U.S. patent application number 12/208768 was filed with the patent office on 2009-02-26 for polymorphic form xvi of fexofenadine hydrochloride.
This patent application is currently assigned to Teva Pharmaceuticals USA, Inc.. Invention is credited to Judith Aronhime, Dov Diller, Ben-Zion Dolitzky, Boaz Gome, Barnaba Krochmal, Igor Lifshitz, Shlomit Wizel.
Application Number | 20090054486 12/208768 |
Document ID | / |
Family ID | 29736394 |
Filed Date | 2009-02-26 |
United States Patent
Application |
20090054486 |
Kind Code |
A1 |
Krochmal; Barnaba ; et
al. |
February 26, 2009 |
POLYMORPHIC FORM XVI OF FEXOFENADINE HYDROCHLORIDE
Abstract
Provided is a crystalline (polymorphic) form of fexofenadine
hydrochloride, denominated fexofenadine hydrochloride Form XVI.
Inventors: |
Krochmal; Barnaba;
(Jerusalem, IL) ; Diller; Dov; (Jerusalem, IL)
; Dolitzky; Ben-Zion; (Petach Tiqva, IL) ;
Aronhime; Judith; (Rehovot, IL) ; Wizel; Shlomit;
(Petah Tiqva, IL) ; Gome; Boaz; (Rishon-Lezion,
IL) ; Lifshitz; Igor; (Petach Tikva, IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Assignee: |
Teva Pharmaceuticals USA,
Inc.
|
Family ID: |
29736394 |
Appl. No.: |
12/208768 |
Filed: |
September 11, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11243496 |
Oct 3, 2005 |
|
|
|
12208768 |
|
|
|
|
10459688 |
Jun 10, 2003 |
|
|
|
11243496 |
|
|
|
|
60387972 |
Jun 10, 2002 |
|
|
|
Current U.S.
Class: |
514/317 |
Current CPC
Class: |
A61P 17/04 20180101;
A61P 37/08 20180101; C07D 211/22 20130101; A61P 11/06 20180101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 9/00 20180101 |
Class at
Publication: |
514/317 |
International
Class: |
A61K 31/445 20060101
A61K031/445 |
Claims
1-10. (canceled)
11. The A pharmaceutical formulation comprising an effective amount
of crystalline fexofenadine hydrochloride hydrate having a PXRD
pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2 degrees
two theta, a pharmaceutically acceptable excipient and
pseudoephedrine hydrochloride.
12. A method of inhibiting binding between an H.sub.1 receptor and
histamine in a patient suffering from contraction of the bronchi,
vasodilation, itching or other inflammation responses to histamine
comprising administering to the patient a pharmaceutical
formulation comprising an effective amount of crystalline
fexofenadine hydrochloride hydrate having a PXRD pattern with peaks
at 10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2 degrees two theta, and a
pharmaceutically acceptable excipient.
13-54. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of prior application U.S.
Ser. No. 11/243,496 filed Oct. 3, 2005 which is a continuation of
prior application U.S. Ser. No. 10/459,688, filed Jun. 10, 2003,
which claims the benefit under 35 U.S.C. .sctn. 119(e) of
provisional application Ser. No. 60/387,972, filed Jun. 10, 2002,
which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the solid state chemistry
of fexofenadine hydrochloride and its use as an active
pharmaceutical agent.
BACKGROUND OF THE INVENTION
[0003]
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-.alp-
ha.,.alpha.-dimethylbenzeneacetic acid of formula (I)
(fexofenadine) is an H.sub.1 receptor antagonist and a useful
antihistaminic drug. It has low permeability into central nervous
system tissues and weak antimuscarinic activity, causing it to have
few systemic side effects.
##STR00001##
[0004] The antihistamic activity of fexofenadine is disclosed in
U.S. Pat. No. 4,254,129, incorporated herein by reference.
According to the '129 patent, fexofenadine can be prepared starting
from ethyl .alpha.,.alpha.-dimethylphenyl acetate and
4-chlorobutyroyl chloride, which are reacted under Freidel-Crafts
conditions. Chloride is displaced from the Freidel-Crafts product
with .alpha.,.alpha.-diphenyl-4-piperidinemethanol to give
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetate, which is isolated as its hydrochloride
salt. The ketone is then reduced with PtO/H.sub.2 and the ester
group is hydrolyzed to yield fexofenadine hydrochloride.
Other methods of preparing fexofenadine are discussed in U.S. Pat.
Nos. 5,578,610, 5,589,487, 5,581,011, 5,663,412, 5,750,703,
5,994,549, 5,618,940, 5,631,375, 5,644,061, 5,650,516, 5,652,370,
5,654,433, 5,663,353, 5,675,009, 5,375,693 and 6,147,216.
[0005] The present invention relates to the solid state physical
properties, i.e., polymorphism, of fexofenadine hydrochloride.
These properties may be influenced by controlling the conditions
under which fexofenadine hydrochloride is obtained in solid form.
