FIELD OF THE INVENTION
The present invention relates to a novel stable amorphous form of carvedilol dihydrogen
phosphate that is highly stable and process for its preparation.
BACKGROUND OF THE INVENTION
Carvedilol has structure as shown in formula 1. Carvedilol is disclosed in US patent No.
4,503.067 (assigned to Boehringer Mannheim, GmbH, Germany) and it is chemically
known as (±)-l-(9H-carbazol-4-yloxy)-3-[[2(2- methoxyphenoxy)ethyl]amino]-2-
propanol.

Carvedilol is a racemic mixture of R(+) and S(-) enantiomers. Both enantiomers are
nonselective ß-adrenergic blocking agent with a1 blocking activity while S(-) enantiomer
also has non-selective ß-adrenoreceptor blocking activity. Carvedilol is used for
treatment of hypertension, congestive heart failure and angina.
There are several patents and patent applications that are directed to crystalline salts and
solvates thereof and also to their preparation.
The product patent US 4,503,067 (Boehringer Mannheim) describes salts of carvedilol
with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid,
acetic acid, citric acid, maleic acid or benzoic acid.
The patent US 6515010 covers carvedilol methane sulfonate.
Another patent US 7,056,942 assigned to Teva discloses crystalline carvedilol
hydrochloride hydrate.
The patent application US 2005/240,027 (assigned to SmithKline Beecham) disclose
crystalline carvedilol dihydrogen phosphate hemihydrate, carvedilol dihydrogen
phosphate dihydrate. carvedilol dihydrogen phosphate, carvedilol dihydrogen phosphate
methanol solvate and carvedilol hydrogen phosphate.
In the patent application US 2005/277,689 (assigned to GlaxoSmithKline) crystalline salt.
forms or solvate of carvedilol selected from the group consisting of carvedilol mandelate,
lactate, maleate. sulfate, glutarate, mesylate, phosphate, citrate, hydrogen bromide,
oxalate, hydrochloride, benzoate and corresponding forms or solvates thereof are
described.
The patent application US 2005/261.355 (assigned to SB Pharmco) covers carvedilol
hydrobromide monohydrate and carvedilol hydrobromide.
The patent application US 2005/148,779 (GlaxoSmithKline) claims crystalline carvedilol
monocitrate monohydrate
We have filed a Indian patent application 119/K.OL/2007 dated 31 January 2007 in Indian
Patent Office on amorphous form of carvedilol dihydrogen phosphate and the process for
its preparation. The amorphous form obtained by the process described in this application
has glass transition temperature below 60°C. The amorphous solids in general having low
glass transition temperature not only create complications during formulation but also has
stability related problems on storage. The glass transition temperature is the temperature,
below which the physical properties of amorphous materials vary in a maner similar to
thise of a crystalline phase (glassy state), and above which amorphous materials behave
like liquids (rubbery state). A materials glass transition temperature is the temperature
below which molecules have little relative mobility. Thus, there exist a need to develop
stable amorphous form of carvedilol dihydrogen phosphate which have improved
characteristics.
The synthetic exploration of novel crystalline forms, amorphous form and/or solvates
thereof of a pharmaceutically active compound provides a possibility to a organic
chemist, to obtain a new form or solavte that has improved characteristics such as bulk
density, particle size, stability, solubility in aqueous solution and ease of processing in the
formulation for preparing suitable pharmaceutical dosages.
In case of carvedilol dihydrogen phosphate, the patent as well publication literature lack
in providing information on stable amorphous form of carvedilol dihydrogen phosphate,
thereby indicating poor attention given by the synthetic chemists for its isolation and
preparation. The present invention is directed to the stable amorphous form of carvedilol
dihydrogen phosphate and to also to the development of process for its preparation .
SUMMARY OF THE INVENTION
The present invention provides a stable amorphous form of carvedilol dihydrogen
phosphate and process for its preparation. The process for the preparation of stable
amorphous form of carvedilol dihydrogen phosphate comprises of:
(a) preparation of a solution of carvedilol base in a suitable solvent or mixture of
solvents.
(b) addition of stabiliser.
(c) addition of ortho phosphoric acid,
(d) removal of solvent, and
(e) isolation of solid.
Another process for the preparation of stable amorphous form of carvedilol dihydrogen
phosphate comprises of:
(a) preparation of a solution of stable amorphous or crystallinbe carvedilol
dihydrogen phosphate in a suitable solvent or mixture of solvents.
(b) addition of stabiliser.
(c) removal of solvent, and
(d) isolation of solid.
Accordingly, the present invention provides a thermodynamically stable amorphous form
of carvedilol dihydrogen phosphate having glass transition temperature in the range
between 50°C-176°C "
DESCRIPTION OF THE DRAWINGS
Figure 1: PXRD of stable amorphous form of carvedilol dihydrogen phosphate
obtained by using 5%PVPK-30 as stabiliser.
