U.S. patent application number 12/657116 was filed with the patent office on 2010-05-13 for candesartan cilexetil polymorphs.
Invention is credited to Marina Yu Etinger, Boris Fedotev, Tamas Koltai, Ziv Kurgan, Omer Malachi.
Application Number | 20100121072 12/657116 |
Document ID | / |
Family ID | 34865409 |
Filed Date | 2010-05-13 |
United States Patent
Application |
20100121072 |
Kind Code |
A1 |
Etinger; Marina Yu ; et
al. |
May 13, 2010 |
Candesartan cilexetil polymorphs
Abstract
Provided are candesartan cilexetil forms and methods of their
preparation. Also provided are pharmaceutical compositions prepared
by combining at least one pharmaceutically-acceptable excipient
with at least one candesartan cilexetil form of the invention.
Inventors: |
Etinger; Marina Yu; (Nesher,
IL) ; Fedotev; Boris; (Haifa, IL) ; Koltai;
Tamas; (Petah Tiqva, IL) ; Kurgan; Ziv;
(Beer-Sheva, IL) ; Malachi; Omer; (Rehovot,
IL) |
Correspondence
Address: |
KENYON & KENYON LLP
ONE BROADWAY
NEW YORK
NY
10004
US
|
Family ID: |
34865409 |
Appl. No.: |
12/657116 |
Filed: |
January 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11056895 |
Feb 11, 2005 |
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12657116 |
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60544131 |
Feb 11, 2004 |
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60572672 |
May 19, 2004 |
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60607180 |
Sep 3, 2004 |
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60613689 |
Sep 28, 2004 |
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Current U.S.
Class: |
548/253 |
Current CPC
Class: |
C07D 403/10
20130101 |
Class at
Publication: |
548/253 |
International
Class: |
C07D 257/04 20060101
C07D257/04 |
Claims
1.-34. (canceled)
35. A process for preparing candesartan cilexetil Form I comprising
the steps of: (a) preparing a solution of the candesartan cilexetil
of any one of claim 17, 20, 26, or 30 in a C.sub.1-C.sub.4 alcohol;
and (b) precipitating from the solution candesartan cilexetil Form
I.
36. The process of claim 35, wherein the alcohol is ethanol.
37. The process of claim 35, wherein the solution of step (b) is
cooled at a temperature of from about 0.degree. C. to about
10.degree. C.
38.-45. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional
application Nos. 60/544,131, filed Feb. 11, 2004; 60/572,672, filed
May 19, 2004; 60/607,180, filed Sep. 3, 2004; and 60/613,689, filed
Sep. 28, 2004; the contents of all of which are hereby incorporated
herein by reference.
FIELD OF INVENTION
[0002] The present invention is directed to polymorphs of
candesartan cilexetil and processes for their preparation. The
invention is also directed to pharmaceutical compositions prepared
by combining at least one pharmaceutically-acceptable excipient
with at least one candesartan cilexetil form of the invention.
BACKGROUND OF THE INVENTION
[0003] Candesartan is a potent, long-acting, selective AT.sub.1
subtype angiotensin II receptor antagonist. Candesartan is a useful
therapeutic agent for treating circulatory system diseases such as
hypertensive diseases, heart diseases (e.g. hypercardia, heart
failure, cardiac infarction, etc.), strokes, cerebral apoplexy, and
nephritis, among others. Candesartan meets the requirement of high
potency but it is poorly absorbed when administered orally.
Therefore; the prodrug candesartan cilexetil was developed. During
absorption from the gastrointestinal tract candesartan cilexetil is
rapidly and completely hydrolyzed to candesartan. The chemical name
for candesartan is:
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole--
7-carboxylic acid. The chemical name for candesartan cilexetil is
(.+-.)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl-2-ethoxy-1-[[2'-(1H-tetrazol-
-5-yl)[1,1'biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylate.
Candesartan cilexetil is a white to off-white powder and is
sparingly soluble in water and in methanol. Although candesartan
cilexetil contains an asymmetric center in the ester portion of the
molecule, it is sold as the racemic mixture.
##STR00001##
[0004] Angiotensin II is formed from angiotensin I in a reaction
catalyzed by angiotensin-converting enzyme (ACE, kininase II).
Angiotensin II is the principal pressor agent of the
renin-angiotensin system, with effects that include
vasoconstriction, stimulation of synthesis and release of
aldosterone, cardiac stimulation, and renal reabsorption of sodium.
Angiotensin II help maintain constant blood pressure despite
fluctuations in a person's state of hydration, sodium intake and
other physiological variables. Angiotensin II also performs the
regulatory tasks of inhibiting excretion of sodium by the kidneys,
inhibiting norephedrin reuptake and stimulating aldosterone
biosynthesis. Candesartan blocks the vasoconstrictor and
aldosterone secreting effects of angiotensin II by selectively
blocking the binding of angiotensin II to the AT.sub.1 receptor in
many tissues, such as vascular smooth muscle and the adrenal gland.
By inhibiting angiotensin II binding to AT.sub.1 receptors,
candesartan disrupts the vasoconstriction mediated by AT.sub.1
receptors. Blocking vasoconstriction by angiotensin II has been
found to be beneficial to patients with hypertension. The United
States Food and Drug Administration has approved candesartan for
the treatment of hypertension alone or in combination with other
antihypertensive agents.
[0005] U.S. Pat. No. 5,196,444 relates to one crystal form of
candesartan cilexetil, the C-type crystal (Form I). The patent also
relates to methods for producing Form I under acidic conditions
that permit esterification.
[0006] The therapeutic effectiveness of candesartan cilexetil has
created a need for more efficient synthetic routes to the product,
as well as purification methods that provide candesartan cilexetil
forms in high yields and purity without further loss of compound or
excessive purification steps that may add cost or time to the
purification process. Therefore, to address this need, the present
invention provides novel candesartan cilexetil polymorphs and
processes for preparing candesartan cilexetil.
SUMMARY OF THE INVENTION
[0007] The invention encompasses crystalline candesartan cilexetil
solvate.
[0008] The candesartan cilexetil may be a solvate of acetone,
tetrahydrofuran, dichloromethane/heptane, toluene, methyl ethyl
ketone, dioxane/water, chloroform/heptane, dichloromethane/isoamyl
acetate, dichloromethane, tetrahydrofuran/water,
acetonitrile/water, chloroform/acetonitrile, methanol or
toluene/methanol.
[0009] One embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form I, the process
comprising dissolving candesartan cilexetil in a solvent to form a
solution; heating the solution at a temperature of at least about
45.degree. C.; and precipitating candesartan cilexetil Form I,
wherein the solvent is at least one of a C.sub.1-C.sub.4 alcohol, a
C.sub.3-C.sub.8 ester, or acetonitrile.
[0010] The preferred solvent is at least one of butanol, methanol,
isopropanol, ethanol, ethyl acetate or acetonitrile. Preferably,
the solution of step (b) is heated at a temperature of from about
45.degree. C. to about 70.degree. C., and more preferably at
reflux. The process may further comprise drying the candesartan
cilexetil at a temperature of from about 35.degree. C. to about
60.degree. C.
[0011] Another process for preparing candesartan cilexetil Form I
comprises dissolving candesartan cilexetil in a solvent to form a
solution; combining water with the solution to form a mixture; and
precipitating from the mixture candesartan cilexetil Form I,
wherein the solvent is at least one of a C.sub.1-C.sub.4 alcohol, a
ketone, an alkyl amide, or acetonitrile.
[0012] The preferred solvent is at least one of methanol,
isopropanol, ethanol, butanol, acetone, dimethylformamide, or
acetonitrile. Preferably, the water is added dropwise to the
solution. The process may further comprise heating the solution at
a temperature of at least about 45.degree. C. before water is
combined.
[0013] Another process for preparing candesartan cilexetil Form I
comprises heating candesartan cilexetil Form VII or Form VIII at a
temperature of about 90.degree. C. to about 120.degree. C. for at
least about 10 hours.
[0014] Another process for preparing candesartan cilexetil Form I
comprises dissolving at least one of candesartan cilexetil Form
XIV, XIV-1, XXII, or XXIII in a C.sub.1-C.sub.4 alcohol to form a
solution and precipitating from the solution candesartan cilexetil
Form I.
[0015] The preferred alcohol is ethanol. Preferably, the solution
is cooled at a temperature of from about 0.degree. C. to about
10.degree. C. to precipitate candesartan cilexetil Form I.
[0016] Another process for preparing candesartan cilexetil Form I
comprises preparing a slurry of candesartan cilexetil Form XIV,
XIV-I, XXII, or XXIII in a C.sub.1-C.sub.4 alcohol; and isolating
from the slurry candesartan cilexetil Form I. The slurry is
preferably cooled at a temperature of from about -20.degree. C. to
about 20.degree. C.
[0017] One embodiment of the invention encompasses a candesartan
cilexetil crystalline form characterized by X-ray powder
diffraction peaks at about 6.1, 7.3, 14.2, 17.5, and 22.4 degrees
two-theta, .+-.0.2 degrees two-theta (Form XIV). Form XIV may be
identified further by X-ray powder diffraction peaks at about 8.1,
10.4, 15.3, 20.5, and 25.3 degrees two-theta, .+-.0.2 degrees
two-theta. Form XIV may be a solvate of dichloromethane; with a
L.O.D. by TGA of about 16% by weight.
[0018] Another embodiment of the invention encompasses candesartan
cilexetil Form XIV prepared by a process comprising dissolving
candesartan cilexetil in dichloromethane to form a solution;
combining toluene with the solution to form a mixture; and
precipitating from the mixture candesartan cilexetil Form XIV.
[0019] One embodiment of the invention encompasses a candesartan
cilexetil crystalline form characterized by at least one of an
X-ray powder diffraction with peaks at about 7.3, 8.2, 14.3, 20.5,
and 23.8 degrees two-theta, .+-.0.2 degrees two-theta, or an FTIR
spectrum with characteristic absorption bands at about 1733, 1479,
1359, 1288, 1253, and 1085 cm.sup.-1 (Form XIV-1). Form XIV-1 may
be identified further by X-ray powder diffraction peaks at about
6.4, 9.3, 16.7, 25.3, and 28.0 degrees two-theta, .+-.0.2 degrees
two-theta.
[0020] Another embodiment of the invention encompasses candesartan
cilexetil Form XIV-1 prepared by a process comprising preparing a
solution of trityl candesartan cilexetil in a first portion of
toluene or dichloromethane, and a first C.sub.1-C.sub.4 alcohol,
acid, or both to deprotect the trityl candesartan cilexetil and
obtain candesartan cilexetil; concentrating the solution into a
residue; combining a second portion of toluene or dichloromethane,
and a second C.sub.1-C.sub.4 alcohol with the residue to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form XIV-1.
[0021] Preferably, the first or second C.sub.1-C.sub.4 alcohol is
methanol. The preferred acid is formic acid. The process may
further comprise combining water with the solution of trityl
candesartan cilexetil.
[0022] One embodiment of the invention encompasses a candesartan
cilexetil crystalline form characterized by at least one of an
X-ray powder diffraction pattern with peaks at about 10.6, 12.1,
17.8, 19.4 and 21.7 degrees two-theta, .+-.0.2 degrees two-theta,
or an FTIR spectrum with characteristic absorption bands at about
1759, 1723, 1429, 1351, 1279, and 1082 cm.sup.-1 (Form XXII). Form
XXII may be identified further by X-ray powder diffraction peaks at
about 7.1, 8.9, 16.3, 20.5 and 24.0 degrees two-theta, .+-.0.2
degrees two-theta. Form XXII may be a solvate of methanol; with a
L.O.D. by TGA of about 4% to about 20% by weight. [0023] Another
embodiment of the invention encompasses candesartan cilexetil Form
XXII prepared by a process comprising dissolving crude candesartan
in a C.sub.1-C.sub.4 alcohol to form a solution; heating the
solution at a temperature of at least about 45.degree. C.; and
precipitating from the solution candesartan cilexetil Form XXII.
The preferred alcohol is methanol.
[0024] One embodiment of the invention encompasses a candesartan
cilexetil crystalline form characterized by at least one of an
X-ray powder diffraction pattern with peaks at about 6.0, 12.0,
18.0, 21.0, and 22.4 degrees two-theta, .+-.0.2 degrees two-theta,
or an FTIR spectrum with characteristic absorption bands at about
1759, 1727, 1464, 1438 and 1071 cm.sup.-1 (Form XXIII). Form XXIII
may be identified further by X-ray powder diffraction peaks at
about 10.3, 16.3, 19.8, 21.6, and 23.1 degrees two-theta, .+-.0.2
degrees two-theta. Form XXIII may be a toluene/methanol solvate;
with a L.O.D. by TGA of about 5% to about 45% by weight.
