U.S. patent application number 12/228317 was filed with the patent office on 2008-12-18 for polymorphs of atomoxetine hydrochloride.
Invention is credited to Judith Aronhime, Stefano Bianchi, Eugenio Castelli, Paola Daverio, Adrienne Kovacsne-Mezei, Silvia Mantovani.
Application Number | 20080312471 12/228317 |
Document ID | / |
Family ID | 35432164 |
Filed Date | 2008-12-18 |
United States Patent
Application |
20080312471 |
Kind Code |
A1 |
Aronhime; Judith ; et
al. |
December 18, 2008 |
Polymorphs of atomoxetine hydrochloride
Abstract
The present invention provides novel crystalline polymorph forms
of atomoxetine hydrochloride denominated Forms B and C and methods
for their preparation, as well as methods for the preparation of
Form A. The present invention provides pharmaceutical compositions
that comprise atomoxetine hydrochloride Form B, Form C, or mixtures
thereof that can be used to treat attention deficit/hyperactivity
disorder.
Inventors: |
Aronhime; Judith; (Rehovot,
IL) ; Bianchi; Stefano; (Como, IT) ; Castelli;
Eugenio; (Arlate di Calco (Lecco), IT) ; Daverio;
Paola; (Villasanta (MI), IT) ; Mantovani; Silvia;
(Cesano Maderno (MI), IT) ; Kovacsne-Mezei; Adrienne;
(Debrecen, HU) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
35432164 |
Appl. No.: |
12/228317 |
Filed: |
August 11, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11187349 |
Jul 21, 2005 |
|
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12228317 |
|
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|
60590851 |
Jul 22, 2004 |
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Current U.S.
Class: |
564/374 |
Current CPC
Class: |
C07C 217/48
20130101 |
Class at
Publication: |
564/374 |
International
Class: |
C07C 211/01 20060101
C07C211/01 |
Claims
1. A process for the preparation of a crystalline form of
atomoxetine hydrochloride characterized by a powder x-ray
diffraction pattern having peaks at about 13.7, 17.3, 18.7, 21.1,
22.6, 24.0, 27.3, 28.4 and 29.3.+-.0.2 degrees two-theta comprising
the steps of: a) combining atomoxetine base in a solvent selected
from C.sub.1-4 alcohol, C.sub.2-4 alkyl ester, C.sub.1-4 alkyl
ether, mixtures thereof, and C.sub.1-6 substituted or unsubstituted
aromatic hydrocarbon to obtain a mixture; b) combining the mixture
with hydrochloric acid or hydrogen chloride to obtain a
precipitate; and c) recovering atomoxetine hydrochloride Form A
from the precipitate.
2. The process of claim 1, wherein the solvent is selected from
methanol, ethanol, isopropanol, methyl acetate, ethyl acetate,
n-butyl acetate, iso-butyl acetate, methyl t-butyl ether, and
mixtures thereof, toluene and xylene.
3. The process of claim 1, wherein the solvent is selected from the
group consisting of: isopropyl alcohol, methyl-t-butyl ether, ethyl
acetate, and mixtures thereof.
4. A crystalline form of atomoxetine hydrochloride characterized by
an x-ray powder diffraction pattern substantially as depicted in
FIG. 2.
5. A crystalline form of atomoxetine hydrochloride characterized by
an infrared absorption spectrum substantially as depicted in FIG.
5.
6. A crystalline form of atomoxetine hydrochloride characterized by
a Raman absorption spectrum substantially as depicted in FIG.
7.
7. A crystalline form of atomoxetine hydrochloride characterized by
an x-ray powder diffraction pattern substantially as depicted in
FIG. 3.
8. A crystalline form of atomoxetine hydrochloride characterized by
a Raman absorption spectrum, substantially as depicted in FIG. 8.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation application of U.S.
patent application Ser. No. 11/187,349 filed Jul. 21, 2005 and
claims the benefit of provisional application Ser. No. 60/590,851
filed Jul. 22, 2004, which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to crystalline polymorph forms
of atomoxetine hydrochloride denominated Forms B and C as well as
to methods for their preparation and use, and to methods for the
preparation of Form A.
BACKGROUND OF THE INVENTION
[0003] Atomoxetine HCl is a selective norepinephrine reuptake
inhibitor. It is marketed under the name STRATTERA.RTM. for the
treatment of attention deficit/hyperactivity disorder (ADHD) and is
available in 10 mg, 18 mg, 25 mg, 40 mg, and 60 mg dosage forms. It
is a white to practically white solid, which has a solubility of
27.8 mg/ml in water.
[0004] Atomoxetine, chemically known as
(R)(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine; has the
following structure:
##STR00001##
[0005] Atomoxetine, the (R)-(-) enantiomer of tomoxetine, is an
aryloxyphenylpropylamine. It is about twice as effective as the
racemic mixture and about nine times more effective than the
(+)-enantiomer, as disclosed in U.S. Pat. No. 4,018,895, European
Patent No. 0 052 492, and European Patent No. 0 721 777 (all by Eli
Lilly and Co.)
