C till pH of 2.0 to 2.5 is obtained. Stir the reaction mass for 1.0 hour at 10°C to 15°C. Centrifuge the product and wash the cake with two 40 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford 40.0 Kg of (+) Duloxetine Hydrochloride (Technical) which is substantially free from a-Naphthol 6 Ex^Biple-4: Preparation of Pure (+) Duloxetine Hydrochloride: Charge 400 L of acetone and 40.0 Kg of (+) Duloxetine Hydrochloride (Technical) (obtained from Example-3) in GLR at 25°C to 35°C. Stir the contents for 1.0 hour at 25°C to 35°C. Centrifuge the product and wash the cake with two 40 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford pure (+) Duloxetine Hydrochloride which is completely free from a-Naphthol. HPLC purity is 99.87 % with a-naphthol content not detected, a-naphthol content is not detected even after long term and accelerated stability conditions. References: 1. Clinical pharmacology and Biopharmaceutics review (Review #2) from Lilly's NDA application no. 21-427 2. Hazardous Substances Data Bank (HSDB), a database of the National Library of Medicine's TOXNET system (http://toxnet.nlm.nih.gov) on June 22, 2005.Toxnet. Query: The chemical name 1-napthol 3. l-Naphthol~single and repeated dose (30-day) oral toxicity studies in the mouse; Poole A, Buckley P.; Food Chem Toxicol. 1989 Apr; 27(4): 233-8. Dated this the 30th day of June 2005 H. SUB^AMANIAM Of Subnmwrfiam, Nataraj & Associates -"'Attorneys for the applicants 7 Abstract: This invention relates to (+) Duloxetine hydrochloride, which is substantially or completely free from a-Napthol, an acid degradation product of (+) Duloxetine hydrochloride, The invention also discloses a process for preparation of (+) Duloxetine Hydrochloride, which is substantially or completely free from a-naphthol. 8

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
85
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
"PRODUCTION OF (+) DULOXETINE HYDROCHLORIDE, SUBSTANTIALLY OR COMPLETELY FREE FROM ct-NAPHTHOL"
We, CADILA HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Cross Road, Ahmedabad-380015, Gujarat, India.
The following specification describes the invention:

Fief3 of the invention
The present invention relates to (+) Duloxetine hydrochloride, which is substantially or completely free from a-Napthol, an acid degradation product of (+) Duloxetine hydrochloride, The invention also discloses a process for preparation of (+) Duloxetine Hydrochloride, which is substantially or completely free from ot-naphthol. Background of the invention:
Duloxetine, N-methyl-3-(l-napthalenyloxy)-3-(2-thienyl) propanamine, is a dual
serotonin and norepinephrine reuptake inhibitor. (+) Duloxetine hydrochloride has particular
therapeutic utility in treatment of major depressive disorder, stress urinary incontinence in
women and painful dialectic peripheral neuropathy. The chemical structure of Duloxetine
Hydrochloride {(S)-(+)-N-methyl-3 -(1 -naphhalenyloxy)-3 -(2-thienyl)-propanamine,
hydrochloride salt} is shown in figure (I).
US Patents Nos. 5023269 and US 4956388 discuss 3-aryloxy-3-substituted propanamines capable of inhibiting the uptake of serotonin and norepinephrine, and methods of preparing them.

H • HC1
(I) The preparation of Duloxetine is described in Tetrahedron Letters, 31, (49), 7101-04,
1990. Seven different routes of synthesis have also been reported in Drugs of the Future
2000, 25(9) 907-916. These synthesis have involved either a resolution of a key intermediate
or a stereospecific reduction of a keto group to the alcohol.
WO 2004/056795 discloses a process for preparing (+) Duloxetine by resolving
Racemic Duloxetine with chiral acid and (+) Duloxetine, substantially free of (-) Duloxetine.
This publication also discloses the process for preparing the acid addition salts of (+)
Duloxetine.
2

