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US20060270731A1 - Pure duloxetine hydrochloride - Google Patents

Pure duloxetine hydrochloride Download PDF

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Publication number
US20060270731A1
US20060270731A1 US11/376,754 US37675406A US2006270731A1 US 20060270731 A1 US20060270731 A1 US 20060270731A1 US 37675406 A US37675406 A US 37675406A US 2006270731 A1 US2006270731 A1 US 2006270731A1
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Prior art keywords
duloxetine
percent
enantiomer
iso3
dlx
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Santiago Ini
Mili Abramov
Anita Liberman
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Teva Pharmaceuticals USA Inc
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Individual
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Priority to US11/376,754 priority Critical patent/US20060270731A1/en
Assigned to TEVA PHARMACEUTICALS USA, INC. reassignment TEVA PHARMACEUTICALS USA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TEVA PHARMACEUTICAL INDUSTRIES LTD
Assigned to TEVA PHARMACEUTICAL INDUSTRIES LTD. reassignment TEVA PHARMACEUTICAL INDUSTRIES LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIBERMAN, ANITA, ABRAMOV, MILI, INI, SANTIAGO
Publication of US20060270731A1 publication Critical patent/US20060270731A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the present invention relates to chemically and/or enantiomerically pure duloxetine hydrochloride.
  • Duloxetine HCl is a dual reuptake inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI), depression, and pain management. It is commercially available as CYMBALTA®.
  • Duloxetine hydrochloride has the chemical name (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt and the following structure.
  • Duloxetine as well as processes for its preparation, is disclosed in a few published documents, such as U.S. Pat. No. 5,023,269, EP Patent No. 457559, and U.S. Pat. No. 6,541,668.
  • duloxetine to its hydrochloride salt is described in U.S. Pat. No. 5,491,243 and in Wheeler W. J., et al, J. Label. Cpds. Radiopharm, 1995, 36, 312. In both cases the reactions are performed in ethyl acetate.
  • duloxetine HCl can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine HCl or any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient being treated with a dosage form of the API in which a sufficient amount of impurities is present. Furthermore, the undesired enantiomeric impurities reduce the level of the API available in the pharmaceutical composition.
  • API active pharmaceutical ingredient
  • impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis.
  • Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
  • the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent.
  • the ICH Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
  • the product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture.
  • an API such as duloxetine hydrochloride
  • it must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product.
  • the API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
  • impurities are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate.
  • a peak position such as that in a chromatogram or a spot on a TLC plate.
  • the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector.
  • the relative position in the chromatogram is known as the “retention time.”
  • the retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors.
  • practitioners use the “relative retention time” (“RRT”) to identify impurities. (Strobel p. 922).
  • RRT relative retention time
  • the RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
  • (+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl)propanamine is disclosed by Olsen B. A et al, as an impurity obtained in the preparation of duloxetine (J. Lib. Chrom. & Rel. Technol, 1996, 19, 1993).
  • duloxetine HCl having improved chemical and/or enantiomeric purity, compared to duloxetine HCl obtained with prior art methods.
  • the present invention provides such a duloxetine hydrochloride, having improved chemical and/or enantiomeric purity.
  • the present invention encompasses pharmaceutically acceptable salts of duloxetine, containing less than about 0.14 percent area by HPLC of the impurity (+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO3).
  • the present invention encompasses pharmaceutically acceptable salts of duloxetine, containing less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • the present invention encompasses pharmaceutically acceptable salts of duloxetine, containing less than about 0.14 percent area by HPLC of the impurity DLX-ISO3 and less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • the present invention encompasses duloxetine hydrochloride (HCl), containing less than about 0.14 percent area by HPLC of the impurity DLX-ISO3.
  • HCl duloxetine hydrochloride
  • the present invention encompasses duloxetine HCl, containing less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • the present invention encompasses duloxetine HCl, containing less than about 0.14 percent area by HPLC of the impurity DLX-ISO3 and less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • the present invention encompasses pharmaceutical formulations comprising the chemically and/or enantiomerically pure duloxetine HCl or any other pharmaceutically acceptable salts of duloxetine, described above.