Solid state physical properties include, for example, the
flowability of the milled solid. Flowability affects the ease with
which the material is handled during processing into a
pharmaceutical product. When particles of the powdered compound do
not flow past each other easily, a formulation specialist must take
that fact into account when developing a tablet or capsule
formulation, which may necessitate the use of glidants such as
colloidal silicon dioxide, talc, starch or tribasic calcium
phosphate.
[0006] Another important solid state property of a pharmaceutical
compound is its rate of dissolution in aqueous fluid. The rate of
dissolution of an active ingredient in a patient's stomach fluid
may have therapeutic consequences because it imposes an upper limit
on the rate at which an orally-administered active ingredient may
reach the bloodstream. The rate of dissolution is also a
consideration in formulating syrups, elixirs and other liquid
medicaments. The solid state form of a compound may also affect its
behavior on compaction and its storage stability.
[0007] These practical physical characteristics are influenced by
the conformation and orientation of molecules in the unit cell,
which defines a particular polymorphic form of a substance. The
polymorphic form may give rise to thermal behavior different from
that of the amorphous material or another polymorphic form. Thermal
behavior is measured in the laboratory by such techniques as
capillary melting point, thermogravimetric analysis (TGA) and
differential scanning calorimetry (DSC), and may be used to
distinguish some polymorphic forms from others. A particular
polymorphic form may also give rise to distinct properties that may
be detectable by powder X-ray diffraction, solid state 13C NMR
spectrometry and infrared spectrometry.
[0008] U.S. Pat. Nos. 5,738,872, 5,932,247 and 5,855,912,
incorporated herein by reference, describe four crystal forms of
fexofenadine hydrochloride which are designated Forms I-IV.
According to the .quadrature.872 and related patents, Forms II and
IV are hydrates and Forms I and III are anhydrates. Each form is
characterized by its melting point, onset of endotherm in the DSC
profile, and PXRD. Form I is reported to have a capillary melting
point range of 196-201.degree. C., a DSC endotherm with onset
between 195-199.degree. C. and a powder X-ray diffraction ("PXRD")
pattern with d-spacings of 14.89, 11.85, 7.30, 6.28, 5.91, 5.55,
5.05, 4.96, 4.85, 4.57, 4.45, 3.94, 3.89, 3.84, 3.78, 3.72, 3.63,
3.07, 3.04, 2.45 .ANG.. Form II is reported to have a capillary
melting point range of 100-105.degree. C., a DSC endotherm with
onset between 124-126.degree. C. and a PXRD pattern with d-spacings
of 7.8, 6.4, 5.2, 4.9, 4.7, 4.4, 4.2, 4.1, 3.7, 3.6, 3.5 .ANG..
Form III is reported to have a capillary melting point range of
166-171.degree. C., a DSC endotherm with onset at 166.degree. C.
and a PXRD pattern with d-spacings of 8.95, 4.99, 4.88, 4.75, 4.57,
4.47, 4.46, 3.67, 3.65 .ANG.. In Example 2, Form IV is reported to
undergo decomposition at 115-116.degree. C. In the general written
description, a DSC endotherm with onset at 146.degree. C. is
reported. Form IV is reported as having a PXRD pattern with
d-spacings of 10.38, 6.97, 6.41, 5.55, 5.32, 5.23, 5.11, 4.98,
4.64, 4.32, 4.28, 4.12, 4.02, 3.83, 3.65, 3.51, 3.46 and 2.83
.ANG..
[0009] The '872 patent discusses methods of interconverting Forms
I-IV. Aqueous recrystallization of Form I can be used to produce
Form II. Water-minimizing recrystallization or azeotropic
distillation of either Form II or Form IV can yield Form I. Form
III is reported to be accessible by water minimizing
recrystallization of Form II. Crystal digestion of Form III can be
used to obtain Form I. Forms II and IV can be obtained directly by
sodium borohydride reduction of
4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-.alpha.,.alpha-
.-dimethylbenzeneacetate as described in Examples 1 and 2.
[0010] International Publication No. WO 00/71124 A1, discloses that
amorphous fexofenadine hydrochloride can be prepared by
lyophilizing or spray drying a solution of fexofenadine
hydrochloride. The product is characterized by its IR spectrum and
a featureless PXRD pattern.
[0011] International Publication Nos. WO 01/94313 and WO 02/066429
are also directed to polymorphic forms of fexofenadine
hydrochloride.
[0012] Fexofenadine hydrochloride Forms V, VI, and VIII through XV
are disclosed in US 20030021849 and US 20020177608 (WO02/080857),
both of which are incorporated herein by reference.
[0013] There is a need in the art for additional polymorphic forms
of fexofenadine hydrochloride.
SUMMARY OF THE INVENTION
[0014] In one aspect, the present invention provides a crystalline
fexofenadine hydrochloride in the solid state characterized by data
selected from the group consisting of: a PXRD pattern with peaks at
10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2 degrees two theta; a DSC
profile with two endothermic peaks at a temperature range of up to
about 125.degree. C. and an additional endotherm at a temperature
of about 135.degree. C.; and a TGA thermogram with a loss on drying
(LOD) of about 6% to about 10% at a temperature range of up to
about 145.degree. C.
