U.S. patent application number 10/136582 was filed with the patent office on 2003-06-05 for form a of fluoxetine hydrochloride.
Invention is credited to Stowell, Grayson Walker, Whittle, Robert R..
Application Number | 20030105360 10/136582 |
Document ID | / |
Family ID | 25096760 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030105360 |
Kind Code |
A1 |
Stowell, Grayson Walker ; et
al. |
June 5, 2003 |
Form a of fluoxetine hydrochloride
Abstract
The present invention relates to novel polymorphic Form A of
fluoxetine hydrochloride.
Inventors: |
Stowell, Grayson Walker;
(Wilmington, NC) ; Whittle, Robert R.;
(Wilmington, NC) |
Correspondence
Address: |
MYERS BIGEL SIBLEY & SAJOVEC
PO BOX 37428
RALEIGH
NC
27627
US
|
Family ID: |
25096760 |
Appl. No.: |
10/136582 |
Filed: |
August 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10136582 |
Aug 20, 2002 |
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09991839 |
Nov 5, 2001 |
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09991839 |
Nov 5, 2001 |
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09772969 |
Jan 31, 2001 |
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6316672 |
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Current U.S.
Class: |
564/346 |
Current CPC
Class: |
A61K 31/138 20130101;
C07C 217/48 20130101 |
Class at
Publication: |
564/346 ;
514/650 |
International
Class: |
C07C 217/56; A61K
031/137 |
Claims
What is claimed is:
1. Form A of fluoxetine hydrochloride in pure form.
2. Form A of fluoxetine hydrochloride in pure form characterized by
having an x-ray powder diffraction pattern consistent with
fluoxetine hydrochloride, and further having a single endotherm as
determined by differential scanning calorimetry run at a maximum
rate of 1.degree. C. per minute.
3. Form A of fluoxetine hydrochloride according to claim 2 wherein
said single DSC endotherm occurs in the temperature range from
about 155.degree. C. to about 160.degree. C.
4. Form A of fluoxetine hydrochloride according to claim 2 wherein
said single DSC endotherm occurs in the temperature range from
about 157.degree. C. to about 159.degree. C.
5. Form A of fluoxetine hydrochloride in pure form characterized by
the following single crystallographic parameters:
10 crystal class orthorhombic space group Pbca (#61) a (.ANG.)
10.3754 (4) b (.ANG.) 10.4603 (2) c (.ANG.) 32.3412 (12) V
(.ANG..sup.3) 3510.0 (3) d calc (g/cm.sup.3) 1.31 R, R.sub.W 0.038,
0.038.
6. Form A of fluoxetine hydrochloride according to claim 5 further
characterized by having an x-ray powder diffraction pattern
consistent with fluoxetine hydrochloride, and further characterized
by having a single endotherm as determined by differential scanning
calorimetry run at a maximum rate of 1.degree. C. per minute.
7. Form A of fluoxetine hydrochloride according to claim 6 wherein
said single DSC endotherm occurs in the temperature range from
about 155.degree. C. to about 160.degree. C.
8. Form A of fluoxetine hydrochloride according to claim 6 wherein
said DSC single endotherm occurs in the temperature range from
about 157.degree. C. to about 159.degree. C.
9. Form A of fluoxetine hydrochloride in essentially pure form.
10. Form A of fluoxetine hydrochloride characterized by having an
x-ray powder diffraction pattern consistent with fluoxetine
hydrochloride, and further characterized by having at least two
endotherms as determined by differential scanning calorimetry run
at a maximum rate of 1.degree. C. per minute, provided that the
amount of fluoxetine hydrochloride polymorphs other than Form A
does not exceed an amount greater than about ten percent (w/w).
11. Form A of fluoxetine hydrochloride according to claim 10
wherein the peak of said DSC endotherms occurs in the temperature
range from about 155.degree. C. to about 160.degree. C.
12. Form A of fluoxetine hydrochloride according to claim 10
wherein said Form A is further characterized by the following
crystallographic parameters:
11 crystal class orthorhombic space group Pbca (#6 1) a (.ANG.)
10.3754 (4) b (.ANG.) 10.4603 (2) c (.ANG.) 32.3412 (12) V
(.ANG..sup.3) 3510.0 (3) d calc (g/cm.sup.3) 1.31 R, R.sub.W 0.038,
0.038.
13. Form A of fluoxetine hydrochloride according to claim 12
wherein the peak of said DSC endotherms occurs in the temperature
range from about 155.degree. C. to about 160.degree. C.
14. Form A of fluoxetine hydrochloride form characterized by having
an x-ray powder diffraction pattern consistent with fluoxetine
hydrochloride, and further characterized by having at least two
endotherms as determined by differential scanning calorimetry run
at a maximum rate of 1.degree. C. per minute, provided that the
amount of fluoxetine hydrochloride polymorphs other than Form A
does not exceed an amount greater than about five percent
(w/w).
15. Form A of fluoxetine hydrochloride according to claim 14
wherein the peak of said DSC endotherms occurs in the temperature
range from about 155.degree. C. to about 160.degree. C.
16. Form A of fluoxetine hydrochloride according to claim 14
wherein said Form A is further characterized by the following
crystallographic parameters:
12 crystal class orthorhombic space group Pbca (#61) a (.ANG.)