  • FIGS. 1 and 2 depict HPLC chromatograms of the commercial tablet CYMBALTA®, showing a RRT of 1.20 for DLX-ISO3 and a RRT of 1.50 for the duloxetine R-enantiomer, respectively.
  • crystallization refers to a process comprising heating a mixture of a starting material and a solvent to a temperature of between about 110° C. below and above the reflux temperature of the solvent to obtain a solution, and cooling the solution to a temperature of about 0° C. to about 30° C.
  • the present invention provides chemically and/or enantiomerically pure pharmaceutically acceptable salts of duloxetine
  • the present invention also provides chemically and/or enantiomerically pure duloxetine hydrochloride.
  • the chemical purity of duloxetine in the present invention relates to the level of the impurity (+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as DLX-ISO3, and represented by the formula:
  • the enantiomeric purity in the present invention relates to the level of the R-enantiomer of duloxetine, (R)-( ⁇ )-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine, represented by the formula:
  • the terms “chemically pure duloxetine HCl” and “chemically pure pharmaceutically acceptable salt of duloxetine” refer to duloxetine hydrochloride/pharmaceutically acceptable salt of duloxetine, containing less than about 0.14 percent area by HPLC of the DLX-ISO3 impurity.
  • the level of DLX-ISO3 is less than about 0.07 percent area by HPLC, and, most preferably, is less than about 0.02 percent area by HPLC.
  • a chemically pure duloxetine HCl/pharmaceutically acceptable salt of duloxetine in accordance with the invention may be substantially free of DLX-ISO3, such that the DLX-ISO3 is below the detection limit; i.e., the chemically pure duloxetine HCl/pharmaceutically acceptable salt of duloxetine preferably contains essentially 0.0 percent DLX-ISO3 within the error limits of the detection.
  • the term “enantiomerically pure duloxetine HCl” and “enantiomerically pure pharmaceutically acceptable salt of duloxetine” refer to a duloxetine HCl/pharmaceutically acceptable salt of duloxetine, containing less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
  • the level of the duloxetine R-enantiomer is less than about 0.03 percent area by HPLC, and, more preferably, is less than about 0.02 percent area by HPLC.
  • An enantiomerically pure duloxetine HCl/pharmaceutically acceptable salt of duloxetine in accordance with the invention may be substantially free of the R-enantiomer, such that the R-enantiomer is below the detection limit; i.e., the enantiomerically pure duloxetine HCl/pharmaceutically acceptable salt of duloxetine preferably contains essentially 0.0 percent R-enantiomer within the error limits of the detection.
  • the present invention also provides a process for the preparation of the duloxetine HCl described above.
  • This process comprises dissolving duloxetine in water or a solvent selected from the group consisting of acetone, methyl ethyl ketone (MEK), methyl t-butyl ether (MTBE), ethanol, isopropanol, and n-butanol, and mixtures thereof with water, and crystallizing duloxetine HCl.
  • the solvent is a mixture of acetone and water or isopropanol.
  • the ratio (vol/vol) of the solvent and water is at least about 97:3 to about 98.25:1.75, and, more preferably, the ratio is at least about 98:2.
  • the ratio (vol/vol) of the starting material and the water or solvent is about 1:10.
  • the dissolution occurs at reflux temperature.
  • the solution is maintained while stirring, for about 10 minutes to about 24 hours.
  • the duloxetine HCl obtained after the crystallization contains less than about 0.14 percent area by HPLC DLX-ISO3 and less than about 0.04 percent of the R-enantiomer of duloxetine.
  • the crystallization process may be repeated in order to increase the chemical and enantiomeric purity even further either with the same or a different solvent that was used for the first crystallization.
  • the present invention further provides pharmaceutical formulations comprising the duloxetine HCl or any other pharmaceutically acceptable salts of duloxetine, described above.
  • compositions may be prepared as medicaments to be administered orally, parenterally, rectally, transdermally, bucally, or nasally.
  • suitable forms for oral administration include tablets, compressed or coated pills, dragees, sachets, hard or gelatin capsules, sub-lingual tablets, syrups, and suspensions.
  • Suitable forms of parenteral administration include an aqueous or non-aqueous solution or emulsion, while for rectal administration, suitable forms for administration include suppositories with hydrophilic or hydrophobic vehicle.
  • the invention provides suitable transdermal delivery systems known in the art, and for nasal delivery, there are provided suitable aerosol delivery systems known in the art.
  • compositions of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
  • Diluents for solid compositions include, for example, microcrystalline cellulose (e.g., AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g., EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL®