[0006] Atomoxetine HCl may be obtained from tomoxetine that
undergoes an optical resolution by any methods known in the art,
such as crystallization with (S)-(+)-mandelic acid, disclosed, for
example in EP Patent No. 0 052 492.
[0007] EP Patent No. 0 052 492 discloses a process for the
preparation of atomoxetine HCl. In this process, (R)-(-)-tomoxetine
(S)-(+)-mandelate is first basified in water to eliminate the
mandelate, then extracted in diethyl ether. HCl gas is bubbled into
the solution to obtain atomoxetime hydrochloride.
[0008] Similarly, U.S. Pat. No. 6,541,668 discloses a process for
the preparation of atomoxetine HCl involving basifying the
mandelate salt, followed by extracting with t-butyl methyl ether,
removing water by azeotropic distillation, and adding hydrogen
chloride.
[0009] Repetition of the processes disclosed in EP Patent No. 0 052
492 and U.S. Pat. No. 6,541,668 yielded a crystalline form of
atomoxetine HCl, denominated Form A. Form A may be characterized by
a powder x-ray diffraction pattern having peaks at about 13.7,
17.3, 18.7, 21.1, 22.6, 24.0, 27.3, 28.4 and 29.3.+-.0.2 degrees
two-theta, and further characterized by a powder x-ray diffraction
pattern having peaks at about 8.5, 13.3, 13.7, 14.7, 17.9, 22.3,
25.0, 25.4, 25.7, 26.4, 29.8 and 32.0.+-.0.2 degrees two-theta,
substantially as depicted in FIG. 1. Form A obtained by these
processes may also be characterized by an infrared absorption
spectrum having peaks at about 2701, 1600, 1492, 1248, 769, 756
cm.sup.-1, and further characterized by infrared absorption
spectrum having peaks at about 3057, 2056, 2857, 2741, 2456, 2408,
1893, 1773, 1476, 1452, 1460, 1391, 1357, 1308, 1287, 1202, 1189,
1175, 1165, 1118, 1068, 1048, 1023, 1011, 933, 884, 821, 769, 705,
630, 579 and 546 cm.sup.-1, substantially as depicted in FIG. 4.
Form A may be further characterized by a Raman absorption spectrum
substantially as depicted in FIG. 6.
[0010] Those skilled in the pharmaceutical arts understand that
crystallization of an active pharmaceutical ingredient offers the
best method for controlling important qualities like chemical
quality, particle size, and polymorphic content. Thus, there is a
need for crystal forms of atomoxetine hydrochloride and processes
to produce such forms. The forms should be suitable for
pharmaceutical use.
SUMMARY OF THE INVENTION
[0011] The present invention provides solid crystalline forms of
atomoxetine as well their preparation.
[0012] The present invention provides processes for the preparation
of crystalline atomoxetine hydrochloride Form A.
[0013] In one embodiment, Form A is prepared by a process
comprising: combining atomoxetine hydrochloride Form B with acetone
to obtain a mixture; and maintaining the mixture for a sufficient
time to obtain atomoxetine hydrochloride Form A.
[0014] In another embodiment, the present invention provides a
process for making atomoxetine hydrochloride Form A, comprising:
[0015] a) combining atomoxetine hydrochloride with water at a
temperature of about 40 to about 60.degree. C. to obtain a mixture;
[0016] b) cooling the mixture to room temperature to obtain a
precipitate; and [0017] c) recovering atomoxetine hydrochloride
Form A.
[0018] In yet another embodiment, the present invention provides a
process for making atomoxetine hydrochloride Form A, comprising:
[0019] a) combining atomoxetine hydrochloride with a solvent
selected from water, methanol and a mixture of acetic acid and
ethyl acetate, at a temperature ranging from room temperature to
about 60.degree. C. to obtain a mixture; [0020] b) removing at
least some of the solvent until a precipitate forms; and [0021] c)
recovering atomoxetine hydrochloride Form A.
[0022] In one embodiment, the present invention provides a process
for making atomoxetine hydrochloride Form A, comprising: [0023] a)
combining atomoxetine base in a solvent selected from C.sub.1-4
alcohol, C.sub.2-4 alkyl ester, C.sub.1-4 alkyl ether, mixtures
thereof, and C.sub.1-6 substituted or unsubstituted aromatic
hydrocarbon to obtain a mixture; [0024] b) combining the mixture
with hydrochloric acid or hydrogen chloride to obtain a
precipitate; and [0025] c) recovering atomoxetine hydrochloride
Form A from the precipitate.
[0026] Preferably, the solvent is selected from the group
consisting of: isopropyl alcohol, methyl-t-butyl ether, ethyl
acetate and mixtures thereof.
