U.S. patent application number 11/376754 was filed with the patent office on 2006-11-30 for pure duloxetine hydrochloride.
Invention is credited to Mili Abramov, Santiago Ini, Anita Liberman.
Application Number | 20060270731 11/376754 |
Document ID | / |
Family ID | 36593962 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270731 |
Kind Code |
A1 |
Ini; Santiago ; et
al. |
November 30, 2006 |
Pure duloxetine hydrochloride
Abstract
Chemically and/or enantiomerically pure duloxetine HCl and
process for preparing chemically and/or enantiomerically pure
duloxetine HCl are provided.
Inventors: |
Ini; Santiago; (Haifa,
IL) ; Abramov; Mili; (Givataim, IL) ;
Liberman; Anita; (Tel-Aviv, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
36593962 |
Appl. No.: |
11/376754 |
Filed: |
March 14, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60726502 |
Oct 12, 2005 |
|
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60736746 |
Nov 14, 2005 |
|
|
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60661711 |
Mar 14, 2005 |
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60773593 |
Feb 14, 2006 |
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Current U.S.
Class: |
514/438 ;
549/76 |
Current CPC
Class: |
C07D 333/20 20130101;
C07D 333/16 20130101; A61P 13/00 20180101; A61K 31/38 20130101;
A61P 29/00 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/438 ;
549/076 |
International
Class: |
A61K 31/381 20060101
A61K031/381; C07D 333/22 20060101 C07D333/22 |
Claims
1. 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).
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-ISO3.
5. Pharmaceutically acceptable salts of duloxetine, containing less
than about 0.04 percent area by HPLC of the duloxetine
R-enantiomer.
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 (HCl), containing less than about 0.14
percent area by HPLC of the impurity
(+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl)propanamine
(DLX-ISO3).
14. The duloxetine HCl of claim 13, containing less than about 0.07
percent area by HPLC of DLX-ISO3.
15. The duloxetine HCl of claim 14, containing less than about 0.02
percent area by HPLC of DLX-ISO3.
16. The duloxetine HCl of claim 15, containing about 0.0 percent
area by HPLC of DLX-ISO3.
17. Duloxetine HCl, containing less than about 0.04 percent area by
HPLC of the duloxetine R-enantiomer.
18. The duloxetine HCl of claim 17, containing less than about 0.03
percent area by HPLC of the duloxetine R-enantiomer.
19. The duloxetine HCl of claim 18, containing less than about 0.02
percent area by HPLC of the duloxetine R-enantiomer.
20. The duloxetine HCl of claim 19, containing about 0.0 percent
area by HPLC of the duloxetine R-enantiomer.
21. The duloxetine HCl 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 HCl of claim 21, containing less than about 0.03
percent area by HPLC of the duloxetine R-enantiomer.
23. The duloxetine HCl of claim 22, containing less than about 0.02
percent area by HPLC of the duloxetine R-enantiomer.
24. The duloxetine HCl 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 HCl of
any of claims 13 to 24.
Description
RELATED APPLICATIONS
[0001] This application claims benefit of U.S. Provisional
Application Nos. 60/726,502, filed Oct. 12, 2005, 60/736,746, filed
Nov. 14, 2005, 60/661,711, filed Mar. 14, 2005, and 60/773,593,
filed Feb. 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 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.RTM..
Duloxetine hydrochloride has the chemical name
(S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine
hydrochloric acid salt and the following structure. ##STR1##
[0004] 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.
[0005] The conversion of 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.
[0006] Like any synthetic compound, 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.
[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.
[0010] 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."
[0011] 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.
[0012] (+)-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).
[0013] There is a need in the art for 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.
SUMMARY OF THE INVENTION
[0014] 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
(+)-N-methyl-3-(1-naphtalenyloxy)-3-(3-thienyl)propanamine
(DLX-ISO3).
[0015] 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.
[0016] 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.
[0017] In another embodiment, the present invention encompasses
duloxetine hydrochloride (HCl), containing less than about 0.14
percent area by HPLC of the impurity DLX-ISO3.
[0018] In another embodiment, the present invention encompasses
duloxetine HCl, containing less than about 0.04 percent area by
HPLC of the duloxetine R-enantiomer.
[0019] In another embodiment, 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.
[0020] In another embodiment, 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.
BRIEF DESCRIPTION OF THE FIGURES
[0021] FIGS. 1 and 2 depict HPLC chromatograms of the commercial
tablet CYMBALTA.RTM., 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
[0022] 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 110.degree. C. below and
above the reflux temperature of the solvent to obtain a solution,
and cooling the solution to a temperature of about 0.degree. C. to
about 30.degree. C.