(+) Duloxetine hydrochloride is acid labile, and acid hydrolysis of the ether linkage produces a-Naphthol. a-Naphthol is extremely toxic and produces cramping, abdominal pain, nausea, and vomiting. Severe systemic effects include nephritis, cystitis, liver damage, convulsions, and acute intravascular hemolysis in individuals with RBC glucose 6-phosphaste deficiency1.
In addition, literature retrieved from toxnet is indicative that that Lens opacities & retinal changes have been described for a-Naphthol. In addition a-isomer of Naphthol is said to be even more toxic than P-naphthol
In animal toxicity studies a-Naphthol was shown to be highly toxic. Poole et al' have reported investigation of toxicological potential of a-Naphthol. The group investigated oral toxicity of a-naphthol in Charles River CD1 mice in single (2, 1 and 0.5 g/kg body weight) and 30-day repeat dosing (200, 100 and 50 mg/kg body weight) studies. In the single-dose study, animals dosed by oral gavage at 2 g/kg body weight either died or were killed in extremis between 15 and 90 min after dosing. Acute dosing was associated with histopathological lesions seen in the kidneys and stomachs of mice from all treatment groups. The kidney lesions consisted of degeneration of the distal tubule epithelium, papillary necrosis and tubular dilatation. Gastric changes characterized by splitting of the epithelium of the fore stomach and sloughing of the superficial epithelium of the glandular mucosa were generally accompanied by vascular congestion and acute inflammatory cell infiltration.
In addition, a search on toxnet2 reveals that a-Naphthol is reported to be toxic in various animal species. An overview of toxicological evaluation is presented below:
1. a-Naphthol (CAS # 90-15-3) was evaluated for acute oral toxicity. The test substance was administered by stomach intubation to non-fasted male albino Harlan-Wistar rats. The observed LD50 was 2.38 (1.56 to 3.65) g/kg, and 1.87 (1.27 to 2.76) g/kg for young and older adult rats, respectively. No further information was submitted.
2. a-Naphthol (CAS # 90-15-3) was evaluated for acute oral toxicity. The test substance was administered as a 50% solution in peanut oil. Rats receiving lethal doses suffered from diarrhea and died within 18 hours after treatment. Pathological examination indicated congestion and edema of the lungs; albumin in the kidney tubules; and superficial necrosis of the stomach. The approximate lethal dose (ALD) was calculated to be 1000 mg/kg.
3. a-Naphthol (CAS # 90-15-3) was evaluated for primary dermal irritation. The test substance was administered at a dosage of 500 mg to the intact and abraded skin of 6
3

albino rabbits. Moderate to severe erythema and edema was noted after 72 hours
(irritation score of 7.09/8.00). 4. a-Naphthol (CAS # 90-15-3) was evaluated for primary eye irritation. The test
substance was administered at a dosage of 100 mg to 6 albino rabbits. Slight to
moderate effects of the cornea, iris, and conjunctivae were noted (irritation score of
61.7/110).
a-Naphthol is a potential degradradation product of (+) Duloxetine hydrochloride and is very toxic for human consumption. The inventors of this patent application have disclosed a unique composition of active pharmaceutical ingredient of (+) Duloxetine hydrochloride, which is substantially or completely free from a-Naphthol. The (+) Duloxetine hydrochloride produced by present invention is substantially or completely free from a-Naphthol and has industrial application in preparing pharmaceutical, formulations having a substantially low quantities or completely free of a-Naphthol thereby reducing the total exposure to a-naphthol and thereby reducing the toxicological liabilities associated with exposure of a-Naphthol. Such an Active Pharmaceutical Ingredient (API) composition of of (+) Duloxetine hydrochloridewould be useful for preparing formulations like enteric coated tablets, capsules, beads and other dosage forms for patients/human beings who are in need of (+) Duloxetine hydrochloride treatment.
Summary of the invention:
The present invention provides:
1. An API composition of (+) Duloxetine hydrochloride, which is substantially free or
completely free from a-Napthol content on a weight/weight basis. Substantially pure
(+) Duloxetine hydrochloride of this invention include, without limitation,
a. (+) Duloxetine hydrochloride preferably containing 0.1% to 0.01% of a-
Naphthol with respect to the weight of (+) Duloxetine hydrochloride.
b. (+) Duloxetine hydrochloride more preferably containing less than 0.01% of
a-Naphthol with respect to the weight of (+) Duloxetine hydrochloride.
c. In another preferred mode the (+) Duloxetine produced by the disclosed
process is completely free of a-Napthol.
2. Process for preparing (+) Duloxetine Hydrochloride, which is substantially free or
completely free from a-naphthol content on a weight-by-weight basis.
4

Present invention is directed to ensure the preparation of (+) Duloxetine Hydrochloride in such a way that a-naphthol content preferably remains in range of 0.1% to 0.01%, in less than 0.01% and most preferably completely free from a-Napthol during normal (25 °C; 60% RH) and accelerated stability conditions (40 °C; 75% RH) as per ICH guidelines. 4. This invention relates to a process for the preparation of (+) Duloxetine Hydrochloride, which is also relatively stable in regard to a-naphthol and other potential impurities and the process with economical aspects and suitable to the plant operations. Disclosure of invention:
Racemic (±) Duloxetine is resolved by (-) p-di-tolyl-L-tartaric acid in an organic solvent from linear, branched or cyclic ketonic solvent of Ci to C6 to obtain (^p-di-tolyl-L-tartaric acid salt of (+) Duloxetine. This (-)p-di-tolyl-L-tartaric acid salt of (+) Duloxetine is converted into (+) Duloxetine by reacting with suitable alkali. The (+) Duloxetine is reacted with dry HCl gas in an organic solvent. The (+) Duloxetine Hydrochloride (technical) formed is then purified from suitable organic solvent to obtain pure (+) Duloxetine Hydrochloride, which is substantially free from a-naphthol (Scheme-1).