[0027] The present invention provides another crystalline form of
atomoxetine hydrochloride, denominated Form B, characterized by
data selected from: an x-ray powder diffraction pattern having
peaks at about 11.5, 17.1, 19.8, 21.3, 22.5, 23.6, 24.6, 27.5 and
28.5.+-.0.2 degrees two-theta; and an infrared absorption spectrum
having peaks at about 2761, 1596, 1493, 1234, 768, and 711
cm.sup.-1.
[0028] The present invention also provides a process for making
atomoxetine hydrochloride Form B. This process comprises: [0029] a)
combining atomoxetine-(S)-(+)-mandelate with toluene and methanol
to obtain a reaction mixture; [0030] b) heating the reaction
mixture to a temperature of about 60.degree. C.; [0031] c)
combining the reaction mixture with gaseous hydrogen; [0032] d)
cooling the reaction mixture of step c) to a temperature of about
20.degree. C. to about 25.degree. C. for a sufficient amount of
time for a slurry to form; and [0033] e) recovering atomoxetine
hydrochloride Form B from the slurry.
[0034] The present invention provides another process for making
atomoxetine hydrochloride Form B. This process comprises: [0035] a)
combining atomoxetine hydrochloride in a solution of water and
acetic acid; [0036] b) heating the mixture to a temperature of
about 40.degree. C. to about 60.degree. C. for a sufficient time to
dissolve the atomoxetine hydrochloride; and [0037] c) removing the
acetic acid and water to form atomoxetine hydrochloride Form B.
[0038] Yet another crystalline form of atomoxetine hydrochloride is
provided, denominated Form C. Atomoxetine hydrochloride Form C is
characterized by an x-ray powder diffraction pattern having peaks
at about 10.1, 16.4, 18.2 and 25.1.+-.0.2 degrees two-theta.
[0039] The invention also provides a process for making atomoxetine
hydrochloride Form C, comprising: [0040] a) combining atomoxetine
hydrochloride in a solution of water and acetone; [0041] b) heating
the mixture to a temperature of about 40.degree. C. to about
60.degree. C. for a sufficient time to dissolve the atomoxetine
hydrochloride; and [0042] c) removing the acetone and water to form
atomoxetine hydrochloride Form C.
[0043] Pharmaceutical compositions comprising a therapeutically
effective amount of atomoxetine hydrochloride Form B, and/or Form C
and a pharmaceutically acceptable carrier are also provided. Also
provided is a method for the treatment of attention
deficit/hyperactivity disorder comprising administering to a human
subject in need of such treatment the pharmaceutical compositions
of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0044] FIG. 1 is a characteristic powder x-ray diffraction spectrum
of atomoxetine hydrochloride Form A.
[0045] FIG. 2 is a characteristic powder x-ray diffraction spectrum
of atomoxetine hydrochloride Form B.
[0046] FIG. 3 is a characteristic powder x-ray diffraction spectrum
of atomoxetine hydrochloride Form C.
[0047] FIG. 4 is a characteristic infrared (IR) absorption spectrum
of atomoxetine hydrochloride Form A.
[0048] FIG. 5 is a characteristic infrared (IR) absorption spectrum
of atomoxetine hydrochloride Form B
[0049] FIG. 6 is a characteristic Raman absorption spectrum of
atomoxetine hydrochloride Form A.
[0050] FIG. 7 is a characteristic Raman absorption spectrum of
atomoxetine hydrochloride Form B.
[0051] FIG. 8 is a characteristic Raman absorption spectrum of
atomoxetine hydrochloride Form C.
[0052] FIG. 9 is a photomicrograph of atomoxetine hydrochloride
Form A.
DETAILED DESCRIPTION OF THE INVENTION
[0053] As used herein, "room temperature" or "RT" is meant to
indicate a temperature of about 18-25.degree. C., preferably about
20-25.degree. C.
[0054] "Therapeutically effective amount" means the amount of a
crystalline form that, when administered to a patient for treating
a disease or other undesirable medical condition, is sufficient to
have a beneficial effect with respect to that disease or condition.
The "therapeutically effective amount" will vary depending on the
crystalline form, the disease or condition and its severity, and
the age, weight, etc., of the patient to be treated. Determining
the therapeutically effective amount of a given crystalline form is
within the ordinary skill of the art and requires no more than
routine experimentation.
[0055] The present invention provides processes for the preparation
of the crystalline atomoxetine hydrochloride denominated Form A.
Form A may be characterized by a powder x-ray diffraction pattern
and an infrared absorption spectrum as described above. Form A has
a particle size of about 35 um or less, as can be seen in FIG.
9.
[0056] One process for preparing Form A comprises combining
atomoxetine hydrochloride Form B with acetone to obtain a mixture,
and maintaining the mixture for a sufficient time to obtain
atomoxetine hydrochloride Form A.
[0057] Preferably, the mixture is maintained for about 20 hours,
but the mixture may be maintained for shorter times as well.