[0015] In another aspect, the present invention provides
pharmaceutical formulations of fexofenadine hydrochloride Form XVI
and their methods of administration.
[0016] In another aspect, the present invention provides a process
for preparing crystalline fexofenadine hydrochloride Form XVI
comprising the steps of combining fexofenadine free base, HCl and
methanol to obtain a solution, precipitating fexofenadine
hydrochloride in the presence of methanol and recovering the
fexofenadine hydrochloride.
[0017] In another aspect, the present invention provides a process
for preparing crystalline fexofenadine hydrochloride Form XVI
comprising the steps of combining fexofenadine base, HCl and
methanol to obtain a solution, evaporating the methanol to obtain a
residue, adding methanol and a C.sub.5 to C.sub.12 hydrocarbon to
the residue to precipitate fexofenadine hydrochloride and
recovering the fexofenadine hydrochloride.
[0018] In another aspect, the present invention provides a process
for preparing crystalline fexofenadine hydrochloride Form XVI
comprising the steps of combining a solution of HCl in a mixture of
methanol and isopropyl alcohol, with fexofenadine base, to obtain a
solution, evaporating the methanol and the isopropyl alcohol to
obtain a residue, adding a mixture of methanol and heptane to the
residue to precipitate crystalline fexofenadine hydrochloride and
recovering the fexofenadine hydrochloride.
[0019] In another aspect, the present invention provides a process
for preparing crystalline fexofenadine hydrochloride Form XVI
comprising the steps of combining fexofenadine free base, HCl and
methanol to obtain a solution, removing the methanol to concentrate
the solution, seeding the solution with fexofenadine hydrochloride
Form XVI, stirring the solution, cooling the solution and
recovering the fexofenadine hydrochloride.
[0020] In another aspect, the present invention provides a process
for preparing fexofenadine hydrochloride Form XVI comprising the
step of stirring a slurry of fexofenadine hydrochloride amorphous
in methanol for a sufficient time to obtain fexofenadine
hydrochloride Form XVI.
[0021] In another aspect, the present invention provides for a
crystalline form of fexofenadine hydrochloride characterized by a
PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2,
wherein the crystalline form has a water content of from about 6%
to about 10%.
[0022] In another aspect, the present invention provides for a
crystalline form of fexofenadine hydrochloride characterized by a
PXRD pattern with peaks at 10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2,
wherein the crystalline form with said PXRD peaks is substantially
stable under storage at relative humidity of about 100% for at
least about 1 week, and storage at about 40.degree. C. and about a
75% relative humidity for at least about 6 months.
[0023] In another aspect, the present invention provides for a
process for preparing a crystalline form of fexofenadine
hydrochloride having a PXRD pattern with peaks at 10.1, 15.2, 18.6,
19.2, 20.1.+-.0.2, comprising the steps of crystallizing the
crystalline form with said PXRD peaks from a solution of
fexofenadine hydrochloride in methanol and recovering the
crystalline form.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 is a PXRD pattern for fexofenadine hydrochloride Form
XVI.
[0025] FIG. 2 is DSC thermogram for fexofenadine hydrochloride Form
XVI.
[0026] FIG. 3 is a TGA thermogram for fexofenadine hydrochloride
Form XVI.
DETAILED DESCRIPTION OF THE INVENTION
[0027] As used herein, "MTBE" refers to methyl t-butyl ether (syn.
t-butyl methyl ether).
[0028] In one aspect the present invention provides for
fexofenadine hydrochloride Form XVI. Fexofenadine hydrochloride
Form XVI is characterized by a PXRD pattern (FIG. 1) with peaks at
5.2, 10.1, 15.2, 15.5, 17.0, 17.3, 18.6, 19.2, 19.6, 20.1, 21.7,
22.5, 23.2, 24.0, 24.3, 25.6.+-.0.2 degrees two theta. The most
characteristic peaks are at 10.1, 15.2, 18.6, 19.2, 20.1.+-.0.2
degrees two theta.
[0029] Fexofenadine hydrochloride Form XVI is also characterized by
a DSC thermogram (FIG. 2) with two large endothermic peaks at a
temperature range of up to about 125.degree. C. and an additional
small endotherm at a temperature of about 135.degree. C. The first
endothermic peak (.apprxeq.75-85 J/g) is observed at a temperature
of about 67.degree. C., while the second endothermic peak
(.apprxeq.60 J/g) is observed at a temperature of about 120.degree.
C., and the third endothermic peak (.apprxeq.0.3-2 J/g) is observed
at a temperature of about 135.degree. C.
[0030] The TGA thermogram of fexofenadine HCl Form XVI shows an LOD
value of about 6% to about 10% in a temperature range of up to
145.degree. C.
[0031] Karl Fischer and elemental analysis of fexofenadine
hydrochloride Form XVI point to a water content higher than an
anhydrate. Fexofenadine hydrochloride Form XVI contains from about
6% to about 10% water by weight as measured by the Karl Fischer
method. At the end of precipitation step, usually a Form XVI
contains about 6% water by KF. But the form absorbs water, and its
water content may increase to as much as 10% water by weight.
