PURE DULOXETINE HYDROCHLORIDE
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional Application Nos.
60/726,502, filed October 12,2005, 60/736,746, filed November 14,2005, 60/661,711, filed March 14, 2005, and 60/773,593, filed February 14, 2006
FIELD OF THE INVENTION
[0002] The present invention relates to chemically and/or enantiomerically
pure duloxetine hydrochloride.
BACKGROUND OF THE INVENTION
[0003] Duloxetine HC1 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-(l-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloric acid salt and the following structure.
(Structure Remoed)
[0004] Duloxetine, as well as processes for its preparation, is disclosed in a
few published documents, such as U.S. Patent No. 5,023,269, EP Patent No. 457559,
and U.S. Patent No. 6,541,668.
[0005] The conversion of duloxetine to its hydrochloride salt is described in
U.S. Patent 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.
[0006] Like any synthetic compound, duloxetine HC1 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 HC1 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.
[0007] It is also known in the art that 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.
[0008] In addition to stability, which is a factor in the shelf life of the API, 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. For example, 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.
[0009] 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. At certain stages during
processing of 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.
[00010] Generally, side products, by-products, and adjunct reagents
(collectively "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. (Strobel p. 953, Strobel, H.A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons: New York 1989)). Thereafter, 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."
[00011] The retention time can vary about a mean value based upon the
condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time" ("RRT") to identify impurities. (Strobel p. 922). 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.
[00012] (+)-N-methyl-3-(l-naphtalenyloxy)-3-(3-thienyl)propanamineis
disclosed by Olsen B.A et al, as an impurity obtained in the preparation of duloxetine (J. Lib. Chrom. &Rel. Techno], 1996, 19, 1993).
[00013] There is a need in the art for duloxetine HC1, having improved
chemical and/or enantiomeric purity, compared to duloxetine HC1 obtained with prior art methods. The present invention provides such a duloxetine hydrochloride, having improved chemical and/or enantiomeric purity.
SUMMARY OF THE INVENTION
[00014] In one embodiment, the present invention encompasses
pharmaceutically acceptable salts of duloxetine, containing less than about 0.14 percent area by HPLC of the impurity (+)-Af-methyl-3-(l-naphtalenyloxy)-3-(3-thienyl)propanamine (DLX-ISO3).
[00015] In another embodiment, the present invention encompasses
pharmaceutically acceptable salts of duloxetine, containing less than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
^^
[00016] In another embodiment, 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.
[00017] In another embodiment, the present invention encompasses duloxetine
hydrochloride (HC1), containing less than about 0.14 percent area by HPLC of the
impurity DLX-ISO3.
[00018] In another embodiment, the present invention encompasses duloxetine
HC1, containing less than about 0.04 percent area by HPLC of the duloxetine
R-enantiomer.
[00019] In another embodiment, the present invention encompasses duloxetine
HC1, 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.
[00020] In another embodiment, the present invention encompasses
pharmaceutical formulations comprising the chemically and/or enantiomerically pure
duloxetine HC1 or any other pharmaceutically acceptable salts of duloxetine,
described above.
BRIEF DESCRIPTION OF THE FIGURES
[00021] Figures 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.
DETAILED DESCRIPTION OF THE INVENTION
[00022] As used herein the term "crystallization" refers to a process comprising
heating a mixture of a starting material and a solvent to a temperature of between
about 10°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.
[00023] The present invention provides chemically and/or enantiomerically
pure pharmaceutically acceptable salts of duloxetine
[00024] The present invention also provides chemically and/or
enantiomerically pure duloxetine hydrochloride.
[00025] The chemical purity of duloxetine in the present invention relates to
the level of the impurity (+)-7V-methyl-3-(l-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as DLX-IS03, and represented by the formula:
(Formula Removed)
DLX-IS03.
[00026] The enantiomeric purity in the present invention relates to the level of
the R-enantiomer of duloxetine, (R)-(-)-7V-methyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine, represented by the formula:
(Formula Removed)

[00027] As used herein, the terms "chemically pure duloxetine HC1" 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. Preferably, 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.
[00028] As used herein, the term "enantiomerically pure duloxetine HC1" 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. Preferably, 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.
[00029] The present invention also provides a process for the preparation of the
duloxetine HC1 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 HC1. Preferably, the solvent is a mixture of acetone and water or isopropanol.