10.3754 (4) b (.ANG.) 10.4603 (2) c (.ANG.) 32.3412 (12) V
(.ANG..sup.3) 3510.0 (3) d calc (g/cm.sup.3) 1.31 R, R.sub.w 0.038,
0.038.
17. Form A of fluoxetine hydrochloride according to claim 16
wherein the peak of said DSC endotherms occurs in the temperature
range from about 155.degree. C. to about 160.degree. C.
18. A method for inhibiting serotonin uptake in mammals comprising
administering to a mammal requiring increased neurotransmission of
serotonin an effective amount of fluoxetine hydrochloride as
claimed in any one of claims 1 through 17.
Description
[0001] The present invention is generally concerned with a novel
polymorphic form of fluoxetine hydrochloride,
(.+-.)-N-methyl-3-phenyl-2--
[.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl) oxy] propylamine
hydrochloride, which is marketed by Dista Products and Eli Lilly
and Company (the "Innovator"), Indianapolis, Ind., under the trade
name Prozac.RTM.. The present invention is further concerned with
the preparation and use of the polymorphic form of fluoxetine
hydrochloride now designated Form A ("Form A").
[0002] Polymorphic forms of the same drug substance (also known as
the active pharmaceutical ingredient or "API"), as administered by
itself or formulated as a drug product (also known as the final or
finished dosage form) are well known in the pharmaceutical art to
affect, for example, the solubility, stability, flowability,
fractability, and compressibility of drug substances and the safety
and efficacy of drug products, (see, e.g. Knapman, K. Modern Drug
Discoveries, March, 2000: 53). So critical are the potential
effects of different polymorphic forms in a single drug substance
on the safety and efficacy of the respective drug product(s) that
the United States Food and Drug Administration (the "FDA") requires
each drug substance manufacturer, in the least, to control its
synthetic processes such that the percentages of the various
respective polymorphic forms, when present, must be consistent
among batches and within the drug substance/product's specification
as approved by the FDA.
[0003] Left uncontrolled in synthetic processes, the percentage of
a given polymorph outside of an FDA approved specification would
render the adulterated batches unfit for commercial sale.
Accordingly, the FDA requires full characterization of each drug
substance used in each drug product marketed in the United States,
including the identification and control of polymorphic forms. The
FDA further requires robust synthetic process specifications and
controls which consistently produce the respective drug substance
and drug product.
[0004] Unfortunately, the detection of various polymorphic forms of
a single drug substance is not always readily discernable by
pharmaceutical chemists. Such a drug substance would not be
manufactured with appropriate controls, potentially leaving the
attendant safety and efficacy risks unaddressed.
[0005] It has been discovered that fluoxetine hydrochloride drug
substance, generally used to prepare Prozac.RTM. and potential
generic drugs thereto (fluoxetine hydrochloride API), has not been
fully or completely characterized. It has been unexpectedly
discovered that such fluoxetine hydrochloride API drug substance
comprises at least three crystalline forms, which occur at varying
and uncontrolled ratios from batch to batch. These three identified
polymorphs have been designated Form A, Form B, and Form C,
correlated to the relative proportion of each polymorph in
fluoxetine hydrochloride, from greatest to least.
[0006] It has further been discovered that Form A can be prepared
in pure or essentially pure polymorphic form in robust,
controllable, synthetic processes.
DETAILED DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 shows an X-ray powder diffraction (XRD) pattern for
fluoxetine hydrochloride API (Lot 1).
[0008] FIG. 2 shows the corresponding differential scanning
calorimeter (DSC) thermogram for the fluoxetine hydrochloride API
sample represented in the XRD pattern shown in FIG. 1.
[0009] FIG. 3 shows another XRD pattern for fluoxetine
hydrochloride API (Lot 2).
[0010] FIG. 4 shows the DSC thermogram for the fluoxetine
hydrochloride API sample represented in the XRD pattern shown in
FIG. 3.
[0011] FIG. 5 shows an XRD pattern for pure Form A of fluoxetine
hydrochloride prepared via the compression method of preparation
taught herein.
[0012] FIG. 6 shows the DSC thermogram for the Form A sample
represented in the XRD pattern shown in FIG. 5.
[0013] FIG. 7 shows an XRD pattern for pure Form A of fluoxetine
hydrochloride prepared via the slurry method of preparation taught
herein.
[0014] FIG. 8 shows the DSC thermogram for the Form A sample
represented in the XRD pattern shown in FIG. 7.
[0015] FIG. 9 shows an initial XRD pattern for amorphous fluoxetine
hydrochloride prepared via the method taught herein.
[0016] FIG. 10 shows the initial DSC thermogram from the amorphous
fluoxetine hydrochloride sample represented in the XRD pattern
shown in FIG. 9.
[0017] FIG. 11 shows a DSC thermogram for Forms A, D, and E, which
formed within three days after pure Form A of fluoxetine
hydrochloride was prepared via the recrystallization method taught
herein when stored at 40.degree. C. and 75% relative humidity.