[0025] Another embodiment of the invention encompasses candesartan
cilexetil Form XXIII prepared by a process comprising preparing a
solution of trityl candesartan cilexetil in a first portion of
toluene or dichloromethane, a first C.sub.1-C.sub.4 alcohol, and
water to deprotect the trityl candesartan cilexetil and obtain
candesartan cilexetil; concentrating the solution into a residue;
combining second portion of toluene or dichloromethane, and a
second C.sub.1-C.sub.4 alcohol a with the residue to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form XXIII.
[0026] Preferably, the first or second C.sub.1-C.sub.4 alcohol is
methanol. The mixture may be seeded with candesartan cilexetil Form
XXII to precipitate candesartan cilexetil Form XXIII.
[0027] The invention also encompasses candesartan cilexetil
characterized by an X-ray powder diffraction pattern having peaks
at about 6.5, 18.8, 20.3, 21.9, and 23.6.+-.0.2 degrees two-theta;
6.1, 10.8, 18.4, 20.0, and 21.6.+-.0.2 degrees two-theta; 6.2, 6.5,
7.3, 12.0, and 18.3.+-.0.2 degrees two-theta; 6.5, 7.3, 9.3, 17.6,
and 19.8.+-.0.2 degrees two-theta; 7.4, 10.1, 17.5, 20.5, and
23.4.+-.0.2 degrees two-theta; 6.4, 10.2, 17.5, 20.5, and
23.5.+-.0.2 degrees two-theta; 6.5, 7.4, 8.4, 15.9, and 25.3.+-.0.2
degrees two-theta; 6.0, 12.1, 18.1, 19.7, and 21.3.+-.0.2 degrees
two-theta; 6.5, 8.5, 18.0, 21.1, and 24.9.+-.0.2 degrees two-theta;
6.2, 11.8, 16.5, 20.1, and 25.7.+-.0.2 degrees two-theta; 6.3, 7.3,
20.0, 21.4, and 24.3.+-.0.2 degrees two-theta; 7.0, 8.9, 16.7,
17.4, and 19.4.+-.0.2 degrees two-theta; 3.6.+-.0.2 degrees
two-theta; 6.2, 10.8, 20.1, 20.7, and 21.6.+-.0.2 degrees
two-theta; 6.4, 7.3, 8.2, 14.7, and 15.7.+-.0.2 degrees two-theta;
6.3, 12.5, 18.7, 20.3, and 23.3.+-.0.2 degrees two-theta; and 6.1,
7.3, 20.0, 21.6, and 24.3.+-.0.2 degrees two-theta.
[0028] The invention further encompasses candesartan cilexetil Form
III, IV, V, VI, VII, VIII, IX, X, XI, XIII, XIV, XIV-1, XV, XVI,
XVII, XVIII, XIX, XX, XXI, XXII, or XXIII, having less than about
5% by weight of other polymorphic forms.
[0029] In one embodiment, the candesartan cilexetil forms of the
invention have an average particle size of up to about 500 microns,
preferably up to about 200 microns, and more preferably up to about
50 microns.
[0030] In another embodiment, the invention encompasses a
pharmaceutical composition prepared by combining at least one
pharmaceutically-acceptable excipient with at least one candesartan
cilexetil form of the invention.
BRIEF DESCRIPTION OF THE FIGURES
[0031] FIG. 1 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form III.
[0032] FIG. 2 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form IV.
[0033] FIG. 3 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form V.
[0034] FIG. 4 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form VI.
[0035] FIG. 5 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form VII.
[0036] FIG. 6 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form VIII.
[0037] FIG. 7 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form IX.
[0038] FIG. 8 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form X.
[0039] FIG. 9 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XI.
[0040] FIG. 10 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XIII.
[0041] FIG. 11 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XIV.
[0042] FIG. 12 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XIV-1.
[0043] FIG. 13 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XV.
[0044] FIG. 14 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XVI.
[0045] FIG. 15 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XVII.
[0046] FIG. 16 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XVIII.
[0047] FIG. 17 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XIX.
[0048] FIG. 18 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XX.
[0049] FIG. 19 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XXI.
[0050] FIG. 20 illustrates the FTIR spectrum for candesartan
cilexetil Form XIV-1.
[0051] FIGS. 21 a-c illustrate the expanded FTIR spectra for
candesartan cilexetil Form XIV-1.
[0052] FIG. 22 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XXII.
[0053] FIG. 23 illustrates the FTIR spectrum for candesartan
cilexetil Form XXII.
[0054] FIGS. 24 a-c illustrate the expanded FTIR spectra for
candesartan cilexetil Form XXII.
[0055] FIG. 25 illustrates the powder X-ray diffraction pattern for
candesartan cilexetil Form XXIII.
[0056] FIG. 26 illustrates the FTIR spectrum for candesartan
cilexetil Form XXIII.
[0057] FIGS. 27 a-c illustrate the expanded FTIR spectra for
candesartan cilexetil Form XXIII.
DETAILED DESCRIPTION OF THE INVENTION
[0058] The invention encompasses candesartan cilexetil solvate.
[0059] The candesartan cilexetil may be a solvate of acetone,
tetrahydrofuran, dichloromethane/heptane, toluene, methyl ethyl
ketone, dioxane/water, chloroform/heptane, dichloromethane/isoamyl
acetate, dichloromethane, tetrahydrofuran/water,
acetonitrile/water, chloroform/acetonitrile, methanol or
toluene/methanol.
[0060] The invention encompasses candesartan cilexetil forms and
processes for preparing them. The invention also encompasses a
pharmaceutical composition comprising the candesartan cilexetil
forms of the invention, which may be in the form of particles, and
methods of treating circulatory system diseases using the
pharmaceutical composition. In addition, the invention encompasses
a method of preparing a pharmaceutical composition comprising
combining at least one of the candesartan cilexetil forms of the
invention with at least one pharmaceutically-acceptable
excipient.
[0061] One embodiment of the invention encompasses a candesartan
cilexetil form, herein defined as Form III, which has about 0.1%
water by weight, and the weight loss as measured by TGA is about 6
to about 8% by weight. Form III may be a solvate of acetone with a
Loss on Drying (L.O.D.) by TGA of about 8.6% by weight. Form III
may also be a solvate of tetrahydrofuran; with a L.O.D. by TGA of
about 6% by weight. Form III may be identified by an X-ray powder
diffraction pattern with peaks at about 6.5, 18.8, 20.3, 21.9, and
23.6 degrees two-theta, .+-.0.2 degrees two-theta. Form III may be
identified further by X-ray powder diffraction peaks at about 12.6,
22.7, 24.6, 25.3, and 25.9 degrees two-theta, .+-.0.2 degrees
two-theta. See FIG. 1.
[0062] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form IV, which has
about 0.2% to 0.3% water by weight and the weight loss measured by
TGA is about 6% by weight. Form IV may be a solvate of
tetrahydrofuran; with a L.O.D. by TGA of about 7% by weight. Form
IV may be identified by an X-ray powder diffraction pattern with
peaks at about 6.1, 10.8, 18.4, 20.0, and 21.6 degrees two-theta,
.+-.0.2 degrees two-theta. Form IV may be identified further by
X-ray powder diffraction peaks at about 7.3, 12.7, 22.5, 23.4, and
25.8 degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 2.
[0063] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form V, which has
about 0.1% water by weight, and the weight loss measured by TGA is
about 6% by weight. Form V may be a solvate of acetone; with a
L.O.D. by TGA of about 6% by weight. Form V may be identified by an
X-ray powder diffraction pattern with peaks at about 6.2, 6.5, 7.3,
12.0, and 18.3 degrees two-theta, .+-.0.2 degrees two-theta. Form V
may be identified further by X-ray powder diffraction peaks at
about 9.2, 13.2, 17.4, 20.0 and 22.8 degrees two-theta, .+-.0.2
degrees two-theta. See FIG. 3.
[0064] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form VI, which has
about 0.4% water by weight, and the weight loss measured by TGA is
about 17% by weight. Form VI may be a dichloromethane/heptane
solvate; with a L.O.D. by TGA of about 17% by weight. Form VI may
be identified by an X-ray powder diffraction pattern with peaks at
about 6.5, 7.3, 9.3, 17.6, and 19.8 degrees two-theta, .+-.0.2
degrees two-theta. Form VI may be identified further by X-ray
powder diffraction peaks at about 12.6, 14.8, 15.5, 24.0, and 25.7
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 4.
[0065] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form VII, which has
about 0.1% water by weight, and the weight loss measured by TGA is
about 3% to about 7% by weight. Form VII may be a solvate of
toluene; with a L.O.D. by TGA of about 7% by weight. Form VII may
also be a dichloromethane/heptane solvate; with a L.O.D. by TGA of
about 3% by weight. Form VII may be identified by an X-ray powder
diffraction pattern with peaks at about 7.4, 10.1, 17.5, 20.5, and
23.4 degrees two-theta, .+-.0.2 degrees two-theta. Form VII may be
identified further by X-ray powder diffraction peaks at about 8.3,
14.4, 18.8, 19.4, and 25.3 degrees two-theta, .+-.0.2 degrees
two-theta. See FIG. 5.
[0066] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form VIII, which has
about 0.2% water by weight, and the weight loss measured by TGA is
about 3% to about 4% by weight. Form VIII may be a solvate of
methyl ethyl ketone; with a L.O.D. by TGA of about 4% by weight.
Form VIII may be identified by an X-ray powder diffraction pattern
with peaks at about 6.4, 10.2, 17.5, 20.5, and 23.5 degrees
two-theta, .+-.0.2 degrees two-theta. Form VIII may be identified
further by X-ray powder diffraction peaks at about 11.9, 18.9,
19.4, 22.5, and 25.3 degrees two-theta, .+-.0.2 degrees two-theta.
See FIG. 6.
[0067] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form IX, which has
about 0.4% water by weight. Form IX may be identified by an X-ray
powder diffraction pattern with peaks at about 6.5, 7.4, 8.4, 15.9,
and 25.3 degrees two-theta, .+-.0.2 degrees two-theta. Form IX may
be identified further by X-ray powder diffraction peaks at about
9.2, 10.2, 14.8, 19.1, and 20.8 degrees two-theta, .+-.0.2 degrees
two-theta. See FIG. 7.
[0068] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form X, which has
about 5% to 11% water by weight, and the weight loss measured by
TGA is about 15% to about 17% by weight. Form X may be a
dioxane/water solvate; with a L.O.D. by TGA of about 16% by weight.
Form X may be identified by an X-ray powder diffraction pattern
with peaks at about 6.0, 12.1, 18.1, 19.7, and 21.3 degrees
two-theta, .+-.0.2 degrees two-theta. Form X may be identified
further by X-ray powder diffraction peaks at about 10.8, 20.7,
22.4, 24.9, and 27.9 degrees two-theta, .+-.0.2 degrees two-theta.
See FIG. 8.
[0069] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XI, which has
about 0.7% water by weight, and the weight loss measured by TGA is
about 6% by weight. Form XI may be a chloroform/heptane solvate;
with a L.O.D. by TGA of about 6% by weight. Form XI may be
identified by an X-ray powder diffraction pattern with peaks at
about 6.5, 8.5, 18.0, 21.1, and 24.9 degrees two-theta, .+-.0.2
degrees two-theta. Form XI may be identified further by X-ray
powder diffraction peaks at about 7.4, 13.4, 15.8, 18.6, and 22.2
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 9.
[0070] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XIII, which has
about 0.2% water by weight, and the weight loss measured by TGA is
about 8% by weight. Form XIII may be a dichloromethane/isoamyl
acetate solvate; with a L.O.D. by TGA of about 8% by weight. Form
XIII may be identified by an X-ray powder diffraction pattern with
peaks at about 6.2, 11.8, 16.5, 20.1, and 25.7 degrees two-theta,
.+-.0.2 degrees two-theta. Form XIII may be identified further by
X-ray powder diffraction peaks at about 10.1, 18.1, 21.3, 23.4, and
24.6 degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 10.
[0071] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XIV, which has
about 0.3% water by weight, and the weight loss measured by TGA is
about 16% by weight. Form XIV may be a solvate of dichloromethane;
with a L.O.D. by TGA of about 16% by weight. Form XIV may be
identified by an X-ray powder diffraction pattern with peaks at
about 6.1, 7.3, 14.2, 17.5, and 22.4 degrees two-theta, .+-.0.2
degrees two-theta. Form XIV may be identified further by X-ray
powder diffraction peaks at about 8.1, 10.4, 15.3, 20.5, and 25.3
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 11.
[0072] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XIV-1. Form
XIV-1 may be characterized by at least one of an X-ray powder
diffraction or by an FTIR. The X-ray powder diffraction pattern has
peaks at about 7.3, 8.2, 14.3, 20.5, and 23.8 degrees two-theta,
.+-.0.2 degrees two-theta, as substantially depicted in FIG. 12.
Form XIV-1 may be further characterized by X-ray powder diffraction
peaks at about 6.4, 9.3, 16.7, 25.3, and 28.0. The FTIR spectrum
has characteristic absorption bands at about 1733, 1479, 1359,
1288, 1253, and 1085 cm.sup.-1. See FIG. 20 and FIGS. 21 a-c for an
expanded view.
