U.S. patent application number 14/196558 was filed with the patent office on 2014-07-03 for crystalline forms of bosentan salts and processes for their preparation.
This patent application is currently assigned to RANBAXY LABORATORIES LIMITED. The applicant listed for this patent is RANBAXY LABORATORIES LIMITED. Invention is credited to Gopal Singh BISHT, Mahavir Singh KHANNA, Anu MITTAL, Mohan PRASAD, Rakesh SINGH, Rajesh Kumar THAPER.
Application Number | 20140187568 14/196558 |
Document ID | / |
Family ID | 43646860 |
Filed Date | 2014-07-03 |
United States Patent
Application |
20140187568 |
Kind Code |
A1 |
SINGH; Rakesh ; et
al. |
July 3, 2014 |
CRYSTALLINE FORMS OF BOSENTAN SALTS AND PROCESSES FOR THEIR
PREPARATION
Abstract
The present invention relates to crystalline forms of bosentan
salts and processes for their preparation.
Inventors: |
SINGH; Rakesh; (Jaunpur,
IN) ; MITTAL; Anu; (Kurukshetra, IN) ; BISHT;
Gopal Singh; (New Delhi, IN) ; KHANNA; Mahavir
Singh; (New Delhi, IN) ; THAPER; Rajesh Kumar;
(Jammu, IN) ; PRASAD; Mohan; (Gurgaon,
IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
RANBAXY LABORATORIES LIMITED |
New Delhi |
|
IN |
|
|
Assignee: |
RANBAXY LABORATORIES
LIMITED
New Delhi
IN
|
Family ID: |
43646860 |
Appl. No.: |
14/196558 |
Filed: |
March 4, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13509125 |
Jul 25, 2012 |
8716477 |
|
|
PCT/IB2010/055153 |
Nov 12, 2010 |
|
|
|
14196558 |
|
|
|
|
Current U.S.
Class: |
514/269 ;
544/296 |
Current CPC
Class: |
C07D 239/69 20130101;
C07D 403/04 20130101 |
Class at
Publication: |
514/269 ;
544/296 |
International
Class: |
C07D 239/69 20060101
C07D239/69 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 12, 2009 |
IN |
2339/DEL/2009 |
Claims
1. Crystalline Form C of bosentan sodium having an XRPD pattern
comprising interplanar spacing (d) values substantially at 2.64,
2.82, 2.88, 2.97, 3.02, 3.16, 3.22, 3.36, 3.43, 3.48, 3.68, 3.79,
3.84, 3.90, 3.95, 4.01, 4.10, 4.11, 4.22, 4.34, 4.48, 4.58, 4.66,
4.74, 4.80, 4.87, 4.97, 5.24, 5.68, 5.79, 6.29, 6.72, 6.85, 7.36,
8.90, 9.73, 10.47, 10.86, 13.70, and 14.29 (.ANG.).
2. Crystalline Form C of bosentan sodium according to claim 1,
wherein the crystalline Form C of bosentan sodium is made by a
process comprising: a) treating bosentan sodium with an organic
solvent or treating bosentan with a sodium ion source in the
presence of an organic solvent or a mixture of organic solvents;
and b) isolating crystalline Form C of bosentan sodium from the
mixture thereof.
3. Crystalline Form C of bosentan sodium according to claim 2,
having a purity of about 98% or above.
4. Crystalline Form C of bosentan sodium according to claim 2,
having a purity of about 99% or above.
5. Crystalline Form C of bosentan sodium according to claim 2,
comprising a) treating bosentan sodium with an organic solvent; and
b) isolating crystalline Form C of bosentan sodium from the mixture
thereof.
6. Crystalline Form C of bosentan sodium according to claim 2,
comprising a) treating bosentan with a sodium ion source in the
presence of an organic solvent or a mixture of organic solvents;
and b) isolating crystalline Form C of bosentan sodium from the
mixture thereof.
7. A pharmaceutical composition comprising crystalline Form C of
bosentan sodium according to claim 1 and one or more carriers.
8. Crystalline Form C of bosentan sodium having an XRPD pattern
substantially as depicted in FIG. 7 or a DSC pattern substantially
as depicted in FIG. 9.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. application Ser.
No. 13/509,125, which is the national phase under 35 U.S.C. 371 of
International Application No. PCT/IB2010/055153, filed on Nov. 12,
2010, which claims the benefit of foreign priority under 35 U.S.C.
119 to Indian Publication No. 2339/DEL/2009, filed on Nov. 12,
2009.
FIELD OF THE INVENTION
[0002] The present invention relates to crystalline forms of
bosentan salts and processes for their preparation.
BACKGROUND OF THE INVENTION
[0003] Bosentan is an endothelin receptor antagonist, belonging to
a class of highly substituted pyrimidine derivatives. Bosentan is
marketed in its monohydrate form, chemically known as
4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']-bipyrim-
idin-4-yl]-benzenesulfonamide monohydrate, which is represented by
Formula 1.
##STR00001##
[0004] Bosentan is useful for the treatment of pulmonary arterial
hypertension (PAH) to improve exercise capacity and symptoms in
patients with Grade III functional status.
[0005] U.S. Pat. No. 5,292,740 describes a purification method for
bosentan with column chromatography using toluene and ethyl acetate
mixture, and U.S. Pat. No. 6,136,971 describes a purification
method for bosentan involving drop-wise addition of water to the
refluxing ethanolic solution of bosentan. However, these patents do
not refer to any polymorphic form of bosentan.
[0006] WO 2008/135795 describes crystalline Form 1, Form 2, Form 3,
and Form 4, and an amorphous form of bosentan characterized by
their XRPD, DSC, and TGA patterns. WO 2009/047637 describes
crystalline Form A1, Form A2, and Form A4, and an amorphous form of
bosentan characterized by their XRPD, IR, and DSC patterns, and
processes for their preparation. WO 2009/093127 describes
crystalline Form A5 of bosentan.
[0007] WO 2009/083739 describes anhydrous crystalline Forms B and C
of bosentan and amorphous Form A of bosentan characterized by their
XRPD, IR, and DSC patterns. It also describes calcium and barium
salts of bosentan along with processes for their preparation.
SUMMARY OF THE INVENTION
[0008] In one general aspect, the present invention provides for
crystalline Form A of bosentan potassium having an XRPD pattern
which includes interplanar spacing (d) values substantially at
3.31, 3.70, 3.73, 3.82, 4.00, 4.26, 4.44, 4.55, 4.74, 4.84, 4.96,
5.29, 5.49, 8.74, 13.78, 14.76, 15.97, 19.89, and 21.54
(.ANG.).
[0009] Embodiments of this aspect may include one or more of the
following features. For example, crystalline Form A of bosentan
potassium may have an XRPD pattern substantially as depicted in
FIG. 1 or a DSC pattern substantially as depicted in FIG. 3.
[0010] In another general aspect, the present invention provides a
process for preparing crystalline Form A of bosentan potassium. The
process includes: [0011] a) treating bosentan with a potassium ion
source in the presence of an organic solvent or a mixture of
organic solvents; and [0012] b) isolating crystalline Form A of
bosentan potassium from the mixture thereof.
[0013] In another general aspect, the present invention provides a
process for preparing crystalline Form A of bosentan potassium. The
process includes: [0014] a) treating bosentan potassium with a
first organic solvent; [0015] b) treating the mixture obtained in
step a) with a second organic solvent; and [0016] c) isolating
crystalline Form A of bosentan potassium from the mixture
thereof.