Preferably, the reaction is performed at room temperature.
[0058] The present invention further provides a process for making
atomoxetine hydrochloride Form A comprising combining atomoxetine
hydrochloride with water at a temperature of about 40 to about
60.degree. C. to obtain a mixture, and precipitating atomoxetine
hydrochloride Form A.
[0059] Preferably, the atomoxetine hydrochloride and water are
heated to a temperature of about 50.degree.. Atomoxetine
hydrochloride Form A may be precipitated by cooling the mixture to
room temperature until a precipitate is formed, and then recovering
atomoxetine hydrochloride Form A.
[0060] Atomoxetine hydrochloride may be recovered by any means
known in the art, such as filtering out the solvent, washing the
filtered solids, and drying of the solid.
[0061] The present invention provides another process for making
atomoxetine hydrochloride Form A comprising: [0062] a) combining
atomoxetine hydrochloride with a solvent selected from water,
methanol, and a mixture of acetic acid and ethyl acetate, at a
temperature ranging from room temperature to about 60.degree. C. to
obtain a mixture; [0063] b) removing at least some of the solvent
until a precipitate forms; and [0064] c) recovering atomoxetine
hydrochloride Form A.
[0065] Preferably, the mixture in step a) is heated to a
temperature of about 50.degree.. Preferably, the ratio of the
acetic acid:ethyl acetate mixture is 1:2. The solvent may be
removed by any method known in the art, preferably by
distillation.
[0066] Atomoxetine hydrochloride Form A may be recovered as
described above.
[0067] The present invention provides yet another process for
making atomoxetine hydrochloride Form A comprising: [0068] a)
combining atomoxetine base in a solvent selected from C.sub.1-4
alcohol, C.sub.2-4 alkyl ester, C.sub.1-4 alkyl ether, mixtures
thereof, and C.sub.1-6 substituted or unsubstituted aromatic
hydrocarbon to obtain a mixture; [0069] b) combining the mixture
with hydrochloric acid or hydrogen chloride to obtain a
precipitate; and [0070] c) recovering atomoxetine hydrochloride
Form A from the precipitate.
[0071] A C.sub.1-4 alcohol includes methanol, ethanol or
isopropanol. A C.sub.2-4 alkyl ester includes methyl acetate, ethyl
acetate, n-butyl acetate or iso-butyl acetate. A C.sub.1-4 alkyl
ether includes methyl t-butyl ether. A C.sub.1-6 substituted or
unsubstituted aromatic hydrocarbon includes toluene or xylene.
[0072] Preferably, the solvent is selected from the group
consisting of: isopropyl alcohol, methyl-t-butyl ether, ethyl
acetate and mixtures thereof. The atomoxetine hydrochloride Form A
may be obtained as described above.
[0073] The present invention provides a crystalline form of
atomoxetine hydrochloride, denominated Form B, characterized by
data selected from: an x-ray powder diffraction pattern having
peaks at about 11.5, 17.1, 19.8, 21.3, 22.5, 23.6, 24.6, 27.5 and
28.5.+-.0.2 degrees two-theta; and an infrared absorption spectrum
having peaks at about 2761, 1596, 1493, 1234, 768, and 711
cm.sup.-1. Form B may be further characterized by an x-ray powder
diffraction pattern having peaks at about 7.8, 8.9, 12.2, 14.3,
14.9, 18.7, 26.0, 29.4, 29.9 and 31.2.+-.0.2 degrees two-theta,
substantially as depicted in FIG. 2. Form B may also be
characterized by an infrared absorption spectrum having the
following additional peaks at about 3017, 2958, 2928, 2845, 2508,
2442, 1479, 1460, 1433, 1371, 1358, 1285, 1207, 1192, 1175, 1164,
1137, 1118, 1072, 1047, 1037, 1023, 1010, 963, 931, 861, 755, 605,
568 and 535 cm.sup.-1, substantially as depicted in FIG. 5. Form B
may be further characterized by a Raman absorption spectrum
substantially as depicted in FIG. 7.
[0074] Atomoxetine hydrochloride Form B may be further
characterized by a melting point at about 163.degree. C. The DSC
thermogram of atomoxetine hydrochloride Form B shows a sharp
endothermic melting peak and an exothermic peak due to
decomposition at about 210.degree. C. Thermal weight change
measurements indicated a weight loss of about 2.6%.
[0075] Atomoxetine hydrochloride Form B may be substantially free
of Form A. In certain embodiments, Form B contains less than about
10%, preferably less than about 5%, and even more preferably less
than about 1% (by weight) of Form A.
[0076] Atomoxetine hydrochloride Form B may be substantially free
of Form C. In certain embodiments, Form B contains less than about
10%, preferably less than about 5%, and even more preferably less
than about 1% (by weight) of Form C.