[0032] Fexofenadine hydrochloride Form XVI is substantially stable
during storage. Fexofenadine hydrochloride Form XVI is stable
against transformation to other crystalline forms upon storage at
relative humidity of up to about 100% for at least about 1 week,
and storage at about 40.degree. C. and about 75% relative humidity
for at least about 6 months. The conversion is preferably less than
about 5%, more preferably less than about 2% by weight.
[0033] In another aspect, the present invention provides for
processes for preparation of fexofenadine hydrochloride Form XVI,
which allow preparing fexofenadine HCl form XVI substantially free
of other polymorphic forms of fexofenadine HCl, including amorphous
form. As used herein, "substantially free" refers to less than
about 5% on a weight basis, preferably less than about 2%, weight
of polymorphic forms other than Form XVI compared to the weight of
all the polymorphic forms, including Form XVI. A suitable method
for determining the presence of other polymorphic forms is with
X-Ray Powder diffraction.
[0034] In another aspect, the present invention provides for
preparation of fexofenadine hydrochloride Form XVI by precipitation
of the crystalline form from a methanol containing mixture. In the
first step, a solution of fexofenadine hydrochloride in methanol is
prepared. Subsequently, fexofenadine hydrochloride Form XVI may be
recovered in various manners, such as by precipitation from the
solution (including concentration of the solution before
precipitation); or removal of the methanol to obtain a residue,
followed by precipitation from methanol, or precipitation from a
mixture of methanol and an anti-solvent. Precipitation may be
carried out from both a slurry and a solution. When a residue is
added to methanol, with or without an anti-solvent, generally a
slurry is obtained.
[0035] In one embodiment, the present invention provides a process
for preparing crystalline fexofenadine hydrochloride Form XVI
comprising combining fexofenadine free base, HCl and methanol to
obtain a solution, precipitating fexofenadine hydrochloride Form
XVI from the solution, and recovering the fexofenadine
hydrochloride Form XVI.
[0036] In another embodiment, the present invention provides a
process for preparing the crystalline fexofenadine hydrochloride
Form XVI comprising the steps of combining fexofenadine free base
with HCl to obtain a solution in methanol, removing the methanol to
obtain a residue, adding methanol and a C.sub.5 to a C.sub.12
hydrocarbon to the residue to cause precipitation of fexofenadine
hydrochloride and recovering the fexofenadine hydrochloride. The
addition of an anti-solvent such as a C.sub.5 to a C.sub.12
hydrocarbon is optional, i.e., the residue may only be taken up in
methanol.
[0037] In one embodiment, a solution of HCl in a mixture of
methanol and a polar organic solvent is added to fexofenadine base,
preferably at a temperature of about 0 to about 10.degree. C. An
ice bath can be used to cool the solution. The resulting solution
can be filtered to remove impurities, including any material that
does not go into solution.
[0038] Suitable polar organic solvents are protic and aprotic polar
solvents such as alcohols, ketones, esters and ethers. Preferred
solvents include acetone and isopropanol. Preferably, a small
amount of the polar solvent relative to methanol is used.
[0039] The solvent is then removed to obtain a residue. Preferably,
the solvent is removed by evaporation, more preferably under
reduced pressure. The temperature can be increased or the pressure
reduced to accelerate the evaporation process. Preferably the
pressure is reduced by an oil pump to remove the solvent by
evaporation.
[0040] Fexofenadine hydrochloride Form XVI is then crystallized
from methanol, or a mixture of methanol and a suitable
anti-solvent, such as a C.sub.5 to a C.sub.12 saturated or a
monoaromatic hydrocarbon. Examples of such hydrocarbons include
heptane and hexane, with saturated hydrocarbons such as heptane
being more preferred. Preferably the ratio of methanol to the
hydrocarbon is from about 1:3 to about 1:33 (v/v). Preferably, the
resulting mixture is stirred.
[0041] The fexofenadine hydrochloride so recovered is then
preferably dried at a temperature of about 50.degree. C. to about
80.degree. C., more preferably at a temperature of from about
60.degree. C. to about 70.degree. C., most preferable under reduced
pressure. Both the wet and the dried samples are fexofenadine
hydrochloride Form XVI.
[0042] In another embodiment, fexofenadine hydrochloride Form XVI
is prepared by concentrating the solution of fexofenadine
hydrochloride in methanol before precipitation, preferably followed
by seeding and cooling to precipitate Form XVI. In this embodiment,
the solution is preferably concentrated to a level of about 2 to
about 2.5 volumes of methanol in comparison to the weight of
fexofenadine base (ml/g). The fexofenadine HCl methanol solution
may optionally be filtered in order to remove foreign
particles.
[0043] In a preferred embodiment, after the seeding step, the
solution is stirred and cooled to enhance precipitation. After
precipitation, the resulting suspension may optionally be stirred,
preferably at a low temperature (about minus 15.degree. C. to about
10.degree. C.) for a sufficient amount of time, preferably for at
least about 20 minutes, to increase the yield.