DETAILED DESCRIPTION OF THE INVENTION
[0018] The existence of the various polymorphic forms of fluoxetine
hydrochloride can not be discerned from the crystallographic
literature. More particularly, literature (Robertson, D. W.; Jones,
N. D.; Swartzendruber, J. K.; Yang, K. S.; Wong, D. T. J. Med Chem.
(1988), 31, 185) reports the crystal structure of fluoxetine
hydrochloride API performed at Lilly Research Laboratories. This
article details the crystal structure and parameters associated
with the structural analysis. The structure was solved in a
non-standard setting (Pcab) of the standard Space Group Pbca (#61)
and refined to a final R of 0.074. We have independently also
solved the identical structure using the standard setting of Pbca
(#61) and have refined the structure to a final R of 0.038.
Generation of a simulated powder pattern from the crystallographic
data reveals a pattern similar to the pattern that Lilly submitted
to the International Center for Diffraction Data (ICDD) for
inclusion as file #36-1895 in its powder diffraction database
[Orthorhombic, Pcab, 10.457.times.10.387.times.32.345 .ANG.].
However, the ICDD database also lists a second file (#44-1517) for
fluoxetine hydrochloride. This file was taken from diffraction data
presented by Risley, D.; Bopp, R. Anal. Profiles Drug Subst.,
(1990), 19, and indexed by the editor of ICDD [Orthorhombic,
10.448.times.14.797.times.32.329 .ANG.]. When actual X-ray powder
diffraction was performed using a zero background sample mount on
the same crystalline material used for single crystal analysis, the
measured pattern was found to match ICDD file #44-1517. The
crystals were platelets and zero background sample mounts can
induce preferred orientations to a powder pattern. To test this,
the respective sample was lightly ground to a more uniform size and
shape and front packed in an aluminum sample well to produce a
random distribution, and reanalyzed by X-ray powder diffraction.
The pattern now matches #36-1895, consistent with the structural
analysis indicating that patterns #36-1895 and #44-1517 in the ICDD
database are the same crystalline phase and differ only by severe
preferred orientation problems. Closer examination of the two ICDD
patterns show they exhibit extremely similar "d" spacings and unit
cell constants which differ only in the b-axis length. Indexing of
ICDD pattern #36-1895 was based upon single crystal analysis and
pattern #44-1517 by indexing from powder diffraction. Indexing (3-D
data) from powder diffraction data (2-D data) is considered
inconsistent at best, and in this case, appears to have problems.
Based upon the axial lengths of 10.457 and 10.387 .ANG. from
#36-1895, a special transformation exists. This type of
transformation converts the axes to a C-centered cell by using the
diagonal of the orthogonal a and b axes, and would generate a cell
length of about 14.74 .ANG. for the diagonal (square root of the
sum of the squares of the a and b axes) which was assigned to the
b-axis. Therefore, the two patterns listed for fluoxetine
hydrochloride in the ICDD database are actually the same, differing
only in severe preferred orientation. Neither sample even remotely
suggests that multiple fluoxetine hydrochloride polymorphs exist.
In fact, a combination of analytical tools were required to
discover the existence of multiple polymorphic forms of fluoxetine
hydrochloride and to confirm that Form A was successfully prepared
in pure and essentially pure form.
[0019] Using the procedure taught in Example 14 herein, Form A of
fluoxetine hydrochloride is characterized by the following single
crystallographic parameters:
1 crystal class orthorhombic space group Pbca (#61) a (.ANG.)
10.3754 (4) b (.ANG.) 10.4603 (2) c (.ANG.) 32.3412 (12) V
(.ANG..sup.3) 3510.0 (3) D calc (g/cm.sup.3) 1.31 R, R.sub.W 0.038,
0.038
[0020] X-ray powder diffraction is another tool typically available
for the characterization of mixtures of polymorphs and individual
polymorphs of the same substance. However, visual review of powder
patterns for fluoxetine hydrochloride API samples (FIGS. 1 and 3)
are indistinguishable from Form A powder patterns (FIGS. 5 and 7).
When such powder patterns are expressed in terms of "d" spacings
and relative intensities, only slight differences among samples are
observed (Table 1 below) and are attributable to the sample height
packing within the sample holder ("d" spacings) and preferred
orientations (relative intensities).
2TABLE 1 X-Ray Powder Diffraction Sample Lot 1 API.sup.1 Lot 2
API.sup.1 Compression.sup.2 Method Slurry.sup.2 d (.ANG.) I.sup.3 d
(.ANG.) I.sup.3 d (.ANG.) I.sup.3 d (.ANG.) I.sup.3 15.68 w 16.12 m
15.89 w 15.93 w 8.62 w 8.77 w/vw 8.64 w/vw 8.67 w/vw 6.63 w/vw 6.71
vw 6.65 w 6.67 w/vw 6.32 vs 6.39 s 6.33 s/vs 6.35 s 6.04 w 6.10
w/vw 6.04 m 6.06 w 5.36 m/s 5.39 vs 5.36 s 5.37 s/vs 4.91 w 4.94 vw
4.92 w 4.92 w/vw 4.83 w 4.86 w/vw 4.83 w 4.84 w/vw 4.58 w 4.61 vw
4.60 m 4.62 w/vw 4.34 vs 4.37 w 4.35 s 4.35 s 4.24 m 4.27 w 4.25
m/s 4.26 w 4.02 s 4.04 vs 4.02 vs 4.03 vs 3.89 w/vw 3.92 w/vw 3.90
w 3.90 w/vw 3.72 m/s 3.77 w 3.74 m/s 3.74 w 3.64 w/vw 3.66 vw 3.64
w 3.65 w/vw 3.57 w/vw 3.59 vw 3.58 m 3.58 w/vw 3.50 m 3.53 w 3.51 m
3.51 w 3.46 w 3.48 vw 3.47 m 3.48 w 3.33 w/vw 3.35 vw 3.34 w/vw
3.34 w/vw 3.26 vw 3.28 vw 3.27 vw 3.27 vw 3.17 m 3.19 w 3.18 m 3.18
w 3.07 m/w 3.09 m/w 3.07 m/w 3.08 m/w 2.86 vw 2.88 vw 2.87 vw 2.87
vw 2.79 vw 2.80 vw 2.79 vw 2.79 vw 2.73 w 2.74 w 2.74 w 2.74 w 2.55
w/vw 2.57 vw 2.56 w/vw 2.56 vw 2.42 vw 2.43 vw 2.42 vw 2.42 vw
.sup.1Typical fluoxetine hydrochloride API .sup.2Form A of
fluoxetine hydrochloride prepared as taught hereinbelow. .sup.3vw =
very weak; w = weak; m = moderate; s = strong; and vs = very strong
intensities.