[00030] Preferably, when the solvent is in a mixture with water, 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. Preferably, the ratio (vol/vol) of the starting material and the water or solvent is about 1:10. Preferably, the dissolution occurs at reflux temperature. Preferably, after cooling, the solution is maintained while stirring, for about 10 minutes to about 24 hours.
[00031] Preferably, the duloxetine HC1 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.
[00032] The present invention further provides pharmaceutical formulations
comprising the duloxetine HC1 or any other pharmaceutically acceptable salts of duloxetine, described above.
[00033] Pharmaceutical 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. For topical administration, 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.
[00034] In addition to the active ingredient(s), the pharmaceutical 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.
[00035] 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.
[00036] 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 sobid 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.
[00037] The dissolution rate of a compacted solid pharmaceutical composition
in the patient's stomach maybe 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.
[0003 8] 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.
[00039] When a dosage form such as a tablet is made by the compaction of a
powdered composition, 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.
[00040] Flavoring agents and flavor enhancers make the dosage form more
palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
[00041 ] 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.
[00042] hi 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.
[00043] 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.
00044] 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. Such agents include acacia, alginic acid
bentomte, 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.
[00045] Sweetening agents such as sorbitol, saccharin, sodium saccharin,
sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the
taste.
[00046] 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.
[00047] According to the present invention, 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.
[00048] Selection of excipients and the amounts used may be readily
determined by the formulation scientist based upon experience and consideration of
standard procedures and reference works in the field.
[00049] 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.
[00050] Dosage forms include solid dosage forms like tablets, powders,
capsules, suppositories, sachets, troches, and lozenges, as well as liquid syrups,
suspensions, and elixirs.
[00051] 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.
[00052] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the art.
[00053] A composition for tableting or capsule filling may be prepared by wet
granulation. In 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.
[00054] A tableting composition may be prepared conventionally by dry
blending. For example, the blended composition of the actives and excipients maybe
compacted into a slug or a sheet, and then comminuted into compacted granules. The
compacted granules may subsequently be compressed into a tablet.
[00055] As an alternative to dry granulation, 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.
[00056] 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.
[00057] Having described the invention with reference to certain preferred
embodiments, other embodiments will become apparent to one skilled in the art from
consideration of the specification. The invention is further defined by reference to the
following examples, describing in detail the analysis of the duloxetine HC1 and
methods for preparing the duloxetine HC1 of the invention.
[00058] It will be apparent to those skilled in the art that many modifications,
both to materials and methods, may be practiced without departing from the scope of
the invention.
EXAMPLES
HPLC method for measuring chemical purity;
Column: Hypersyl Gold (150 x 4.6 5/i)
Mobile phase: (A) 63% (KH2PO4 (0.02M) pH-2.5): 37% (35%MeOH: 10%THF)
(B) 20% (KH2PO4 (0.02M) pH-2.5): 80% ACN
Gradient: From 0 to 15 min (A) isocraticaly
From 15 to 60 min (B) increases from 0 to 100%
Detection: 230 nm
Flow: 1 mL/min
Detection limit: 0.02%
HPLC method for measuring enantiomeric purity:
Column: Diacel Chiral OD 250 x 4.6 5/t
Eluent: Hexane (900mL):IPA (lOOmL): DEA(2mL)
Flow: 1 mL/min
Detection: 230 nm
Sample cone: 0.5mg/mL
S ample vol: 100/^L
Column temp: 20°C
Detection limit: 0.02%
Example 1: Purification of Duloxetine hydrochloride in acetone/water Example la:
[00059] A mixture of 20 g Duloxetine hydrochloride in 204 ml acetone/water
(98:2) was heated to reflux. After the compound was dissolved, the oil bath was removed, and the solution was cooled to 15°C overnight. The solid was filtered, washed with acetone, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (78 percent yield), containing DLX-ISO3 (0.21 percent) and enantiomer R (<0.03 percent)
Example Ib:
[00060] A mixture of 13 g of the previously obtained Duloxetine hydrochloride
in 130 ml acetone/water (98:1.5) was heated to reflux. After the compound was dissolved, the oil bath was removed, and the solution was cooled to 10°C for 2 hours. The solid was filtered, washed with acetone, and dried hi a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (87 percent yield), containing DLX-ISO3 (0.15 percent) and free of enantiomer R.