[0044] The fexofenadine hydrochloride so recovered is then
preferably dried at a temperature of about 50.degree. C. to about
80.degree. C., more preferably at a temperature of from about
60.degree. C. to about 70.degree. C., most preferable under reduced
pressure. Both the wet and the dried samples are fexofenadine
hydrochloride Form XVI.
[0045] In another embodiment, the present invention provides for
preparation fexofenadine hydrochloride Form XVI through stirring a
slurry of amorphous fexofenadine hydrochloride in methanol. An
anti-solvent may optionally be added to the methanol.
[0046] In one embodiment, the anti-solvent is a C.sub.5 to C.sub.12
hydrocarbon, more preferably a saturated hydrocarbon and most
preferably heptane. Preferably a small amount of methanol compared
to heptane is used, more preferably from about 3% to about 26%
volume of methanol compared to volume of heptane. The slurry
process is carried out for a sufficient time to obtain fexofenadine
hydrochloride Form XVI. Preferably the slurry process is carried
out for at least about 5 hours, more preferably from at least about
10 hours and most preferably for at least about 15 hours.
[0047] One skilled in the art would appreciate that the polymorphs
of the present invention can be selectively obtained from
fexofenadine hydrochloride generally through crystallization with
different recrystallization solvent systems. The starting material
can be anhydrous fexofenadine hydrochloride or any fexofenadine
hydrochloride hydrate or lower alcohol solvate. The use of other
solvates, such as the ethyl acetate solvate of the present
invention, is not believed to interfere with the effectiveness of
the process. The starting fexofenadine hydrochloride can also be in
an amorphous or any crystalline crystal form. The process can be
used as a purification method by using the desired form in an
unacceptably pure state as starting material. The processes of the
present invention can also be practiced as the last step in the
methods discussed in U.S. Pat. Nos. 5,578,610, 5,589,487,
5,581,011, 5,663,412, 5,750,703, 5,994,549, 5,618,940, 5,631,375,
5,644,061, 5,650,516, 5,652,370, 5,654,433, 5,663,353, 5,675,009,
5,375,693 and 6,147,216 to prepare a novel polymorph of the present
invention.
[0048] Many processes of the present invention involve
crystallization out of a particular solvent. One skilled in the art
would appreciate that the conditions concerning crystallization can
be modified without affecting the form of the polymorph obtained.
For example, when mixing fexofenadine hydrochloride or free base in
a solvent to form a solution, warming of the mixture can be
necessary to completely dissolve the starting material. If warming
does not clarify the mixture, the mixture can be diluted or
filtered. To filter, the hot mixture can be passed through paper,
glass fiber or other membrane material, or a clarifying agent such
as celite. Depending upon the equipment used and the concentration
and temperature of the solution, the filtration apparatus may need
to be preheated to avoid premature crystallization.
[0049] The conditions can also be changed to induce precipitation.
A preferred way of inducing precipitation is to reduce the
solubility of the solvent. The solubility of the solvent can be
reduced, for example, by cooling the solvent.
[0050] In one embodiment, an anti-solvent is added to a solution to
decrease its solubility for a particular compound, thus resulting
in precipitation. In another embodiment, an anti-solvent is added
to an oily residue or a gummy material, wherein the low solubility
of the anti-solvent for a particular compound results in
precipitation of that compound.
[0051] Another manner to accelerate crystallization is by seeding
with a crystal of the product or scratching the inner surface of
the crystallization vessel with a glass rod. Other times,
crystallization can occur spontaneously without any inducement. The
present invention encompasses both embodiments where precipitation
happens spontaneously or is induced, unless if such inducement is
critical for obtaining a particular polymorphic form of
fexofenadine hydrochloride.
[0052] As an antihistamine, fexofenadine is effective at relieving
symptoms caused by airborne and contact inducers of histamine
release. Such substances include pollen, spores, animal dander,
cockroach dander, industrial chemicals, dust and dust mites.
Symptoms that can be alleviated by fexofenadine include bronchial
spasms, sneezing, rhinorrhia, nasal congestion, lacrimation,
redness, rash, urticaria and itch.
[0053] Fexofenadine hydrochloride Forms XVI useful for delivering
fexofenadine to the gastrointestinal tract, mucus membranes,
bloodstream and inflamed tissues of a patient suffering from
inflammation caused by a histamine. They can be formulated into a
variety of compositions for administration to humans and
animals.
[0054] Pharmaceutical compositions of the present invention contain
fexofenadine hydrochloride Form XVI, optionally in a mixture with
other forms or amorphous fexofenadine and/or active ingredients
such as pseudoephedrine. They can also be optionally mixed with
pseudoephedrine. In addition to the active ingredient(s), the
pharmaceutical compositions of the present invention can contain
one or more excipients. Excipients are added to the composition for
a variety of purposes.
[0055] Diluents increase the bulk of a solid pharmaceutical
composition and can make a pharmaceutical dosage form containing
the composition easier for the patient and care giver to handle.