[0021] Accordingly, x-ray powder diffraction serves as a useful
tool for confirming the presence of fluoxetine hydrochloride, but
is not a useful tool for differentiating among the various
individual or mixtures of polymorphs of fluoxetine hydrochloride.
However, when used in combination with differential scanning
calorimetry (DSC), x-ray powder diffraction is used to confirm the
presence of fluoxetine hydrochloride (see, e.g., Example 15), and
DSC is used to confirm the presence of Form A, in pure and
essentially pure form, and mixtures of fluoxetine hydrochloride
polymorphs.
[0022] Using the appropriately precise DSC method set forth in
Example 12 herein, wherein the analysis is conducted at a maximum
rate of 1.degree. C. per minute, multiple levels of polymorph Forms
A, B, and C each are typically present in fluoxetine hydrochloride
API (FIGS. 2 and 4). When such API is prepared via any one of the
methods of the present invention, recrystallization, slurry, and
compression, and analyzed using said DSC method, a single endotherm
occurring at a temperature range from about 155.degree. C. to about
160.degree. C., and more preferably from about 157.degree. C. to
about 159.degree. C., confirms the presence of Form A of fluoxetine
hydrochloride (FIGS. 6 and 8 for the compression and slurry
methods, respectively). Interestingly, when such DSC method was
used to analyze Form A prepared via such recrystallization method
and placed under accelerated stability conditions (40.degree. C.
and 75% relative humidity) for less than one week, the presence of
Form A was confirmed, but two additional polymorphs of fluoxetine
hydrochloride, Forms D and E, were prepared (FIG. 11). Accordingly,
the slurry method for preparing pure and essentially pure Form A is
preferred, while the compression method is especially
preferred.
[0023] For additional confirmation of the presence of Form of
fluoxetine hydrochloride in pure form, single x-ray
crystallography, x-ray powder diffraction, and differential
scanning calorimetry can be used together.
[0024] Furthermore, x-ray powder diffraction and differential
scanning calorimetry can be used to identify essentially pure Form
A. The powder pattern for essentially pure Form A is consistent
with those for fluoxetine hydrochloride API and pure Form A as
taught herein. However, essentially pure Form A is further
characterized by having at least two endotherms as determined by
DSC run at a maximum rate of 1.degree. C. per minute. Essentially
pure Form A is defined by an increase in Form A and decrease of
other polymorphs of fluoxetine hydrochloride compared to the
starting material when prepared, for example, as taught herein, but
the crystallization process is not permitted to run to completion
which would form pure Form A. However, it is preferred that the
amount of fluoxetine hydrochloride polymorphs other than Form A
does not exceed an amount greater than about ten percent (w/w) and,
more preferably, does not exceed an amount greater than about five
percent (w/w).
[0025] For the purpose of this invention, the term "pure" refers to
Form A of fluoxetine hydrochloride being in a concentration such
that other fluoxetine polymorphs are present in amounts generally
below limits detectable by conventional technology, particularly
the Differential Scanning Calorimetry (DSC) method taught in
Example 12 herein. Although the present invention provides for pure
and essentially pure Form A of fluoxetine hydrochloride, it is
particularly preferred, of course, to eliminate all of the other
polymorphic impurities to provide pure Form A of the present
invention.
[0026] Fluoxetine hydrochloride API can be prepared by a multitude
of processes known in the art (see, e.g., U.S. Pat. Nos. 4,314,081;
5,166,437; and 5,225,585). The compositions of the present
invention are preferably prepared by using such fluoxetine
hydrochloride API as the starting material. The recrystallization
and slurry methods set forth below can be used as the final steps
in many crystallization processes in situ for the preparation of
fluoxetine hydrochloride, without requiring a "recrystallization"
processes, resulting in the preparation of Form A, preferably in
pure and essentially pure form. Preferred methods for the
preparation of Form A are set forth below, but are not intended to
limit the scope of the present invention.
[0027] Preparation of Form A
[0028] I. Recrystallization Method. Fluoxetine hydrochloride API is
recrystallized (or crystallized in situ, as the case may be) into
Form A by dissolving such API in a suitable solvent in excess.