Example Ic:
[00061] A mixture of 10 g of the previously obtained Duloxetine hydrochloride
in 100 ml acetone/water (98:2) was heated to reflux. After the compound was dissolved, the oil bath was removed, and the solution was cooled to room temperature and stirred for 1 hour. The solid was filtered, washed with acetone, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (80 percent yield), containing DLX-IS03 (0.07 percent), and free of enantiomer R.
Example Id:
[00062] A mixture of 7.5 g of the previously obtained Duloxetine
hydrochloride in 75 ml acetone/water (98:2) was heated to reflux. After the compound was dissolved, the oil bath was removed, and the solution was cooled to room temperature, and stirred for 2 hours. The solid was filtered, washed with acetone, and dried in a vacuum oven at 40°C for 16 hours, giving Duloxetine hydrochloride (73 percent yield), containing DLX-ISO3 (0.03 percent), and free of enantiomer R.
Example 2: Purification of Duloxetine hydrochloride in acetone/water under different conditions Example 2a:
[00063] A mixture of 16 g Duloxetine hydrochloride (contaminated with 0.30
percent DLX-ISO3 and 0.13 percent enantiomer R) in 160 ml acetone was heated to reflux, and then 4 ml of water were added till complete dissolution. After the compound was dissolved, the oil bath was removed, and the solution was cooled to room temperature and stirred for one hour. The solid was filtered, washed with acetone, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (68 percent yield), containing DLX-ISO3 (0.10 percent) and free of enantiomer R.
Example 2b:
[00064] A mixture of 8 g of the previously obtained Duloxetine hydrochloride
in 80 ml acetone was heated to reflux, and 2 ml of water were added. After the compound was dissolved, the oil bath was removed, and the solution was cooled to room temperature and stirred for half hour. The solid was filtered, washed with
acetone, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (36 percent yield), containing DLX-ISO3 (0.06 percent).
Example 2c:
[00065] A mixture of 2 g of the previously obtained Duloxetine hydrochloride
in 20 ml of acetone was heated to reflux, and 0.4 ml of water were added. After the compound was dissolved, the oil bath was removed, and the solution was cooled to room temperature and stirred for three hours. The solid was filtered, washed with acetone, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (50 percent yield) free of DLX-ISO3.
Example 3: Purification of Duloxetine hydrochloride in ethyl acetate
[00066] A mixture of 2 g Duloxetine hydrochloride (contaminated with 0.46
percent DLX-ISO3 and 0.13 percent enantiomer R) in 10 ml ethyl acetate was heated
to reflux, and 50 ml of ethyl acetate were added. The mixture was stirred at the same
temperature for 40 minutes, followed by cooling to room temperature and stirring for
two hours. The solid was filtered, washed with ethyl acetate, and dried in a vacuum
oven at 45°C for 16 hours, giving Duloxetine hydrochloride (93 percent yield),
containing DLX-ISO3 (0.28 percent) and 0.07 percent of enantiomer R.
[00067] Example 3 was repeated to yield Duloxetine hydrochloride, containing
less than 0.14 percent DLX-ISO3.
Example 4: Purification of Duloxetine hydrochloride in IPA Example 4a:
[00068] A mixture of 8.4 g Duloxetine hydrochloride (contaminated with 0.29
percent DLX-IS03 and 0.17 percent enantiomer R) in 84 ml IPA was heated to reflux. The solution was stirred at the same temperature for 15 minutes, followed by cooling to room temperature and stirring for two hours. The solid was filtered, washed with IPA, and dried in a vacuum oven at 45 °C for 16 hours, giving Duloxetine hydrochloride (62 percent yield), containing DLX-ISO3 (0.21 percent) and free of enantiomer R.
example 4b:
[00069] A mixture of 8.8 g Duloxetine hydrochloride (contaminated with 0.21
percent DLX-ISO3) in 70 ml IPA was heated to reflux. The solution was stirred at the same temperature for 15 minutes, followed by cooling to room temperature and stirring for two hours. The solid was filtered, washed with IPA, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (83 percent yield), containing DLX-ISO3 (0.17 percent).
Example 4c
[00070] A mixture of 5 g Duloxetine hydrochloride (contaminated with 0.17
percent DLX-ISO3) in 40 ml IPA was heated to reflux. The solution was stirred at the same temperature for 15 minutes, followed by cooling to room temperature and stirring for two hours. The solid was filtered, washed with EPA, and dried in a vacuum oven at 45 °C for 16 hours, giving Duloxetine hydrochloride (65 percent yield), containing DLX-ISO3 (0.13 percent)
Example 5: Purification of Duloxetine hydrochloride in MTBE/water: Example 5a
[00071 ] A mixture of 12 g 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.