Diluents for solid compositions include, for example,
microcrystalline cellulose (e.g. Avicel.RTM.), microfine cellulose,
lactose, starch, pregelitinized starch, calcium carbonate, calcium
sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium
phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium
carbonate, magnesium oxide, maltodextrin, mannitol,
polymethacrylates (e.g. Eudragit.RTM.), potassium chloride,
powdered cellulose, sodium chloride, sorbitol and talc.
[0056] Solid pharmaceutical compositions that are compacted into a
dosage form like a tablet can include excipients whose functions
include helping to bind the active ingredient and other excipients
together after compression. Binders for solid pharmaceutical
compositions include acacia, alginic acid, carbomer (e.g.
carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose,
gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl
cellulose, hydroxypropyl cellulose (e.g. Klucel.RTM.),
hydroxypropyl methyl cellulose (e.g. Methocel.RTM.), liquid
glucose, magnesium aluminum silicate, maltodextrin,
methylcellulose, polymethacrylates, povidone (e.g. Kollidon.RTM.,
Plasdone.RTM.), pregelatinized starch, sodium alginate and
starch.
[0057] The dissolution rate of a compacted solid pharmaceutical
composition in the patient's stomach can be increased by the
addition of a disintegrant to the composition. Disintegrants
include alginic acid, carboxymethylcellulose calcium,
carboxymethylcellulose sodium (e.g. Ac-Di-Sol.RTM.,
Primellose.RTM.), colloidal silicon dioxide, croscarmellose sodium,
crospovidone (e.g. Kollidon.RTM., Polyplasdone.RTM.), guar gum,
magnesium aluminum silicate, methyl cellulose, microcrystalline
cellulose, polacrilin potassium, powdered cellulose, pregelatinized
starch, sodium alginate, sodium starch glycolate (e.g.
Explotab.RTM.) and starch.
[0058] Glidants can be added to improve the flowability of
non-compacted solid composition and improve the accuracy of dosing.
Excipients that can function as glidants include colloidal silicon
dixoide, magnesium trisilicate, powdered cellulose, starch, talc
and tribasic calcium phosphate.
[0059] When a dosage form such as a tablet is made by compaction of
a powdered composition, the composition is subjected to pressure
from a punch and dye. Some excipients and active ingredients have a
tendency to adhere to the surfaces of the punch and dye, which can
cause the product to have pitting and other surface irregularities.
A lubricant can be added to the composition to reduce adhesion and
ease release of the product form the dye. Lubricants include
magnesium stearate, calcium stearate, glyceryl monostearate,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable oil, mineral oil, polyethylene glycol, sodium benzoate,
sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc
and zinc stearate.
[0060] Flavoring agents and flavor enhancers make the dosage form
more palatable to the patient. Common flavoring agents and flavor
enhancers for pharmaceutical products that can be included in the
composition of the present invention include maltol, vanillin,
ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol,
and tartaric acid.
[0061] Solid and liquid compositions can also be dyed using any
pharmaceutically acceptable colorant to improve their appearance
and/or facilitate patient identification of the product and unit
dosage level.
[0062] In liquid pharmaceutical compositions of the present
invention, fexofenadine hydrochloride Form XVI and any other solid
excipients are dissolved or suspended in a liquid carrier such as
water, vegetable oil, alcohol, polyethylene glycol, propylene
glycol or glycerin.
[0063] Liquid pharmaceutical compositions can contain emulsifying
agents to disperse uniformly throughout the composition an active
ingredient or other excipient that is not soluble in the liquid
carrier. Emulsifying agents that can be useful in liquid
compositions of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol
and cetyl alcohol.
Liquid pharmaceutical compositions of the present invention can
also contain a viscosity enhancing agent to improve the mouth-feel
of the product and/or coat the lining of the gastrointestinal
tract. Such agents include acacia, alginic acid bentonite,
carbomer, carboxymethylcellulose calcium or sodium, cetostearyl
alcohol, methyl cellulose, ethylcellulose, gelatin guar gum,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methyl cellulose, maltodextrin, polyvinyl alcohol, povidone,
propylene carbonate, propylene glycol alginate, sodium alginate,
sodium starch glycolate, starch tragacanth and xanthan gum.
[0064] Sweetening agents such as sorbitol, saccharin, sodium
saccharin, sucrose, aspartame, fructose, mannitol and invert sugar
can be added to improve the taste.
[0065] Preservatives and chelating agents such as alcohol, sodium
benzoate, butylated hydroxy toluene, butylated hydroxyanisole and
ethylenediamine tetraacetic acid can be added at levels safe for
ingestion to improve storage stability.
[0066] A liquid composition according to the present invention can
also contain a buffer such as guconic acid, lactic acid, citric
acid or acetic acid, sodium guconate, sodium lactate, sodium
citrate or sodium acetate.
[0067] Selection of excipients and the amounts to use can be
readily determined by the formulation scientist based upon
experience and consideration of standard procedures and reference
works in the field.
[0068] The solid compositions of the present invention include
powders, granulates, aggregates and compacted compositions. The
dosages include dosages suitable for oral, buccal, rectal,
parenteral (including subcutaneous, intramuscular, and
intravenous), inhalant and ophthalmic administration. Although the
most suitable route in any given case will depend on the nature and
severity of the condition being treated, the most preferred route
of the present invention is oral. The dosages can be conveniently
presented in unit dosage form and prepared by any of the methods
well-known in the pharmaceutical arts.