Suitable solvents are those which are capable of dissolving
fluoxetine hydrochloride so that a solution is formed, and include
solvents across various classes including, for example, protic,
aprotic, polar, and non-polar. Alcohol-based solvents are preferred
and methanol is especially preferred. The resulting solution is
filtered and permitted to recrystallize, most preferably at a fixed
temperature, by evaporation. The temperature used for the
evaporation step should be held constant at a temperature which
permits the recrystallization of the starting material to Form A. A
temperature range from about 0.degree. C. to about 60.degree. C. is
preferred, while a temperature range from about 15.degree. C. to
about 40.degree. C. is more preferred, and about ambient
temperature is most preferred. This method has provided pure and
essentially pure Form A of fluoxetine hydrochloride depending upon
whether this recrystallization process is allowed to run to
completion. However, this method is the least preferred of the
methods taught herein. This method typically produces Form A,
which, due to the method used, may transform to at least two more
previously unidentified polymorphic forms of fluoxetine
hydrochloride, designated as Forms D and E.
[0029] II. Slurry Method. Fluoxetine hydrochloride API is
recrystallized (or crystallized in situ, as the case may be) into
stable Form A by adding such API to a suitable solvent until a
slurry is formed. Suitable solvents are those which are capable of
sufficiently dissolving such API to form a slurry and establish a
dynamic solubility equilibrium. Alcohol-based solvents are
preferred and methanol is especially preferred. The resulting
slurry is stirred until Form A is in pure or essentially pure form,
as desired. Typically, the slurry is stirred for about two days
depending upon batch size and solvent used, preferably at ambient
temperature, and filtered. Most preferably, this process is run at
a fixed temperature. For the preparation of pure Form A, it is
preferred to allow this process to run to completion, as
demonstrated by the preferred DSC method taught herein. Acceptable
temperature ranges are those which will permit the transformation
of the starting material to Form A, while a temperature range from
about 0.degree. C. to about 60.degree. C. is preferred, a
temperature range from about 15.degree. C. to about 40.degree. C.
is more preferred, and about ambient temperature is most
preferred.
[0030] III. Compression Method. Particularly surprising was the
discovery that Form A of fluoxetine hydrochloride can be prepared
via compression. Various pieces of equipment may be used during the
preparation of pharmaceutical products to provide a pressure of
about 100 pounds per square inch (psi) to about 5000 psi, or
greater. Such equipment includes, for example, hydraulic presses.
Such equipment can provide sufficient pressure to convert the
existing multiple polymorphic forms of fluoxetine hydrochloride to
stable, pure or essentially pure Form A by regulating the amount of
pressure used in this method. Preferably, at least about 100 psi is
used. It is also preferred to use sufficient pressure without
changing the other physical properties of Form A which are
reasonably necessary for preparation of the respective drug
product. Confirmation of the relative purity of Form A prepared by
this process is also confirmed using DSC.
[0031] Accordingly, the present invention provides, in part, pure
and essentially pure Form A of fluoxetine hydrochloride, and
methods for the preparation thereof. The present invention further
provides methods for reducing, minimizing, and eliminating
polymorphic contaminants (i.e., fluoxetine hydrochloride Forms B
and C), and inhibiting the formation of other polymorphic forms of
fluoxetine hydrochloride (i.e., Forms D and E).
[0032] It was also unexpectedly discovered that amorphous
fluoxetine hydrochloride can be used as an intermediate for the
preparation of Form A of the present invention. The starting
material for this process, generally, is fluoxetine hydrochloride.
Such starting material is heated to above the melting point
thereof, then slowly cooled to about ambient temperature. It is
preferred to heat such starting material to just beyond the melting
point thereof (generally, just beyond about 155.degree. C. to about
160.degree. C.) to avoid over heating such starting material to the
point that it decomposes in part or in whole. The sample initially
remains in the amorphous state, as confirmed by x-ray powder
diffraction, but recrystallized into Form A following nucleation.
Nucleation can actively be induced (i.e., physically disturbing the
sample) or passively induced by the use of natural forces by
permitting the sample to be exposed to nucleation forces including,
for example, dust particles, vibration, or air currents.
[0033] Accordingly, the present invention further provides
amorphous fluoxetine hydrochloride, generally useful as an
intermediate for the preparation of Form A of the present
invention, and methods for preparing such Form A therefrom.
[0034] The present invention further provides methods of using Form
A of fluoxetine hydrochloride, preferably in pure and essentially
pure form, for inhibiting serotonin uptake in mammals comprising
administering to a mammal requiring increased neurotransmission of
serotonin an effective amount of one or more desired form(s) of
fluoxetine hydrochloride of the present invention. Pure Form A is
preferred. Disease states requiring such inhibition of serotonin
uptake include, for example, depression, anxiety, alcoholism,
chronic pain, eating disorders such as, for example, obesity and
bulimia, and smoking cessation.
[0035] For the most effective administration of novel Form A of the
present invention, it is preferred to prepare a pharmaceutical
formulation preferably in unit dose form, comprising one or more of
the active ingredients of the present invention and one or more
pharmaceutically acceptable carrier, diluent, or excipient. As used
herein, the term "active ingredient" refers to any of the
embodiments set forth herein, particularly Form A of fluoxetine
hydrochloride in pure or essentially pure form.
[0036] Such pharmaceutical formulation may, without being limited
by the teachings set forth herein, include a solid form of the
present invention which is blended with at least one
pharmaceutically acceptable excipient, diluted by an excipient or
enclosed within such a carrier that can be in the form of a
capsule, sachet, tablet, buccal, lozenge, paper, or other
container. When the excipient serves as a diluent, it may be a
solid, semi-solid, or liquid material which acts as a vehicle,
carrier, or medium for the active ingredient(s). Thus, the
formulations can be in the form of tablets, pills, powders,
elixirs, suspensions, emulsions, solutions, syrups, capsules (such
as, for example, soft and hard gelatin capsules), suppositories,
sterile injectable solutions, and sterile packaged powders.
[0037] Examples of suitable excipients include, but are not limited
to, starches, gum arabic, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and
methyl cellulose. The formulations can additionally include
lubricating agents such as, for example, talc, magnesium stearate
and mineral oil; wetting agents; emulsifying and suspending agents;
preserving agents such as methyl-and propyl-hydroxybenzoates;
sweetening agents; or flavoring agents. Polyols, buffers, and inert
fillers may also be used. Examples of polyols include, but are not
limited to: mannitol, sorbitol, xylitol, sucrose, maltose, glucose,
lactose, dextrose, and the like. Suitable buffers encompass, but
are not limited to, phosphate, citrate, tartrate, succinate, and
the like. Other inert fillers which may be used encompass those
which are known in the art and are useful in the manufacture of
various dosage forms. If desired, the solid pharmaceutical
compositions may include other components such as bulking agents
and/or granulating agents, and the like. The compositions of the
invention can be formulated so as to provide quick, sustained,
controlled, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in
the art.
[0038] In certain embodiments of the invention, the active
ingredient(s) may be made into the form of dosage units for oral
administration. The active ingredient(s) may be mixed with a solid,
pulverant carrier such as, for example, lactose, saccharose,
sorbitol, mannitol, starch, amylopectin, cellulose derivatives or
gelatin, as well as with an antifriction agent such as for example,
magnesium stearate, calcium stearate, and polyethylene glycol
waxes. The mixture is then pressed into tablets or filled into
capsules. If coated tablets, capsules, or pulvules are desired,
such tablets, capsules, or pulvules may be coated with a
concentrated solution of sugar, which may contain gum arabic,
gelatin, talc, titanium dioxide, or with a lacquer dissolved in the
volatile organic solvent or mixture of solvents. To this coating,
various dyes may be added in order to distinguish among tablets
with different active compounds or with different amounts of the
active compound present.
[0039] Soft gelatin capsules may be prepared in which capsules
contain a mixture of the active ingredient(s) and vegetable oil or
non-aqueous, water miscible materials such as, for example,
polyethylene glycol and the like. Hard gelatin capsules may contain
granules or powder of the active ingredient in combination with a
solid, pulverulent carrier, such as, for example, lactose,
saccharose, sorbitol, mannitol, potato starch, corn starch,
amylopectin, cellulose derivatives, or gelatin.
[0040] Tablets for oral use are typically prepared in the following
manner, although other techniques may be employed. The solid
substances are gently ground or sieved to a desired particle size,
and a binding agent is homogenized and suspended in a suitable
solvent. The active ingredient(s) and auxiliary agents are mixed
with the binding agent solution. The resulting mixture is moistened
to form a uniform suspension. The moistening typically causes the
particles to aggregate slightly, and the resulting mass is gently
pressed through a stainless steel sieve having a desired size. The
layers of the mixture are then dried in controlled drying units for
a pre-determined length of time to achieve a desired particle size
and consistency. The granules of the dried mixture are gently
sieved to remove any powder. To this mixture, disintegrating,
anti-friction, and anti-adhesive agents are added. Finally, the
mixture is pressed into tablets using a machine with the
appropriate punches and dies to obtain the desired tablet size.
[0041] In the event that the above formulations are to be used for
parenteral administration, such a formulation typically comprises
sterile, aqueous and non-aqueous injection solutions comprising one
or more active ingredients for which preparations are preferably
isotonic with the blood of the intended recipient. These
preparations may contain anti-oxidants, buffers, bacteriostats, and
solute; which render the formulation isotonic with the blood of the
intended recipient. Aqueous and non-aqueous suspensions may include
suspending agents and thickening agents. The formulations may be
present in unit-dose or multi-dose containers, for example, sealed
ampules and vials. Extemporaneous injection solutions and
suspensions may be prepared from sterile powders, granules, and
tablets of the kind previously described.
[0042] Liquid preparations for oral administration are prepared in
the form of solutions, syrups, or suspensions with the latter two
forms containing, for example, active ingredient(s), sugar, and a
mixture of ethanol, water, glycerol, and propylene glycol. If
desired, such liquid preparations contain coloring agents,
flavoring agents, and saccharin. Thickening agents such as
carboxymethylcellulose may also be used.
[0043] As such, the pharmaceutical formulations of the present
invention are preferably prepared in a unit dosage form, each
dosage unit containing from about 5 mg to about 200 mg, more
usually from about 10 mg to about 40 mg of the active
ingredient(s). In liquid form, dosage unit contains from about 5 to
about 200 mg, more usually about 10 mg to about 40 mg of active
ingredient(s). The term "unit dosage form" refers to physically
discrete units suitable as unitary dosages for human
subjects/patients or other mammals, each unit containing a
predetermined quantity of active ingredient calculated to produce
the desired therapeutic effect, in association with preferably, at
least one pharmaceutically acceptable carrier, diluent, or
excipient.
[0044] The following examples are illustrative and are not intended
to limit the scope of the invention in any way.
3FORMULATION 1 Hard gelatin 20 mg capsules are prepared using the
following ingredients: Quantity (mg/capsule) active ingredient 20
ethanedioate starch, dried 200 magnesium stearate 10 Total 230 The
above ingredients are mixed and filled into hard gelatin capsules
in 230 mg quantities.
[0045]
4FORMULATION 2 A 20 mg tablet is prepared using the ingredients
below: Quantity (mg/tablet) active ingredient 20 cellulose,
microcrystalline 400 silicon dioxide, fumed 10 stearic acid 5 Total
435 The components are blended and compressed to form tablets each
weighing 435 mg.
[0046]
5FORMULATION 3 Tablets each containing 20 mg of active ingredient
are made as follows: active ingredient 20 mg starch 45 mg
microcrystalline cellulose 35 mg polyvinylpyrrolidone 4 mg (as 10%
solution in water) sodium carboxymethyl starch 4.5 mg magnesium
stearate 0.5 mg talc 1 mg Total 110 mg The active ingredient,
starch and cellulose are passed through a No. 45 mesh U.S. sieve
and mixed thoroughly. the solution of polyvinylpyrrolidone # is
mixed with the resultant powders which are then passed through a
No. 14 mesh U.S. sieve. The granules so produced are dried at
50.degree. C. and passed # through a No. 18 mesh U.S. sieve. The
sodium carboxymethyl starch, magnesium stearate and talc,
previously passed through a No. 60 mesh U.S. sieve, are # then
added to the granules which, after mixing are compressed on a
tablet machine to yield tablets each weighing 110 mg.
[0047]
6FORMULATION 4 Capsules each containing 10 mg of medicament are
made as follows: active ingredient 10 mg starch 59 mg
microcrystalline cellulose 59 mg magnesium stearate 2 mg Total 130
mg The active ingredient, cellulose, starch and magnesium stearate
are blended, passed through a No. 45 mesh U.S. sieve, and filled
into hard gelatin capsules in 130 mg quantities.
[0048]
7FORMULATION 5 Suspensions each containing 20 mg of medicament per
5 ml dose are made as follows: active ingredient 20 mg sodium
carboxymethyl cellulose 50 mg syrup 1.25 ml benzoic acid solution
0.10 ml flavor q.v. color q.v. purified water to total 5 ml The
medicament is passed through a No. 45 mesh U.S. sieve and mixed
with the sodium carboxymethyl cellulose and syrup to form a smooth
paste. The benzoic acid solution, flavor and color are diluted with
some of the water and added, with stirring. Sufficient water is
then added to produce the required volume.
[0049]
8FORMULATION 6 An intravenous formulation may be prepared as
follows: active ingredient 100 mg isotonic saline 1000 ml The
solution of the above ingredients is administered intravenously at
a rate of 1 ml per minute to a subject suffering from
depression.
[0050] The following examples are intended to illustrate the
invention, and are not to be construed as limiting the scope of the
present invention.
EXAMPLE 1
[0051] Form A via the recrystallization method. To a 20 mL beaker
containing 10 mL of methanol was added an amount of fluoxetine
hydrochloride API such that the resulting suspension was at or near
the saturation point. The suspension was then magnetically stirred
for about 15 minutes and filtered through a 0.45 .mu.m
polytrifluoroethylene ("PTFE") filter. The resulting solution was
allowed to stand undisturbed at ambient temperature until the
solvent evaporated (about 1 to 2 days). X-ray powder diffraction
(XRD) confirmed the end product is fluoxetine hydrochloride, and
differential scanning calorimetry (DSC) confirmed the presence of
pure Form A polymorph of fluoxetine hydrochloride.
EXAMPLE 2
[0052] Form A via the recrystallization method. The process set
forth in Example 1 above was used, but water rather than methanol
was used as a solvent. XRD confirmed the end product is fluoxetine
hydrochloride, and DSC confirmed the presence of pure Form A
polymorph of fluoxetine hydrochloride.
EXAMPLE 3
[0053] Form A via the recrystallization method. The process set
forth in Example 1 above was used, but dimethylfornamide rather
than methanol was used as a solvent. XRD confirmed the end product
is fluoxetine hydrochloride, and DSC confirmed the presence of pure
Form A polymorph of fluoxetine hydrochloride.
EXAMPLE 4
[0054] Form A via the slurry method. To a 20 mL beaker containing
10 mL of methanol was added sufficient fluoxetine hydrochloride
API, in excess, to form a slurry. The resulting slurry was
magnetically stirred for about 48 hours at ambient temperature. The
slurry was filtered (using a 0.45 .mu.m PTFE filter) and the
collected solid material was dried under a vacuum at ambient
temperature for about 4 hours. XRD confirmed the end product is
fluoxetine hydrochloride, and DSC confirmed the presence of pure
Form A polymorph of fluoxetine hydrochloride.
EXAMPLE 5
[0055] Form A via the compression method. A 100 mg sample of
fluoxetine hydrochloride API was placed in a dye and compressed by
a Carver Press (Fred S. Carver, Inc.; Menomonee Falls, Wis.) at
about 100 psi to obtain a pellet. The pellet was broken apart using
a scalpel and tested. XRD confirmed the end product is fluoxetine
hydrochloride, and DSC confirmed the presence of pure Form A
polymorph of fluoxetine hydrochloride.
EXAMPLES 6-9
[0056] Form A via the compression method. Using the procedure set
forth in Example 5 above, fluoxetine hydrochloride API samples were
compressed at 1000, 2000, 4000, and 4500 psi. XRD confirmed that
each sample is fluoxetine hydrochloride, and DSC confirmed the
presence of pure Form A polymorph of fluoxetine hydrochloride.
EXAMPLE 10
[0057] Form A via amorphous fluoxetine hydrochloride. A sample of
50 mg of fluoxetine hydrochloride API was heated by hot stage
microscopy to 170.degree. C. until the entire sample entered the
"glass" phase. The sample was allowed to cool at ambient
temperature. XRD confirmed the resulting fluoxetine hydrochloride
is in amorphous form, and no melting point was observed using DSC.
Following nucleation, XRD and DSC confirmed that the resulting
material is crystalline fluoxetine hydrochloride as Form A
thereof.
EXAMPLE 11
[0058] Differential Scanning Calorimetry for fluoxetine
hydrochloride. A sample of about 10 mg was placed in a sealed
aluminum sample holder and was heated from 30.degree. C. to
180.degree. C., at 10.degree. C. per minute under a 40 mL per
minute nitrogen purge, using a Mettler-Toledo (Columbus, Ohio)
DSC821.sup.e differential scanning calorimeter with Star.sup.e
software package (also from Mettler-Toledo). Endotherms
demonstrated the presence of at least two polymorphs in fluoxetine
hydrochloride API, designated Forms A and B of fluoxetine
hydrochloride API. However, the resolution was less than desired,
and the method set forth in Example 12 herein was developed as a
required method.
EXAMPLE 12
[0059] Differential Scanning Calorimetry for fluoxetine
hydrochloride. The method described in Example 11 was used, except
the heating rate was changed from 10.degree. C. per minute to a
heating rate of 1.degree. C. per minute from 145.degree. C. to
175.degree. C. The improved resolution from use of this method
resulted in the observation of at least three polymorphs of
fluoxetine hydrochloride API, designated Forms A, B, and C
fluoxetine hydrochloride API.
EXAMPLE 13
[0060] Differential Scanning Calorimetry for pure Form A of
fluoxetine hydrochloride. The method used in Example 12 was used,
except the fluoxetine hydrochloride from Examples 2 and 3 were
tested rather than fluoxetine hydrochloride API. A single endotherm
from about 155.degree. C. to about 160.degree. C. confirmed the
presence of a single fluoxetine hydrochloride polymorph, identified
as pure Form A via the method taught in Example 14.
EXAMPLE 14
[0061] Determination of the single crystal structure of Form A of
fluoxetine hydrochloride. Single Crystal X-Ray Diffraction was used
to determine the single crystal structure of Form A of fluoxetine
hydrochloride. Without being bound to theory, it is believed that a
crystalline material diffracts X-rays due to the constructive and
destructive interference of the scattering of X-rays from the atoms
of the molecule within the crystal lattice. The intensity and
positions of the diffraction spots produced by the crystal is
capable of generating structural information about the locations of
the atoms in the molecule of a crystal.
[0062] In this instance, a single crystal of the material to be
examined is mounted at the end of a glass fiber. The crystal is
aligned in the diffractometer in a specific orientation. The
diffraction spots are measured, then the crystal is rotated to the
next position. The above sequence is then repeated until thousands
of individual diffraction spots are measured and recorded. The
diffraction spots are then analyzed and the data phased to generate
an electron density map from which a molecular structure of the
molecule is uniquely determined. The X-ray diffraction data is
generated using either a Nonius CAD4 diffractometer or a Nonius
Kappa CCD diffractometer made commercially available by Nonius
Corporation of Delft, Netherlands. Pure Form A of fluoxetine
hydrochloride prepared in the methods taught herein is
characterized by the following single crystallization
parameters:
9 crystal class orthorhombic space groups Pbca (#61) a (.ANG.)
10.3754 (4) b (.ANG.) 10.4603 (2) c (.ANG.) 32.3412 (12) V
(.ANG..sup.3) 3510.0 (3) d calc (g/cm.sup.3) 1.31 R, R.sub.W 0.038,
0.038
EXAMPLE 15
[0063] X-ray Powder Diffraction for fluoxetine hydrochloride. A
sample of about 50 mg of fluoxetine hydrochloride was placed on a
zero-background sample plate and analyzed using copper K.alpha.
Radiation (.lambda.=1.5418 .ANG.) from 2 to 40 degrees in 2-theta
at 2.4 degrees per minute. A Siemens D500 automated diffractometer
(Munich, Germany) with MDI software (Livermore, Calif.) was used
for the analysis and processing of the data.
* * * * *