[0017] In another general aspect, the present invention provides
for crystalline Form B of bosentan potassium having an XRPD pattern
which includes interplanar spacing (d) values substantially at
3.02, 3.11, 3.25, 3.33, 3.40, 3.44, 3.63, 3.79, 3.98, 4.04, 4.44,
4.53, 4.57, 4.73, 4.82, 5.05, 5.16, 6.03, 8.29, 10.08, and 13.29
(.ANG.).
[0018] Embodiments of this aspect may include one or more of the
following features. For example, the crystalline Form B of bosentan
potassium may have an XRPD pattern substantially as depicted in
FIG. 4 or a DSC pattern substantially as depicted in FIG. 6.
[0019] In another general aspect, the present invention provides a
process for preparing crystalline Form B of bosentan potassium. The
process includes: [0020] a) treating bosentan with a potassium ion
source in the presence of water; and [0021] b) isolating
crystalline Form B of bosentan potassium from the mixture
thereof.
[0022] In another general aspect, the present invention provides a
process for preparing crystalline Form B of bosentan potassium. The
process includes: [0023] a) treating bosentan potassium with water;
and [0024] b) isolating crystalline Form B of bosentan potassium
from the mixture thereof.
[0025] In yet another general aspect, the present invention
provides for crystalline Form C of bosentan sodium having an XRPD
pattern which includes interplanar spacing (d) values substantially
at 2.64, 2.82, 2.88, 2.97, 3.02, 3.16, 3.22, 3.36, 3.43, 3.48,
3.68, 3.79, 3.84, 3.90, 3.95, 4.01, 4.10, 4.11, 4.22, 4.34, 4.48,
4.58, 4.66, 4.74, 4.80, 4.87, 4.97, 5.24, 5.68, 5.79, 6.29, 6.72,
6.85, 7.36, 8.90, 9.73, 10.47, 10.86, 13.70, and 14.29 (.ANG.).
[0026] Embodiments of this aspect may include one or more of the
following features. For example, the crystalline Form C of bosentan
sodium may have an XRPD pattern substantially as depicted in FIG. 7
or a DSC pattern substantially as depicted in FIG. 9.
[0027] In another general aspect, the present invention provides a
process for preparing crystalline Form C of bosentan sodium. The
process includes: [0028] a) treating bosentan with a sodium ion
source in the presence of an organic solvent or a mixture of
organic solvents; and [0029] b) isolating crystalline Form C of
bosentan sodium from the mixture thereof.
[0030] In another general aspect, the present invention provides a
process for preparing crystalline Form C of bosentan sodium. The
process includes: [0031] a) treating bosentan sodium with an
organic solvent; and [0032] b) isolating crystalline Form C of
bosentan sodium from the mixture thereof.
[0033] In another general aspect, the present invention provides
for crystalline Form D of bosentan sodium having an XRPD pattern
which includes interplanar spacing (d) values substantially at
2.58, 2.65, 2.81, 2.99, 3.19, 3.29, 3.34, 3.38, 3.45, 3.58, 3.72,
3.82, 3.89, 3.95, 4.04, 4.08, 4.22, 4.39, 4.45, 4.54, 4.72, 4.77,
5.17, 5.27, 5.48, 5.86, 5.95, 7.30, 9.34, 10.05, 10.94, and 21.77
(.ANG.).
[0034] Embodiments of this aspect may include one or more of the
following features. For example, the crystalline Form D of bosentan
sodium may have an XRPD pattern substantially as depicted in FIG.
10 or a DSC pattern substantially as depicted in FIG. 12.
[0035] In another general aspect, the present invention provides a
process for preparing crystalline Form D of bosentan sodium. The
process includes: [0036] a) treating bosentan with a sodium ion
source in the presence of water; and [0037] b) isolating
crystalline Form D of bosentan sodium from the mixture thereof.
[0038] In another general aspect, the present invention provides a
process for preparing crystalline Form D of bosentan sodium. The
process includes: [0039] a) treating bosentan sodium with water;
and [0040] b) isolating crystalline Form D of bosentan sodium from
the mixture thereof.
[0041] In another general aspect, the present invention provides
for crystalline Form E of bosentan ammonium having an XRPD pattern
which includes interplanar spacing (d) values substantially at
3.45, 3.58, 3.68, 4.08, 4.19, 4.55, 4.59, 4.72, 4.96, 5.24, 5.76,
7.23, and 13.69 (.ANG.).
[0042] Embodiments of this aspect may include one or more of the
following features. For example, the crystalline Form E of bosentan
ammonium may have an XRPD pattern substantially as depicted in FIG.
13 or a DSC pattern as depicted in FIG. 15.
[0043] In another general aspect, the present invention provides a
process for preparing crystalline Form E of bosentan ammonium. The
process includes: [0044] a) treating bosentan with ammonia in the
presence of an organic solvent or a mixture of organic solvents;
and [0045] b) isolating crystalline Form E of bosentan ammonium
from the mixture thereof.
[0046] In another general aspect, the present invention provides
for crystalline Form F of bosentan ammonium having an XRPD pattern
which includes interplanar spacing (d) values substantially at
2.51, 2.61, 2.71, 2.87, 2.91, 3.08, 3.19, 3.26, 3.35, 3.39, 3.46,
3.58, 3.65, 3.76, 3.91, 3.94, 4.13, 4.17, 4.31, 4.38, 4.56, 4.66,
4.74, 4.78, 5.00, 5.32, 5.51, 5.72, 5.82, 6.72, 7.82, 9.57, and
10.63 (.ANG.).
[0047] Embodiments of this aspect may include one or more of the
following features. For example, the crystalline Form F of bosentan
ammonium may have an XRPD pattern substantially as depicted in FIG.
16 or a DSC pattern as depicted in FIG. 18.
[0048] In another general aspect, the present invention provides a
process for preparing crystalline Form F of bosentan ammonium. The
process includes: [0049] a) treating bosentan ammonium with water;
and [0050] b) isolating crystalline Form F of bosentan
ammonium.
[0051] In another general aspect, the present invention provides a
process for the preparation of an alkali metal or ammonium salt of
bosentan. The process includes: [0052] a) treating bosentan with an
alkali metal ion source or ammonia in the presence of an organic
solvent, water, or a mixture thereof and [0053] b) isolating the
alkali metal or ammonium salt of bosentan from the mixture
thereof.
[0054] In yet another general aspect, the present invention
provides for an alkali metal salt or ammonium salt of bosentan
having a purity of about 98% or above.
[0055] In a final general aspect, the present invention provides
for an alkali metal salt or ammonium salt of bosentan having a
purity of about 99% or above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0056] FIG. 1 depicts X-Ray Powder Diffraction (XRPD) pattern of
Form A of bosentan potassium.
[0057] FIG. 1A provides the table of values for the XRPD of FIG.
1.
[0058] FIG. 2 depicts Thermal Gravimetric Analysis (TGA) of Form A
of bosentan potassium.
[0059] FIG. 3 depicts Differential Scanning calorimetry (DSC)
pattern of Form A of bosentan potassium.
[0060] FIG. 4 depicts the XRPD pattern of Form B of bosentan
potassium.
[0061] FIG. 4A provides the table of values for the XRPD of FIG.
4.
[0062] FIG. 5 depicts the TGA of Form B of bosentan potassium.
[0063] FIG. 6 depicts the DSC pattern of Form B of bosentan
potassium.
[0064] FIG. 7 depicts the XRPD pattern of Form C of bosentan
sodium.
[0065] FIG. 7A provides the table of values for the XRPD of FIG.
7.
[0066] FIG. 8 depicts the TGA of Form C of bosentan sodium.