[0073] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XV, which has
about 0.5% water by weight, and the weight loss measured by TGA is
about 8% by weight. Form XV may be a chloroform/acetonitrile
solvate; with a L.O.D. by TGA of about 8% by weight. Form XV may be
identified by an X-ray powder diffraction pattern with peaks at
about 6.3, 7.3, 20.0, 21.4, and 24.3 degrees two-theta, .+-.0.2
degrees two-theta. Form XV may be identified further by X-ray
powder diffraction peaks at about 9.3, 12.0, 13.3, 18.3, and 23.3
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 13.
[0074] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XVI, which has
about 0.8% water by weight. Form XVI may be identified by an X-ray
powder diffraction pattern with peaks at about 7.0, 8.9, 16.7,
17.4, and 19.4 degrees two-theta, .+-.0.2 degrees two-theta. Form
XVI may be identified further by X-ray powder diffraction peaks at
about 8.3, 11.3, 15.1, 20.5, and 23.7 degrees two-theta, .+-.0.2
degrees two-theta. See FIG. 14.
[0075] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XVII, which has
about 1.2% water by weight. Form XVII may be identified by an X-ray
powder diffraction pattern with a peak at about 3.6 degrees
two-theta, .+-.0.2 degrees two-theta. Form XVII may be identified
further by a broad X-ray powder diffraction peak with a maximum at
about 20.0 degrees two-theta, as illustrated by FIG. 15.
[0076] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XVIII, which has
about 30% water by weight, and the weight loss measured by TGA is
about 35% by weight. Form XVIII may be a dioxane/water solvate;
with a L.O.D. by TGA of about 35% by weight. Form XVIII may also be
a tetrahydrofuran/water solvate; with a L.O.D. by TGA of about 27%
by weight. Form XVIII may be identified by an X-ray powder
diffraction pattern with peaks at about 6.2, 10.8, 20.1, 20.7, and
21.6 degrees two-theta, .+-.0.2 degrees two-theta. Form XVIII may
be identified further by X-ray powder diffraction peaks at about
12.8, 16.3, 18.0, 23.3, and 25.7 degrees two-theta, .+-.0.2 degrees
two-theta. See FIG. 16.
[0077] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XIX, which has
about 0.2% water by weight. Form XIX may also have water content of
about 11% by weight, and the weight loss measured by TGA is about
16% by weight. Form XIX may be an acetonitrile/water solvate; with
a L.O.D. by TGA of about 16% by weight. Form XIX may be identified
by an X-ray powder diffraction pattern with peaks at about 6.4,
7.3, 8.2, 14.7, and 15.7 degrees two-theta, .+-.0.2 degrees
two-theta. Form XIX may be identified further by X-ray powder
diffraction peaks at about 9.1, 12.0, 15.1, 20.6, and 25.0 degrees
two-theta, .+-.0.2 degrees two-theta. See FIG. 17.
[0078] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XX, which has
about 0.1% water by weight, and the weight loss measured by TGA is
about 16% by weight. Form XX may be a chloroform/acetonitrile
solvate; with a L.O.D. by TGA of about 16% by weight. Form XX may
be identified by an X-ray powder diffraction pattern with peaks at
about 6.3, 12.5, 18.7, 20.3, and 23.3 degrees two-theta, .+-.0.2
degrees two-theta. Form XX may be identified further by X-ray
powder diffraction peaks at about 7.4, 11.8, 21.5, 25.0, and 31.4
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 18.
[0079] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XXI, which has
about 0.1% water by weight, and the weight loss measured by TGA is
about 6% by weight. Form XXI may be a solvate of tetrahydrofuran;
with a L.O.D. by TGA of about 6% by weight. Form XXI may be
identified by an X-ray powder diffraction pattern with peaks at
about 6.1, 7.3, 20.0, 21.6, and 24.3 degrees two-theta, .+-.0.2
degrees two-theta. Form XXI may be identified further by X-ray
powder diffraction peaks at about 10.8, 18.3, 22.4, 23.3, and 25.6
degrees two-theta, .+-.0.2 degrees two-theta. See FIG. 19.
[0080] Another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XXII, which has
about 0.5% moisture by weight, and the weight loss measured by TGA
is about 4% to 20% by weight. Form XXII may be a solvate of
methanol; with a L.O.D. by TGA of about 4% to about 20% by weight.
Form XXII may be characterized by at least one of X-ray powder
diffraction pattern or FTIR. Form XXII may be characterized by an
X-ray powder diffraction pattern with peaks at about 10.6, 12.1,
17.8, 19.4, and 21.7 degrees two-theta, .+-.0.2 degrees two-theta.
Form XXII may be further characterized by XRD peaks at about 7.1,
8.9, 16.3, 20.5, and 24.0 degrees two-theta, .+-.0.2 degrees
two-theta. Form XXII X-ray powder diffraction spectrum is
substantially depicted in FIG. 22. Form XXII may be characterized
by an FTIR spectrum with characteristic absorption bands at about
1759, 1723, 1429, 1351, 1279, and 1082 cm.sup.-1. The FTIR spectrum
for Form XXII is substantially depicted in FIG. 23. An expanded
FTIR of Form XXII is substantially depicted in FIGS. 24 a-c.
[0081] Yet another embodiment of the invention encompasses another
candesartan cilexetil form, herein defined as Form XXIII, which has
about 0.2% to about 0.4% moisture by weight, and the weight loss
measured by TGA is about 5 to about 45% by weight. Form XXIII may
be a toluene/methanol solvate; with a L.O.D. by TGA of about 5% to
about 45% by weight. Form XXIII may be characterized by data from
at least one of X-ray powder diffraction or FTIR. Form XXIII may be
characterized by an X-Ray diffraction pattern having peaks at about
6.0, 12.0, 18.0, 21.0, and 22.4 degrees two-theta, .+-.0.2 degrees
two-theta. Form XXIII may be further characterized by X-ray powder
diffraction peaks at about 10.3, 16.3, 19.8, 21.6, and 23.1 degrees
two-theta, .+-.0.2 degrees two-theta. The X-ray powder diffraction
pattern for Form XXIII is substantially depicted in FIG. 25. Form
XXIII may be characterized by an FTIR spectrum having absorption
bands at about 1759, 1727, 1464, 1438, and 1071 cm.sup.-1. The FTIR
of Form XXIII is substantially depicted in FIG. 26. An expanded
FTIR of Form XXIII is substantially depicted in FIGS. 27 a-c.
[0082] The invention also encompasses polymorphically pure
candesartan cilexetil Form III, IV, V, VI, VII, VIII, IX, X, XI,
XIII, XIV, XIV-1, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, or
XXIII. The term "polymorphically pure" means that the candesartan
cilexetil form contains other polymorphic forms in an amount of
less than about 5% total weight. Preferably, the other polymorphic
form is Form I.
[0083] The invention encompasses candesartan cilexetil polymorphs
having an average particle size of no more than about 500 .mu.m,
preferably no more than about 300 .mu.m, and more preferably no
more than about 200 .mu.m. Even more preferably, candesartan
cilexetil polymorphs may have an average particle size of no more
than about 100 .mu.m, and most preferably, an average particle size
of no more than about 50 .mu.m.
[0084] The term "average particle size" refers to the average
particle diameter, which may be measured by any of the methods
commonly known in the art. The following methods, for example, may
be used: sieves, sedimentation, electrozone sensing (coulter
counter), microscopy, or Low Angle Laser Light Scattering
(LALLS).
[0085] Candesartan cilexetil particles in sizes disclosed herein
can be obtained by methods well known in the art. (See U.S. Pat.
Nos. 4,151,273; 4,196,188; 4,302,446; 4,840,799; and 5,271,944.).
One common technique to decrease particle size is by micronization.
Micronization is a mechanical process that involves the application
of force to a particle, thereby resulting in the break-up of the
particle. Such force may be applied by collision of particles at
high speeds. Micronization may be carried out, for example, by
grinding or by an air-jet micronizer.
[0086] The invention also encompasses processes for preparing
candesartan cilexetil forms of the invention.
[0087] In one embodiment of the invention, the processes for
preparing candesartan cilexetil comprise heating a first form of
candesartan cilexetil to obtain a second form of candesartan
cilexetil. The process may further comprise heating at a reduced
pressure. Preferably, the temperature is about 100.degree. C., and
if heating is conducted under reduced pressure, such as 20 mbar,
the temperature is about 48.degree. C. to about 50.degree. C. Table
1 summarizes the transformations of the process.
TABLE-US-00001 TABLE 1 Transformation of Candesartan Cilexetil
Forms Temp. Starting Form (.degree. C.) Time Pressure.sup.a Product
III, V, IX, XI, or 100 13 h amorphous XIV VII or VIII 100 13 h IV
III 48-50 30 min 20 mbar IV III 48-50 aprox. 1 h.sup.b 20 mbar V VI
48-50 b 20 mbar VII X 100 13 h IX VI 100 13 h XVI XII or XV 100 13
h XVI .sup.aUnless otherwise indicated the reaction was run at
atmospheric pressure. .sup.bSufficient time to obtain a constant
weight measurement of the candesartan cilexetil form.
[0088] Another process encompassed by the invention comprises
dissolving candesartan cilexetil in a solvent to form a solution;
allowing the solution to cool for a time to form a precipitate; and
collecting the precipitate. Optionally, the process further
comprises heating the solution. Optionally, the product may be
dried at a specific temperature and at a reduced pressure. The
solvent used in the dissolving step, the temperature to which the
solvent is heated, the cooling temperature, and the time for the
precipitate to form depend on the desired product. Examples 3, 4,
9, 15, 20, and 30 illustrate the process of the invention. The
solvent includes, but is not limited to, at least one of acetone,
acetonitrile, butanol, dichloromethane (DCM), dioxane, ethanol,
ethyl acetate, isopropyl alcohol (IPA), methanol, or
tetrahydrofuran (THF). The amount of the first solvent should be
sufficient to substantially dissolve the candesartan cilexetil. The
term "substantially dissolved" as used herein, means that about 80%
of the candesartan cilexetil is dissolved. One of ordinary skill in
the art with little or no experimentation can easily determine the
sufficient amount of the solvent.
[0089] Another process encompassed by the invention comprises
dissolving candesartan cilexetil in a first solvent and heating the
mixture to form a solution; adding water to the solution, allowing
the solution to cool for a time to form a precipitate; and
collecting the precipitate. Water may be added to the solution
dropwise, or the solution may be poured into water, wherein the
water may be at room temperature (20.degree. C. to 25.degree. C.)
or cooled in an ice bath. Optionally, the process may further
comprise at least one step of cooling the solution for a second
time, or drying the precipitate. The optional drying step may
comprise drying the product at a specific temperature and at a
reduced pressure. The solvent used in the dissolving step; the mode
of water addition; the temperature to which the solvent is heated;
the cooling temperature; and the time for the precipitate to form
depend on the desired product. Examples 2, 5, 6, 19, 27, and 28
illustrate the process of the invention. The solvent includes, but
is not limited to, at least one of acetone, acetonitrile,
dimethylforamide (DMF), dioxane, ethanol, isopropyl alcohol (IPA),
methanol, or tetrahydrofuran (THF).
[0090] Another process encompassed by the invention comprises
dissolving candesartan cilexetil in a first solvent and heating the
mixture to form a solution; adding a second solvent to the
solution, allowing the solution to cool for a time to form a
precipitate; and collecting the precipitate. The second solvent may
be added to the solution dropwise. Optionally, the process may
further comprise at least one step of heating the solution; cooling
the solution for a second time; or drying the precipitate. The
optional drying step may comprise drying the product at a specific
temperature and at a reduced pressure. The solvent used in the
dissolving step; the mode of second solvent addition; the
temperature to which the solvent is heated; the cooling
temperature; and the time for the precipitate to form depend on the
desired product. Examples 12, 21-24, and 29 illustrate the process
of the invention. The first solvent includes, but is not limited
to, at least one of chloroform, or dichloromethane (DCM). The
second solvent includes, but is not limited to, acetonitrile,
butanol, cyclohexane, isoamyl acetate, heptane, tert-butyl methyl
ether (TBME), or toluene.
[0091] Another process encompassed by the invention comprises
dissolving candesartan cilexetil in a first solvent to form a
solution; adding a second solvent to the solution, allowing the
solution to cool to a first cooling temperature; adding a third
solvent; cooling the solution to a second cooling temperature for a
time to form a precipitate; and collecting the precipitate. The
second solvent and third solvent may be added to the solution
dropwise. Optionally, the process may further comprise drying the
precipitate. The optional drying step may comprise drying the
product at a specific temperature and at a reduced pressure. The
solvents used in the dissolving step and second and third addition
steps; the mode of second or third solvent addition; the first or
second cooling temperature; and the time for the precipitate to
form depend on the desired product. Example 17 illustrates the
process of the invention.