[0023] The present invention provides chemically and/or
enantiomerically pure pharmaceutically acceptable salts of
duloxetine
[0024] The present invention also provides chemically and/or
enantiomerically pure duloxetine hydrochloride.
[0025] 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:
##STR2##
[0026] 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: ##STR3##
[0027] As used herein, 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. 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.
[0028] As used herein, 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. 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.
[0029] 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.
Preferably, the solvent is a mixture of acetone and water or
isopropanol.
[0030] 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.
[0031] Preferably, 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.
[0032] The present invention further provides pharmaceutical
formulations comprising the duloxetine HCl or any other
pharmaceutically acceptable salts of duloxetine, described
above.
[0033] 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.
[0034] 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.
[0035] 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.RTM.), 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.RTM.), potassium
chloride, powdered cellulose, sodium chloride, sorbitol, and
talc.
[0036] 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.RTM.), hydroxypropyl methyl cellulose (e.g., METHOCEL.RTM.),
liquid glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON.RTM.,
PLASDONE.RTM.), pregelatinized starch, sodium alginate, and
starch.
[0037] 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.RTM.,
PRIMELLOSE.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g., KOLLIDON.RTM., POLYPLASDONE.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.,
Explotab.RTM.), and starch.
[0038] 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.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] In 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.
[0043] 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.
[0044] 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
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.
[0045] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar
may be added to improve the taste.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches, and lozenges,
as well as liquid syrups, suspensions, and elixirs.
[0051] 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.
[0052] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0053] 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.
[0054] A tableting composition may be prepared conventionally by
dry blending. For example, 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.
[0055] 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.
[0056] 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.
[0057] 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 HCl
and methods for preparing the duloxetine HCl of the invention.
[0058] 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.times.4.6 5.mu.)
Mobile phase:
[0059] (A) 63% (KH.sub.2PO.sub.4 (0.02M) pH-2.5): 37% (35% MeOH:
10% THF) [0060] (B) 20% (KH.sub.2PO.sub.4 (0.02M) pH-2.5): 80% ACN
Gradient: [0061] From 0 to 15 min (A) isocraticaly [0062] 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.times.4.6 5.mu.
Eluent: Hexane (900 mL): IPA (100 mL): DEA (2 mL) Flow: 1 mL/min
Detection: 230 nm Sample conc: 0.5 mg/mL Sample vol: 100 .mu.L
Column temp: 20.degree. C. Detection limit: 0.02%
Example 1
Purification of Duloxetine Hydrochloride in Acetone/Water
Example 1a
[0063] 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.degree. C. overnight. The solid was filtered, washed with
acetone, and dried in a vacuum oven at 45.degree. C. for 16 hours,
giving Duloxetine hydrochloride (78 percent yield), containing
DLX-ISO3 (0.21 percent) and enantiomer R (<0.03 percent)
Example 1b
[0064] 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 110.degree. C. for 2 hours. The
solid was filtered, washed with acetone, and dried in a vacuum oven
at 45.degree. C. for 16 hours, giving Duloxetine hydrochloride (87
percent yield), containing DLX-ISO3 (0.15 percent) and free of
enantiomer R.
Example 1c
[0065] 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.degree. C. for 16 hours, giving Duloxetine hydrochloride (80
percent yield), containing DLX-ISO3 (0.07 percent), and free of
enantiomer R.
Example 1d
[0066] 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.degree. 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
[0067] 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.degree. C.
for 16 hours, giving Duloxetine hydrochloride (68 percent yield),
containing DLX-ISO3 (0.10 percent) and free of enantiomer R.
Example 2b
[0068] 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.degree. C. for 16 hours, giving
Duloxetine hydrochloride (36 percent yield), containing DLX-ISO3
(0.06 percent).
Example 2c
[0069] 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.degree. C. for 16 hours,
giving Duloxetine hydrochloride (50 percent yield) free of
DLX-ISO3.
Example 3
Purification of Duloxetine Hydrochloride in Ethyl Acetate
[0070] 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.degree. C. for 16 hours, giving
Duloxetine hydrochloride (93 percent yield), containing DLX-ISO3
(0.28 percent) and 0.07 percent of enantiomer R.