[0069] Dosage forms include solid dosage forms like tablets,
powders, capsules, suppositories, sachets, troches and losenges as
well as liquid syrups, suspensions and elixirs.
[0070] A dosage form of the present invention is a capsule
containing the composition, preferably a powdered or granulated
solid composition of the invention, within either a hard or soft
shell. The shell can be made from gelatin and optionally contain a
plasticizer such as glycerin and sorbitol, and an opacifying agent
or colorant.
[0071] The active ingredient and excipients can be formulated into
compositions and dosage forms according to methods known in the
art.
[0072] A composition for tableting or capsule filing can be
prepared by wet granulation. In wet granulation some or all of the
active ingredients and excipients in powder form are blended and
then further mixed in the presence of a liquid, typically water,
which causes the powders to clump up into granules. The granulate
is screened and/or milled, dried and then screened and/or milled to
the desired particle size. The granulate can then be tableted or
other excipients can be added prior to tableting, such as a glidant
and/or a lubricant.
[0073] A tableting composition can be prepared conventionally by
dry blending. For instance, the blended composition of the actives
and excipients can be compacted into a slug or a sheet and then
comminuted into compacted granules. The compacted granules can be
compressed subsequently into a tablet.
[0074] As an alternative to dry granulation, a blended composition
can be compressed directly into a compacted dosage form using
direct compression techniques. Direct compression produces a more
uniform tablet without granules. Excipients that are particularly
well-suited to direct compression tableting include
microcrystalline cellulose, spray dried lactose, dicalcium
phosphate dihydrate and colloidal silica. The proper use of these
and other excipients in direct compression tableting is known to
those in the art with experience and skill in particular
formulation challenges of direct compression tableting.
[0075] A capsule filling of the present invention can comprise any
of the aforementioned blends and granulates that were described
with reference to tableting, only they are not subjected to a final
tableting step.
[0076] Capsules, tablets and lozenges and other unit dosage forms
preferably contain a dosage level of about 30 to about 180 mg of
fexofenadine hydrochloride. Other dosages may also be administered
depending on the need.
[0077] The following describes the instrumentation used by the
present invention to characterize the new polymorphs. The PXRD
patterns (such as that for fexofenadine HCl Form XVI) were obtained
by methods known in the art using a Scintag X-ray powder
diffractometer, a variable goniometer, an X-Ray tube with Cu target
anode (Cu radiation .lamda.=1.5418 .ANG.) and a solid state
detector. A round standard aluminum sample holder with a round zero
background quartz plate was used. Scans were performed over a range
of 2 to 40 degrees two-theta, continuously, with a scan rate of 3
degrees/min.
[0078] The DSC thermogram was obtained using a DSC Mettler 821
Star. The temperature range of scans was 30-350.degree. C. at a
rate of 10.degree. C./min. The weight of the sample was 2-5 mg. The
sample was purged with nitrogen gas at a flow rate of 40 mL/min.
Standard 40 .PHI.l aluminum crucibles having lids with three small
holes were used.
[0079] The TGA thermogram for fexofenadine hydrochloride Form XVI
was performed on Mettler TG50 using standard alumina pan and a
sample weight: 7-15 mg.
EXAMPLES
Example 1
Preparation of Fexofenadine Hydrochloride Form XVI
[0080] HCl/IPA (1.6 ml) (6.05-6.24 N) was added to methanol (20 ml)
and was cooled in an ice water bath. This solution was added to
fexofenadine free base (5 grams) in a round bottom flask with a
magnetic stirrer in an ice bath. The fexofenadine base dissolved
immediately. The solution was filtered thru a glass fiber filter
(GF/F), and the solvent evaporated off in a water bath at a
temperature of 25.degree. C. using a water aspirator, followed by a
diaphragm pump, which was followed by an oil pump. Heptane (15 ml)
was added. The stirrer was turned on, 5 ml of methanol was added
and the slurry was stirred overnight. The next day it was filtered
and dried in the vacuum oven for 2 hours at 65.degree. C. PXRD
analysis confirmed presence of Form XVI of fexofenadine
hydrochloride.
[0081] KF=6.685% Elemental analysis: C: 66.28% H: 7-89% Cl:
5.65%
Example 2
Preparation of Fexofenadine Hydrochloride Form XVI
[0082] Example 1 was repeated, except 4 ml of methanol was used in
the crystallization step instead of 5 ml. PXRD analysis confirmed
presence of Form XVI of fexofenadine hydrochloride.
[0083] KF=6.507% Elemental analysis: C: 66.80% H: 7.91% Cl:
6.23%
Example 3
Preparation of Fexofenadine Hydrochloride Form XVI
[0084] Example 1 was repeated, except 3 ml of methanol was used in
the crystallization step instead of 5 ml. PXRD analysis confirmed
presence of Form XVI of fexofenadine hydrochloride.