[0077] The present invention also provides a process for making
atomoxetine hydrochloride Form B. This process comprises: [0078] a)
combining atomoxetine-(S)-(+)-mandelate with toluene and methanol
to obtain a reaction mixture; [0079] b) heating the reaction
mixture to a temperature of about 60.degree. C.; [0080] c)
combining the reaction mixture with gaseous hydrogen chloride;
[0081] d) cooling the reaction mixture of step c) to a temperature
of about 20.degree. C. to about 25.degree. C. for a sufficient
amount of time for a slurry to form; and [0082] e) recovering
atomoxetine hydrochloride Form B from the slurry.
[0083] Preferably, the atomoxetine hydrochloride Form B is
recovered by further cooling the slurry of step d) to about
0.degree. C., and then the solid is separated from the solvents by
any method known in the art, such as described above.
[0084] The present invention provides another process for making
atomoxetine hydrochloride Form B. This process comprises: [0085] a)
combining atomoxetine hydrochloride in a solution of water and
acetic acid; [0086] b) heating the mixture to a temperature of
about 40.degree. C. to about 60.degree. C. for a sufficient time to
dissolve the atomoxetine hydrochloride; and [0087] c) removing the
acetic acid and water to form atomoxetine hydrochloride Form B.
[0088] Preferably, the mixture is heated in step b) to a
temperature of about 50.degree. C. Preferably, the mixture in step
b) is maintained for at least 2 hours. Preferably, the ratio of the
water and acetic acid in the solution of step a) is 2:1. The acetic
acid and water may be removed from the mixture by evaporation.
[0089] The present invention provides a crystalline form of
atomoxetine hydrochloride, denominated Form C, characterized by an
x-ray powder diffraction pattern having peaks at about 10.1, 16.4,
18.2 and 25.1.+-.0.2 degrees two-theta. Form C may be further
characterized by an x-ray powder diffraction pattern having peaks
at about 11.1, 19.0, 20.9, 21.4, 22.1, 23.0, 23.6, 25.7, 26.8,
27.3, 29.0, 30.2, 31.1, 31.9, and 33.4.+-.0.2 degrees two-theta,
substantially as depicted in FIG. 3. Form C may be also
characterized by a Raman absorption spectrum substantially as
depicted in FIG. 8.
[0090] Atomoxetine hydrochloride form C may be further
characterized by a melting point of about 168.degree. C. The DSC
thermogram of atomoxetine hydrochloride Form C shows a sharp
endothermic melting peak followed by decomposition at about
210.degree. C. Thermal weight change measurements indicated a
weight loss of about 1.7%.
[0091] Atomoxetine hydrochloride Form C may be substantially free
of Form A. In certain embodiments, Form C contains less than about
10%, preferably less than about 5%, and even more preferably less
than about 1% (by weight) of Form A.
[0092] Atomoxetine hydrochloride Form C may be substantially free
of Form B. In certain embodiments, Form C contains less than about
10%, preferably less than about 5%, and even more preferably less
than about 1% (by weight) of Form B.
[0093] The invention also provides a process for making atomoxetine
hydrochloride Form C comprising: [0094] a) combining atomoxetine
hydrochloride in a solution of water and acetone; [0095] b) heating
the mixture to a temperature of about 40.degree. C. to about
60.degree. C. for a sufficient time to dissolve the atomoxetine
hydrochloride; and [0096] c) removing the acetone and water to form
atomoxetine hydrochloride Form C.
[0097] Preferably, the mixture is heated in step b) to a
temperature of about 50.degree. C. Preferably, the mixture in step
b) is maintained for at least 2 hours. Preferably, the ratio of the
water and acetone in the solution of step a) is 2:1. The acetic
acid and water may be removed from the mixture by evaporation.
[0098] Pharmaceutical Compositions Containing Atomoxetine
Hydrochloride Polymorphs
[0099] Another embodiment of the present invention is a
pharmaceutical formulation comprising a therapeutically effective
amount of an atomoxetine hydrochloride form selected from the group
consisting of Form B, Form C, and mixtures thereof, combined with a
pharmaceutically acceptable excipient or carrier.
[0100] Another embodiment of the present invention is a method for
treating a patient suffering from attention deficit/hyperactivity
disorder comprising the step of administering to the patient a
pharmaceutical formulation comprising a therapeutically effective
amount of atomoxetine hydrochloride selected from the group
consisting of Form B, Form C, and mixtures thereof.
[0101] Alternatively, pharmaceutical formulations of the present
invention may also contain mixtures of the crystalline polymorphs
of atomoxetine hydrochloride disclosed herein.
[0102] In addition to the active ingredient(s), the pharmaceutical
formulations of the present invention may contain one or more
excipients. Excipients are added to the formulation for a variety
of purposes.
[0103] Diluents may be added to the formulations of the present
invention. 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.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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 dye. Some excipients and active
ingredients have a tendency to adhere to the surfaces of the punch
and dye, 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
dye. 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.