[0071] 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
[0072] A mixture of 8.4 g Duloxetine hydrochloride (contaminated
with 0.29 percent DLX-ISO3 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.degree. C. for 16 hours,
giving Duloxetine hydrochloride (62 percent yield), containing
DLX-ISO3 (0.21 percent) and free of enantiomer R.
Example 4b
[0073] 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.degree. C. for 16 hours, giving Duloxetine hydrochloride (83
percent yield), containing DLX-ISO3 (0.17 percent).
Example 4c
[0074] 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 IPA, and dried in a vacuum oven
at 45.degree. 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
[0075] 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.degree. 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
[0076] 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 the same solvents, and dried in a vacuum oven at
45.degree. C. for 16 hours, giving Duloxetine hydrochloride (29
percent yield).
Example 6
Purification of Duloxetine Hydrochloride in MEK/Water
Example 6a
[0077] 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.degree. to 5.degree. C. and
stirring for two hours. The solid was filtered, washed with the
same solvents, and dried in a vacuum oven at 45.degree. C. for 16
hours, giving Duloxetine hydrochloride (32 percent yield),
containing DLX-ISO3 (0.10 percent) and free of enantiomer R.
Example 6b
[0078] A mixture of 0.5 g 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.degree. to 5.degree. C. and stirring for two hours.
The solid is filtered, washed with the same solvents, and dried in
a vacuum oven at 45.degree. C. for 16 hours, giving Duloxetine
hydrochloride (32 percent yield).
Example 7
Purification of Duloxetine Hydrochloride in Water
[0079] A mixture of 2.7 g Duloxetine hydrochloride (contaminated
with 0.50 percent DLX-ISO3 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.degree. C. for 16
hours, giving Duloxetine hydrochloride (61 percent yield),
containing DLX-ISO3 (0.25 percent) and free of enantiomer R.
[0080] Example 7 is repeated to yield Duloxetine hydrochloride,
containing less than 0.14 percent DLX-ISO3.
Example 8
Purification of Duloxetine Hydrochloride in MEK
[0081] A mixture of 2 g Duloxetine hydrochloride (contaminated with
0.26 percent DLX-ISO3 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.degree. to
5.degree. C. and stirring for 2 hours. The solid was filtered,
washed with MEK, and dried in a vacuum oven at 45.degree. C. for 16
hours, giving Duloxetine hydrochloride (60 percent yield)
contaminated with DLX-ISO3 (0.21 percent) and free of enantiomer
R.
[0082] Example 8 is repeated to yield Duloxetine hydrochloride,
containing less than 0.14 percent DLX-ISO3.
Example 9
Purification of Duloxetine Hydrochloride in Acetone
Example 9a
[0083] 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.degree. C. The
solid was filtered at the same temperature, and dried in a vacuum
oven at 45.degree. C. for 16 hours, giving Duloxetine hydrochloride
(59.50 percent yield), containing DLX-ISO3 (0.17 percent) and free
of enantiomer R.
Example 9b
[0084] 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.degree. C. The solid was filtered at the same
temperature, and dried in a vacuum oven at 45.degree. C. for 16
hours, giving Duloxetine hydrochloride (59.50 percent yield).
Example 10
Purification of Duloxetine Hydrochloride in n-Butanol
[0085] 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.degree. C. for 16
hours, giving Duloxetine hydrochloride (75 percent yield),
containing DLX-ISO3 (0.24 percent) and 0.07 percent of enantiomer
R.
[0086] Example 10 is repeated, using a solvent selected from:
C.sub.2-5 ketones, C.sub.2-5 alkyl esters, C.sub.2-5 alkyl ethers,
C.sub.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
Purification of Duloxetine Hydrochloride in Ethanol
[0087] 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.degree. C. for 16
hours, giving Duloxetine hydrochloride (36 percent yield),
containing DLX-ISO3 (0.21 percent) and free of enantiomer R.
[0088] Example 11 is repeated to yield Duloxetine hydrochloride,
containing less than 0.14 percent DLX-ISO3.
Example 12
Analysis of CYMBALTA.RTM. Tablets
[0089] CYMBALTA.RTM. 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.RTM. 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.
COMPARATIVE EXAMPLE
[0090] The procedure disclosed in U.S. Pat. No. 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 HCl and stirred at
room temperature. After an hour the solution was cooled to
0-5.degree. 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.degree. C. for 16 hours. Duloxetine
hydrochloride was obtained in 42 percent yield, containing DLX-ISO3
(0.30 percent) and 0.35 percent of enantiomer R.
[0091] 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.
* * * * *