[0067] FIG. 9 depicts the DSC pattern of Form C of bosentan
sodium.
[0068] FIG. 10 depicts the XRPD pattern of Form D of bosentan
sodium.
[0069] FIG. 10A provides the table of values for the XRPD of FIG.
10.
[0070] FIG. 11 depicts the TGA of Form D of bosentan sodium.
[0071] FIG. 12 depicts the DSC pattern of Form D of bosentan
sodium.
[0072] FIG. 13 depicts the XRPD pattern of Form E of bosentan
ammonium.
[0073] FIG. 13A provides the table of values for the XRPD of FIG.
13.
[0074] FIG. 14 depicts the TGA of Form E of bosentan ammonium.
[0075] FIG. 15 depicts the DSC pattern of Form E of bosentan
ammonium.
[0076] FIG. 16 depicts the XRPD pattern of Form F of bosentan
ammonium.
[0077] FIG. 16A provides the table of values for the XRPD of FIG.
16.
[0078] FIG. 17 depicts the TGA of Form F of bosentan ammonium.
[0079] FIG. 18 depicts the DSC pattern of Form F of bosentan
ammonium.
DETAILED DESCRIPTION OF THE INVENTION
[0080] The present invention provides for crystalline Form A of
bosentan potassium. Crystalline Form A of bosentan potassium has
substantially the same XRPD pattern as depicted in FIG. 1. The XRPD
of crystalline Form A of bosentan potassium shows characteristic
interplanar spacing (d) values substantially at 3.31, 3.70, 3.73,
3.82, 4.00, 4.26, 4.44, 4.55, 4.74, 4.84, 4.96, 5.29, 5.49, 8.74,
13.78, 14.76, 15.97, 19.89, and 21.54 (.ANG.). The XRPD of
crystalline Form A of bosentan potassium shows characteristic
2.theta. values substantially at 26.97, 24.02, 23.83, 23.26, 22.20,
20.85, 20.01, 19.49, 18.72, 18.33, 17.87, 16.74, 16.12, 10.12,
6.42, 5.99, 5.53, 4.44, and 4.10.+-.0.2 .theta.. The TGA of
crystalline Form A of bosentan potassium has substantially the same
pattern as depicted in FIG. 2 and the DSC has substantially the
same pattern as depicted in FIG. 3. The DSC exhibits one melting
endotherm between about 160.degree. C. and about 170.degree. C.
[0081] The present invention also provides a process for preparing
crystalline Form A of bosentan potassium, wherein the process
includes: [0082] a) treating bosentan with a potassium ion source
in the presence of an organic solvent or a mixture of organic
solvents; and [0083] b) isolating crystalline Form A of bosentan
potassium from the mixture thereof.
[0084] The bosentan used as the starting material may be prepared
according to the methods provided in U.S. Pat. Nos. 6,136,971 and
5,292,740. The starting bosentan may be in the form of a
monohydrate. The bosentan is treated with a potassium ion source in
the presence of an organic solvent or a mixture of organic
solvents. The organic solvent is selected from the group consisting
of halogenated solvents, for example, chloroform, carbon
tetrachloride, dichloromethane, or ethylene dichloride; alcoholic
solvents, for example, methanol, ethanol, n-propanol, n-butanol,
isopropyl alcohol, n-pentanol, n-hexanol, or n-octanol; ester
solvents, for example, ethyl acetate, methyl acetate, propyl
acetate, or butyl acetate; cyclic ethers, for example,
tetrahydrofuran or dioxane; aromatic hydrocarbons, for example,
toluene or xylene; and aliphatic hydrocarbons, for example,
n-hexane, pentane, n-heptane, or n-octane.
[0085] The potassium ion source may be, for example, potassium
hydroxide, potassium alkoxide, or potassium carbonate. The
potassium ion source may be employed in solid or solution form, for
example, an alcoholic solution. The mixture may be heated to about
40.degree. C. to about 60.degree. C. and cooled to about 25.degree.
C. or below. The mixture may be stirred for about 0.5 hours to
about 25 hours, for example, for about 1 hour to about 4 hours.
Crystalline Form A of bosentan potassium is isolated from the
mixture by conventional methods, for example, filtration,
distillation, decantation, centrifugation, or a combination
thereof, and optionally washed and dried.
[0086] The present invention also provides a process for preparing
crystalline Form A of bosentan potassium, wherein the process
includes: [0087] a) treating bosentan potassium with a first
organic solvent; [0088] b) treating the mixture obtained in step a)
with a second organic solvent; and [0089] c) isolating crystalline
Form A of bosentan potassium from the mixture thereof.
[0090] The bosentan potassium used as the starting material may be
in any solid form. The bosentan potassium used as the starting
material may be prepared by treating bosentan with a potassium ion
source. The bosentan potassium is treated with a first organic
solvent. The first organic solvent is a halogenated solvent, for
example, chloroform, carbon tetrachloride, dichloromethane, or
ethylene dichloride; or an alcoholic solvent, for example,
methanol, ethanol, n-propanol, n-butanol, isopropyl alcohol,
n-pentanol, n-hexanol, or n-octanol; or a mixture thereof. The
mixture of bosentan potassium with the first organic solvent may be
heated to about 40.degree. C. to about 60.degree. C. and the
solvent may be partially recovered. The mixture is then treated
with a second organic solvent. The second organic solvent is an
ester, for example, ethyl acetate, methyl acetate, propyl acetate,
or butyl acetate. The mixture so obtained may be cooled to about
25.degree. C. and stirred for about 1 hour to about 50 hours.
Crystalline Form A of bosentan potassium solid is isolated by
conventional methods, for example, decantation, filtration,
distillation, centrifugation, or a combination thereof, and
optionally washed and dried.
[0091] The present invention also provides for crystalline Form B
of bosentan potassium. Crystalline Form B of bosentan potassium has
substantially the same XRPD pattern as depicted in FIG. 4. The XRPD
of crystalline Form B of bosentan potassium shows characteristic
interplanar spacing (d) values substantially at 3.02, 3.11, 3.25,
3.33, 3.40, 3.44, 3.63, 3.79, 3.98, 4.04, 4.44, 4.53, 4.57, 4.73,
4.82, 5.05, 5.16, 6.03, 8.29, 10.08, and 13.29 (.ANG.). The XRPD of
crystalline Form B of bosentan potassium shows characteristic
2.theta. values substantially at 29.60, 28.72, 27.43, 26.73, 26.19,
25.88, 24.53, 23.46, 22.32, 21.99, 19.98, 19.60, 19.40, 18.76,
18.39, 17.56, 17.19, 14.69, 10.66, 8.77, and 6.65.+-.0.2 .theta..
The TGA of crystalline Form B of bosentan potassium has
substantially the same pattern as depicted in FIG. 5 and the DSC
has substantially the same pattern as depicted in FIG. 6. The DSC
exhibits two melting endotherms, between about 102.degree. C. and
about 112.degree. C. and between about 285.degree. C. and about
290.degree. C.
[0092] The present invention also provides a process for preparing
crystalline Form B of bosentan potassium, wherein the process
includes: [0093] a) treating bosentan with a potassium ion source
in the presence of water; and [0094] b) isolating the crystalline
Form B of bosentan potassium from the mixture thereof.
[0095] The bosentan used as the starting material may be prepared
according to the methods provided in U.S. Pat. Nos. 6,136,971 and
5,292,740. The starting bosentan may be in the form of a
monohydrate. The bosentan is treated with a potassium ion source in
the presence of water. The mixture may be heated to about
40.degree. C. to about 80.degree. C. and cooled to about 25.degree.