S
*DTTA
(-)p-di-tolyl-L-tartaric acid
(DTTA)

NaOH

NT . HCl
H
HCl, gas

Scheme -1
5

Hydroxylated and non-hydroxylated solvents are used to decrease or remove a-Naphthol contents from (+) Duloxetine hydrochloride technical (Example-3) to produce (+) duloxetine hydrochloride, which is substantially or completely free from a-Naphthol (Example-4)
The present invention will now be described with reference to the following non-limiting examples: Example-1 : Preparation of (-)p-di-tolyl-L-tartaric acid salt of (+) Duloxetine :
Charge 924 L of acetone and 77.0 Kg of (±)Duloxetine base in a SS reactor. Charge 100.1 Kg of (-)p-di-tolyl-L-tartaric acid, at 25°C to 35°C. Stir for 90 minutes at 25°C to 35°C. Centrifuge the product and wash with two 77 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford 61.6 Kg of (-)p-di-tolyl-L-tartaric acid salt of (+)Duloxetine.
Example-2 :
Preparation of (+) Duloxetine base :
Charge 956 L of water and 95.6 Kg of (-)p-di-tolyl-L-tartaric acid salt of (+)Duloxetine (obtained from Example-1) in SS reactor. Stir for 10 minutes. Charge 574 L of Methylene chloride. Stir for 10 minutes. Slowly add sodium hydroxide solution (14.34 Kg of sodium hydroxide and 143.4 L process water) upto pH 9.0 to 9.5 at 25°C to 35°C. Stir the contents for 1.0 hour and allow the layers to settle for 15 minutes. Separate Methylene chloride layer from bottom. Wash the organic layer with 143.4 L of process water. Filter Methylene chloride layer through Hyflosupercel bed and wash the Hyflosupercel bed with 47.8 L of Methylene chloride. Distil out Methylene chloride under vacuum below 50°C to afford 40.0 Kg of (+)Duloxetine base. Example-3 : Preparation of (+) Duloxetine Hydrochloride (Technical):
Charge 400 L of acetone and 40.0 Kg of (+) Duloxetine base (obtained from Example-2) in SS reactor. Stir to get clear solution at 25°C to 35°C. Filter the solution through fine filter pads. Charge filtrate in GLR. Cool the reaction content to 10°C to 15°C . Purge dry HC1 gas at 10°C to 15°C till pH of 2.0 to 2.5 is obtained. Stir the reaction mass for 1.0 hour at 10°C to 15°C. Centrifuge the product and wash the cake with two 40 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford 40.0 Kg of (+) Duloxetine Hydrochloride (Technical) which is substantially free from a-Naphthol
6

Ex^Biple-4:
Preparation of Pure (+) Duloxetine Hydrochloride:
Charge 400 L of acetone and 40.0 Kg of (+) Duloxetine Hydrochloride (Technical) (obtained from Example-3) in GLR at 25°C to 35°C. Stir the contents for 1.0 hour at 25°C to 35°C. Centrifuge the product and wash the cake with two 40 L portions of acetone. Dry the product at 50°C to 55°C for 8.0 hours to afford pure (+) Duloxetine Hydrochloride which is completely free from a-Naphthol.
HPLC purity is 99.87 % with a-naphthol content not detected, a-naphthol content is not detected even after long term and accelerated stability conditions. References:
1. Clinical pharmacology and Biopharmaceutics review (Review #2) from Lilly's NDA application no. 21-427
2. Hazardous Substances Data Bank (HSDB), a database of the National Library of Medicine's TOXNET system (http://toxnet.nlm.nih.gov) on June 22, 2005.Toxnet. Query: The chemical name 1-napthol
3. l-Naphthol~single and repeated dose (30-day) oral toxicity studies in the mouse; Poole A, Buckley P.; Food Chem Toxicol. 1989 Apr; 27(4): 233-8.
Dated this the 30th day of June 2005
H. SUB^AMANIAM Of Subnmwrfiam, Nataraj & Associates -"'Attorneys for the applicants
7

Abstract:
This invention relates to (+) Duloxetine hydrochloride, which is substantially or completely free from a-Napthol, an acid degradation product of (+) Duloxetine hydrochloride, The invention also discloses a process for preparation of (+) Duloxetine Hydrochloride, which is substantially or completely free from a-naphthol.
8

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Patent Number

250027

Indian Patent Application Number

791/MUM/2005

PG Journal Number

48/2011

Publication Date

02-Dec-2011

Grant Date

30-Nov-2011

Date of Filing

04-Jul-2005

Name of Patentee

CADILA HEALTHCARE LIMITED

Applicant Address

ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015

Inventors:

#	Inventor's Name	Inventor's Address
1	PATEL, MAHESH SHANKARBHAI	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015
2	PATEL, DHIMANT JASHUBHAI	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015
3	HADIYA, MAHESH NAYABHAI	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015
4	SHARMA, RAJIV KUMAR	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015
5	KOTHARI,JAY SHANTILAL	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015
6	AGARWAL, VIRENDRA KUMAR	ZYDUS TOWER, SATELLITE CROSS ROAD, AHMEDABAD- 380 015

PCT International Classification Number

C07D333/20,C07D333/0

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA