U.S. patent application number 12/151530 was filed with the patent office on 2008-09-04 for pure darifenacin hydrobromide substantially free of oxidized darifenacin and salts thereof and processes for the preparation thereof.
This patent application is currently assigned to Teva Pharmaceuticals USA, Inc. for Barbados. Invention is credited to Augusto Canavesi, Paola Daverio, Valeriano Merli, Alessandra Vailati.
Application Number | 20080214846 12/151530 |
Document ID | / |
Family ID | 38611049 |
Filed Date | 2008-09-04 |
United States Patent
Application |
20080214846 |
Kind Code |
A1 |
Merli; Valeriano ; et
al. |
September 4, 2008 |
Pure darifenacin hydrobromide substantially free of oxidized
darifenacin and salts thereof and processes for the preparation
thereof
Abstract
Provided are darifenacin hydrobromide free of oxidized
darifenacin, and processes for the preparation thereof.
Inventors: |
Merli; Valeriano; (Cremella
Lecco, IT) ; Canavesi; Augusto; (Locate Varesino
(CO), IT) ; Daverio; Paola; (Milano, IT) ;
Vailati; Alessandra; (Seregno (MI), IT) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Teva Pharmaceuticals USA, Inc. for
Barbados
|
Family ID: |
38611049 |
Appl. No.: |
12/151530 |
Filed: |
May 6, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11646915 |
Dec 27, 2006 |
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12151530 |
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60754395 |
Dec 27, 2005 |
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60772250 |
Feb 9, 2006 |
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60776311 |
Feb 23, 2006 |
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60809147 |
May 25, 2006 |
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60813579 |
Jun 14, 2006 |
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60836557 |
Aug 8, 2006 |
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60837407 |
Aug 10, 2006 |
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60850184 |
Oct 5, 2006 |
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60859332 |
Nov 15, 2006 |
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60873680 |
Dec 7, 2006 |
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Current U.S.
Class: |
549/469 |
Current CPC
Class: |
C07D 307/79 20130101;
C07D 207/48 20130101; C07D 405/06 20130101; A61P 13/00 20180101;
C07D 207/09 20130101 |
Class at
Publication: |
549/469 |
International
Class: |
C07D 307/78 20060101
C07D307/78 |
Claims
1. A compound of the following formula I ##STR00034## wherein Y is
a leaving group selected from the group consisting of Cl, I,
brosyl, mesyl, tosyl, trifluoroacetyl, and
trifluoromethansulfonyl.
2. The compound of claim 1, wherein Y is Cl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. patent application
Ser. No. 11/646,915, filed Dec. 27, 2006, which claims the benefit
of priority to U.S. provisional application Ser. Nos. 60/754,395,
filed Dec. 27, 2005; 60/772,250, filed Feb. 9, 2006; 60/776,311,
filed Feb. 23, 2006; 60/809,147, filed May 25, 2006; 60/813,579,
filed Jun. 8, 2006; 60/836,557, filed Aug. 8, 2006; 60/837,407,
filed Aug. 10, 2006; 60/850,184, filed Oct. 5, 2006; 60/859,332,
filed Nov. 15, 2006; and 60/873,680, filed Dec. 7, 2006, hereby
incorporated by reference. This application is also related to U.S.
application Ser. Nos. 11/647,109 and 11/646,919, each filed Dec.
27, 2006 and entitled "Processes for Preparing Darifenacin
Hydrobromide," hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention encompasses substantially pure darifenacin
hydrobromide free of oxidized darifenacin and salts thereof, and
processes for the preparation thereof.
BACKGROUND OF THE INVENTION
[0003] Darifenacin,
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphen-
ylacetamide, a compound having the chemical structure,
##STR00001##
is a selective M3 receptor antagonist. Blockade of destructor
muscle activity manifests in an increase in urine volume that the
bladder can contain, reduction of urination frequency, and decrease
in pressure and urgency associated with the urge to urinate, and
thereby episodes of incontinence are reduced.
[0004] Darifenacin is administered as the hydrobromide salt,
(S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphen-
ylacetamide hydrobromide, of the structure
##STR00002##
and is marketed under the trade name ENABLEX.RTM. by Novartis.
[0005] Darifenacin hydrobromide and three routes for its
preparation are disclosed in U.S. Pat. No. 5,096,890. The routes
are illustrated by the following scheme:
##STR00003## ##STR00004##
[0006] Darifenacin free base is purified by column chromatography
on silica gel, and then converted to darifenacin hydrobromide by
dissolving it in acetone and reacting with 48% hydrobromic
acid.
[0007] Another process for preparing darifenacin HBr is disclosed
in U.S. publication No. 2003/0191176, and is illustrated by the
following scheme:
##STR00005##
[0008] Darifenacin free base is purified by crystallization from
acetonitrile-water mixture providing hydrate form of Darifenacin
and from toluene providing toluene solvate of Darifenacin. Both
purified darifenacin free base forms (hydrate or toluene solvate)
are then converted to Darifenacin HBr by dissolving them in
butan-2-one and adding 48% hydrobromic acid.
[0009] Like any synthetic compound, darifenacin hydrobromide can
contain extraneous compounds or impurities. These impurities may
be, for example, starting materials, by-products of the reaction,
products of side reactions, or degradation products. Impurities in
darifenacin hydrobromide, 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 containing
the API.
[0010] The purity of an API produced in a manufacturing process is
critical for commercialization. The U.S. Food and Drug
Administration ("FDA") requires that process impurities be
maintained below set limits. For example, in its ICH Q7A guidance
for API manufacturers, the FDA specifies the quality of raw
materials that may be used, as well as acceptable process
conditions, such as temperature, pressure, time, and stoichiometric
ratios, including purification steps, such as crystallization,
distillation, and liquid-liquid extraction. See ICH Good
Manufacturing Practice Guide for Active Pharmaceutical Ingredients,
Q7A, Current Step 4 Version (Nov. 10, 2000).
[0011] The product 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. At certain stages during processing of an
API, such as darifenacin hydrobromide, it must be analyzed for
purity, typically, by high performance liquid chromatography
("HPLC") or thin-layer chromatography ("TLC"), to determine if it
is suitable for continued processing and, ultimately, for use in a
pharmaceutical product. The FDA requires that an API is as free of
impurities as possible, so that it is as safe as possible for
clinical use. For example, the FDA recommends that the amounts of
some impurities be limited to less than 0.1 percent. See ICH Good
Manufacturing Practice Guide for Active Pharmaceutical Ingredients,
Q7A, Current Step 4 Version (Nov. 10, 2000).
[0012] 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.
See Strobel, H. A., et al., CHEMICAL INSTRUMENTATION: A SYSTEMATIC
APPROACH, 953, 3d ed. (Wiley & Sons, New York 1989). Once a
particular impurity has been associated with a peak position, the
impurity can be identified in a sample by its relative position in
the chromatogram, where the position in the chromatogram is
measured in minutes between injection of the sample on the column
and elution of the impurity through the detector. The relative
position in the chromatogram is known as the "retention time."
[0013] 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 often use "relative
retention time" ("RRT") to identify impurities. See supra Strobel
at 922. The RRT of an impurity is calculated by dividing the
retention time of the impurity by the retention time of a reference
marker. The reference marker may be the API in which the impurity
is present, or may be another compound that is either present in or
added to the sample. A reference marker should be present in the
sample in an amount that is sufficiently large to be detectable,
but not in an amount large enough to saturate the column.
[0014] Those skilled in the art of drug manufacturing research and
development understand that a relatively pure compound can be used
as a "reference standard." A reference standard is similar to a
reference marker, except that it may be used not only to identify
the impurity, but also to quantify the amount of the impurity
present in the sample.
[0015] A reference standard is an "external standard," when a
solution of a known concentration of the reference standard and an
unknown mixture are analyzed separately using the same technique.
See supra Strobel at 924; Snyder, L. R., et al., INTRODUCTION TO
MODERN LIQUID CHROMATOGRAPHY, 549, 2d ed. (John Wiley & Sons,
New York 1979). The amount of the impurity in the sample can be
determined by comparing the magnitude of the detector response for
the reference standard to that for the impurity. See U.S. Pat. No.
6,333,198, hereby incorporated by reference.
[0016] The reference standard can also be used as an "internal
standard," i.e., one that is directly added to the sample in a
predetermined amount. When the reference standard is an internal
standard, a "response factor," which compensates for differences in
the sensitivity of the detector to the impurity and the reference
standard, is used to quantify the amount of the impurity in the
sample. See supra Strobel at 894. For this purpose, the reference
standard is added directly to the mixture, and is known as an
"internal standard." See supra Strobel at 925; Snyder at 552.
[0017] The technique of "standard addition" can also be used to
quantify the amount of the impurity. This technique is used where
the sample contains an unknown detectable amount of the reference
standard. In a "standard addition," at least two samples are
prepared by adding known and differing amounts of the internal
standard. See supra Strobel at 391-393; Snyder at 571-572. The
proportion of the detector response due to the reference standard
present in the sample can be determined by plotting the detector
response against the amount of the reference standard added to each
of the samples, and extrapolating the plot to zero. See supra
Strobel at 392, FIG. 11.4. The response of a detector in HPLC
(e.g., UV detectors or refractive index detectors) can be and
typically is different for each compound eluting from the HPLC
column. Response factors, as known, account for this difference in
the response signal of the detector to different compounds eluting
from the column.
[0018] As is known by those skilled in the art, the management of
process impurities is greatly enhanced by understanding their
chemical structures and synthetic pathways, and by identifying the
parameters that influence the amount of impurities in the final
product.
[0019] Thus, providing substantially pure darifenacin hydrobromide,
preferably, free of oxidized Darifenacin and salts thereof, and
means for preparation thereof is beneficial.
SUMMARY OF THE INVENTION
[0020] In one embodiment, the invention encompasses darifenacin
hydrobromide having less than 0.1% of oxidized Darifenacin and
salts thereof of the following formula
##STR00006##
wherein n is either 0 or 1 and HA is an acid. Preferably, HA is
HBr.
[0021] In another embodiment, the present invention encompasses a
process for preparing darifenacin hydrobromide having less than
0.1% of oxidized Darifenacin and salts thereof comprising a)
combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
tartrate or the free base derivative of the following formula,
##STR00007##
the compound of the following formula II,
##STR00008##
having less than 0.25% of compound of formula I, a solvent selected
from the group consisting of a C.sub.6-9 aromatic hydrocarbon, a
polar organic solvent, water, and mixtures thereof, and a base to
form a mixture; and b) admixing HBr with the mixture to obtain
darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof; wherein Y is a leaving group
selected from the group consisting of Cl, I, brosyloxy, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.
[0022] In another embodiment, the invention encompasses a HPLC
method for determining the presence and amount of oxidized
Darifenacin and salts thereof in a sample of darifenacin
hydrobromide comprising: a) combining a sample of darifenacin
hydrobromide with a mixture of acetonitrile:water in a ratio of
about 1:1, to obtain a solution; b) injecting the solution into a
column, preferably, a 150.times.4.6 mm.times.0.5 .mu.m Phenyl C6
column; c) eluting the sample from the column using a mixture of
acetonitrile:water in a ratio of 9:1 (referred to as eluent A) and
buffer (referred to as eluent B) as an eluent; and d) measuring the
oxidized darifenacin and salts thereof content in the sample with a
UV detector.
[0023] In another embodiment, the invention encompasses a compound
of the following formula I
##STR00009##
wherein Y is a leaving group selected from the group consisting of
Cl, I, brosyloxy, mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy.
[0024] In one embodiment, the present invention encompasses a
process of determining the presence of the compound of formula I in
a sample comprising the compound of formula I and the compound of
formula II by a process comprising carrying out HPLC or TLC with
the compound of formula I as a reference marker.
[0025] In another embodiment, the present invention encompasses a
process of determining the amount of the compound of formula I in a
sample comprising the compound of formula I and the compound of
formula II by a process comprising carrying out HPLC with the of
formula I as a reference standard.
[0026] In yet another embodiment, the invention encompasses an HPLC
method for determining the presence and the amount of a compound of
formula I
##STR00010##
in a sample of a compound of formula II
##STR00011##
[0027] comprising: (a) combining a sample of a derivative of
ethyl-dihydrobenzofuran of formula I with a mixture of
acetonitrile:water in a ratio of about 1:1, to obtain a solution;
(b) injecting the solution into a column, preferably, a
250.times.4.6 mm.times.0.5 .mu.m C18 column; (c) eluting the sample
from the column using a mixture of acetonitrile and buffer as an
eluent; and (d) measuring the amount of the compound of formula I
in the sample with a UV detector, wherein Y is a leaving group
selected from the group consisting of Cl, I, brosyloxy, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.
[0028] In one embodiment, the invention encompasses a process for
preparing darifenacin hydrobromide having less than 0.1% of
oxidized Darifenacin and salts thereof of the following formula
##STR00012##
[0029] comprising: a) obtaining one or more samples of one of one
or more batches of a compound of formula II;
##STR00013##
[0030] b) measuring the level of the compound of formula I
##STR00014##
[0031] in one or more of the samples of one or more of the batches
of step a); c) selecting a batch that has less than about 0.25% of
the compound of formula I based upon the measurements of step b);
and d) using the batch selected in step (c) to prepare the
darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof, wherein Y is a leaving group
selected from the group consisting of Cl, I, brosyloxy, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy,
preferably, Cl, n is either 0 or 1, and HA is an acid. Preferably,
HA is HBr.
[0032] In another embodiment, the invention encompasses a
pharmaceutical composition comprising darifenacin hydrobromide
having less than 0.1% of oxidized Darifenacin and salts thereof and
at least one pharmaceutically acceptable excipient.
[0033] In another embodiment, the invention encompasses a process
for preparing the pharmaceutical composition, comprising combining
darifenacin hydrobromide having less than 0.1% of oxidized
darifenacin and salts thereof and the pharmaceutically acceptable
excipient.
[0034] In another embodiment, the invention encompasses a method of
treating urinary incontinence reducing urgency and increasing urine
volume that the bladder can contain comprising administering a
therapeutically effective amount of a pharmaceutical composition
comprising darifenacin hydrobromide having less than 0.1% of
oxidized Darifenacin and salts thereof and at least one
pharmaceutically acceptable excipient to a patient in need
thereof.
[0035] In another embodiment, the invention encompasses the use of
darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof in the manufacture of a
pharmaceutical composition for the treatment of urinary
incontinence reducing urgency and increasing urine volume that the
bladder can contain.
DETAILED DESCRIPTION OF THE INVENTION
[0036] The present invention is directed to substantially pure
Darifenacin-HBr. Especially, the invention is directed to
Darifenacin-HBr free of oxidized Darifenacin and salts thereof, as
well as processes for its preparation.
[0037] Oxidized Darifenacin and salts thereof are impurities that
have been difficult to separate from darifenacin hydrobromide by
conventional methods because of their close structural similarity
to darifenacin hydrobromide.
[0038] As used herein, unless otherwise defined, the term "free of
oxidized Darifenacin and salts thereof" when referring to
darifenacin hydrobromide means darifenacin hydrobromide having very
low levels of oxidized Darifenacin and salts thereof of the
following formula,
##STR00015##
and preferably less than 0.1% of oxidized darifenacin and salts
thereof; wherein n is either 0 or 1 and HA is an acid. Preferably,
HA is HBr.
[0039] The level of oxidized Darifenacin and salts thereof in
Darifenacin hydrobromide can be measured by w/w units. The
measurement can be done by any method known to a skilled artisan,
such as an HPLC method.
[0040] The invention encompasses darifenacin hydrobromide having
less than 0.1% of oxidized Darifenacin and salts thereof of the
following formula
##STR00016##
wherein n is either 0 or 1, wherein HA is an acid, preferably, HBr.
Preferably, darifenacin hydrobromide has less than 0.08%, more
preferably, less than 0.05% of oxidized darifenacin and salts
thereof.
[0041] When n is 0, the above formula refers to oxidized
Darifenacin.
[0042] When n is 1, the above formula refers to oxidized
Darifenacin salt.
[0043] When n is 1 and HA is HBr, the above formula refers to
oxidized Darifenacin HBr.
[0044] Darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof is prepared by a process comprising
a) combining 3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine
tartrate or the free base derivative of the following formula,
##STR00017##
the compound of the following formula II,
##STR00018##
having less than 0.25% of the compound of formula I, a solvent
selected from the group consisting of a C.sub.6-9 aromatic
hydrocarbon, a polar organic solvent, water, and mixtures thereof,
and a base to form a mixture; and b) admixing HBr with the mixture
to obtain darifenacin hydrobromide having less than 0.1% of
oxidized Darifenacin and salts thereof; wherein Y is a leaving
group selected from the group consisting of Cl, I, brosyloxy,
mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy, preferably, Cl.
[0045] Preferably, when the compound of formula II has less than
0.15% of the compound of formula I, the obtained Darifenacin
hydrobromide has less than 0.08% of oxidized Darifenacin and salts
thereof.
[0046] More preferably, when the compound of formula II has less
than 0.1% of the compound of formula I, the obtained Darifenacin
hydrobromide has less than 0.05% of oxidized Darifenacin and salts
thereof.
[0047] Preferably, the polar aprotic organic solvent is selected
from the group consisting of an amide, a C.sub.1-10 halogenated
aliphatic hydrocarbon, a sulfoxide, an ester, a nitrile, and a
ketone. A preferred amide is dimethylformamide (DMF). A preferred
C.sub.1-10 halogenated aliphatic hydrocarbon is a C.sub.1-5
halogenated aliphatic hydrocarbon, more preferably, dichloromethane
(DCM). Preferably, the sulfoxide is a C.sub.2-5 sulfoxide, more
preferably, dimethylsulfoxide (DMSO). Preferably, the ester is a
C.sub.2-5 ester, more preferably, ethyl acetate (EtOAc). A
preferred ketone is a C.sub.3-6 ketone, more preferably, methyl
ethyl ketone (MEK). Preferably, the nitrile is a C.sub.24 nitrile,
more preferably, acetontirile (ACN). Preferably, the C.sub.6-9
aromatic is toluene or xylene. Preferred mixtures are either that
of toluene and water or that of DCM and water. The more preferred
solvent is water.
[0048] The base may be an inorganic base or an organic base. A
preferred organic base is selected from the group consisting of
aliphatic and aromatic amines. Preferably, the aliphatic amine is
triethylamine, tribytulamine, methylmorpholine, or
N,N-diisopropylethyl amine. Preferably, the aromatic amine is
pyridine. A preferred inorganic base is either alkali carbonate or
alkali bicarbonate. Preferably, the alkali carbonate is sodium
carbonate or potassium carbonate. Preferably, the alkali
bicarbonate is either sodium bicarbonate or potassium bicarbonate.
The most preferred base is an alkali carbonate, even most
preferably, potassium carbonate.
[0049] Preferably, the mixture is heated to a temperature of about
50.degree. C. to about reflux, and more preferably to a temperature
of about 60.degree. C. to about reflux, prior to admixing with HBr.
Preferably, the mixture is maintained, under heating, for about 1
to about 5 hours, and more preferably for about 2 to about 3 hours.
After maintaining the mixture, the mixture is cooled to a
temperature of about 35.degree. C. to about 15.degree. C., and
preferably to about 25.degree. C. to about 15.degree. C.
Preferably, after cooling, an organic solvent selected from the
group consisting of DCM, EtOAc, and butyl acetate is added to the
mixture, to give a mixture having an aqueous phase and an organic
phase. The phases are then separated, and HBr is admixed with the
organic phase. Preferably, HBr is added to the organic phase.
[0050] Preferably, a small amount of an anhydride may be added to
the organic phase, after separating the phases, followed by
maintaining for about 1 to about 3 hours. After maintaining, the
organic solvent is removed, and a C.sub.2-5 alcohol and hydrobromic
acid are added, to obtain darifenacin hydrobromide. Preferably, the
C.sub.2-5 alcohol is n-butanol, sec-butanol, ethanol,
2-methyl-2-butanol, or isopropanol, more preferably, n-butanol.
[0051] Darifenacin hydrobromide having less than 0.1%, preferably,
less than 0.08%, more preferably, less than 0.05% of oxidized
Darifenacin and salts thereof may be recovered by removing the
residual water and the organic solvent from the acidic mixture
obtained after the addition of HBr, preferably, by distillation
under vacuum, to induce precipitation of the darifenacin
hydrobromide. The mixture is then cooled to room temperature and
the resulting precipitate of darifenacin hydrobromide is separated
from the mixture by filtration.
[0052] Darifenacin hydrobromide may be further purified by
crystallizing the recovered precipitate from a C.sub.2-5 alcohol.
The process comprises suspending the precipitate in a C.sub.2-5
alcohol, heating the suspension to a temperature sufficient to
induce dissolution of the darifenacin hydrobromide, and cooling the
resulting solution to induce crystallization of the darifenacin
hydrobromide. Prior to cooling, the solution may be purified with
active charcoal. The crystallized product may be isolated by
filtration, washing and drying. Preferably, the C.sub.2-5 alcohol
is n-butanol, sec-butanol, ethanol, 2-methyl-2-butanol, or
isopropanol, and more preferably n-butanol.
[0053] The presence and level of oxidized darifenacin and salts
thereof in a darifenacin-HBr sample is determined by an HPLC method
comprising: (a) combining a darifenacin-HBr sample with a mixture
of acetonitrile:water in a ratio of about 1:1, to obtain a
solution; (b) injecting the solution into a column, preferably, a
150.times.4.6 mm.times.0.5 .mu.m Phenyl C6 column; (c) eluting the
sample from the column using a mixture of acetonitrile:water in a
ratio of 9:1 (referred to as eluent A) and buffer (referred to as
eluent B) as an eluent; and (d) measuring the oxidized darifenacin
content in the sample with a UV detector.
[0054] Preferably, the buffer used in this method is a phosphate
buffer. The phosphate buffer comprises an aqueous solution of
K.sub.2HPO.sub.4 having a pH of about 9.
[0055] Typically, the sample is eluted through the column by
gradient elution. Preferably, the eluent is a mixture of eluent A
and eluent B. More preferably, the sample is eluted through the
column by gradient elution under the following conditions: At the
time 0 minutes, the eluent contains 40% of eluent A and 60% of
eluent B, at 20 minutes, the eluent contains 70% of eluent A and
30% of eluent B, and at 30 minutes, the eluent contains 70% of
eluent A and 30% of eluent B.
[0056] Preferably, the presence and content of the oxidized
darifenacin and salts thereof are measured at a wavelength of 215
nm.
[0057] The invention also encompasses a compound of the of formula
I;
##STR00019##
wherein Y is a leaving group selected from the group consisting of
Cl, I, brosyloxy, mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy. Preferably, Y is Cl.
[0058] When Y is Cl, the compound of formula I refers to
5-(2-chloroethyl)-2,3-benzofuran of the following formula.
##STR00020##
[0059] The compound of formula I can be prepared by any method
known to one skilled in the art. Such methods include, but are not
limited to, the method disclosed in U.S. Pat. No. 5,096,890, hereby
incorporated by reference. Such methods also include reacting a the
compound of formula II
##STR00021##
with an oxidizing agent, as exemplified in example 5, or via
2-(benzofuran-5-yl)ethanol of formula V.
##STR00022##
The 2-(benzofuran-5-yl)ethanol of formula V can be produced from
commercially available 2-(benzofuran-5-yl)acetic acid, according to
any method known to one skilled in the art. Such methods include,
but are not limited to, converting the acid to the corresponding
ester and reducing the ester to obtain the alcohol, as exemplified
in examples 1-3.
[0060] It is believed that oxidized Darifenacin and salts thereof
are formed during the above-described synthesis of darifenacin-HBr
by reaction of an the compound of formula I, which is an impurity
often present in the starting compound of formula II, with the
starting (S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine of formula
XI or salt thereof.
[0061] Accordingly, because separating the oxidized Darifenacin and
salts thereof from the darifenacin-HBr is difficult, a method for
obtaining darifenacin-HBr free of oxidized Darifenacin and salts
thereof would be of a great advantage.
[0062] It was found that starting with compound of formula II
having very low levels of the compound of formula I, and preferably
less than 0.25% of the compound of formula I leads to
darifenacin-HBr free of oxidized Darifenacin and salts thereof.
[0063] The level of the compound of formula I in the compound of
formula II can be measured by area % units. The said measurement
can be obtained by any method known to a skilled artisan, such as
an HPLC method.
[0064] The compound of formula II having less than 0.25% of the
compound of formula I can be prepared by the process disclosed in
U.S. application Ser. No. 11/646,919, filed Dec. 27, 2006 and
entitled "Processes for Prepared Darifenacin Hydrobromide," wherein
the starting commercially available acid analogue
2,3-dihydrobenzofuran-5-acetic acid
##STR00023##
has less than 0.4% area by HPLC of 5-benzofuranacetic acid,
providing
##STR00024##
5-(2-hydroxyethyl)-2,3-dihydrobenzofuran of formula III
##STR00025##
having less than 0.5% of 2-(benzofuran-5-yl)ethanol of formula
V,
##STR00026##
[0065] and the solvent is an aromatic hydrocarbon, more preferably,
C.sub.6-9 aromatic hydrocarbon, most preferably toluene, as
exemplified in examples 8 and 9.
[0066] The present invention encompasses a process of determining
the presence of the compound of formula I in a sample comprising
the compound of formula I and the compound of formula II by a
process comprising carrying out HPLC or TLC with the compound of
formula I as a reference marker.
[0067] The above process comprises determining the relative
retention time of a compound of formula I
##STR00027##
[0068] in a sample of a compound of formula II
##STR00028##
[0069] by a process comprising: (a) measuring by HPLC or TLC the
relative retention time (referred to as RRT, or RRF, respectively)
corresponding to a compound of formula I in a reference marker
sample; (b) determining by HPLC or TLC the relative retention time
corresponding to a compound of formula I in a sample comprising a
compound of formula I and a compound of formula II; and (c)
determining the relative retention time of the compound of formula
I in the sample by comparing the relative retention time (RRT or
RRF) of step (a) to the RRT or RRF of step (b), wherein Y is a
leaving group selected from the group consisting of Cl, I,
brosyloxy, mesyloxy, tosyloxy, trifluoroacetyloxy, and
trifluoromethansulfonyloxy, preferably, Cl.
[0070] The invention also encompasses a process of determining the
amount of the compound of formula I in a sample comprising the
compound of formula I and the compound of formula II by a process
comprising carrying out an HPLC with the compound of formula I as a
reference standard.
[0071] The above process comprises: (a) measuring by HPLC the area
under a peak corresponding to a compound of formula I in a
reference standard comprising a known amount of the compound of
formula I; (b) measuring by HPLC the area under a peak
corresponding to a compound of formula I in a sample comprising a
compound of formula I and a compound of formula II; and (c)
determining the amount of the compound of formula I in the sample
by comparing the area of step (a) to the area of step (b), wherein
Y is a leaving group selected from the group consisting of Cl, I,
brosyloxy, mesyloxy, tosyloxy, trifluoroacetyoxyl, and
trifluoromethansulfonyloxy, preferably, Cl.
[0072] The HPLC method used to determine the presence and the
presence and the amount of a compound of formula I
##STR00029##
in a sample of a compound of formula II
##STR00030##
[0073] comprises: (a) combining a sample of a derivative of
ethyl-dihydrobenzofuran of formula I with a mixture of
acetonitrile:water in a ratio of about 1:1, to obtain a solution;
(b) injecting the solution into a column, preferably, a
250.times.4.6 mm.times.0.5 .mu.m C18 column; (c) eluting the sample
from the column using a mixture of acetonitrile and buffer as an
eluent; and (d) measuring the amount of the compound of formula I
in the sample with a UV detector, wherein Y is a leaving group
selected from the group consisting of Cl, I, brosyloxy, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy.
[0074] Preferably, the buffer used in this method is a phosphate
buffer. The phosphate buffer comprises an aqueous solution of
K.sub.2HPO.sub.4 having a pH of about 9.
[0075] Typically, the sample is eluted through the column by
gradient elution. Preferably, the eluent is a mixture of eluent A
and buffer. More preferably, the sample is eluted through the
column by gradient elution under the following conditions: At the
time 0 minutes, the eluent contains 50% of eluent A and 50% of
buffer, at 20 minutes, the eluent contains 70% of eluent A and 30%
of buffer, and at 30 minutes, the eluent contains 70% of eluent A
and 30% of buffer.
[0076] Preferably, the presence and content of the compound of
formula I is measured at a wavelength of 215 nm.
[0077] The invention also encompasses a process for preparing
darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof of the following formula
##STR00031##
[0078] comprising: a) obtaining one or more samples of one of one
or more batches of a compound of formula II;
##STR00032##
[0079] b) measuring the level of a compound of formula I
##STR00033##
[0080] in one or more of the samples of one or more of the batches
of step a); c) selecting a batch that has less than about 0.25% of
the compound of formula I based upon the measurements of step b);
and d) using the batch selected in step (c) to prepare the
darifenacin hydrobromide having less than 0.1% of oxidized
Darifenacin and salts thereof, wherein Y is a leaving group
selected from the group consisting of Cl, I, brosyloxy, mesyloxy,
tosyloxy, trifluoroacetyloxy, and trifluoromethansulfonyloxy;
wherein n is either 0 or 1, wherein HA is an acid, preferably,
HBr.
[0081] Typically, the one or more samples of compound of formula II
of step (a) has less than about 0.25% of the compound of formula
I.
[0082] When the sample of the compound of formula II of step (a)
has more than about 0.25% of the compound of formula I, according
to the measurement in step (b), the sample may be purified, prior
to performing step (c). The purification may be performed by at
least one crystallization process or by column chromatography.
[0083] Typically, the purified sample compound of formula II has a
lower level of compound of formula I than the level present before
purification. Preferably, the compound of formula II sample of step
(a) obtained after purification has less than about 0.25% of the
compound of formula I.
[0084] The preparation of Darifenacin hydrobromide having less than
0.1% of oxidized Darifenacin and salts thereof from the selected
batch of compound of formula II, can be done for example, by the
process described before.
[0085] Unless specified otherwise, the darifenacin-HBr of step (d)
of the above process may be in any physical form, including, for
example, crystalline forms and amorphous forms.
[0086] The darifenacin-HBr having less than 0.10% of oxidized
Darifenacin and salts thereof may be formulated into pharmaceutical
compositions for the treatment of urinary incontinence reducing
urgency and increasing urine volume that the bladder can
contain.
[0087] The invention encompasses a pharmaceutical composition
comprising darifenacin hydrobromide having less than 0.10% of
oxidized Darifenacin and salts thereof, and at least one
pharmaceutically acceptable excipient. Suitable excipients include,
but are not limited to, diluents, carriers, fillers, bulking
agents, binders, disintegrants, disintegration inhibitors,
absorption accelerators, wetting agents, lubricants, glidants,
surface active agents, flavoring agents, and the like. Selection of
excipients and the amounts to use can be readily determined by an
experienced formulation scientist in view of standard procedures
and reference works known in the art.
[0088] The pharmaceutical composition can be formulated into a
solid or a liquid dosage form for administration to a patient.
Dosage forms include, but are not limited to, tablets, capsules,
powders, syrups, suspensions, emulsions, injection preparations,
and the like.
[0089] The invention also encompasses a process for preparing a
pharmaceutical composition comprising combining darifenacin
hydrobromide having less than 0.10% of oxidized Darifenacin and
salts thereof with at least one pharmaceutically acceptable
excipient.
[0090] The invention also encompasses a method of treating urinary
incontinence reducing urgency and increasing urine volume that the
bladder can contain comprising administering a therapeutically
effective amount of a pharmaceutical composition of darifenacin
hydrobromide having less than 0.10% of oxidized Darifenacin and
salts thereof, and at least one pharmaceutically acceptable
excipient to a patient in need thereof.
[0091] The invention also encompasses use of darifenacin
hydrobromide having less than 0.10% of oxidized Darifenacin and
salts thereof in the manufacture of a pharmaceutical composition
for the treatment of urinary incontinence reducing urgency and
increasing urine volume that the bladder can contain.
[0092] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one of ordinary skill in the art from consideration of the
specification. The invention is further defined by reference to the
following examples. It will be apparent to those of ordinary skill
in the art that many modifications, both to materials and methods,
may be practiced without departing from the scope of the
invention.
EXAMPLES
Analytical Methods
(a) Impurities Determination in Darifenacin-HBr by HPLC
Analysis:
TABLE-US-00001 [0093] Column & Phenyl-C6 150 mm .times. 4.6 mm
.times. 5.0 .mu.m Packing: Buffer: K.sub.2HPO.sub.4 0.02M pH 9.0:
3.48 g of K.sub.2HPO.sub.4 in 1000 mL of water; Filter on a 0.45
.mu.m filter. Eluent A: acetonitrile/water--90/10 Eluent B: Buffer
Time (min) % Eluent B % Eluent A Gradient 0 60 40 20 30 70 30 30 70
Equilibrium time: 15 minutes Sample volume: 5.0 .mu.L Flow Rate:
1.2 mL/min Detector: UV at 215 nm Column temperature: 35.degree. C.
Diluent H.sub.2O:Acetonitrile (50:50)
Typical retention times are:
TABLE-US-00002 Retention Time Relative Compound (minutes) Retention
Time (S)-(1-carbamoyl-1,1- 2.6 0.19 diphenylmethyl)pyrrolidine
(DIPAMP) of formula IV 5-(2-chloroethyl)-2,3- 12.6 0.91
dihydrobenzofuran (DBF-EtCl) of formula II Darifenacin 13.8 1.00
Oxidized darifenacin 16.0 1.16 The detection limit is 0.01%.
(b) Impurities Determination in
5-(2-chloroethyl)-2,3-dihydrobenzofuran of Formula II by HPLC
Analysis:
TABLE-US-00003 Column & Packing: C18 250 mm .times. 4.6 mm
.times. 5.0 .mu.m Buffer: K.sub.2HPO.sub.4 0.02M pH 7.0: 3.48 g of
K.sub.2HPO.sub.4 in 1000 mL of deionized water, adjust pH at 7.0
.+-. 0.2 with H.sub.3PO.sub.4 15% (w/v). Filter on a 0.45 .mu.m
filter. Eluent A: Acetonitrile Eluent B: Buffer Time (min) % Eluent
B % Eluent A Gradient 0 50 50 20 30 70 30 30 70 Equilibrium time: 8
minutes Sample volume: 5.0 .mu.L Flow Rate: 1.0 mL/min Detector: UV
at 215 nm Column temperature: 35.degree. C. Diluent
H.sub.2O:Acetonitrile (50:50)
A typical Retention time of the
5-(2-chloroethyl)-2,3-dihydrobenzofuran of formula II is 12.7 min
and a typical retention time of the oxidized impurity
1-(benzofuran-5-yl)ethyl chloride of formula I is 14.9 min. The
detection limit is 0.01%.
(c) TLC Analysis
[0094] TLC is performed with silica gel as the stationary phase and
a mixture of hexane and toluene (95:5 vol:vol) as the eluent.
Example 1
Preparation of 2,3-dihydrobenzofuran-5-acetic Acid Methyl Ester
(DBFAcOMe)
[0095] 98% H.sub.2SO.sub.4 (2 g, 0.02 mol)) was added to a solution
of 2,3-dihydrobenzofuran-5-acetic acid (DBFACOH) (200 g; 1.12 mol)
in methanol (500 ml) and the mixture was refluxed for 3 hrs. After
cooling to room temperature, NaHCO.sub.3 (6.7 g, 0.11 mol) was
added to the reaction mixture and the solvent was distilled off at
atmospheric pressure (about 440 ml) to give a light pink oily
residue.
[0096] The oily residue was dissolved in toluene (250 ml) and
washed with NaHCO.sub.3 6% (50 ml). After phase separation the
solvent was eliminated under vacuum distillation obtaining an oily
residue (227 g).
Example 2
Preparation of 5-(2-hydroxyethyl)-2,3-dihydrobenzofuran
(DBFEtOH)
[0097] DBFAcOMe (227 g residue from Example 1) was dissolved in
t-BuOH (600 ml) and NaBH.sub.4 (46.8 g; 1.23 mol) was added. The
resulting suspension was warmed to reflux and methanol (100 ml) was
added very slowly in about 6 hrs followed by maintaining the
reaction mixture at reflux. After Methanol addition, the reaction
was maintained at reflux for half an hour (IPC revealed complete
ester transformation). 400 ml of t-BuOH-- MeOH mixture was
distilled off at atmospheric pressure. Water (400 ml) was added to
residue and distillation was continued till complete solvent
elimination. The reaction mixture was cooled to 70-75.degree. C.
and Toluene (300 ml) was added. Separated organic phase was washed
with water (100 ml) and NaCl 15% (100 ml).
[0098] After solvent elimination under vacuum distillation an oily
residue (176.8 g; 1.076 mol) was obtained. The residue solidified
upon cooling.).
Example 3
Preparation of 5-(2-chloroethyl)-2,3-dihydrobenzofuran (DBF-EtCl)
of Formula II
[0099] SOCl.sub.2 (74.7 g; 0.63 mol) was added to a solution of
DBF-EtOH (80 g; 0.48 mol) in toluene (400 mL) maintaining the
temperature below 25.degree. C. The reaction mixture was stirred at
60.degree. C. for 14 h and then cooled to room temperature.
[0100] The mixture pH was adjusted to 10-11 by addition of 10% NaOH
(about 480 ml) while maintaining T<30.degree. C. The organic
phase was separated. Aqueous phase was extracted with Toluene (50
ml). Collected organic phases were washed twice with H.sub.2O (100
mL each) and anhydrified by vacuum distillation. 20 g of Tonsil and
4.2 g of charcoal were added to the organic phase, and stirred for
30 min at room temperature, filtered off and washed with toluene
(2.times.30 ml). The decolorized solution was concentrated under
vacuum to eliminate toluene. The residue was dissolved in methanol
(373 ml) and charcoal (2 g) was added. After 20 min at
50-55.degree. C. charcoal was filtered off and washed with hot
methanol (2.times.10 ml). Decolorized solution was cooled at
20-30.degree. C. and DBF-EtCl crystallized. To the suspension was
added at 25-30.degree. C. in about 60 min, water (280 ml) obtaining
a sticky but stirrable suspension. After 1 hr at 20-25.degree. C.
solid was filtered and washed three times with MeOH-Water 1:1 (20
ml each). Wet solid was dried at 35-40.degree. C. for 15 hrs. Dry
weight 81.8 g (0.45 mol). Yield 92%).
Example 4
Preparation of Darifenacin Hydrobromide
[0101] Water (203 ml) Potassium carbonate (65 g) and DBF-EtCl (29.7
g) were heated to 60-65.degree. C. To the mixture
3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine tartrate
((S)-DIPAMP Tartrate) (65 g) was added and the heterogeneous
mixture was heated to reflux (101-102.degree. C.) for 5 hrs. After
cooling to 85-90.degree. C., n-Butanol (325 ml) was added and after
stirring phases were separated.
[0102] The organic phase was washed twice with water (160 ml each)
and then water was removed from organic phase by vacuum
distillation. N-Butanol (160 ml) and acetic anhydride (3.25 ml)
were added and the solution was stirred at 20-30.degree. C. for 1
hr.
[0103] 48% HBr (g 25.5) was added drop-wise and the water was
removed by vacuum distillation and DRF. HBr crystallised. Initial
volume was restored by addition of n-BuOH. Suspension was stirred
at 15-20.degree. C. for 2 hrs, than product was recovered by
filtration. The cake was washed with n-Butanol (3.times.30 ml) and
wet solid (85-90 g) was crystallized without drying to obtain crude
wet darifenacin hydrobromide.
[0104] The crude wet darifenacin hydrobromide (85 g), n-Butanol
(455 ml) and charcoal (4.63 g) were warmed to reflux to obtain a
solution. After half an hour charcoal was filtered off keeping
mixture at near reflux. The clear solution at 100.degree. C. was
seeded with darifenacin hydrobromide and after 30 min at
100.degree. C. the solution was cooled to 15-20.degree. C. in 2
hrs. The suspension was stirred at 15-20.degree. C. for 2 hrs and
then the darifenacin hydrobromide was recovered by filtration. The
filer cake was washed with n-butanol (3.times.25 ml) to give wet
purified darifenacin hydrobromide. The wet purified darifenacin
hydrobromide was dried under vacuum at 50-55.degree. C. for 10-12
hrs. Dry weight 59.2 g. Overall Yield 77.2%).
Example 5
Synthesis of 5-(2-chloroethyl)-2,3-benzofuran (BF-EtCl) of Formula
I
[0105] In a 500 ml reactor DBF-EtCl (30 g); NBS
[N-Bromosuccinimide] freshly crystallized (29.3 g)
Dibenzoylperoxide (0.67 g) and CCl.sub.4 (210 ml) were loaded.
Suspension was heated at gentle reflux (76.degree. C.) for two hrs:
vigorous gas evolution was observed. After two hrs reaction mixture
was cooled and treated with Na.sub.2S.sub.2O.sub.5 15% (150 ml).
After phase separation and washings solvent was eliminated by under
vacuum distillation obtaining a red oil (35 g). 20 g of oil were
purified by silica gel column chromatography (eluent: hexane).
Fractions with HPLC purity higher then 85% were collected and after
solvent elimination 8.64 g of BF-EtCl were isolated, HPLC purity
87.7%.).
Example 6
Preparation of (S)-darifenacin Hydrobromide
[0106] A 50 ml reactor was loaded with
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine Tartrate (4
g, 9.29 mmoles), 5-(2-chloroethyl)-2,3-dihydrobenzofuran (1.95 g,
10.68 mmoles), potassium carbonate (6.14 g, 44.42 mmoles), and
water (12.5 ml), to obtain a heterogeneous mixture. The
heterogeneous mixture was heated to reflux (103.degree. C.) for 2.5
hours. After cooling dichloromethane, EtOAc or BuOAc (15 ml) were
added, and, after stirring, the phases were separated. Acetic
anhydride (0.5 ml) was added to the organic phase, and, after 1
hour at room temperature, the residual
3-(S)-(+)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine was
transformed into N-Acetyl derivative. The solvent was removed by
distillation, and n-butanol (25 ml) was added to the residue. 48%
hydrobromic acid (1.72 g) was also added, and the residual DCM was
removed under vacuum distillation. In the case of EtOAc or BuOAc,
distillation under vacuum is useful to eliminate water. Darifenacin
hydrobromide crystallized, and, after cooling to room temperature,
it was filtered and washed. (Wet solid 4.17 g).
Example 7
Preparing Darifenacin-HBr from
5-(2-chloroethyl)-2,3-dihydrobenzofuran of Formula II
[0107] The process of Example 6 was repeated to obtain crude
darfienacin hydrobromide, and the crude darifeancin hydrobromide
was recrystallized from n-butanol to obtain purified darifenacin
hydrobromide. The purity of the purified darifenacin hydrobromide
thus obtained was then analyzed. The results are summarized in the
table below.
TABLE-US-00004 Level of oxidized Level of oxidized impurity
impurity (area % by (w/w % HPLC) by HPLC) 5-(2-chloroethyl)-2,3-
Oxidized Trial Components of Product benzofuran darifenacin 1
5-(2-chloroethyl)-2,3- 0.40 N/A dihydrobenzofuran of formula II
darifenacin hydrobromide N/A 0.12 (crude) darifenacin hydrobromide
N/A 0.12 (purified) 2 5-(2-chloroethyl)-2,3- 0.50 N/A
dihydrobenzofuran of formula II darifenacin hydrobromide N/A 0.19
(crude) darifenacin hydrobromide N/A 0.20 (purified) 3
5-(2-chloroethyl)-2,3- 0.16 N/A dihydrobenzofuran of formula II
darifenacin hydrobromide N/A 0.06 (crude) 4 5-(2-chloroethyl)-2,3-
0.16 N/A dihydrobenzofuran of formula II darifenacin hydrobromide
N/A 0.06 (crude) darifenacin hydrobromide N/A 0.07 (purified) 5
5-(2-chloroethyl)-2,3- 0.19 N/A dihydrobenzofuran of formula II
darifenacin hydrobromide N/A 0.09 (crude) * N/A = not
applicable
Example 8
Preparing 5-(2-chloroethyl)-2,3-dihydrobenzofuran of Formula II in
DMF, Toluene and in a Mixture of Dimethylformamide (DMF) and
Toluene
TABLE-US-00005 [0108] Level of 2- Level of 5-(2- (benzofuran-5-
chloroethyl)-2,3- Temperature yl)ethanol of formula benzofuran of
formula Solvent (.degree. C.) V (area % by HPLC) I (area % by HPLC)
DMF 20.degree. C. nd 0.3 DMF 0-5.degree. C. nd 0.44 Toluene/
55.degree. C. 0.01 1.15 DMF 99:1 Toluene 60.degree. C. 0.03 0.21
Toluene 60.degree. C. nd 0.19 Toluene 60.degree. C. nd 0.14 * nd =
not determined
Example 9
Correlation Between the Levels of the Oxidized Impurities in the
Intermediates for Preparing Darifenacin Hydrobromide to the Level
of Oxidized Darifenacin
TABLE-US-00006 [0109] Level of impurity Level of Level of Level of
(area % by impurity (area impurity (area Level of impurity impurity
(w/w HPLC) % by HPLC) % by HPLC) (area % by HPLC) % by HPLC)
BF-AcOH BF-AcOMe BF-EtOH BF-EtCl Oxidized darifenacin 0.18 0.17
0.16 0.18 0.09 0.50 0.53 0.47 0.30 0.49 * BF-AcOH is
benzofuran-5-acetic acid; BF-AcOMe is benzofuran-5-methylester
acetic acid; BF-EtOH is benzofuran-ethanol; and BF-EtCl is
5-(2-chloroethyl)-benzofuran.
Example 10
Analysis of ENABLEX.RTM. Tablet
[0110] A commercially available tablet of ENABLEX.RTM. was analyzed
by the HPLC method described above for analysis of darifenacin HBr.
A sample of ENABLEX.RTM. was prepared by crushing a tablet of
ENABLEX.RTM. into a powder, adding 7 ml of methanol to the powder
to form a suspension, and sonicating the suspension for 10 minutes.
The resulting solution was filtered and 0.5 ml of the filtered
solution was diluted with 0.5 ml of a 1:1 mixture of buffer (pH 7)
and acetonitrile. The sample was then analyzed according to the
HPLC method described above.
[0111] The analysis revealed that the ENABLEX.RTM. tablet contains
a total amount of impurities of 1.07% area by HPLC, which
distributes as follows: 0.03% area by HPLC of
3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine, 0.12% area by
HPLC of oxidized darifenacin, and unidentified impurities in a
total amount of 0.15% area by HPLC.
[0112] 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.
* * * * *