C. or below. The potassium ion source may be, for example,
potassium hydroxide or potassium carbonate. The potassium ion
source may be employed in solid or solution form, for example, an
aqueous solution. The mixture may be stirred for about 0.5 hours to
about 25 hours, for example, for about 1 hour to about 4 hours.
Crystalline Form B of bosentan potassium is isolated from the
mixture by conventional methods, for example, filtration,
distillation, decantation, centrifugation, or a combination
thereof, and optionally washed and dried.
[0096] The present invention also provides a process for preparing
crystalline Form B of bosentan potassium, wherein the process
includes: [0097] a) treating bosentan potassium with water; and
[0098] b) isolating crystalline Form B of bosentan potassium from
the mixture thereof.
[0099] The bosentan potassium used as the starting material may be
in any solid form. The bosentan potassium used as the starting
material may be prepared by treating bosentan with a potassium ion
source. The bosentan potassium is treated with water. The mixture
containing bosentan potassium and water may be heated to about
60.degree. C. to about 70.degree. C. The mixture may be cooled to
about 25.degree. C. or below and stirred for a period of about 0.5
hours to about 50 hours. Crystalline Form B of bosentan potassium
may be isolated by conventional methods, for example, decantation,
filtration, distillation, centrifugation, or a combination thereof,
and optionally washed and dried.
[0100] The present invention also provides for crystalline Form C
of bosentan sodium. Crystalline Form C of bosentan sodium has
substantially the same XRPD pattern as depicted in FIG. 7. The XRPD
of crystalline Form C of bosentan sodium shows characteristic
interplanar spacing (d) values substantially at 2.64, 2.82, 2.88,
2.97, 3.02, 3.16, 3.22, 3.36, 3.43, 3.48, 3.68, 3.79, 3.84, 3.90,
3.95, 4.01, 4.10, 4.11, 4.22, 4.34, 4.48, 4.58, 4.66, 4.74, 4.80,
4.87, 4.97, 5.24, 5.68, 5.79, 6.29, 6.72, 6.85, 7.36, 8.90, 9.73,
10.47, 10.86, 13.70, and 14.29 (.ANG.). The XRPD of crystalline
Form C of bosentan sodium shows characteristic 2.theta. values
substantially at 33.97, 31.68, 31.01, 30.07, 29.58, 28.19, 27.71,
26.49, 25.92, 25.55, 24.16, 23.44, 23.12, 22.76, 22.47, 22.13,
21.69, 21.59, 21.04, 20.48, 19.82, 19.38, 19.06, 18.17, 18.47,
18.21, 17.84, 16.92, 15.59, 15.31, 14.07, 13.17, 12.92, 12.02,
9.94, 9.09, 8.45, 8.14, 6.45, and 6.18.+-.0.2 .theta.. The TGA of
crystalline Form C of bosentan sodium has substantially the same
pattern as depicted in FIG. 8 and the DSC has substantially the
same pattern as depicted in FIG. 9. The DSC exhibits two melting
endotherms, between about 100.degree. C. and about 115.degree. C.
and between about 180.degree. C. and about 210.degree. C.
[0101] The present invention also provides a process for preparing
crystalline Form C of bosentan sodium, wherein the process
includes: [0102] a) treating bosentan with a sodium ion source in
the presence of an organic solvent or a mixture of organic
solvents; and [0103] b) isolating crystalline Form C of bosentan
sodium from the mixture thereof.
[0104] The bosentan used as the starting material may be prepared
according to the methods provided in U.S. Pat. Nos. 6,136,971 and
5,292,740. The starting bosentan may be in the form of a
monohydrate. The bosentan is treated with a sodium ion source in
the presence of an organic solvent or a mixture of organic
solvents. The organic solvent is selected from the group consisting
of halogenated solvents, for example, chloroform, carbon
tetrachloride, dichloromethane, or ethylene dichloride; alcoholic
solvents, for example, methanol, ethanol, n-propanol, n-butanol,
isopropyl alcohol, n-pentanol, n-hexanol, or n-octanol; ester
solvents, for example, ethyl acetate, methyl acetate, propyl
acetate, or butyl acetate; cyclic ethers, for example,
tetrahydrofuran or dioxane; aromatic hydrocarbons, for example,
toluene or xylene; and aliphatic hydrocarbons, for example,
n-hexane, pentane, n-heptane, or n-octane. The sodium ion source
may be, for example, sodium hydroxide, sodium alkoxide, or sodium
carbonate. The sodium ion source may be employed in solid or
solution form, for example, an alcoholic solution. The mixture is
optionally heated to about 40.degree. C. to about 60.degree. C. and
cooled to about 25.degree. C. or below. The mixture may be stirred
for about 0.5 hours to about 25 hours, for example, for about 1
hour to about 10 hours. Crystalline Form C of bosentan sodium is
isolated from the mixture by conventional methods, for example,
filtration, distillation, decantation, centrifugation, or a
combination thereof, and optionally washed and dried.
[0105] The present invention also provides a process for preparing
crystalline Form C of bosentan sodium, wherein the process
includes: [0106] a) treating bosentan sodium with an organic
solvent or a mixture of organic solvents; and [0107] b) isolating
crystalline Form C of bosentan sodium from the mixture thereof.
[0108] The bosentan sodium used as the starting material may be in
any solid form. The bosentan sodium used as the starting material
may be prepared by treating bosentan with a sodium ion source. The
bosentan sodium is treated with an organic solvent or a mixture of
organic solvents. The organic solvent is selected from the group
consisting of halogenated solvents, for example, chloroform, carbon
tetrachloride, dichloromethane, or ethylene dichloride; alcoholic
solvents, for example, methanol, ethanol, n-propanol, n-butanol,
isopropyl alcohol, n-pentanol, n-hexanol, or n-octanol; ester
solvents, for example, ethyl acetate, methyl acetate, propyl
acetate, or butyl acetate; cyclic ethers, for example,
tetrahydrofuran or dioxane; aromatic hydrocarbons, for example,
toluene or xylene; and aliphatic hydrocarbons, for example,
n-hexane, pentane, n-heptane, or n-octane. The mixture may be
optionally heated from to about 40.degree. C. to about 60.degree.
C. and the solvent may be partially recovered. The mixture may be
optionally further treated with an ester solvent, for example,
ethyl acetate, methyl acetate, propyl acetate, or butyl acetate.
The mixture may be optionally cooled to about 25.degree. C. or
below and stirred for a period of from about 1 hour to about 50
hours. Crystalline Form C of bosentan sodium is isolated by
conventional means, for example decantation, filtration,
distillation, centrifugation, or a combination thereof, and
optionally washed and dried.
[0109] The present invention also provides for crystalline Form D
of bosentan sodium. Crystalline Form D of bosentan sodium has
substantially the same XRPD pattern as depicted in FIG. 10. The
XRPD of crystalline Form D of bosentan sodium shows the
characteristic interplanar spacing (d) values substantially at
2.58, 2.65, 2.81, 2.99, 3.19, 3.29, 3.34, 3.38, 3.45, 3.58, 3.72,
3.82, 3.89, 3.95, 4.04, 4.08, 4.22, 4.39, 4.45, 4.54, 4.72, 4.77,
5.17, 5.27, 5.48, 5.86, 5.95, 7.30, 9.34, 10.05, 10.94, and 21.77
(.ANG.). The XRPD of Form D of bosentan sodium shows the
characteristic 2.theta. values substantially at 34.81, 33.83,
31.81, 29.79, 28.01, 27.12, 26.66, 26.36, 25.86, 24.90, 23.92,
23.30, 22.86, 22.51, 22.03, 21.79, 21.07, 20.24, 19.94, 19.55,
18.81, 18.59, 17.16, 16.82, 16.18, 15.11, 14.89, 12.12, 9.47, 8.80,
8.09, or 4.06.+-.0.2 .theta.. The TGA of crystalline Form D of
bosentan sodium has substantially the same pattern as depicted in
FIG. 11 and the DSC has substantially the same pattern as depicted
in FIG. 12. The DSC exhibits two melting endotherms, between about
75.degree. C. and about 95.degree. C. and between about 200.degree.
C. and about 220.degree. C.
[0110] The present invention also provides a process of preparing
crystalline Form D of bosentan sodium, wherein the process
includes: [0111] a) treating bosentan with a sodium ion source in
the presence of water; and [0112] b) isolating crystalline Form D
of bosentan sodium from the mixture thereof.
[0113] The bosentan used as the starting material may be prepared
according to the methods provided in U.S. Pat. Nos. 6,136,971 and
5,292,740. The starting bosentan may be in the form of a
monohydrate. The bosentan is treated with a sodium ion source in
the presence of water. The sodium ion source may be, for example,
sodium hydroxide or sodium carbonate. The sodium ion source may be
employed in solid or solution form, for example, an aqueous
solution. The mixture may be heated to about 40.degree. C. to about
80.degree. C. and cooled to about 25.degree. C. or below. The
mixture may be stirred for about 0.5 hours to about 50 hours, for
example, for about 1 hour to about 4 hours. Crystalline Form D of
bosentan sodium is isolated from the mixture by conventional
methods, for example, filtration, distillation, decantation,
centrifugation, or a combination thereof, and optionally washed and
dried.
[0114] The present invention provides a process for preparing
crystalline Form D of bosentan sodium, wherein the process
comprises: [0115] a) treating bosentan sodium with water; and
[0116] b) isolating crystalline Form D of bosentan sodium from the
mixture thereof.
[0117] The bosentan sodium used as the starting material may be in
any solid form. The bosentan sodium used as the starting material
may be prepared by treating bosentan with a sodium ion source. The
bosentan sodium is treated with water. The mixture containing
bosentan sodium and water may be heated to about 50.degree. C. to
about 70.degree. C. and cooled to about 25.degree. C. or below. The
mixture may be stirred for a period of about 0.5 hours to about 50
hours. Crystalline Form D of bosentan sodium may be isolated by
conventional methods, for example, decantation, filtration,
distillation, centrifugation, or a combination thereof, and
optionally washed and dried.
[0118] The present invention also provides for crystalline Form E
of bosentan ammonium. Crystalline Form E of bosentan ammonium has
substantially the same XRPD pattern as depicted in FIG. 13. The
XRPD of crystalline Form E of bosentan ammonium shows
characteristic interplanar spacing (d) values substantially at
3.45, 3.58, 3.68, 4.08, 4.19, 4.55, 4.59, 4.72, 4.96, 5.24, 5.76,
7.23, and 13.69 (.ANG.). The XRPD of Form E of bosentan ammonium
shows characteristic 2.theta. values substantially at 25.83, 24.84,
24.19, 21.77, 21.16, 19.50, 19.31, 18.78, 17.89, 16.91, 15.39,
12.25, and 6.45.+-.0.2 .theta.. The TGA of crystalline Form E of
bosentan ammonium has substantially the same pattern as depicted in
FIG. 14 and the DSC has substantially the same pattern as depicted
in FIG. 15. The DSC exhibits two melting endotherms, between about
100.degree. C. and about 120.degree. C. and between about
140.degree. C. and about 165.degree. C.
[0119] The present invention provides a process of preparing
crystalline Form E of bosentan ammonium, wherein the process
includes: [0120] a) treating bosentan with ammonia in the presence
of an organic solvent or a mixture of organic solvents; and [0121]
b) isolating crystalline Form E of bosentan ammonium from the
mixture thereof.
[0122] The bosentan used as the starting material may be prepared
according to the methods provided in U.S. Pat. Nos. 6,136,971 and
5,292,740. The starting bosentan may be in the form of a
monohydrate. The bosentan is treated with ammonia in the presence
of an organic solvent or a mixture of organic solvents. The organic
solvent is selected from the group consisting of halogenated
solvents, for example, chloroform, carbon tetrachloride,
dichloromethane, or ethylene dichloride; alcoholic solvents, for
example, methanol, ethanol, n-propanol, n-butanol, isopropyl
alcohol, n-pentanol, n-hexanol, or n-octanol; ester solvents, for
example, ethyl acetate, methyl acetate, propyl acetate, or butyl
acetate; cyclic ethers, for example, tetrahydrofuran or dioxane;
aromatic hydrocarbons, for example, toluene or xylene; and
aliphatic hydrocarbons, for example, n-hexane, pentane, n-heptane
or n-octane. The ammonia may be employed in gaseous form. The
mixture may be partially or completely concentrated and treated
further with an organic solvent or a mixture of organic solvents.
The mixture may be stirred for about 0.5 hours to about 25 hours,
for example, for about 1 hour to about 5 hours. Crystalline Form E
of bosentan ammonium is isolated from the mixture by conventional
methods, for example, filtration, distillation, decantation,
centrifugation, or a combination thereof, and optionally washed and
dried.
[0123] The present invention also provides for crystalline Form F
of bosentan ammonium. Crystalline Form F of bosentan ammonium has
substantially the same XRPD pattern as depicted in FIG. 16. The
XRPD of crystalline Form F of bosentan ammonium shows
characteristic interplanar spacing (d) values substantially at
2.51, 2.61, 2.71, 2.87, 2.91, 3.08, 3.19, 3.26, 3.35, 3.39, 3.46,
3.58, 3.65, 3.76, 3.91, 3.94, 4.13, 4.17, 4.31, 4.38, 4.56, 4.66,
4.74, 4.78, 5.00, 5.32, 5.51, 5.72, 5.82, 6.72, 7.82, 9.57, and
10.63 (.ANG.). The XRPD of crystalline Form F of bosentan ammonium
shows characteristic 2.theta. values substantially at 35.84, 33.07,
31.21, 30.73, 29.01, 27.96, 27.39, 26.63, 26.31, 25.75, 24.85,
24.37, 23.69, 22.73, 22.59, 21.53, 21.30, 20.59, 20.27, 19.46,
19.06, 18.71, 18.57, 17.73, 16.68, 16.09, 15.49, 15.23, 13.18,
11.31, 9.24, and 8.32.+-.0.2 .theta.. The TGA of crystalline Form F
of bosentan ammonium has substantially the same pattern as depicted
in FIG. 17 and the DSC has substantially the same pattern as
depicted in FIG. 18. The DSC exhibits a melting endotherm between
about 160.degree. C. and about 170.degree. C.
[0124] The present invention also provides a process of preparing
crystalline Form F of bosentan ammonium, wherein the process
includes: [0125] a) treating bosentan ammonium with water; and
[0126] b) isolating crystalline Form F of bosentan ammonium from
the mixture thereof.
[0127] The bosentan ammonium used as the starting material may be
in any solid form. The bosentan ammonium used as the starting
material may be prepared by treating bosentan with ammonia. The
bosentan ammonium is treated with water. The mixture containing
bosentan potassium and water may be heated to about 60.degree. C.
to about 80.degree. C. The mixture may be stirred for a period of
about 0.5 hours to about 50 hours. Crystalline Form F of bosentan
ammonium may be isolated by conventional methods, for example,
decantation, filtration, distillation, centrifugation, or a
combination thereof, and optionally washed and dried.