[0092] Preferably, the second solvent is poured into the solution
before allowing the solution to precipitate. The second or third
solvent includes, but is not limited to, at least one of
acetonitrile, tert-butyl methyl ether (TBME), or toluene.
[0093] Another process encompassed by the invention comprises
triturating candesartan cilexetil in a solvent until a precipitate
forms and collecting the precipitate. Optionally, the process may
further comprise at least one step of heating the solution; cooling
the solution; or drying the precipitate. The optional drying step
may comprise drying the product at a specific temperature and at a
reduced pressure. The solvent used in the triturating step; the
temperature to which the solvent is heated; the cooling
temperature; and the time for the precipitate to form depend on the
desired product. Examples 8 and 14 illustrate the process of the
invention.
[0094] Allowing the solution to precipitate can be performed
continuously or stepwise. For example, the cooling step can be
performed continuously at about 20.degree. C. to 27.degree. C. The
cooling step can also be performed stepwise, first at about
25.degree. C. to 27.degree. C. and then at about 0.degree. C. to
5.degree. C. Another example of stepwise cooling is allowing the
solution to reach a first temperature of about 0.degree. C. to
5.degree. C. and then allowing the solution to reach a temperature
of about 25.degree. C. to 27.degree. C. Preferably, the cooling
step comprises allowing the solution to cool with stirring.
[0095] The process may further comprise drying the precipitate. In
one embodiment of the invention, drying comprises drying the
precipitate on the filter used for collecting the precipitate. In
another embodiment of the invention, drying the precipitate can be
performed at reduced pressure, 20 mbar for example, at about
40.degree. C. to 50.degree. C. to a constant weight. Drying the
precipitate can be performed continuously or stepwise.
[0096] The following are processes for preparing each candesartan
cilexetil form according to the invention.
[0097] One embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form I, the process
comprising dissolving candesartan cilexetil in a solvent to form a
solution; heating the solution at a temperature of at least about
45.degree. C.; and precipitating candesartan cilexetil Form I. The
solvent may include a C.sub.1-C.sub.4 alcohol, a C.sub.3-C.sub.8
ester, acetonitrile, or mixtures thereof. Preferably, the alcohol
is at least one of butanol, methanol, isopropanol, or ethanol.
Preferably, the ester is ethyl acetate.
[0098] The amount of solvent, including all other solvents
disclosed herein, should be sufficient to substantially dissolve
the candesartan cilexetil. The term "substantially dissolved" means
that about 80% of the candesartan cilexetil is dissolved. One of
ordinary skill in the art with little or no experimentation can
easily determine the sufficient amount of the solvent.
[0099] The solution may be heated at a temperature of from about
45.degree. C. to about 70.degree. C. Preferably, the solution is
heated at a temperature of from about 50.degree. C. to about
64.degree. C. Also preferably, when the solvent is methanol, the
solution is heated at reflux. The solution is heated in order to
facilitate the dissolution of candesartan cilexetil.
[0100] The solution may be cooled, preferably at room temperature,
to form a precipitate. Since the solution was previously heated in
order to completely dissolve candesartan cilexetil, no extreme
cooling is necessary for crystallization to occur, and there is no
decrease in the yield caused by easy dissolution. When a material
dissolves easily, cooling to lower temperature is necessary in
order to properly crystallize the material and increase the
yield.
[0101] The recovered candesartan cilexetil Form I may optionally be
dried at a temperature of from about 35.degree. C. to about
60.degree. C., preferably from about 40.degree. C. to about
50.degree. C. The candesartan cilexetil Form I may be dried under
reduced pressure such as a pressure of less than about 50 mbar,
preferably under a pressure of from about 20 mbar to about 30
mbar.
[0102] Another process for preparing candesartan cilexetil Form I
comprises dissolving candesartan cilexetil in a solvent to form a
solution; combining water with the solution to form a mixture; and
precipitating from the mixture candesartan cilexetil Form I,
wherein the solvent is at least one of a C.sub.1-C.sub.4 alcohol, a
ketone, an alkyl amide, or acetonitrile. Preferably, the alcohol is
at least one of methanol, isopropanol, or ethanol. Preferably, the
ketone is acetone. Preferably, the alkyl amide is
dimethylformamide.
[0103] The solution may be kept around room temperature, or it may
be heated. The solution is preferably heated at a temperature of
from about 45.degree. C. to about 80.degree. C., and more
preferably at a temperature of from about 50.degree. C. to about
75.degree. C.
[0104] Preferably, the water is added dropwise to the solution.
Where the solvent is acetone, the solution is preferably poured
into water. Water in this process is used as an anti-solvent.
[0105] The recovered candesartan cilexetil Form I may optionally be
dried at a temperature of from about 35.degree. C. to about
60.degree. C., preferably from about 40.degree. C. to about
50.degree. C. The candesartan cilexetil Form I may be dried under
reduced pressure such as a pressure of less than about 50 mbar, or
a pressure about 30 mbar.
[0106] Another process for preparing candesartan cilexetil Form I
comprises heating candesartan cilexetil Form VII or Form VIII. The
Form VII or Form VIII may be heated at a temperature of from about
90.degree. C. to about 120.degree. C., preferably at about
100.degree. C. The Form VII or Form VIII may be heated for at least
about 10 hours, preferably for about 13 hours.
[0107] Another process for preparing candesartan cilexetil Form I
comprises dissolving at least one of candesartan cilexetil Form
XIV, XIV-1, XXII or XXIII in a C.sub.1-C.sub.4 alcohol to form a
solution and precipitating from the solution candesartan cilexetil
Form I. Preferably, the alcohol is ethanol.
[0108] The solution may optionally be cooled. If cooled, the
solution is preferably cooled at a temperature of from about
0.degree. C. to about 10.degree. C., more preferably from about
4.degree. C. to about 8.degree. C.
[0109] The recovered candesartan cilexetil Form I may optionally be
dried at a temperature of from about 40.degree. C. to about
60.degree. C., preferably at about 50.degree. C. The candesartan
cilexetil Form I may be dried under reduced pressure such as a
pressure of less than about 50 mbar, preferably under a pressure of
about 10 mbar.
[0110] Another process for preparing candesartan cilexetil Form I
comprises preparing a slurry of candesartan cilexetil Form XIV,
XIV-I, XXII, or XXIII in absolute ethanol; and isolating
candesartan cilexetil Form I from the slurry.
[0111] Preferably, the mixture is cooled at a temperature of from
about -20.degree. C. to about 20.degree. C., more preferably from
about -10.degree. C. to about 10.degree. C.
[0112] One embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form II, the process
comprising triturating candesartan cilexetil in water until a
precipitate forms, and collecting from the precipitate Form II.
Preferably, the triturated candesartan cilexetil is Form V.
Trituration may be carried out at room temperature. The precipitate
may be collected by filtration.
[0113] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form III, the process
comprising dissolving candesartan cilexetil in a solvent to form a
solution; heating the solution at a temperature of at least about
45.degree. C.; and precipitating from the solution candesartan
cilexetil Form III, wherein the solvent is at least one of a ketone
or tetrahydrofuran. Preferably, the ketone is acetone.
[0114] The solution may optionally be heated. If heated, the
solution is preferably heated at a temperature of from about
40.degree. C. to about 60.degree. C., more preferably from about
55.degree. C. to about 56.degree. C.
[0115] Another process for preparing candesartan cilexetil Form III
comprises dissolving candesartan cilexetil in tetrahydrofuran to
form a solution; combining water with the solution to form a
precipitate; isolating the precipitate; and drying the precipitate
to obtain candesartan cilexetil Form III.
[0116] The solution may optionally be heated before water is
combined. If heated, the solution is preferably heated at a
temperature of from about 40.degree. C. to about 60.degree. C.,
more preferably from about 55.degree. C. to about 56.degree. C.
[0117] After the addition of water, the mixture may optionally be
cooled. If cooled, the mixture is preferably cooled at a
temperature of from about 0.degree. C. to about 10.degree. C., more
preferably from about 4.degree. C. to about 8.degree. C.
[0118] The precipitate may be dried at a temperature of from about
40.degree. C. to about 60.degree. C., preferably from about
50.degree. C. to about 52.degree. C. Preferably, the precipitate is
dried under a pressure of less than about 50 mbar, more preferably
under a pressure of about 10 mbar.
[0119] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form IV, the process
comprising drying candesartan cilexetil Form III to a weight loss
of about 8.9%.
[0120] Preferably, Form III is dried at a temperature of from about
40.degree. C. to about 60.degree. C., more preferably from about
48.degree. C. to about 50.degree. C. Preferably, Form III is dried
under a pressure of less than about 50 mbar, more preferably under
a pressure of about 20 mbar.
[0121] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form V, the process
comprising drying candesartan cilexetil Form I11 to a weight loss
of about 11%.
[0122] Preferably, Form III is dried at a temperature of from about
40.degree. C. to about 60.degree. C., more preferably from about
48.degree. C. to about 50.degree. C. Preferably, Form III is dried
under a pressure of less than about 50 mbar, more preferably under
a pressure of about 20 mbar.
[0123] Another process for preparing candesartan cilexetil Form VI
comprises dissolving candesartan cilexetil in dichloromethane to
form a solution; combining heptane with the solution to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form VI.
[0124] The mixture may optionally be cooled after the addition of
heptane. If cooled, the mixture is preferably cooled at a
temperature of from about -5.degree. C. to about 15.degree. C.,
more preferably from about 0.degree. C. to about 5.degree. C.
[0125] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form VII, the process
comprising drying candesartan cilexetil Form VI.
[0126] Preferably, Form VI is dried to a constant weight. The term
"constant weight" means that the weight of the candesartan
cilexetil form will not fluctuate for more than about 3% of the
total weight during the drying process. Preferably, Form VI is
dried at a temperature of from about 40.degree. C. to about
60.degree. C., more preferably from about 48.degree. C. to about
50.degree. C. Preferably, Form VI is dried under a pressure of less
than about 50 mbar, more preferably under a pressure of about 20
mbar.
[0127] Another process for preparing candesartan cilexetil Form VII
comprises triturating candesartan cilexetil in toluene until a
precipitate forms and collecting the precipitate. Trituration may
be carried out at an elevated temperature, preferably at from about
40.degree. C. to about 60.degree. C., more preferably at about
50.degree. C. Preferably, the candesartan cilexetil is triturated
for about 1 hour at a temperature of about 50.degree. C.
Preferably, the triturated candesartan cilexetil is Form I.
[0128] Also preferably, the candesartan cilexetil is triturated for
about 24 hours at a temperature of from about 50.degree. C. to
about 70.degree. C., more preferably from about 60.degree. C. to
about 62.degree. C.
[0129] The precipitate may be collected by filtration. The
precipitate may be dried at a temperature of from about 40.degree.
C. to about 60.degree. C., preferably from about 50.degree. C. to
about 52.degree. C. Preferably, the precipitate is dried under a
pressure of less than about 50 mbar, more preferably under a
pressure of about 30 mbar.
[0130] Another process for preparing candesartan cilexetil Form VII
comprises dissolving candesartan cilexetil in dichloromethane to
form a solution; combining butanol with the solution to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form VII.
[0131] The mixture may optionally be cooled after the addition of
butanol. If cooled, the mixture is preferably cooled at a
temperature of from about -5.degree. C. to about -20.degree. C.,
more preferably from about -11.degree. C. to about -14.degree.
C.
[0132] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form VIII, the process
comprising dissolving candesartan cilexetil in methyl ethyl ketone
solvent to form a solution; heating the solution at a temperature
of at least about 45.degree. C.; and precipitating from the
solution candesartan cilexetil Form VIII.
[0133] The solution may be heated at a temperature of from about
50.degree. C. to about 70.degree. C. Preferably, the solution is
heated at a temperature of from about 60.degree. C. to about
62.degree. C. The solution may optionally be cooled to precipitate
candesartan cilexetil Form VIII. If cooled, the solution is
preferably cooled to room temperature, more preferably followed by
cooling at a temperature of from about 0.degree. C. to about
10.degree. C., most preferably from about 4.degree. C. to about
6.degree. C.
[0134] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form IX, the process
comprising dissolving candesartan cilexetil in dichloromethane to
form a solution; combining a first portion of a solvent with the
solution to form a first mixture; cooling the first mixture at a
temperature of less than about 10.degree. C.; combining a second
portion of the solvent with the first mixture to form a second
mixture; and precipitating from the second mixture candesartan
cilexetil Form IX, wherein the solvent is at least one of
acetonitrile, tert butyl methyl ether, or toluene.
[0135] Preferably, the first portion of the solvent is added
dropwise.
[0136] Preferably, before the addition of the second portion of the
solvent, the first mixture is cooled at a temperature of from about
-10.degree. C. to about 10.degree. C., more preferably, the first
mixture is cooled to about 0.degree. C. on an ice bath.