  • microfine cellulose lactose
  • starch pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL®), hydroxypropyl methyl cellulose (e.g., METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • carboxymethylcellulose sodium, dextrin eth
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab®), and starch.
  • alginic acid include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g.,
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and die.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and die, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the die.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
  • Solid and liquid compositions may also be died using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention the active ingredient and any other solid excipients are suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
  • Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodium acetate.
  • the solid compositions of the present invention include powders, granulates, aggregates, and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant, and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.
  • the dosage form of the present invention may be a capsule, containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
  • the shell may be made from gelatin, and, optionally, contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
  • compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried, and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry blending.
  • the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
  • a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a more uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • Duloxetine hydrochloride (contaminated with 0.29 percent DLX-ISO3 and 0.11 percent enantiomer) in 120 ml MTBE was heated to reflux, and 3.6 ml of water were added until complete dissolution. The two phase solution was stirred at the same temperature for 15-30 minutes, followed by cooling to room temperature and stirring overnight. The solid was filtered, washed with the same solvents, and dried in a vacuum oven at 45° C. for 16 hours, giving Duloxetine hydrochloride (29 percent yield), containing DLX-ISO3 (0.16 percent) and less than 0.02 percent of enantiomer R.
  • Duloxetine hydrochloride (contaminated with 0.16 percent DLX-ISO3 and less than 0.03 percent of enantiomer R) in 20 ml MTBE is heated to reflux, and 0.36 ml of water are added until complete dissolution. The two phase solution is stirred at the same temperature for 15 to 30 minutes, followed by cooling to room temperature and stirring overnight. The solid is filtered, washed with the same solvents, and dried in a vacuum oven at 45° C. for 16 hours, giving Duloxetine hydrochloride (29 percent yield).
  • Duloxetine hydrochloride (contaminated with 0.10 percent DLX-ISO3) in 2.5 ml MEK is heated to reflux, and 0.1 ml of water are added until complete dissolution. The solution is stirred at the same temperature for 15 to 30 minutes, followed by cooling to 0° to 5° C. and stirring for two hours. The solid is filtered, washed with the same solvents, and dried in a vacuum oven at 45° C. for 16 hours, giving Duloxetine hydrochloride (32 percent yield).
  • Duloxetine hydrochloride contaminated with 0.50 percent DLX-ISO3 and 0.29 percent enantiomer R
  • 27 ml water was heated to reflux.
  • the solution was stirred at the same temperature for 10 to 15 minutes, followed by cooling to room temperature and stirring overnight.
  • the solid was filtered, washed with water, and dried in a vacuum oven at 45° C. for 16 hours, giving Duloxetine hydrochloride (61 percent yield), containing DLX-ISO3 (0.25 percent) and free of enantiomer R.
  • Example 7 is repeated to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
  • Example 8 is repeated to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
  • Duloxetine hydrochloride (contaminated with 0.17 percent DLX-ISO3) in 65 ml acetone was heated to reflux. The solution was stirred at the same temperature for one hour, followed by cooling to 27° C. The solid was filtered at the same temperature, and dried in a vacuum oven at 45° C. for 16 hours, giving Duloxetine hydrochloride (59.50 percent yield).
  • Example 10 is repeated, using a solvent selected from: C 2-5 ketones, C 2-5 alkyl esters, C 2-5 alkyl ethers, C 2-4 alkanols other than n-butanol and mixtures thereof with water to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
  • a solvent selected from: C 2-5 ketones, C 2-5 alkyl esters, C 2-5 alkyl ethers, C 2-4 alkanols other than n-butanol and mixtures thereof with water to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
  • Example 11 is repeated to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
  • CYMBALTA® tablets were analyzed, and found to contain 0.16 percent of the impurity (+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl)propanamine. The tablet also contained 0.04 percent of the undesired R-enantiomer.
  • HPLC chromatograms of a CYMBALTA® tablet are depicted in FIGS. 1 and 2 , showing a RRT of 1.20 for DLX-ISO3 and a RRT of 1.50 for the duloxetine R-enantiomer, respectively.