[0128] The present invention also provides a process of the
preparation of an alkali metal or ammonium salt of bosentan,
wherein the process includes: [0129] a) treating bosentan with an
alkali metal ion source or ammonia in the presence of an organic
solvent, water, or a mixture thereof; and [0130] b) isolating an
alkali metal or ammonium salt of bosentan from the mixture
thereof.
[0131] The bosentan used as the starting material may be prepared
according to the methods provided in for example U.S. Pat. Nos.
6,136,971 and 5,292,740. The bosentan may be in the form of a
monohydrate. The bosentan is treated with an alkali metal ion
source or ammonia in the presence of an organic solvent, water, or
a mixture thereof. The organic solvent is selected from the group
consisting of halogenated solvents, for example, chloroform, carbon
tetrachloride, dichloromethane, or ethylene dichloride; alcoholic
solvents, for example, methanol, ethanol, n-propanol, n-butanol,
isopropyl alcohol, n-pentanol, n-hexanol, or n-octanol; ester
solvents, for example, ethyl acetate, methyl acetate, propyl
acetate, or butyl acetate; cyclic ethers, for example,
tetrahydrofuran or dioxane; aromatic hydrocarbons, for example,
toluene or xylene; and aliphatic hydrocarbons, for example,
n-hexane, pentane, n-heptane, or n-octane.
[0132] The alkali metal ion source is selected from the group
comprising of alkali metal hydroxides, for example, sodium
hydroxide, potassium hydroxide, or lithium hydroxide; alkali metal
alkoxides, for example, lithium methoxide, potassium methoxide,
sodium methoxide, sodium ethoxide, or potassium ethoxide; and
alkali metal carbonates, for example, sodium carbonate or potassium
carbonate. The alkali metal ion source may be employed in solid
form or in solution form.
[0133] The ammonia may be employed in gaseous form or in solution
form. The mixture may be heated from about 40.degree. C. to about
reflux temperature of the solvent. The solvent may be partially or
completely recovered. The solvent recovery may be followed by the
further addition of the organic solvent or water. The reaction
mixture may be cooled 25.degree. C. or below. The reaction mixture
may be stirred for a period of about 1 hour to about 50 hours. The
alkali metal or ammonium salt of bosentan obtained is isolated by
conventional methods, for example decantation, filtration,
distillation, centrifugation, or a combination thereof.
[0134] The alkali metal or ammonium salt of bosentan so obtained
may be further purified by treating with an organic solvent, or a
mixture of organic solvents, or water. The organic solvent is
selected from the group consisting of halogenated solvents, for
example, chloroform, carbon tetrachloride, dichloromethane, or
ethylene dichloride; alcoholic solvents, for example, methanol,
ethanol, n-propanol, n-butanol, isopropyl alcohol, n-pentanol,
n-hexanol, or n-octanol; ester solvents, for example, ethyl
acetate, methyl acetate, propyl acetate, or butyl acetate; cyclic
ethers, for example, tetrahydrofuran or dioxane; aromatic
hydrocarbons, for example, toluene or xylene; and aliphatic
hydrocarbons, for example, n-hexane, pentane, n-heptane, or
n-octane. The alkali metal or ammonium salt of bosentan, so
obtained, has a purity of about 97% or above, for example, about
98% or above, or about 99% or above. The pure alkali metal or
ammonium salt of bosentan may be obtained as crystalline forms, for
example, Form A and Form B of bosentan potassium, Form C and Form D
of bosentan sodium, and Form E and Form F of bosentan ammonium. The
pure alkali metal or ammonium salt of bosentan so obtained may be
further converted into bosentan by treating with an organic or
inorganic acid, for example, sulfuric acid, hydrochloric acid,
phosphoric acid, or nitric acid.
[0135] The present invention also provides for a pharmaceutical
composition that includes an alkali metal or ammonium salt of
bosentan, and a carrier. The alkali metal or ammonium salt of
bosentan may be in crystalline forms, for example, Form A and Form
B of bosentan potassium, Form C and Form D of bosentan sodium, and
Form E and Form F of bosentan ammonium.
[0136] The High performance liquid chromatography (HPLC) was
performed using Intertsil.RTM.ODS-3V, 5 .mu.m as column,
acetonitrile and buffer solution such as orthophosphoric acid
(50:50) as mobile phase, and a temperature of 5.degree. C.
[0137] XRPD of the samples were determined using a Rigaku.RTM.
RU-H3R X-Ray diffractometer, Goniometer CN2155A3, X-Ray tube with
Cu target anode, Power: 40 KV, 100 Ma; Scanning speed: 2 deg/min;
Step: 0.02 deg; Wave length: 1.5406 .ANG..
[0138] The TGA and DSC patterns were recorded using TA
Instruments.RTM. Q500 and Mettler Toledo.RTM. DSC 821e,
respectively.
[0139] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
EXAMPLES
Example 1
Preparation of Form A of Bosentan Potassium
Step 1: Preparation of Bosentan
[0140] Sodium hydroxide (26.66 g), ethylene glycol (400 mL),
tetrabutylammonium bromide (10 g),
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benze-
nesulfonamide (100 g), and dimethylsulphoxide (400 mL) were mixed
together at 25.degree. C. The reaction mixture was heated to
60.degree. C. to 65.degree. C. and the mixture was stirred for 12
hours to 14 hours at 60.degree. C. to 65.degree. C. The reaction
mixture was cooled to 25.degree. C. followed by the addition of
dichloromethane (600 mL) and de-ionized water (1000 mL). The pH of
the mixture was adjusted to 2 to 3 with concentrated hydrochloric
acid and the mixture was stirred for 10 minutes. The organic layer
of the reaction mixture was separated. The aqueous layer was
extracted with dichloromethane (200 mL). Both the organic layers
were combined, washed with de-ionized water (500 mL), and the
solvent was recovered. The residue was dried under vacuum at
40.degree. C. to 50.degree. C. to obtain bosentan.
Weight: 89 g
[0141] Chromatographic purity: 96.29%
Step 2: Preparation of Bosentan Potassium
[0142] The bosentan, as obtained in Step 1, was dissolved in
methanol (200 mL) at 40.degree. C. to 50.degree. C. The mixture was
cooled to about 20.degree. C. to 25.degree. C. Dichloromethane (50
mL), ethyl acetate (800 mL), and potassium hydroxide (12.8 g) were
added to the mixture and a clear solution was obtained. The
solution was stirred for 3 hours at 20.degree. C. to 25.degree. C.
and the solid obtained was filtered and dried to obtain bosentan
potassium.
Weight: 85 g
[0143] Chromatographic purity: 98.96%
Step 3: Preparation of Form A of Bosentan Potassium
[0144] Methanol (200 mL) and dichloromethane (200 mL) were added to
the bosentan potassium as obtained in Step 2. The mixture was
heated to 50.degree. C. to 55.degree. C. The mixture was stirred
for 20 minutes at the same temperature and dichloromethane
(.about.150 mL) was recovered at atmospheric pressure at 40.degree.
C. to 55.degree. C. Ethyl acetate (800 mL) was added to the residue
at 50.degree. C. to 55.degree. C. The reaction mixture was cooled
to 20.degree. C. to 25.degree. C., stirred for 3 hours, filtered,
and washed with a mixture of methanol (20 mL) and ethyl acetate (80
mL). The solid obtained was dried under vacuum at 55.degree. C. to
60.degree. C. until the loss on drying was not more than 2.0% w/w,
to obtain the title compound.