[0137] The second mixture may optionally be cooled after the
addition of a second portion of the solvent, preferably at a
temperature of from about -25.degree. C. to about 5.degree. C.,
more preferably from about -15.degree. C. to about 0.degree. C.
[0138] The precipitate may optionally be dried at a temperature of
from about 35.degree. C. to about 60.degree. C., preferably from
about 40.degree. C. to about 50.degree. C. Preferably, the
precipitate is dried under a pressure of less than about 50 mbar,
more preferably under a pressure of about 30 mbar.
[0139] Another process for preparing candesartan cilexetil Form IX
comprises dissolving candesartan cilexetil in chloroform to form a
solution; combining toluene with the solution to form a mixture;
and precipitating from the mixture candesartan cilexetil Form
IX.
[0140] Preferably, the toluene is added dropwise. The mixture may
optionally be cooled after the addition of toluene, preferably at a
temperature of from about -25.degree. C. to about 5.degree. C.,
more preferably from about -15.degree. C. to about 0.degree. C.
[0141] The precipitate may optionally be dried at a temperature of
from about 35.degree. C. to about 60.degree. C., preferably from
about 40.degree. C. to about 45.degree. C. Preferably, the
precipitate is dried under a pressure of less than about 50 mbar,
more preferably under a pressure of about 30 mbar.
[0142] Another process for preparing candesartan cilexetil Form IX
comprises heating candesartan cilexetil Form X. Form X may be
heated at a temperature of from about 90.degree. C. to about
120.degree. C., preferably at about 100.degree. C. Form X may be
heated for at least about 10 hours, preferably for about 13
hours.
[0143] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form X, the process
comprising dissolving candesartan cilexetil in dioxane to form a
solution; combining water with the solution to form a mixture; and
precipitating from the mixture candesartan cilexetil Form X.
[0144] Preferably, the water is added dropwise.
[0145] The solution may optionally be heated before water is
combined. If heated, the solution is preferably heated at a
temperature of from about 40.degree. C. to about 60.degree. C.,
more preferably at about 50.degree. C. The mixture may optionally
be cooled after the addition of water, preferably on an ice
bath.
[0146] The precipitate may be dried at a temperature of from about
35.degree. C. to about 50.degree. C., preferably from about
40.degree. C. to about 45.degree. C. The precipitate may be dried
under a pressure of less than about 50 mbar, preferably under a
pressure of about 30 mbar.
[0147] Another process for preparing candesartan cilexetil Form X
comprises dissolving candesartan cilexetil in dioxane to form a
solution and precipitating from the solution candesartan cilexetil
Form X.
[0148] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XI, the process
comprising dissolving candesartan cilexetil in chloroform to form a
solution; combining a solvent with the solution to form a mixture;
and precipitating from the mixture candesartan cilexetil Form XI,
wherein the solvent is at least one of heptane, cyclohexane, or
tert butyl methyl ether.
[0149] Preferably, the solvent is added dropwise. The mixture may
optionally be cooled after the addition of the solvent, preferably
at a temperature of from about -10.degree. C. to about 10.degree.
C., more preferably at about 0.degree. C.
[0150] The precipitate may optionally be dried at a temperature of
from about 35.degree. C. to about 60.degree. C., preferably from
about 40.degree. C. to about 50.degree. C. Preferably, the
precipitate is dried under a pressure of less than about 50 mbar,
more preferably under a pressure of about 30 mbar.
[0151] Another process for preparing candesartan cilexetil Form XI
comprises dissolving candesartan cilexetil in dichloromethane to
form a solution; combining cyclohexane with the solution to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form XI.
[0152] Preferably, the cyclohexane is added dropwise. The mixture
may optionally be cooled after the addition of cyclohexane,
preferably at a temperature of from about -10.degree. C. to about
10.degree. C., more preferably at about 0.degree. C.
[0153] The precipitate may optionally be dried at a temperature of
from about 40.degree. C. to about 60.degree. C., preferably at
about 50.degree. C. The precipitate may be dried under a pressure
of less than about 50 mbar, preferably under a pressure of about 30
mbar.
[0154] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XIII, the process
comprising dissolving candesartan cilexetil in dichloromethane to
form a solution; combining isoamyl acetate with the solution to
form a mixture; and precipitating from the mixture candesartan
cilexetil Form XIII.
[0155] Preferably, the isoamyl acetate is added dropwise. The
mixture may optionally be cooled after the addition of isoamyl
acetate, and preferably at a temperature of about 0.degree. C.
[0156] The precipitate may optionally be dried at a temperature of
from about 40.degree. C. to about 60.degree. C., preferably at
about 50.degree. C. Preferably, the precipitate is dried under a
pressure of less than about 50 mbar, more preferably under a
pressure of about 30 mbar.
[0157] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XIV, the process
comprising dissolving candesartan cilexetil in dichloromethane to
form a solution; combining toluene with the solution to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form XIV.
[0158] Preferably, the toluene is added dropwise. Optionally, the
toluene may be added in two portions, wherein the mixture is
cooled, preferably in an ice bath, after the addition of a first
portion of toluene, and followed by the addition of a second
portion of toluene. The mixture may optionally be cooled again to
precipitate Form XIV, preferably at a temperature of from about
-20.degree. C. to about 0.degree. C., more preferably at about
-10.degree. C. Preferably, the precipitate is dried by
filtration.
[0159] Candesartan cilexetil Form XIV may be converted to
candesartan cilexetil Form I by dissolving Form XIV in a
C.sub.1-C.sub.4 alcohol to form a solution and precipitating from
the solution, candesartan cilexetil Form I.
[0160] Candesartan cilexetil Form XIV can also be converted to
candesartan cilexetil Form I by preparing a slurry of candesartan
cilexetil Form XIV in absolute ethanol; and isolating candesartan
cilexetil Form I from the slurry.
[0161] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XIV-1, the process
comprising preparing a solution of trityl candesartan cilexetil in
a first portion of toluene or dichloromethane, and a first
C.sub.1-C.sub.4 alcohol, acid, or both to deprotect the trityl
candesartan cilexetil and obtain candesartan cilexetil;
concentrating the solution into a residue; combining a second
portion of toluene or dichloromethane, and a second C.sub.1-C.sub.4
alcohol with the residue to form a mixture; and precipitating from
the mixture candesartan cilexetil Form XIV-1.
[0162] Concentration may be by evaporation. Evaporation may be
carried out at a temperature of from about 50.degree. C. to about
70.degree. C., more preferably at about 60.degree. C. Evaporation
may be carried out under a pressure of less than about 50 mbar,
more preferably under a pressure of about 30 mbar. The residue may
be in the form a viscous oil.
[0163] Optionally, water may be added to the solution of trityl
candesartan cilexetil. Preferably, the toluene or dichloromethane
used to prepare the trityl candesartan cilexetil solution is
toluene. Preferably, the first C.sub.1-C.sub.4 alcohol is methanol.
Preferably, the second C.sub.1-C.sub.4 alcohol is methanol.
Preferably, the first and second C.sub.1-C.sub.4 alcohol are the
same, more preferably methanol. Preferably, the acid is selected
from the group consisting of formic acid, trifluoroacetic acid,
methane sulfonic acid, a mixture of hydrobromic acid with acetic
acid, and a mixture of hydrochloric acid and sulfuric acid. More
preferably, the acid is formic acid.
[0164] Preferably, the reaction time is at least about 10 hours.
Reaction time may easily be determined by monitoring the reaction
progress and/or completion by HPLC.
[0165] Preferably, after dissolving the residue, candesartan
cilexetil Form XIV-1 is precipitated by cooling the mixture at a
temperature of from about 0.degree. C. to about 10.degree. C.,
preferably at a temperature of from about 4.degree. C. to about
8.degree. C.
[0166] Candesartan cilexetil Form XIV-1 may be converted to
candesartan cilexetil Form I by dissolving Form XIV-1 in a
C.sub.1-C.sub.4 alcohol to form a solution and precipitating from
the solution candesartan cilexetil Form I.
[0167] Candesartan cilexetil Form XIV-1 can also be converted to
candesartan cilexetil Form I by preparing a slurry of candesartan
cilexetil Form XIV-1 in absolute ethanol; and isolating candesartan
cilexetil Form I from the slurry.
[0168] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XV, the process
comprising dissolving candesartan cilexetil in chloroform to form a
solution; combining acetonitrile with the solution to form a
precipitate; isolating the precipitate; and drying the precipitate
to recover candesartan cilexetil Form XV.
[0169] Preferably, the acetonitrile is added dropwise. The mixture
may optionally be cooled after the addition of acetonitrile,
preferably in an ice bath until a precipitate forms.
[0170] Preferably, the precipitate is dried at a temperature of
from about 40.degree. C. to about 60.degree. C., more preferably at
about 45.degree. C. Preferably, the precipitate is dried under a
pressure of less than about 50 mbar, more preferably under a
pressure of about 30 mbar.
[0171] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XVI, the process
comprising heating candesartan cilexetil Form VI. Form VI may be
heated at a temperature of from about 90.degree. C. to about
120.degree. C., preferably at about 100.degree. C. Form VI may be
heated for at least about 10 hours, preferably for about 13
hours.
[0172] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XVII, the process
comprising heating candesartan cilexetil Form XIII or Form XV. The
Form XIII or Form XV may be heated at a temperature of from about
90.degree. C. to about 120.degree. C., preferably at about
100.degree. C. The Form XIII or Form XV may be heated for at least
about 10 hours, preferably for about 13 hours.
[0173] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XVIII, the process
comprising dissolving candesartan cilexetil in tetrahydrofuran to
form a solution; pouring the solution into water to form a mixture;
and precipitating from the mixture candesartan cilexetil Form
XVIII.
[0174] The solution may optionally be heated before being poured
into water. If heated, the solution is preferably heated at a
temperature of from about 50.degree. C. to about 70.degree. C.,
more preferably from about 60.degree. C. to about 62.degree. C.
[0175] The water may be at a temperature of from about -10.degree.
C. to about 10.degree. C., more preferably at about 5.degree. C.
The mixture may optionally be cooled after the addition of water,
preferably at a temperature of from about -5.degree. C. to about
10.degree. C., more preferably from about 5.degree. C. to about
7.degree. C.
[0176] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XIX, the process
comprising dissolving candesartan cilexetil in acetonitrile to form
a solution; pouring the solution into water to form a mixture; and
precipitating from the mixture candesartan cilexetil Form XIX.
[0177] The solution may optionally be heated before being poured
into water. If heated, the solution is preferably heated at a
temperature of from about 50.degree. C. to about 70.degree. C.,
more preferably about 60.degree. C. to about 64.degree. C.
[0178] The water may be at a temperature of from about -10.degree.
C. to about 10.degree. C., more preferably from about 0.degree. C.
about 5.degree. C. The mixture may optionally be cooled after the
addition of water, preferably at a temperature of from about
-10.degree. C. to about 10.degree. C., more preferably from about
0.degree. C. to about 5.degree. C.
[0179] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XX, the process
comprising dissolving candesartan cilexetil in chloroform to form a
solution; combining acetonitrile with the solution to form a
mixture; and precipitating from the mixture candesartan cilexetil
Form XX.
[0180] Preferably, the acetonitrile is added dropwise. The mixture
may optionally be cooled after the addition of acetonitrile,
preferably in an ice bath until a precipitate forms. Preferably,
the precipitate is collected by filtration.
[0181] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XXI, the process
comprising dissolving candesartan cilexetil in tetrahydrofuran to
form a solution; and precipitating from the solution candesartan
cilexetil Form XXI.
[0182] Preferably, the candesartan cilexetil Form XXI is
precipitated after at least about 7 days, more preferably after
about 3 weeks.
[0183] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XXII, the process
comprising dissolving crude candesartan in a C.sub.1-C.sub.4
alcohol at a temperature of at least about 45.degree. C. to form a
solution; and precipitating candesartan cilexetil Form XXII.
Preferably, the alcohol is methanol.
[0184] Preferably, the solution is heated at a temperature of from
about 50.degree. C. to about 60.degree. C., preferably at a
temperature of about 50.degree. C.
[0185] The candesartan cilexetil Form XXII may be precipitated by
cooling the solution, preferably at a temperature of from about
-10.degree. C. to about 20.degree. C., more preferably at a
temperature of about -5.degree. C. to about 5.degree. C., for about
6 hours to about 16 hours, preferably for about 16 hours, until a
precipitate forms.
[0186] The precipitate may optionally be dried at a temperature of
from about 40.degree. C. to about 60.degree. C., preferably at
about 50.degree. C. Preferably, the precipitate is dried under a
pressure of less than about 50 mbar, more preferably under a
pressure of about 10 mbar.
[0187] Candesartan cilexetil Form XXII may be converted to
candesartan cilexetil Form I by dissolving Form XXII in a
C.sub.1-C.sub.4 alcohol to form a solution and precipitating from
the solution candesartan cilexetil Form I.