[0108] 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.
[0109] Solid and liquid compositions may also be dyed using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0110] The present invention is not intended to encompass true
solutions of atomoxetine hydrochloride whereupon the crystal
structure of the novel crystalline forms and the properties that
characterize the novel crystalline forms of atomoxetine
hydrochloride of the present invention are lost. However, the use
of the novel forms to prepare such solutions (e.g., so as to
deliver atomoxetine hydrochloride in a liquid pharmaceutical
formulation) is considered to be within the contemplation of the
invention.
[0111] In liquid pharmaceutical-compositions prepared using the
crystalline forms of the present invention, atomoxetine
hydrochloride and any other solid excipients are dissolved or
suspended in a liquid carrier such as water, vegetable oil,
alcohol, polyethylene glycol, propylene glycol, or glycerin.
[0112] 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.
[0113] Liquid pharmaceutical compositions 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.
[0114] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar
may be added to improve the taste.
[0115] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and
ethylenediamine tetraacetic acid may be added at levels safe for
ingestion to improve storage stability.
[0116] A liquid composition may also contain a buffer such as
guconic acid, lactic acid, citric acid or acetic acid, sodium
guconate, sodium lactate, sodium citrate, or sodium acetate.
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.
[0117] 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.
[0118] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and lozenges, as
well as liquid syrups, suspensions and elixirs.
[0119] The dosage of STRATTERA.RTM. may be used as guidance. The
oral dosage form of the present invention is preferably in the form
of an oral capsule or tablet having a dosage of about 5 mg to about
160 mg, more preferably from about 20 mg to about 80 mg, and most
preferably capsules or tablets of 10, 18, 20, 25, 40, 60 and 80 mg.
Daily dosages may include 1, 2, or more capsules per day.
[0120] 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.
[0121] 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.
[0122] 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.
[0123] 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.
[0124] 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.
[0125] The active ingredient and excipients may be formulated into
compositions and dosage forms according to methods known in the
art.
[0126] It is not necessary that the formulations of the present
invention contain only one crystalline form of atomoxetine
hydrochloride. The crystalline forms of the present invention may
be used in pharmaceutical formulations or compositions as single
components or mixtures together with other crystalline forms of
atomoxetine hydrochloride or with amorphous atomoxetine
hydrochloride. However, it is preferred that the pharmaceutical
formulations or compositions of the present invention contain
25-100% by weight, especially 50-100% by weight, of at least one of
the novel forms, based on the total amount of atomoxetine
hydrochloride in the formulation or composition. Preferably, such
an amount of the novel crystalline form of atomoxetine
hydrochloride is 75-100% by weight, especially 90-100% by weight.
Highly preferred is an amount of 95-100% by weight.
Experimental
[0127] Powder x-ray diffraction data were obtained by ARL X-Ray
powder diffractometer model X'TRA-030, Peltier detector, round
standard aluminium sample holder with round zero background quartz
plate was used. Scanning parameters: range: 2-40 deg. 2.theta.,
continuous scan, rate: 3 deg./min. The accuracy of peak positions
was defined as +/-0.2 degrees due to such experimental differences
as instrumentation, sample preparations etc. Data were obtained
with a Bruker D8 Discover equipped with a xyz translation stage
(with x, y, z travel of 100 mm, 150 mm and 100 mm, respectively).
The x-ray detector was a high-performance HI-STAR two-dimensional
detector that was set to 15 cm from the centre of the goniometer.
At this distance, the detector has a typical FWHM of 0.15-0.2
degrees in 2.theta.. The x-ray generator was typically set to 40 KV
and 40 mA. The data was collected in one frame with a typical data
acquisition time of 3 minutes. The 2.theta. range covered by the
HI-STAR detector is from 4.5 to 39.5 degrees. The sample is
typically oscillated in the y direction (perpendicular to the x-ray
travel direction) with oscillation amplitude of .+-.2-3 mm.
Omega-scan (rocking the x-ray source and the detector
synchronously) was also used occasionally to reduce preferred
orientation in samples that were producing very spotty diffraction
patterns. Crystals grown on a universal substrate were analyzed
either uncrushed or crushed. The crushing of crystalline samples
was achieved with a pneumatic compactor that has 96 pins whose
diameter is 0.25 inches, sufficient to encompass the area of the
samples. The force on each pin was about 12 lb. Epoch software was
used to facilitate the translation of the stage to the elements of
interest and a joystick to control translation and a knob to adjust
the Z height were used to focus the beam on samples of interest.
Epoch then stored the images and coordinates of each of the user
specified locations to the database. Epoch was also used to control
the data acquisition and stored the acquisition parameters, area
plots, and 2-theta plots to the database as one experiment.
[0128] The differential scanning thermograms (DSC) were obtained
using a DSC 822.sup.e/700, Mettler Toledo. Typical sample weight
was approximately 3-5 mg. The samples were heated to 30-350.degree.