Weight: 80 g
[0145] Chromatographic purity: 99.69%
Example 2
Preparation of Form A of Bosentan Potassium
[0146] Potassium hydroxide (0.45 g) was added to a mixture of
bosentan monohydrate (3.5 g), methanol (7 mL), dichloromethane
(1.75 mL), and ethyl acetate (28 mL). The reaction mixture was
stirred for 3 hours at 20.degree. C. to 25.degree. C. and the solid
obtained was filtered. Methanol (7 mL) and dichloromethane (7 mL)
were added to the solid. The mixture was heated to 40.degree. C. to
45.degree. C. The reaction mixture was stirred for 15 minutes at
same temperature and dichloromethane (.about.5 mL) was recovered at
atmospheric pressure at 40.degree. C. to 50.degree. C. Ethyl
acetate (28 mL) was added to the reaction mixture at 50.degree. C.
to 55.degree. C., cooled to 20.degree. C. to 25.degree. C., and
stirred for 3 hours. The solid obtained was filtered, washed with a
mixture of methanol (0.7 mL) and ethyl acetate (2.8 mL), and dried
under vacuum at 55.degree. C. to 60.degree. C. to obtain the title
compound.
Weight: 2.5 g
[0147] Chromatographic purity: 99.76%
Example 3
Preparation of Form A of Bosentan Potassium
[0148] Potassium methoxide (0.59 g) was added to a mixture of
bosentan monohydrate (4 g) in methanol (6 mL), dichloromethane
(1.75 mL), and ethyl acetate (24 mL). The reaction mixture was
stirred for 30 minutes at 55.degree. C. to 60.degree. C. The
reaction mixture was cooled to 25.degree. C. and stirred for 2
hours at the same temperature. The solid obtained was filtered,
washed with a mixture of methanol (0.8 mL) and ethyl acetate (3.2
mL), and dried under vacuum at 55.degree. C. to 60.degree. C. to
obtain the title compound.
Weight: 3.5 g
[0149] Chromatographic purity: 98.76%
Example 4
Preparation of Form B of Bosentan Potassium
[0150] Bosentan potassium (3 g) was dissolved in de-ionized water
(18 mL) by heating to 65.degree. C. to 70.degree. C., stirred for 2
hours at 65.degree. C. to 70.degree. C., cooled, and further
stirred for 1 hour at 25.degree. C. to 20.degree. C. The solid was
filtered and washed with de-ionized water (10 mL). The wet material
obtained was dried under vacuum at 40.degree. C. to 45.degree. C.
to obtain the title compound.
Weight: 2.4 g
[0151] Chromatographic purity: 99.7%
Example 5
Preparation of Form B of Bosentan Potassium
Step 1: Preparation of Bosentan
[0152] Sodium hydroxide (6.65 g), ethylene glycol (100 mL),
tetrabutylammonium bromide (2.5 g),
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benze-
nesulfonamide (25 g), and dimethylsulphoxide (100 mL) were mixed
and heated to 60.degree. C. to 65.degree. C. The reaction mixture
was stirred for 12 hours to 14 hours at 60.degree. C. to 65.degree.
C. The reaction mixture was cooled to 25.degree. C., followed by
the addition of dichloromethane (150 mL) and de-ionized water (250
mL). The pH of the mixture was adjusted to 2 to 3 with concentrated
hydrochloric acid. The mixture was stirred for 10 minutes and the
organic layer was separated. The aqueous layer was extracted with
dichloromethane (50 mL). Both the organic layers were combined and
washed with de-ionized water (125 mL). The dichloromethane was
recovered and the residue dried under vacuum at 40.degree. C. to
50.degree. C. to obtain the title compound.
Weight of residue: 22.5 g Chromatographic purity: 96.12%
Step 2: Preparation of Bosentan Potassium
[0153] Bosentan (residue as obtained in Step 1; 5 g), de-ionized
water (15 mL), and potassium hydroxide (0.64 g) were mixed. The
reaction mixture was heated to 55.degree. C. and stirred for 15
minutes at 55.degree. C. The reaction mixture was cooled to
25.degree. C. to 20.degree. C. and stirred overnight. The solid was
filtered and washed with de-ionized water (5 mL). The wet material
obtained was dried under vacuum at 50.degree. C. to 55.degree. C.
to obtain the title compound.
Weight: 3.99 g
[0154] Chromatographic purity: 98.14%
Example 6
Preparation of Form B of Bosentan Potassium
[0155] Bosentan potassium (5 g) was mixed with de-ionized water (25
mL) and the mixture was heated to 65.degree. C. to 70.degree. C.
The reaction mixture was stirred for 2 hours (solid started
separating after 30 minutes). The solid was filtered, washed with
de-ionized water (10 mL), and dried under vacuum at 40.degree. C.
to 45.degree. C. to obtain the title compound.
Weight: 3.8 g
[0156] Chromatographic purity: 98.76%
Example 7
Preparation of Form C of Bosentan Sodium
Step 1: Preparation of Bosentan Sodium
[0157] Sodium hydroxide (0.44 g) was added to a mixture of bosentan
(5 g) in methanol (10 mL), dichloromethane (2.5 mL), and ethyl
acetate (40 mL). The reaction mixture was stirred for 3.5 hours at
20.degree. C. to 25.degree. C. and the solid was filtered to obtain
the title compound.
Chromatographic purity: 98.06%
Step 2: Preparation of Form C of Bosentan Sodium
[0158] Methanol (10 mL) and dichloromethane (10 mL) were added to
the solid as obtained in Step 1. The mixture was heated to
50.degree. C. to 55.degree. C. and stirred for 20 minutes at
50.degree. C. to 55.degree. C. Dichloromethane (.about.6 mL) was
recovered from the reaction mixture at atmospheric pressure at
40.degree. C. to 55.degree. C. and ethyl acetate (40 mL) was added
to the residue at 50.degree. C. to 55.degree. C. The reaction
mixture was cooled to 20.degree. C. to 25.degree. C. and stirred
for 3 hours. The solid obtained was filtered, washed with a mixture
of methanol (1 mL) and ethyl acetate (4 mL), and dried under vacuum
at 55.degree. C. to 60.degree. C.
Weight: 2.3 g
[0159] Chromatographic purity: 99.71%
Example 8
Preparation of Form C of Bosentan Sodium
[0160] Ethyl acetate (30 mL) was added to the solid as obtained in
Step 1 and the mixture was stirred for 3 hours at 25.degree. C. The
solid so obtained was filtered, washed with ethyl acetate (30 mL),
and dried under vacuum at 45.degree. C. to 50.degree. C. to obtain
the title compound.
Weight: 1.8 g
[0161] Chromatographic purity: 95.74%
Example 9
Preparation of Form C of Bosentan Sodium
[0162] Sodium methoxide solution (30% methanolic solution) was
added to a mixture of bosentan monohydrate (10 g) in methanol (20
mL) and ethyl acetate (80 mL). The reaction mixture was stirred for
3 hours and the solid was filtered, washed with ethyl acetate (20
mL), and dried in a hot air oven at 50.degree. C. to 55.degree. C.
to obtain the title compound.
Weight: 8.7 g
Example 10
Preparation of Form C of Bosentan Sodium
[0163] Sodium methoxide solution (30% methanolic solution; 3.9 mL)
was added to a mixture of bosentan monohydrate (5 g) in methanol
(15 mL). Ethyl acetate (80 mL) was added to the reaction mixture.