[0188] Candesartan cilexetil Form XXII can also be converted to
candesartan cilexetil Form I by preparing a slurry of candesartan
cilexetil Form XXII in absolute ethanol; and isolating candesartan
cilexetil Form I from the slurry.
[0189] Another embodiment of the invention is directed towards a
process for preparing candesartan cilexetil Form XXIII, the process
comprising preparing a solution of trityl candesartan cilexetil in
a first portion of toluene or dichloromethane, a first
C.sub.1-C.sub.4 alcohol, and water to deprotect the trityl
candesartan cilexetil and obtain candesartan cilexetil;
concentrating the solution into a residue; combining a second
portion of toluene or dichloromethane, and a second C.sub.1-C.sub.4
alcohol with the residue to form a mixture; and precipitating from
the mixture candesartan cilexetil Form XXIII.
[0190] Preferably, the toluene or dichloromethane used to prepare
the trityl candesartan cilexetil solution is toluene. Preferably,
the first C.sub.1-C.sub.4 alcohol is methanol. Preferably, the
second C.sub.1-C.sub.4 alcohol is methanol. Preferably, the first
and second C.sub.1-C.sub.4 alcohol are the same, more preferably
methanol. Preferably, the solution of trityl candesartan cilexetil
is maintained at a reflux temperature for about 2.5 to about 6
hours, preferably for about 3 hours.
[0191] Concentration may be by evaporation. Evaporation may be
carried out at a temperature of from about 30.degree. C. to about
60.degree. C., more preferably at about 45.degree. C. Evaporation
may be carried out under a pressure of less than about 100 mbar,
more preferably under a pressure of about 90 mbar. The residue may
be in the form a viscous oil.
[0192] Preferably, the residue is combined with the second portion
of dichloromethane or toluene and the second C.sub.1-C.sub.4
alcohol at a temperature of from about 45.degree. C. to about
55.degree. C., more preferably at a temperature of about 50.degree.
C. The resulting mixture may optionally be cooled at a temperature
of from about 35.degree. C. to about 45.degree. C.; and further
cooled at a temperature of from about -15.degree. C. to about
15.degree. C., preferably at from about -5.degree. C. to about
5.degree. C. for about 1-12 hours, until a precipitate is obtained.
Optionally, the mixture may be seeded with candesartan cilexetil
Form XXII to obtain candesartan cilexetil Form XXIII.
[0193] The precipitate may optionally be dried at a temperature of
from about 40.degree. C. to about 60.degree. C., preferably at
about 50.degree. C. The precipitate may be dried under a pressure
of less than about 50 mbar, preferably under a pressure of about 10
mbar.
[0194] Candesartan cilexetil Form XXIII may be converted to
candesartan cilexetil Form I by dissolving Form XXIII in a
C.sub.1-C.sub.4 alcohol to form a solution and precipitating from
the solution candesartan cilexetil Form I.
[0195] Candesartan cilexetil Form XXIII can also be converted to
candesartan cilexetil Form I by preparing a slurry of candesartan
cilexetil Form XXIII in absolute ethanol; and isolating candesartan
cilexetil Form I from the slurry.
[0196] Another embodiment of the invention is directed towards a
process for preparing amorphous candesartan cilexetil, the process
comprising heating candesartan cilexetil Form III, V, IX, XI, or
XIV at about 100.degree. C. for about 13 hours.
[0197] Another process for preparing amorphous candesartan
cilexetil comprises dissolving candesartan cilexetil in dioxane to
form a solution; pouring the solution into water to form a mixture;
and precipitating from the mixture amorphous candesartan
cilexetil.
[0198] Preferably, the solution is heated at a temperature of from
about 50.degree. C. to about 70.degree. C., more preferably from
about 60.degree. C. to about 62.degree. C. Preferably, after the
solution is poured into water, the resulting mixture is stirred and
cooled. Preferably, the mixture is cooled at a temperature of from
about -15.degree. C. to about 15.degree. C., more preferably at
about -10.degree. C. to about 0.degree. C.
[0199] Candesartan cilexetil forms of the invention can be used in
the form of pharmaceutical composition. The invention encompasses a
pharmaceutical composition prepared by combining at least one
pharmaceutically-acceptable excipient with at least one candesartan
cilexetil form of the invention. The invention also encompasses a
pharmaceutical composition comprising at least one
pharmaceutically-acceptable excipient and at least one candesartan
cilexetil form of the invention. In another embodiment, the
invention encompasses a method of preparing a pharmaceutical
composition comprising combining at least one candesartan cilexetil
form of the invention with at least one pharmaceutically-acceptable
excipient.
[0200] The invention further encompasses a method of treating
circulatory system diseases comprising administering a
therapeutically effective amount of the pharmaceutical composition
of the invention to a mammal in need thereof.
[0201] The pharmaceutical composition can include at least one
diluent or excipient, such as carriers, fillers, bulking agents,
binders, wetting agents, disintegrating agents, surface active
agents, lubricants, and the like. Any excipient commonly known and
used widely in the art can be used in the pharmaceutical
composition. Carriers include, but are not limited to, lactose,
white sugar, sodium chloride, glucose, urea, starch, calcium
carbonate, kaolin, crystalline cellulose, and silicic acid. Binders
include, but are not limited to, water, ethanol, propanol, simple
syrup, glucose solutions, starch solutions, gelatin solutions,
carboxymethyl cellulose, shelac, methyl cellulose, potassium
phosphate, and polyvinylpyrrolidone. Disintegrating agents include,
but are not limited to, dried starch, sodium alginate, agar powder,
laminalia powder, sodium hydrogen carbonate, calcium carbonate,
fatty acid esters of polyoxyethylene sorbitan, sodium
laurylsulfate, monoglyceride of stearic acid, starch, and lactose.
Disintegration inhibitors include, but are not limited to, white
sugar, stearin, coconut butter, and hydrogenated oils. Absorption
accelerators include, but are not limited to, quaternary ammonium
base, and sodium laurylsulfate. Wetting agents include, but are not
limited to, glycerin, and starch. Adsorbing agents include, but are
not limited to, starch, lactose, kaolin, bentonite, and colloidal
silicic acid. Lubricants used include, but are not limited to,
purified talc, stearates, boric acid powder, and polyethylene
glycol. Tablets can be further coated with commonly known coating
materials such as sugar coated tablets, gelatin film coated
tablets, tablets coated with enteric coatings, tablets coated with
films, double layered tablets, and multi-layered tablets.
[0202] One embodiment of the invention is directed towards a method
of preparing a pharmaceutical composition comprising combining at
least one pharmaceutically-acceptable excipient with any of the
forms encompassed by the invention. Various types of dosage forms
can be prepared from this method, depending on the therapeutic
purpose, for example tablets, pills, powders, liquids, solutions,
suspensions, emulsions, granules, capsules, suppositories,
injection preparations (solutions and suspensions), and the
like.
[0203] When tableting the pharmaceutical composition, any commonly
known excipient used in the art can be used. For example, carriers
include, but are not limited to, lactose, starch, coconut butter,
hardened vegetable oils, kaolin, and talc. Binders include, but are
not limited to, gum arabic powder, tragacanth gum powder, gelatin,
and ethanol. Disintegrating agents include, but are not limited to,
agar, and laminalia.
[0204] For the purpose of shaping the pharmaceutical composition in
the form of suppositories, any commonly known excipient used in the
art can be used. For example, excipients include, but are not
limited to, polyethylene glycols, coconut butter, higher alcohols,
esters of higher alcohols, gelatin, and semisynthesized
glycerides.
[0205] When preparing injectable pharmaceutical compositions,
solutions and suspensions are sterilized and are preferably made
isotonic to blood. Injection preparations may use carriers commonly
known in the art. For example, carriers for injectable preparations
include, but are not limited to, water, ethyl alcohol, propylene
glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl
alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of
ordinary skill in the art can easily determine with little or no
experimentation the amount of sodium chloride, glucose, or glycerin
necessary to make the injectable preparation isotonic. Additional
ingredients, such as dissolving agents, buffer agents, and
analgesic agents may be added. If necessary, coloring agents,
preservatives, perfumes, seasoning agents, sweetening agents, and
other medicines may also be added to the desired preparations
during the treatment of circulatory system diseases.
[0206] Methods of administration of a pharmaceutical composition
for treating circulatory system diseases of the present invention
are not specifically restricted, and can be administered in various
preparations depending on the age, sex, and symptoms of the
patient. For example, tablets, pills, solutions, suspensions,
emulsions, granules and capsules may be orally administered.
Injection preparations may be administered individually or mixed
with injection transfusions such as glucose solutions and amino
acid solutions intravenously. If necessary, the injection
preparations are administered singly intramuscularly,
intracutaneously, subcutaneously or intraperitoneally.
Suppositories may be administered into the rectum.
[0207] The therapeutically-effective amount of candesartan
cilexetil contained in a pharmaceutical composition for treating
circulatory system diseases according to the present invention
should be a dose sufficient to treat, ameliorate, or reduce the
symptoms associated with the circulatory system disease. The dosage
of a pharmaceutical composition for treating circulatory system
diseases according to the present invention will depend on the
method of use, the age, sex, and condition of the patient.
Typically, about 4 mg to 32 mg of candesartan cilexetil may be
contained in an administration form unit.
[0208] Having described the invention with reference to certain
preferred embodiments, other embodiments will become apparent to
one skilled, in the art from consideration of the specification.
The invention is further defined by reference to the following
examples describing in detail the polymorph forms and processes for
making them. It will be apparent to those skilled in the art that
many modifications, both to materials and methods, may be practiced
without departing from the scope of the invention.
EXAMPLES
[0209] The candesartan cilexetil forms were identified using
Scintag X-ray powder diffractometer model X'TRA, Cu-tube solid
state detector. The sample holder was a round standard aluminum
sample holder with rough zero background quartz plate with a cavity
of 25 (diameter)*0.5 mm (depth). The scanning parameters were
range: 2-40 and in some cases 2-30 degrees two-theta; scan mode:
continuous scan; step size: 0.05 deg.; and a rate of 3 deg/min.
[0210] Typically to determine the Loss on Dry (L.O.D.) by Thermal
Gravimetric Analysis (TGA), a sample was heated from about
25.degree. C. to about 200.degree. C. at a heating rate of about
10.degree. C. per minute, while purging with nitrogen gas at a flow
rate of 40 ml/min.
Example 1
Preparation of Amorphous Candesartan Cilexetil
[0211] Candesartan cilexetil Form III (0.5 g) was placed in a glass
container and heated in a static oven at about 100.degree. C. for
about 13 hours to obtain amorphous candesartan cilexetil. The
process was also performed with Forms V, IX, XI, and XIV to obtain
amorphous candesartan cilexetil.
Example 2
Preparation of Amorphous Candesartan Cilexetil
[0212] Candesartan cilexetil (5 g) was dissolved in dioxane (15.5
g) and heated to about 60.degree. C. to 62.degree. C. to form a
solution. When the solution was poured into water (50 g, about
20.degree. C. to 25.degree. C.), a solid formed as a sticky mass.
Subsequently, the solution was stirred and cooled first to about
5.degree. C. to 7.degree. C. for about 30 minutes and then to about
-10.degree. C. to 0.degree. C. for about 30 minutes, a precipitate
formed within the solution. The precipitate was collected by
filtration and dried on the filter for about 2 hours and a wet
amorphous form (7 g) was obtained. A portion of the wet amorphous
form (4.63 g) was dried at reduced pressure, 20 mbar, at about
50.degree. C. to 52.degree. C. for about 2 hours to obtain
amorphous form (3.41 g).
Example 3
Preparation of Candesartan Cilexetil Form I
[0213] Candesartan cilexetil (5 g) was dissolved in butanol (64.7
g) under argon and heated to about 62.degree. C. to 64.degree. C.
to form a solution. The solution was cooled to 20.degree. C. to
25.degree. C. and stirred for about 12 hours after which a
precipitate formed. The precipitate was collected by filtration to
obtain (wet) Form I.
Example 4
Preparation of Candesartan Cilexetil Form I
[0214] The procedure of Example 3 was repeated using a variety of
solvents and temperatures. Generally, the process comprises
dissolving candesartan cilexetil Form I (C) (5 g) in a solvent,
heating the mixture to a temperature to form a solution, cooling
the solution to a temperature of 20.degree. C. to 25.degree. C. and
maintaining the temperature until a precipitate formed (time),
collecting the precipitate by filtration, and drying the
precipitate. Optionally, if necessary the precipitate may be
washed. The results are summarized in Table 1.