C. at a rate of 10.degree. C./min. and purged with nitrogen gas at
a flow rate of 40 ml/min. Standard crucibles used had 3 small
holes.
[0129] Thermal weight change measurements were made on a TGA 2950
Thermogravimetric analyzer by TA Instruments. Samples of 0.1-2 mg
were placed in an aluminum pan and placed in the device. The data
was collected from about 50 to about 350.degree. C. at a rate of
10.degree. C./min.
[0130] The infrared (IR) Raman spectroscopy experiments were
performed with a JY/Horiba LabRam spectrometer. The excitation
laser was a HeNe laser operating at 632.8 nm. The beam was focused
onto the sample through the objective of an Olympus BX microscope.
The microscope was equipped with crossed polarizing filters so that
birefringence images could be used to facilitate the identification
of crystalline material. Typically, the laser spot was sufficiently
narrow as to allow the acquisition of the Raman spectra from
individual crystals. Epoch software was used to facilitate the
translation of the stage to the elements of interest and a joystick
to control translation and a knob to adjust the Z height were used
to focus the beam on samples of interest. Epoch then stored the
images and coordinates of each of the user specified locations,
including multiple locations per element, to the database as a
mapping experiment. The software then executed a sequence so that
Raman spectra were obtained for each set of coordinates defined in
the mapping experiment. The scattered photons were collected at 180
degrees to the incident beam, the laser line was removed with a
holographic notch filter, and the light was then separated with a
grating and imaged onto a CCD. The spectra were collected at either
a single grating position or the grating was scanned to collect
signal over a larger Raman shift. Data collection times ranged from
10 seconds to several minutes depending on the scattering cross
section of the sample. The spectra and acquisition parameters were
then stored to the database for analysis.
[0131] FT-IR Spectroscopy was performed on Perkin-Elmer
spectrum--One spectrophotometer. The samples were analyzed using
diffuse reflectance technique (DRIFT). The samples were finely
ground with Potassium Bromide and the spectrum was recorded using
Potassium Bromide as background in a diffuse reflectance accessory.
Scanning parameters were: range: 4000-400 cm-1, 16 scans,
resolution:4.0 cm-1.z
[0132] The photomicrograph of atomoxetine hydrochloride Form A was
taken with Zeiss Axiolab Pol polarization microscope. The
magnification was 200-1 scale unit corresponds to 10
micrometer.
[0133] 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 preparation of the composition and methods
of use of the invention. 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
Preparation of Atomoxetine Hydrochloride Form A
Example 1
[0134] Atomoxetine HCl Form B (0.2 g, 0.0006854 mol) was mixed with
2 ml of acetone and stirred for 20 hours at 20-25.degree. C. The
solid was filtered and then washed with a few milliliters of
dioxane and dried at room temperature to yield polymorph A.
Example 2
[0135] Ten grams (0.03427 mol) of atomoxetine HCl were mixed with a
mixture of 180 ml of acetic acid/ethyl acetate (ratio 1:2) at room
temperature. Most of the solvent was distilled off by under vacuum
distillation at T<30.degree. C. The solution was let to stand
and after 4 days two crops of solid were collected and dried under
vacuum at room temperature.
Example 3
[0136] Ten grams (0.03427 mol) of atomoxetine HCl were mixed with
33 ml of water at 50.degree. C. The solution was cooled at
20-25.degree. C. and a solid precipitated. The solid was collected
by filtration and dried under vacuum at room temperature.
Example 4
[0137] Ten grams (0.03427 mol) of atomoxetine HCl was mixed with 33
ml of water at 50.degree. C. A small amount of solvent was
distilled off by distillation under vacuum at 50.degree. C. A solid
precipitated, and was stirred at room temperature. The solid was
collected by filtration and dried under vacuum at room
temperature.
Example 5
[0138] Five grams (0.01713 mol) of atomoxetine HCl were mixed with
30 ml of methanol at 50.degree. C. Solvent was distilled off by
distillation under vacuum at 50.degree. C. until the solution
became turbid. At room temperature a solid precipitated, and was
collected by filtration and dried under vacuum at room temperature
to yield polymorph A.
Example 6
[0139] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of a mixture of isopropyl
alcohol/methyl-t-butyl ether (ratio of 1:2). The temperature was
kept at 20-25.degree. C. by means of water-ice bath cooling while
0.81 g of aqueous (37%) hydrogen chloride was dropped into the
obtained solution. When the solid crystallized, the slurry was
stirred for 1 hour at 20-25.degree. C. The solid was then collected
by filtration, washed with methyl-t-butyl ether, and dried under
vacuum at 45.degree. C. for 2 hours.
Example 7
[0140] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of a mixture of isopropyl
alcohol/methyl-t-butyl ether (ratio of 1:2). The temperature was
kept at 20-25.degree. C. by means of water-ice bath cooling while
gaseous hydrogen chloride was bubbled into the obtained solution.