The reaction mixture was heated to 55.degree. C. and stirred for 30
minutes at 55.degree. C. The reaction mixture was cooled to
25.degree. C. The reaction mixture was stirred for 1.5 hours and
the solid was filtered at 10.degree. C. to 15.degree. C., then
washed with a mixture of ethyl acetate (4 mL) and methanol (1 mL).
The wet material obtained was dried in a hot air oven at 50.degree.
C. to 55.degree. C. to obtain the title compound.
Weight: 3.1 g
Example 11
Preparation of Form D of Bosentan Sodium
[0164] Sodium hydroxide powder (0.43 g) was added to a mixture of
bosentan (5 g) in de-ionized water (20 mL) and the resultant
mixture was heated to 55.degree. C. The reaction mixture was
stirred for 15 minutes at the same temperature. The reaction
mixture was cooled to 25.degree. C. and the mixture was further
stirred for 5 hours. The solid obtained was filtered, washed with
de-ionized water, and dried in air for 12 hours at 55.degree. C. to
60.degree. C. to obtain the title compound.
Weight: 3.57 g
[0165] Chromatographic purity: 96.55%
Example 12
Preparation of Form D of Bosentan Sodium
[0166] Sodium pieces (2.19 g) were added slowly to ethylene glycol
(55 mL) at 50.degree. C. and cooled to room temperature.
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benze-
nesulfonamide (5 g) was added to the mixture and heated to
98.degree. C. to 100.degree. C. The reaction mixture was stirred
for 1 hour and cooled to 25.degree. C. The cooled reaction mixture
was poured slowly into ice made of de-ionized water and stirred for
4 hours at 25.degree. C. The solid was filtered and dried under
vacuum for overnight at 25.degree. C. De-ionized water (30 mL) was
added to the solid and the reaction mixture was heated to
50.degree. C. for 10 minutes. The reaction mixture was further
stirred for 3 hours at 25.degree. C. The solid obtained was
filtered, washed with de-ionized water (10 mL), and dried under
vacuum at 45.degree. C. to 50.degree. C. to obtain the title
compound.
Weight: 4.3 g
[0167] Chromatographic purity: 98.65%
Example 13
Preparation of Form D of Bosentan Sodium
[0168] A mixture of bosentan (2 g) in de-ionized water (24 mL) was
heated to 50.degree. C. followed by the addition of sodium
hydroxide (0.175 g). The reaction mixture was stirred for 3.5 hours
at the same temperature and the solid was filtered, washed with
de-ionized water (6 mL), and dried in a hot air oven at 55.degree.
C. to 60.degree. C. to obtain the title compound.
Weight: 1.48 g
Example 14
Preparation of Form D of Bosentan Sodium
[0169] A mixture of bosentan sodium (2 g) in de-ionized water (24
mL) was heated to 55.degree. C. and stirred for 15 minutes to 20
minutes at the 55.degree. C. The reaction mixture was cooled to
25.degree. C. and stirred for overnight. The solid so obtained was
filtered, washed with de-ionized water (6 mL), and dried in an air
oven at 55.degree. C. to 60.degree. C.
Weight: 1.75 g
Example 15
Preparation of Form E of Bosentan Ammonium
Step 1: Preparation of Bosentan
[0170] A mixture of sodium hydroxide (2.66 g), ethylene glycol (60
mL), tetrabutylammonium bromide (1 g), and
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benze-
nesulfonamide (10 g) was heated to 95.degree. C. to 100.degree. C.
and the reaction mixture was stirred for 4 hours at 95.degree. C.
to 100.degree. C. The mixture was cooled to 25.degree. C. followed
by the addition of dichloromethane (40 mL) and de-ionized water
(180 mL). The pH of the reaction mixture was adjusted to 2 to 3
with concentrated hydrochloric acid. The reaction mixture was
stirred for 10 minutes and the organic layer was separated. The
aqueous layer was extracted with dichloromethane (10 mL). Both the
organic layers were combined and washed with de-ionized water (50
mL). The dichloromethane was recovered under vacuum at 40.degree.
C. to 50.degree. C. to obtain the title compound.
Step 2: Preparation of Form E of Bosentan Ammonium
[0171] Ammonia gas was passed for 15 minutes through a mixture of
the residue as obtained in Step 1 in ethyl acetate (100 mL). The
reaction mixture was stirred for 1 hour and the ethyl acetate was
recovered under vacuum at 50.degree. C. to obtain a residue. The
residue was mixed with a solvent mixture of methanol (20 mL) and
dichloromethane (4 mL) to obtain a solution. Ethyl acetate (80 mL)
was added to the solution to precipitate the solid. The resultant
mixture was stirred for 4 hours and the solid obtained was
filtered, washed with a mixture of methanol (4 mL) and ethyl
acetate (80 mL), and dried under vacuum at 55.degree. C. to
60.degree. C. for 12 hours to obtain the title compound.
Weight: 6.55 g
[0172] Chromatographic purity: 99.12%
Example 16
Preparation of Form F of Bosentan Ammonium
[0173] A mixture of bosentan ammonium (4 g) in de-ionized water (20
mL) was heated to 70.degree. C. to obtain a clear solution. The
reaction mixture was stirred for 2 hours. The solid obtained was
filtered, washed with de-ionized water (4 mL) at 40.degree. C. to
45.degree. C., and dried in a hot air oven at 60.degree. C. to
65.degree. C.
Weight: 1.29 g
[0174] Chromatographic purity: 99.60%
Example 17
Preparation of Bosentan Sodium from Bosentan
[0175] A mixture of bosentan monohydrate (10 g) in de-ionized water
(120 mL) was heated to 50.degree. C. and an aqueous solution of
sodium hydroxide (0.875 g of sodium hydroxide dissolved in 4 mL of
de-ionized water) was added to the mixture. The resultant mixture
was stirred for 1.5 hours and cooled to 20.degree. C. to 25.degree.
C. The mixture was stirred for further 0.5 hours. The solid was
filtered, washed with de-ionized water, and dried for 12 hours at
40.degree. C. to 45.degree. C. to obtain the title compound.
Example 18
Preparation of Bosentan Potassium
[0176] Sodium hydroxide (266 g), ethylene glycol (6 L),
tetrabutylammonium bromide (100 g),
4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2,2'-bipyrimidin-4-yl]benze-
nesulfonamide (1 kg), and dimethylsulphoxide (100 mL) were mixed at
25.degree. C. and the mixture was heated to 90.degree. C. to
100.degree. C. The reaction mixture was cooled to 25.degree. C.,
followed by the addition of dichloromethane (4 L) and de-ionized
water (18 L). The pH of the mixture was adjusted to 2 to 3 with
concentrated hydrochloric acid and the mixture was stirred for 10
minutes. The organic layer was separated. The aqueous layer was
extracted with dichloromethane (1 L). Both the organic layers were
combined and washed with de-ionized water (5 L). Dichloromethane
was recovered and dried under vacuum at 40.degree. C. to 50.degree.
C. Methanol (1.5 L) and potassium methoxide (146.3 g) were added to
the residue so obtained. The reaction mixture was heated to
40.degree. C. to 50.degree. C. and the mixture was stirred for 15
minutes at 40.degree. C. to 50.degree. C. Ethyl acetate (6 L) was
added to the mixture and the mixture was heated and stirred at
55.degree. C. to 60.degree. C. The reaction mixture was cooled to
25.degree. C. and stirred for 2 hours. The solid obtained was
filtered, washed with methanol (0.2 L) and ethyl acetate (0.8 L),
and dried in a hot air oven at 45.degree. C. to 50.degree. C. to
obtain the title compound.
Weight: 0.9 g
[0177] Chromatographic purity: 96.65%
* * * * *