TABLE-US-00002 TABLE 1 Preparation of candesartan cilexetil Form I
Temp. Time Solvent (.degree. C.) (hr) Drying conditions % Yield
Acetonitrile 50 6 40.degree. C., 1 hr.sup.a 84% (80 ml) methanol
(21.5 g) 65 4 40.degree. C. to 50.degree. C., 1 hr.sup.a 88%
methanol (21.5 g) reflux 4 c IPA (70 g) 60 to 62 2 40.degree. C. to
50.degree. C., 1 hr.sup.a 80% butanol (64.6 g) 62 to 64 12
40.degree. C. to 50.degree. C., 1 hr.sup.a 74% ethyl acetate 60 to
62 16 46.degree. C. to 48.degree. C., 20 mbar 22% (60 g).sup.b
ethanol (43 g) 60 to 62 2 46.degree. C. to 48.degree. C., 20 mbar
82.6% .sup.aDrying was carried out at a reduced pressure of about
30 mbar. .sup.bA portion of the wet form I (1.34 g) was dried under
reduced pressure (20 mbar) to the constant weight to obtain Form I
(1.13 g). c The solution was hot filtered, cooled to 25.degree. C.
to 27.degree. C., and the collected precipitate was not dried.
Example 5
Preparation of Candesartan Cilexetil Form I
[0215] Candesartan cilexetil Form I (C) (5 g) was dissolved in a
solvent and heated to form a solution. Water was added dropwise to
the heated solution until a precipitate started to form. The
solution was cooled to about 20.degree. C. to 25.degree. C. and
stirred (time 1). Subsequently, the solution was cooled to about
0.degree. C. with ice water and stirred (time 2). The precipitate
was collected by filtration and dried under reduced pressure (30
mbar) to obtain Form I. Optionally, the precipitate may be washed
with water (20 ml) before drying. The results are summarized in
Table 2.
TABLE-US-00003 TABLE 2 Preparation of candesartan cilexetil Form I
Solvent (ml) Temp (.degree. C.) Water (ml) Time 1 (h) Time 2 (h)
Drying conditions % Yield Acetone (55) 50 to 55 36 0.5 1 40.degree.
C. to 45.degree. C., 1 hr 80% Methanol (45) 60 to 65 14 0.5 2
40.degree. C. to 45.degree. C., 1 hr 80% DMF (10) 20 to 25 4 0.75 1
50.degree. C., 1 hr 90% Acetonitrile (100) 70 to 75 65 1 1
50.degree. C., 4 hrs 90% IPA (300) 60 370 1.5 2 50.degree. C., 5
hrs 90% Ethanol (16) 60 to 64 12 a 2 50 to 52.degree. C., 4.5 hrs
.sup.aThe solution was cooled to 5.degree. C. to 7.degree. C.
instead of 0.degree. C.
Example 6
Preparation of Candesartan Cilexetil Form I
[0216] Candesartan cilexetil Form I (C) (5 g) was dissolved in
acetone and heated to 62.degree. C. to 64.degree. C. to form a
solution. The solution was poured into water (50 g, about
20.degree. C. to 25.degree. C.) to form a precipitate. The solution
was stirred for about 30 minutes to obtain a sticky mass, then
cooled to 0.degree. C. for about 30 minutes. The precipitate was
collected by filtration and dried on the filter for about 0.5 to 1
hours to obtain the wet sample Form I, which was dried at 20 mbar
and 50.degree. C. to 52.degree. C. to a constant weight to obtain
Form I.
Example 7
Preparation of Candesartan Cilexetil Form I
[0217] Candesartan cilexetil Form VII (0.5 g) was placed in a glass
container and heated in a static oven at about 100.degree. C. for
about 13 hours to obtain candesartan cilexetil Form I. The process
was also performed with Form VIII.
Example 8
Preparation of Candesartan Cilexetil Form II
[0218] Candesartan cilexetil Form V (3.26 g) was triturated with
water (60 g) at about 20.degree. C. to 25.degree. C. for about 24
hours to form a precipitate. The precipitate was collected by
filtration and dried on the filter for about 30 minutes to obtain
Form II.
Example 9
Preparation of Candesartan Cilexetil Form III
[0219] Candesartan cilexetil Form I (C) (5 g) was dissolved in a
solvent under argon and heated to 55.degree. C. to 56.degree. C. to
form a solution. The solution was filtered, cooled to about
25.degree. C. to 27.degree. C., and stirred for about 2 hours
during which time a precipitate formed. The precipitate was
collected by filtration, washed, and dried on the filter for about
15 minutes to obtain Form III. When the solvent was acetone (17.4
g), after the first cooling, the solution was stirred at about
0.degree. C. to 5.degree. C. for about 1 hour. The process yielded
Form III (5.35 g). When the solvent was THF (7 g), the process
yielded Form III (4.7 g).
[0220] The process was repeated with THF but water (5 g) was added
to the solution and the solution was cooled with stirring first to
about 20.degree. C. to 25.degree. C. and then to about 5.degree. C.
to 7.degree. C. for about 1 hour, and subsequently at 4.degree. C.
to 8.degree. C. for about 44 hours. A precipitate formed and was
collected by filtration, and dried on the filter for about 30
minutes to obtain Form II and Form III. The precipitate mixture was
dried under reduced pressure (10 mbar) at about 50.degree. C. to
52.degree. C. to obtain Form III.
Example 10
Preparation of Candesartan Cilexetil Form Iv
[0221] Candesartan cilexetil Form III (1.78 g) was dried at about
48.degree. C. to 50.degree. C. under reduced pressure (20 mbar) to
a constant weight (about 30 minutes) to obtain Form IV (1.62
g).
Example 11
Preparation of Candesartan Cilexetil Form V
[0222] Candesartan cilexetil Form I (2.09 g) was dried at about
48.degree. C. to 50.degree. C. under reduced pressure (20 mbar) to
a constant weight (about 1 hour) to obtain Form V (1.86 g).
Example 12
Preparation of Candesartan Cilexetil Form VI
[0223] Candesartan cilexetil Form I (C) (5 g) was dissolved in DCM
(6.6 ml) under argon at about 20.degree. C. to 25.degree. C. to
form a solution. Heptane (9 ml) was slowly added to the solution,
the solution was cooled to about 0.degree. C. to 5.degree. C., and
stirred for about 15 minutes until a precipitate formed. The
solution was warmed to about 25.degree. C. to 27.degree. C. The
precipitate was collected by filtration, washed with heptane (10
ml), and dried on the filter for about 30 minutes to obtain Form
VI.
Example 13
Preparation of Candesartan Cilexetil Form VII
[0224] Candesartan cilexetil Form VI (2.05 g) was dried at about
48.degree. C. to 50.degree. C. under reduced pressure (20 mbar) to
a constant weight (about 1 hour) to obtain Form VII (1.90 g).
Example 14
Preparation of Candesartan Cilexetil Form VII
[0225] Candesartan cilexetil Form I (C) (5 g) was triturated with
toluene (30 ml) at 50.degree. C. for 1 hour. The suspension was
cooled to about 20.degree. C. to 25.degree. C. and a precipitate
formed. The precipitate was collected by filtration and dried on
the filter for about 30 minutes to obtain Form VII.
[0226] The procedure was repeated by dissolving Form I in toluene
(50 ml) and heating to about 60.degree. C. to 62.degree. C. for
about 24 hours. The precipitate was collected and dried on the
filter to obtain wet Form VII (4.26 g). A portion of the wet Form
VII (1.73 g) was dried under reduced pressure (30 mbar) at about
50.degree. C. to 52.degree. C. to the constant weight to obtain dry
Form VII (1.73 g).
Example 15
Preparation of Candesartan Cilexetil Form VII
[0227] Candesartan cilexetil (1 g) was dissolved in DCM (1.9 g) at
about 20.degree. C. to 25.degree. C. to form a solution, followed
by the addition of butanol (8.1 g). The solution was kept at about
-11.degree. C. to -14.degree. C. for six days until a precipitate
formed. The precipitate was collected by filtration (about 5 hours)
and dried on the filter for about 30 minutes to obtain Form
VII.
Example 16
Preparation of Candesartan Cilexetil Form VIII
[0228] Candesartan cilexetil Form I (C) (5 g) was dissolved in MEK
(21.1 g) under argon and heated to about 60.degree. C. to
62.degree. C. to form a solution. The hot solution was filtered,
first allowed to cool to about 25.degree. C. to 27.degree. C., and
subsequently allowed to cool to about 4.degree. C. to 6.degree. C.
for about 48 hours after which a precipitate formed. The
precipitate was collected by filtration and dried on the filter for
about 30 minutes to obtain Form VIII (2.88 g).
Example 17
Preparation of Candesartan Cilexetil Form IX
[0229] Candesartan cilexetil Form I (C) (5 g) was dissolved in a
first solvent to form a solution, and a second solvent was added
dropwise at about 25.degree. C. The solution was cooled to
0.degree. C. in an ice bath, and a third solvent was added. The
solution was kept cool until a precipitate formed. The precipitate
was collected by filtration, and dried under reduced pressure (30
mbar) to obtain Form IX. The results are summarized in Table 3
below.
TABLE-US-00004 TABLE 3 Preparation of candesartan cilexetil Form IX
First solvent Second Third solvent Precipitation Drying (ml)
solvent (ml) (ml) conditions conditions % Yield DCM (6.6)
acetonitrile acetonitrile 0.degree. C., 30 min. 30 to 40 min. 70%
(18) (2) at 40.degree. C. DCM (6.6) TBME (30) TBME (20) -10 to
-15.degree. C., 2 hrs 2 hrs at 45.degree. C. 64% DCM.sup.a (6.6)
toluene (15) toluene (3) -10.degree. C., 2 hrs 8 hrs at 50.degree.
C. 95% chloroform.sup.b toluene (15) 25.degree. C. for 30 min., 1
hr 40-45.degree. C. 92% (8.5) 0.degree. C. for 3 hrs; -10 to
-15.degree. C. for 18 hrs .sup.aThe precipitate was washed with
toluene (25 ml) prior to drying. .sup.bThe precipitate was washed
with toluene (10 ml) prior to drying.
Example 18
Preparation of Candesartan Cilexetil Form IX
[0230] Candesartan cilexetil Form X (0.5 g) was placed in a glass
container and heated in a static oven at about 100.degree. C. for
about 13 hours to obtain candesartan cilexetil Form IX.
Example 19
Preparation of Candesartan Cilexetil Form X
[0231] Candesartan cilexetil Form I (C) (5 g) was dissolved in
dioxane (25 ml), heated to about 50.degree. C., and water (15 ml)
was added dropwise to the solution until a precipitate started to
form. The solution was stirred and allowed to cool to about
25.degree. C. for about 30 minutes and then, cooled with ice water
and stirred for about 1 hour. The precipitate was collected by
filtration, washed on the filter with water (10 ml), and dried
under reduced pressure (30 mbar) at 40.degree. C. to 45.degree. C.
for about 2 hours to obtain Form X.
Example 20
Preparation of Candesartan Cilexetil Form X
[0232] Candesartan cilexetil was dissolved in dioxane to form a
solution. The solution was kept at about 20.degree. C. to
25.degree. C. for about 1 to 3 weeks to form a precipitate. The
precipitate was collected by filtration and dried on the filter to
obtain Form X. Candesartan cilexetil Form I (C) (2 g) yielded Form
X after 1 week at 25.degree. C. in 65.5%. When left for 3 weeks,
candesartan cilexetil (4 g) in dioxane (25.4 g) yielded Form X
(2.87 g).
Example 21
Preparation of Candesartan Cilexetil Form XI
[0233] Candesartan cilexetil Form I (C) (5 g) was dissolved in a
first solvent and a second solvent was added dropwise at 25.degree.
C. to the solution. The solution was allowed to cool in an ice bath
and a precipitate formed. The precipitate was collected by
filtration and dried under reduced pressure (30 mbar) at 50.degree.
C. to obtain Form XI. The results are summarized in Table 4
below.
TABLE-US-00005 TABLE 4 Preparation of candesartan cilexetil Form XI
First solvent (ml) Second solvent (ml) Cooling conditions Drying
conditions % Yield chloroform (8) heptane.sup.a (15) 0.degree. C.,
1 hr 40.degree. C. to 45.degree. C., 1 hr 98% DCM (6.5)
cyclo-hexane (28) 0.degree. C. for 30 min, 50.degree. C., 2.5 hrs
84% then 20.degree. C. to 25.degree. C. for 2 hrs chloroform (8.5)
cyclo-hexane (28) 20.degree. C. to 25.degree. C. for 40.degree. C.,
1 hr 98% 30 min, then 0.degree. C. for 1 hr chloroform (7.5) TBME
(40) 0.degree. C., 2 hrs 50.degree. C., 1 hr 73% .sup.aThe
precipitate was washed on the filter with heptane (30 ml) before
drying.
Example 22
Preparation of Candesartan Cilexetil Form XIII
[0234] Candesartan cilexetil Form I (C) (2.5 g) was dissolved in
DCM (3.5 ml) at about 25.degree. C. to form a solution, and isoamyl
acetate (35 ml) was added dropwise. The solution was cooled in an
ice bath and stirred for about 3 hours to obtain a precipitate. The
precipitate was collected by filtration and dried under reduced
pressure (30 mbar) at 50.degree. C. for about 7.5 hours to obtain
Form XIII.