Example 5b:
[00072] A mixture of 2 g 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
me same solvents, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (29 percent yield).
Example 6: Purification of Duloxetine hvdrochloride in MEK7water: Example 6a:
[00073] A mixture of 4 g Duloxetine hydrochloride (contaminated with 0.30
percent DLX-ISO3 and 0.17 percent enantiomer R) in 20 ml MEK was heated to reflux, and 0.6 ml of water were added until complete dissolution. The solution was stirred at the same temperature for 15-30 minutes, followed by cooling to 0° to 5°C and stirring for two hours. The solid was filtered, washed with the same solvents, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine hydrochloride (32 percent yield), containing DLX-ISO3 (0.10 percent) and free of enantiomer R.
Example 6b:
[00074] A mixture of 0.5 g Duloxetine hydrochloride (contaminated with 0.10
percent DLX-IS03) 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).
Example 7: Purification of Duloxetine hydrochloride in water
[00075] A mixture of 2.7 g Duloxetine hydrochloride (contaminated with 0.50
percent DLX-IS03 and 0.29 percent enantiomer R) in 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.
[00076] Example 7 is repeated to yield Duloxetine hydrochloride, containing
less than 0.14 percent DLX-ISO3.
Example 8: Purification of Duloxetine hydrochloride in MEK
[00077] A mixture of 2 g Duloxetine hydrochloride (contaminated with 0.26
percent DLX-IS03 and 0.17 percent enantiomer R) in 40 ml MEK was heated to
reflux. The solution was stirred at the same temperature for 30 minutes, followed by
cooling to 0° to 5°C and stirring for 2 hours. The solid was filtered, washed with
MEK, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine
hydrochloride (60 percent yield) contaminated with DLX-ISO3 (0.21 percent) and
free of enantiomer R.
[00078] Example 8 is repeated to yield Duloxetine hydrochloride, containing
less than 0.14 percent DLX-IS03.
Example 9: Purification of Duloxetine hvdrochloride in acetone Example 9 a:
[00079] A mixture of 2 g Duloxetine hydrochloride (contaminated with 0.46
percent DLX-ISO3 and 0.13 percent enantiomer R) in 130 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), containing DLX-ISO3 (0.17 percent) and free of enantiomer R.
Example 9b:
[00080] A mixture of 1 g 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: Purification of Duloxetine hvdrochloride in n-butanol
[00081] A mixture of 2 g Duloxetine hydrochloride (contaminated with 0.26
percent DLX-ISO3 and 0.17 percent enantiomer R) in 12 ml n-butanol was heated to reflux. The solution was stirred at the same temperature for 10 minutes, followed by cooling to room temperature and stirring for 1 hour. The solid was filtered, washed with n-butanol, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine
hydrochloride (75 percent yield), containing DLX-ISO3 (0.24 percent) and 0.07 percent of enantiomer R.
[00082] Example 10 is repeated, using a solvent selected from: C2-5 ketones,
C2-5 alkyl esters, C2-5 alkyl ethers, C2-4 alkanols other than n-butanol and mixtures thereof with water to yield Duloxetine hydrochloride, containing less than 0.14 percent DLX-ISO3.
Example 11: Purification of Duloxetine hydrochloride in ethanol
[00083] A mixture of 2.22 g Duloxetine hydrochloride (contaminated with 0.28
percent DLX-ISO3 and 0.50 percent enantiomer R) in 22.2 ml ethanol was heated to
reflux. The solution was stirred at the same temperature for 15 minutes, followed by
cooling to room temperature and stirring for 1 hour. The solid was filtered, washed
with n-butanol, and dried in a vacuum oven at 45°C for 16 hours, giving Duloxetine
hydrochloride (36 percent yield), containing DLX-ISO3 (0.21 percent) and free of
enantiomer R.
[00084] Example 11 is repeated to yield Duloxetine hydrochloride, containing
less than 0.14 percent DLX-ISO3.
Example 12: Analysis of CYMBALTA® tablets
[00085] CYMBALTA® tablets were analyzed, and found to contain 0.16
percent of the impurity (+)-N-methyl-3-(l-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 Figures 1 and 2, showing a
RRT of 1.20 for DLX-ISO3 and a RRT of 1.50 for the duloxetine R-enantiomer,
respectively.