The solid crystallized and the slurry was stirred for 1 hour at
20-25.degree. C. The solid was collected by filtration, washed with
methyl-t-butyl ether, and dried under vacuum at 45.degree. C. for 2
hours.
Example 8
[0141] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of ethyl acetate. The temperature
was kept at 20-25.degree. C. by means of water-ice bath cooling,
while 0.81 g of aqueous (37%) hydrogen chloride was dropped into
the obtained solution. The solid crystallized and the slurry was
stirred for 1 hour at 20-25.degree. C. The solid was collected by
filtration, washed with ethyl acetate, and dried under vacuum at
45.degree. C. for 2 hours.
Example 9
[0142] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of ethyl acetate. The temperature
was kept at 20-25.degree. C. by means of water-ice bath cooling
while gaseous hydrogen chloride was bubbled into the obtained
solution. The solid crystallized and the slurry was stirred for 1
hour at 20-25.degree. C. The solid was then collected by
filtration, washed with ethyl acetate, and dried under vacuum at
45.degree. C. for 2 hours.
Example 10
[0143] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of iso-propyl alcohol. The
temperature was kept at 20-25.degree. C. by means of water-ice bath
cooling while 0.81 g of aqueous (37%) hydrogen chloride was dropped
into the obtained solution. The solid crystallized and the slurry
was stirred for 1 hour at 20-25.degree. C. The solid was collected
by filtration, washed with iso-propyl alcohol, and dried under
vacuum at 45.degree. C. for 2 hours.
Example 11
[0144] Two grams (0.00741 mol) of atomoxetine free base were mixed
at room temperature with 18 ml of iso-propyl alcohol. The
temperature was kept at 20-25.degree. C. by means of water-ice bath
cooling while gaseous hydrogen chloride was bubbled into the
obtained solution. The solid crystallized and the slurry stirred
for 1 hour at 20-25.degree. C. The solid was collected by
filtration, washed with iso-propyl alcohol, and dried under vacuum
at 45.degree. C. for 2 hours.
Example 12
[0145] Atomoxetine free base (32.9 g, 0.1169 mol) was mixed at room
temperature with 376.3 ml of ethyl acetate. Keeping the temperature
at 15-20.degree. C. by means of water-ice bath cooling, 12.7 g of
aqueous (37%) hydrogen chloride was dropped into the obtained
solution. The solid crystallized and the slurry was stirred for 1
hour at 5.degree. C. The solid was collected by filtration, washed
with ethyl acetate, and dried under vacuum at 45.degree. C. for 18
hours.
Preparation of Atomoxetine Hydrochloride Form B
Example 13
[0146] Two grams (0.00491) of atomoxetine (S)-(+)-mandelate were
mixed at room temperature with 10 ml of toluene and 1 ml of MeOH
and under stirring was heated to about 60.degree. C. Keeping the
temperature at 60.degree. C. by means of oil bath heating, gaseous
hydrogen chloride was bubbled into the obtained solution. The
solution was cooled at 20-25.degree. C. and a solid crystallized.
The slurry was stirred for 1 hour at 0.degree. C., and then the
solid collected by filtration, washed with toluene, and dried under
vacuum at 45.degree. C. for 5 hours.
Example 14
[0147] 50 mg of atomoxetine HCl were mixed with 4 ml of water and 2
ml of acetic acid. The mixture was heated at 50.degree. C. for 2
hours until it became clear. The solution was evaporated and the
resulting Form B crystals were collected.
Preparation of Atomoxetine Hydrochloride Form C
Example 15
[0148] 50 mg of atomoxetine HCl were mixed with 4 ml of water and 2
ml of acetone. The mixture was heated at 50.degree. C. for 2 hours
until it became clear. The solution was evaporated and the
resulting atomoxetine Form C was collected.
[0149] Table 1 shows the DSC data for the atomoxetine polymorphs
obtained from the examples above:
TABLE-US-00001 TABLE 1 EXPERIMENT Cryst. form DSC mp Example 1 A
169.4 Example 2 A 169.3 Example 2 A 168.9 Example 3 A 169.6 Example
4 A 169.6 Example 5 A 169.8 Example 6 A 168.1 Example 7 A 167.3
Example 8 A 168.5 Example 9 A 167.3 Example 10 A 168.7 Example 11 A
168.5 Example 12 A 164.0 + 169.8 Example 13 B 163.2 Example 14 B
168.3 Example 15 C 168.2
[0150] Samples that have a small additional peak in DSC before
melting may contain either a small amount of form B or a small
amount of the intermediate.
[0151] It should be understood that some modification, alteration,
and substitution is anticipated and expected from those skilled in
the art without departing from the teachings of the invention.
Accordingly, it is appropriate that the following claims be
construed broadly and in a manner consistent with the scope and
spirit of the invention.
* * * * *