Example 23
Preparation of Candesartan Cilexetil Form XIV
[0235] Candesartan cilexetil Form I (C) (5 g) was dissolved in DCM
(6.6 ml) at 25.degree. C., and toluene (15 ml) was added dropwise.
The solution was cooled in an ice bath, and then toluene (3 ml) was
slowly added until a precipitate formed. The solution was cooled to
about -10.degree. C. for about 2 hours. The precipitate was
collected by filtration, washed on the filter with toluene (5 ml),
and dried on the filter for about 30 minutes to obtain Form
XIV.
Example 24
Preparation of Form I from Form XIV by Crystallization
[0236] Form XIV (43.75 g wet) was dissolved in absolute ethanol
(215-363 mL, 6-10 volumes) at 40-60.degree. C. The solution was
filtered and returned to the reactor, cooled to -15.degree. C. to
5.degree. C., and kept at this temperature for about 2-24 hours.
The precipitated solids were filtered off, washed with cold
absolute ethanol (23-35 mL) and dried at 50.degree. C./10 mbar to
constant weight to give Form I.
Example 25
Preparation of Form I from Form XIV by Re-Slurry
[0237] Form XIV (40 g on dry basis, L.O.D.<15%) was re-slurried
at 25.degree. C. in absolute ethanol (244 mL, 6 ml/g) for 1-20
hours. The solution was cooled to -10.degree. C. to 10.degree. C.,
and kept at this temperature for 1-72 hours. The precipitated
solids were filtered off, washed with cold absolute ethanol (80 mL)
and dried at 50.degree. C./10 mbar to constant weight to give Form
I.
Example 26
Preparation of Candesartan Cilexetil Form XV
[0238] Candesartan cilexetil Form I (C) (5 g) was dissolved in
chloroform (7.5 ml) at 25.degree. C. to form a solution, and
acetonitrile (55 ml) was added dropwise. The solution was cooled in
an ice bath until a precipitate started to form. The solution was
stirred for about 2 hours. The precipitate was collected by
filtration, washed on the filter with cold acetonitrile (5 ml), and
dried under reduced pressure (30 mbar) at 45.degree. C. for about 1
hour to obtained Form XV (3.7 g).
Example 27
Preparation of Candesartan Cilexetil Form XVI
[0239] Candesartan cilexetil Form VI (0.5 g) was placed in a glass
container and heated in a static oven at about 100.degree. C. for
about 13 hours to obtain candesartan cilexetil Form XVI.
Example 28
Preparation of Candesartan Cilexetil Form XVII
[0240] Candesartan cilexetil Form XIII (0.5 g) was placed in a
glass container and heated in a static oven at about 100.degree. C.
for about 13 hours to obtain candesartan cilexetil Form XVII. The
procedure was also performed with Form XV.
Example 29
Preparation of Candesartan Cilexetil Form XVIII
[0241] Candesartan cilexetil Form I (C) (5 g) was dissolved in THF
(8.9 g) and heated to about 60.degree. C. to 62.degree. C. to form
a solution. The solution was poured into cold water (50 g, about
5.degree. C.) to form a precipitate. The solution was cooled to
about 5.degree. C. to 7.degree. C. and stirred for about 1 hour.
The precipitate was collected by filtration and dried on the filter
for about 30 minutes to obtain Form XVIII.
Example 30
Preparation of Candesartan Cilexetil Form XIX
[0242] Candesartan cilexetil (5 g) was dissolved in acetonitrile
(86.5 g) and heated to about 60.degree. C. to 64.degree. C. to form
a solution. The solution was poured into cold water (250 g, about
0.degree. C. to 5.degree. C.) to form a precipitate. The solution
was stirred at 0.degree. C. to 5.degree. C. for about 1 hour. The
precipitate was collected by filtration and dried on the filter for
about 30 minutes to obtain wet Form XIX (5.83 g). A portion of the
wet Form XIX (3.16 g) was dried under reduced pressure (20 mbar) at
about 50.degree. C. to 52.degree. C. to a constant weight to obtain
Form XIX (2.63 g).
Example 31
Preparation of Candesartan Cilexetil Form XX
[0243] Candesartan cilexetil (5 g) was dissolved in chloroform (7.5
ml) at about 25.degree. C. to form a solution, and acetonitrile (55
ml) was added dropwise. The solution was cooled in an ice bath
until a precipitate started to form, and the solution was stirred
for about 2 hours. The precipitate was collected by filtration,
washed on the filter with cold acetonitrile (5 ml) to obtain Form
XX.
Example 32
Preparation of Candesartan Cilexetil Form XXI
[0244] Candesartan cilexetil (2 g) was dissolved in THF (5.2 g) at
about 20.degree. C. to 25.degree. C. to form a solution. The
solution was filtered and kept for about 3 weeks at about
20.degree. C. to 25.degree. C. to form a precipitate. The
precipitate was collected by filtration and dried on the filter for
about 30 minutes to obtain Form XXI (2.12 g).
Example 33
Preparation of Candesartan Cilexetil Form XXII
[0245] Crude candesartan (31 g) was dissolved at 50.degree. C. in
methanol (198 ml), the solution was filtered and returned to a
reactor, then the solution was cooled to a temperature of
-5.degree. C. to 5.degree. C. and kept at the temperature for about
16 h, the solids were collected by filtration, and washed with cold
methanol (18.6 ml) to give Form XXII which was dried at 50.degree.
C. at 10 mbar until the weight was constant to give (25.4 g, 81.1%)
Form XXII.
[0246] As used herein, "crude candesartan" refers to candesartan
containing traces of toluene, wherein toluene is present in an
amount one of skill in the art would recognize as an impurity.
Example 34
Preparation of Form I from Form XXII by Crystallization
[0247] Form XXII (25 g wet) was dissolved at 40-60.degree. C. in
absolute ethanol (90-280 mL, 5-10 volumes). The solution was
filtered and returned to the reactor, cooled to -15.degree. C. to
5.degree. C., and kept at this temperature for about 2-24 h. The
precipitated solids were filtered off, washed with cold absolute
ethanol (20-35 mL) to give a white solid which was dried at
50.degree. C./10 mbar to constant weight to give Form I.
Example 35
Preparation of Form I from Form XXII by Re-Slurry
[0248] Form XXIII (20 g on dry basis, L.O.D.<15%) was
re-slurried at 25.degree. C. in absolute ethanol (100 mL, 5 ml/g)
for 1-20 hours. The solution was cooled to -10.degree. C. to
10.degree. C. and kept at this temperature for 1-72 hours. The
precipitated solids were filtered off, washed with cold absolute
ethanol (20 mL) to give Form I.
Example 36
Preparation of Candesartan Cilexetil Form XXIII
[0249] A solution of trityl candesartan cilexetil (TCS, 350 g,
410.3 mmol), toluene (1050 ml), methanol (2100 ml), and water (17.5
ml) was refluxed for about 3 h (HPLC control). The solvents were
evaporated at 45.degree. C. at 90 mbar to give a residue as a
viscous oil, the residue was dissolved at 50.degree. C. in a
mixture of toluene/methanol (1041 g, 95:5 w/w) to give 1391 g of a
clear solution.
[0250] 230 g of the solution was cooled to 35.degree. C. to about
45.degree. C. and then seeded with CNS crystalline dry. The mixture
was cooled to a temperature of -5.degree. C. to 5.degree. C.; the
solution was kept at this temperature for about 1 h; the
precipitated solids were collected by filtration, washed with a
cold mixture of toluene and methanol (35 ml, 95:5 w/w) to give Form
XXIII which was dried at 50.degree. C. at 10 mbar until the weight
was constant to give a white solid (33.66 g, 89.1%) Form XXIII.
Example 37
Preparation of Form I from Form XXIII by Crystallization
[0251] Form XXIII (33 g wet) was dissolved at 40-60.degree. C. in
absolute ethanol (170-280 mL, 6-10 volumes). The solution was
filtered and returned to the reactor, cooled to -15.degree. C. to
5.degree. C., and kept at this temperature for about 2-24 h. The
precipitated solids were filtered off, washed with cold absolute
ethanol (23-35 mL), and dried at 50.degree. C./10 mbar to constant
weight to give Form I.
Example 38
Preparation of Form I from Form XXIII by Re-Slurry
[0252] Form XXIII (40 g on dry basis, L.O.D.<15%) was
re-slurried at 25.degree. C. in absolute ethanol (241 mL, 6 ml/g)
for 1-20 hours. The solution was cooled to -10.degree. C. to
10.degree. C. and kept at this temperature for 1-72 hours. The
precipitated solids were filtered off, washed with cold absolute
ethanol (40 mL), and dried at 50.degree. C./10 mbar to constant
weight to give Form I.
Example 39
Preparation of Candesartan Cilexetil Form XIV-1
[0253] A solution of trityl candesartan cilexetil (TCC, 30.0 g,
35.17 mmol), toluene (180 mL), methanol (180 mL), and water (1.6
mL) was refluxed for about 13 h (HPLC control), and the solvents
were evaporated at 60.degree. C./30 mbar to give a residue as a
viscous oil.
[0254] Part of the residue (10.4 g) was dissolved at 50.degree. C.
in a mixture of toluene/methanol (20.8 g, 9:1, w/w). the solution
was kept at 4-8.degree. C. for about 17 h, the precipitated solids
were filtered off, washed on the filter with a cold mixture of
toluene/methanol (5.0 g, 9:1, w/w), and dried at 50.degree. C./10
mbar to constant weight to give as a white solid (5.5 g, 78.6%)
Form XIV-I.
Example 40
Preparation of Candesartan Cilexetil Form XIV-1
[0255] A solution of trityl candesartan cilexetil (TCC, 30.0 g,
35.17 mmol), toluene (180 mL), methanol (180 mL) and formic acid
(1.6 g) was refluxed for about 10 h (HPLC control), the solvents
were evaporated at 60.degree. C./30 mbar to give a residue as a
viscous oil.
[0256] The residue was dissolved in a mixture of toluene/methanol
(73.0 g, 9:1 w/w) and kept at 4-8.degree. C. for about 22 h. The
precipitated solids were filtered off, washed on the filter with a
cold mixture of toluene/methanol (15.0 g, 9:1 w/w) and dried at
50.degree. C./10 mbar to the constant weight to give Form XIV-I as
a white solid (16.9 g, 78.6%).
Example 41
Preparation of Candesartan Cilexetil Form XIV-1
[0257] A solution of trityl candesartan cilexetil (TCC, 30.0 g,
35.17 mmol), toluene (180 mL), methanol (180 mL), formic acid (1.6
g) and water (0.63 g) was refluxed for about 10 h (HPLC control),
the solvents were evaporated at 60.degree. C./30 mbar to give a
residue as a viscous oil, (about 31 g, theoretical yield of
candesartan cilexetil is 21.47 g).
[0258] A part of the residue (10.8 g) was dissolved at 50.degree.
C. in a mixture of toluene/methanol (21.6 g, 8:2, w/w) and the
solution was kept at 4-8.degree. C. for about 17 h. The
precipitated solids were filtered off, washed on the filter with a
mixture of toluene/methanol (5.0 g, 8:2, w/w) and dried at
50.degree. C./10 mbar to the constant weight to give as a white
solid (4.7 g, 63.0%), 97.66% pure by HPLC, Form XIV-I.
[0259] A part of the residue (10.1 g) was dissolved at 50.degree.
C. in a mixture of toluene/methanol (20.2 g, 7.5:2.5 w/w), the
solution was kept at 4-8.degree. C. for about 17 h and after this
at -11.degree. C. to -13.degree. C. for about 6 h. The precipitated
solids were filtered off, washed on the filter with a mixture of
toluene/methanol (5.0 g, 7.5:2.5 w/w) and dried at 50.degree. C./10
mbar to the constant weight to give a white solid (4.8 g, 67.0%)
Form XIV-I.
Example 42
Preparation of Form I from Form XIV-1 by Crystallization
[0260] Form XIV-1 (35 g wet) was dissolved at 40-60.degree. C. in
absolute ethanol (170-280 mL, 6-10 volumes). The solution was
cooled to -15.degree. C. to 5.degree. C. and kept at this
temperature for about 2-24 h. The precipitated solids were filtered
off, washed with cold absolute ethanol (23-35 mL), and dried at
50.degree. C./10 mbar to constant weight to give Form I.
Example 43
Preparation of Form I from Form XIV-1 by Re-Slurry
[0261] Form XIV-1 (445 g on dry basis, L.O.D.<17%) was
re-slurried at 25.degree. C. in absolute ethanol (2670 mL, 6 ml/g)
for 1-20 hours. The solution was cooled to -10.degree. C. to
10.degree. C. and kept at this temperature for 1-72 hours. The
precipitated solids were filtered off, washed with cold absolute
ethanol (450 mL), and dried at 50.degree. C./10 mbar to the
constant weight to give Form I.
* * * * *