Comparative Example
[00086] The procedure disclosed in US 5,491,243 was repeated as follows: to a
solution of 7 g Duloxetine base in 21 ml ethyl acetate were added 0.8 ml. of concentrated HC1 and stirred at room temperature. After an hour the solution was cooled to 0-5 °C and stirred for an additional two hours. The resulting solid was filtered., washed with the same solvent, and dried in a vacuum oven at 45°C for 16 hours. Duloxetine hydrochloride was obtained in 42 percent yield, containing DLX-IS03 (0.30 percent) and 0.35 percent of enantiomer R.
[00087] While it is apparent that the invention disclosed herein is well
calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.

What is claimed:
1. Pharmaceutically acceptable salts of duloxetine, containing less than about
0.14 percent area by HPLC of the impurity (+)-A/-methyl-3-(l~
naphtalenyloxy)-3-(3-thienyl)propanamine(DLX-IS03).
2. The pharmaceutically acceptable salts of claim 1, containing less than about
0.07 percent area by HPLC of DLX-ISO3.
3. The pharmaceutically acceptable salts of claim 2, containing less than about
0.02 percent area by HPLC of DLX-ISO3.
4. The pharmaceutically acceptable salts of claim 3, containing about 0.0 percent
area by HPLC of DLX-IS03.
5. Pharmaceutically acceptable salts of duloxetine, containing less than about
0.04 percent area by HPLC of the duloxetine R-enantioiner.
6. The pharmaceutically acceptable salts of claim 5, containing less than about
0.03 percent area by HPLC of the duloxetine R-enantiomer.
7. The pharmaceutically acceptable salts of claim 6, containing less than about
0.02 percent area by HPLC of the duloxetine R-enantiomer.
8. The pharmaceutically acceptable salts of claim 7, containing about 0.0 percent
area by HPLC of the duloxetine R-enantiomer.
9. The pharmaceutically acceptable salts of any of claims 1 to 4, containing less
than about 0.04 percent area by HPLC of the duloxetine R-enantiomer.
10. The pharmaceutically acceptable salts of claim 9, containing less than about
0.03 percent area by HPLC of the duloxetine R-enantiomer.
11. The pharmaceutically acceptable salts of claim 10, containing less than about
0.02 percent area by HPLC of the duloxetine R-enantiomer.
12. The pharmaceutically acceptable salts of claim 11, containing about 0.0
percent area by HPLC of the duloxetine R-enantiomer.
13. Duloxetine hydrochloride (HC1), containing less than about 0.14 percent area
by HPLC of the impurity (+)-A^-methyl-3-(l-naphtalenyloxy)-3-(3-
thienyl)propanamine (DLX-IS03).
14. The duloxetine HC1 of claim 13, containing less than about 0.07 percent area
byHPLCofDLX-ISO3.
15. The duloxetine HC1 of claim 14, containing less than about 0.02 percent area
byHPLCofDLX-ISO3.


The duloxetine HC1 of claim 15, containing about 0.0 percent area by HPLC ofDLX-ISO3.
17. Duloxetine HC1, containing less than about 0.04 percent area by HPLC of the
duloxetine R-enantiomer.
18. The duloxetine HC1 of claim 17, containing less than about 0.03 percent area
by HPLC of the duloxetine R-enantiomer.
» •#
19. The duloxetine HC1 of claim 18, containing less than about 0.02 percent area
by HPLC of the duloxetine R-enantiomer.
20. The duloxetine HC1 of claim 19, containing about 0.0 percent area by HPLC
of the duloxetine R-enantiomer.
21. The duloxetine HC1 of any of claims 13 to 16, containing less than about 0.04
percent area by HPLC of the duloxetine R-enantiomer.
22. The duloxetine HC1 of claim 21, containing less than about 0.03 percent area
by HPLC of the duloxetine R-enantiomer.
23. The duloxetine HC1 of claim 22, containing less than about 0.02 percent area
by HPLC of the duloxetine R-enantiomer.
24. The duloxetine HC1 of claim 23, containing about 0.0 percent area by HPLC
of the duloxetine R-enantiomer.
25. A pharmaceutical formulation, comprising the pharmaceutically acceptable
salts of any of claims 1 to 12.
26. A pharmaceutical formulation, comprising the duloxetine HC1 of any of
claims 13 to 24.