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US66171105P 2005-03-14 2005-03-14
US72650205P 2005-10-12 2005-10-12
US73674605P 2005-11-14 2005-11-14
US77359306P 2006-02-14 2006-02-14
US11/376,754 US20060270731A1 (en) 2005-03-14 2006-03-14 Pure duloxetine hydrochloride

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US11/376,573 Abandoned US20060270861A1 (en) 2005-03-14 2006-03-14 Process for the preparation of optically active (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
US11/376,552 Expired - Fee Related US7534900B2 (en) 2005-03-14 2006-03-14 Process for the purification of duloxetine hydrochloride
US11/376,574 Abandoned US20060258871A1 (en) 2005-03-14 2006-03-14 (S)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof

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US11/376,552 Expired - Fee Related US7534900B2 (en) 2005-03-14 2006-03-14 Process for the purification of duloxetine hydrochloride
US11/376,574 Abandoned US20060258871A1 (en) 2005-03-14 2006-03-14 (S)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine-di-p-toluoyl-l-tartarate and methods of preparation thereof

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GB0612509D0 (en) 2006-06-23 2006-08-02 Arrow Int Ltd Crystalline duloxetine hydrochloride
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EP2303244A2 (fr) * 2008-06-13 2011-04-06 KRKA, D.D., Novo Mesto Compositions orales pharmaceutiques gastro-résistantes comportant du duloxétine ou ses dérivés pharmaceutiques acceptables
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Publication number Priority date Publication date Assignee Title
US20060194869A1 (en) * 2004-12-23 2006-08-31 Santiago Ini Process for preparing pharmaceutically acceptable salts of duloxetine and intermediates thereof
US20090012316A1 (en) * 2005-03-08 2009-01-08 Teva Pharmaceuticals Usa, Inc. Crystal forms of (S)-(+)-N,N-dimethyl-3-(1-Napathalenyloxy)-3-(2-thienyl)propanamine oxalate and the preparation thereof
US20060276660A1 (en) * 2005-03-14 2006-12-07 Santiago Ini Process for the purification of duloxetine hydrochloride
US7534900B2 (en) 2005-03-14 2009-05-19 Teva Pharmaceutical Industries Ltd Process for the purification of duloxetine hydrochloride
US20080207923A1 (en) * 2005-09-22 2008-08-28 Santiago Ini Pure DNT-maleate and methods of preparation thereof
US20080027128A1 (en) * 2006-05-23 2008-01-31 Santiago Ini Duloxetine HCL polymorphs
US20070281989A1 (en) * 2006-05-31 2007-12-06 Santiago Ini Process for preparing duloxetine and intermediates thereof
WO2011148380A1 (fr) * 2010-05-25 2011-12-01 Hetero Research Foundation Composition pharmaceutique à base de duloxétine destinée à la voie orale

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EP1874754A1 (fr) 2008-01-09
MX2007011254A (es) 2007-10-18
CA2599475A1 (fr) 2006-09-21
IL184184A0 (en) 2007-10-31
US20060258871A1 (en) 2006-11-16
WO2006099457A1 (fr) 2006-09-21
WO2006099468A2 (fr) 2006-09-21
EP1858873A2 (fr) 2007-11-28
TW200639161A (en) 2006-11-16
EP1858859A1 (fr) 2007-11-28
US20060270861A1 (en) 2006-11-30
WO2006099468A3 (fr) 2007-04-05
US7534900B2 (en) 2009-05-19
TW200639162A (en) 2006-11-16
IL184189A0 (en) 2007-10-31
EP1858874A1 (fr) 2007-11-28
CA2599478A1 (fr) 2006-09-21
US20060276660A1 (en) 2006-12-07
WO2006099459A1 (fr) 2006-09-21
MX2007011255A (es) 2007-10-18
IL184185A0 (en) 2007-10-31

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