[0085] KF=6.221% Elemental analysis: C: 67.18% H: 7.74% Cl:
6.35%
Example 4
Preparation of Fexofenadine Hydrochloride Form XVI
[0086] Example 1 was repeated, except 2 ml of methanol was used in
the crystallization step instead of 5 ml. PXRD analysis confirmed
presence of Form XVI of fexofenadine hydrochloride.
[0087] KF=7.314% Elemental analysis: C: 65.95% H: 7.77% Cl:
6.34%
Example 5
Preparation of Fexofenadine Hydrochloride Form XVI
[0088] Example 1 was repeated, except 2.5 ml of methanol was used
in the crystallization step instead of 5 ml. PXRD analysis
confirmed presence of Form XVI of fexofenadine hydrochloride.
[0089] KF=6.250% Elemental analysis: C: 66.70% H: 7.64% Cl:
6.40%
Example 6
Preparation of Fexofenadine Hydrochloride Form XVI
[0090] Fexofenadine free base (20 grams) was crushed and put into a
250 ml round bottom flask in an ice bath with a magnetic stirrer.
HCl/IPA (6.5 ml) was added to 80 ml methanol and cooled in an ice
bath, and then added to the flask with mixing. After 15 minutes,
the flask was filtered, and the filtrate evaporated off at room
temperature first with a water aspirator then with a diaphragm pump
and finally with an oil pump. The remaining material (5 grams) was
stirred as a slurry overnight with a mixture of heptane (15 ml) and
methanol (1.5 ml), filtered and dried for 1 hour at 65.degree. C.
under vacuum. PXRD analysis confirmed presence of Form XVI of
fexofenadine hydrochloride.
Example 7
Process for Preparation of Fexofenadine-HCl Form XVI by
Crystallization from Methanol
[0091] Step 1: Preparation of HCl Gas Solution in Methanol
[0092] HCl gas was dissolved in cold methanol (T<10.degree. C.),
until about 5% w/w concentration was achieved.
[0093] Step 2: Dilution of HCl/Methanol Solution
[0094] Methanol/HCl solution (79.9 grams) (4.5 w/w) was diluted
with 121.8 grams of methanol to obtain diluted HCl/methanol
solution.
[0095] Step 3: Titration of Fexofenadine-Base with Diluted
HCl/Methanol Solution
[0096] The diluted HCl/methanol solution was cooled
(T<10.degree. C.). Fexofendine base (50 grams) (1.88% H.sub.2O)
was reacted with the diluted HCl/methanol solution, to form a
fexofenadine-HCl solution. The molar ratio between
fexofenadine-base and HCl was 1:1.
[0097] Step 4: Removal of Particulate Matter
[0098] The fexofenadine-HCl solution was filtered under reduced
pressure to remove particulate matter (foreign particles).
[0099] Alternative A--Step 5: Isolation of the Product
[0100] The clear solution was distilled under reduced pressure at a
jacket temperature of not more than 40.degree. C. until the ratio
of the residual solvent in the reactor was 2 to 2.5 volumes vs. the
weight of fexofenadine base (ml/g).
[0101] After the final solvent volume was reached, the solution was
seeded with fexofenadine HCl Form XVI crystals, and then stirred
for an additional 30 to 90 minutes. The seeded solution was cooled
and kept at a temperature of 0 to 10.degree. C. for at least 4
hours, and the slurry was stirred for an additional 30 to 90
minutes. The solid was separated from the mother liquor by
filtration under reduced pressure. The wet product was dried under
reduce pressure at a temperature of 50-65.degree. C.
[0102] Alternative B--Step 5: Isolation of the Product
[0103] The clear solution was distilled under reduced pressure at a
jacket temperature not more than 40.degree. C. until there was no
more distillate. Methanol in the ratio of 2 to 2.5 volumes vs. the
weight of fexofenadine base was added to the reactor (ml/g), and
the fexofenadine HCl in methanol mixture was heated to
dissolution.
[0104] After the final solvent volume was reached, the solution was
seeded with fexofenadine HCl Form XVI crystals, and then stirred
for an additional 30 to 90 minutes. The seeded solution was cooled
and kept at a temperature of 0 to 10.degree. C. for at least 4
hours, and the slurry was stirred for an additional 30 to 90
minutes. The solid was separated from the mother liquor by
filtration under reduced pressure. The wet product was dried under
reduce pressure at a temperature of 50-65.degree. C.
Example 8
Preparation of Fexofenadine Hydrochloride Form XVI from Amorphous
Form
[0105] Amorphous fexofenadine HCl (5 gr) was stirred in a mixture
of heptane (15 ml) and methanol (1.5 ml) at room temperature. After
stirring overnight, a solid was filtered and dried at 65.degree. C.
The PXRD pattern of the solid confirmed that the product was
fexofenadine hydrochloride Form XVI.
[0106] Having thus described the invention with reference to
particular preferred embodiments and illustrated it with examples,
those in the art will appreciate modifications to the invention as
described and illustrated that do not depart from the spirit and
scope of the invention as disclosed in the specification. All the
references cited herein are incorporated by reference in their
entirety.
* * * * *