Figure 2: FT-IR spectrum of stable amorphous form of carvedilol dihydrogen
phosphate obtained by using 5%PVPK-30 as stabiliser.
Figure 3: Differential Scanning Calorimetry (DSC) of stable amorphous form of
carvedilol dihydrogen phosphate obtained by using 5%PVPK-30 as
stabiliser.
Figure 4: Thermal Gravimetric Analysis (TGA) of stable amorphous form of
carvedilol dihydrogen phosphate obtained by using 5%PVPK-30 as
stabiliser.
Figure 5: Stability of stable amorphous form of carvedilol dihydrogen phosphate
obtained by using 5%PVPK-30 as stabiliser at 15 days. 1 month and 2
month at 40OC ± 2°C (RH 75%).
Figure 6: PXRD of amorphous form of carvedilol dihydrogen phosphate without
stabiliser.
Figure 7: FT-IR sopectrum of amorphous form of carvedilol dihydrogen phosphate
without stabiliser.
Figure 8: Differential Scanning Calorimetry (DSC) of stable amorphous form of
carvedilol dihydrogen phosphate obtained by using 5%PVPK-30 as
stabiliser.
Figure 9: TGA of amorphous form of carvedilol dihydrogen phosphate obtained
without stabiliser.
Figure 10: PXRD of amorphous form of carvedilol dihydrogen phosphate without
stabiliser after 1 month at 40°C ± 2°C (RH 75%).
DETAILED DESCRIPTION OF THE INVENTION
The inventors of the present patent application have surprisingly and unexpectedly found
that a novel stable amorphous form of carvedilol dihydrogen phosphate can be prepared
which is highly stable.
Accordingly, the present invention provides a thermodynamically stable novel form of
carvedilol dihydrogen phosphate that is highly stable.
The novel stable amorphous form of carvedilol dihydrogen phosphate of the present
invention is characterized by X-ray diffractogram as shown in figure 1. FT-IR spectrum
as shown in figure 2. DSC as shown in figure 3 and TGA as shown in figure 4. The
amorphous carvedilol obtained without stabiliser having glass transition temprature 55-
56°C while the stable amorphous form of the present invention has glass transition
temperature in the range between 76 to 185°C. The phosphorous content of the the stable
amorphous form of the present invention is between 18-20% on anhydrous basis.
The amorphous form of carvedilol dihydrogen phosphate without stabilser was prepared
according to the method described in application 119/KOL/2007 dated 31 January 2007
files in Indian Patent Office which are described in examples 8 and 9 in the experimental
section. The amorphous form of carvedilol dihydrogen phosphate obtained without
stabliser is characterized by X-ray diffractogram as shown in figure 6, FT-IR spectrum as
shown in figure 7. DSC as shown in figure 8 and TGA as shown in figure 9.
The PXRD of amorphous form of carvedilol dihydrogen phosphate without stabiliser
after 1 month at 40°C ± 2°C (RH 75%) is shown in figure 10. It shows appearance of
several sharp peaks indicating slow conversion of amorphous form in to crystalline form.
The PXRD of stable amorphous form of carvedilol dihydrogen phosphate obtained with
stabiliser 5% PVPK-30 after 15 days, 1 month and 2 month at 40°C ± 2°C (RH 75%) is
shown in figure 5. It does not show sharp peaks that can arise from crystalline form, thus
indicating that the amorphous form of carvedilol dihydrogen phosphate obtained with
stabiliser is highly stable and does not undergo conversion in to crystalline form.
Thus, it has been unexpectedly found that the stable amorphous form of carvedilol
dihydrogen phosphate can be obtained in a simple and reproducible manner. Therefore,
the most preferred embodiment of the present invention is to provide highly stable novel
amorphous form of carvedilol dihydrogen phosphate.
In an another preferred embodiment, the present inventione provide a process for the
preparation of stable amorphous form of carvedilol dihydrogen phosphate comprises of:
(a) preparation of a solution of carvedilol base in a suitable solvent or mixture
of solvents,
(b) addition of stabiliser,
(c) addition of ortho phosphoric acid,
(d) removal of solvent, and
(e) isolation of solid.
Generally, the aqueous or ortho phosphoric acid is added to the solution of carvedilol
base in a suitable solvent. The addition may be performed at a temperature 0-50 °C,
preferably at 25-30 °C. The quantity of carvedilol base and ortho phosphoric acid may be
molar equivalent or ortho phosphoric acid may be in slight molar excess.
The present invention further provide an another process for the preparation of stable
amorphous form of carvedilol dihydrogen phosphate comprises of:
(a) preparation of a solution of stable amorphous or crystallinbe carvedilol
dihydrogen phosphate in a suitable solvent or mixture of solvents,
(b) addition of stabiliser.
(c) removal of solvent, and
(d) isolation of solid.
The term "suitable solvent" in either of the processes described above includes any protic
or aprotic polar solvent or mixture of solvents in which carvedilol is soluble, for example,
lower alkanol. dihydroxy solvents, lower aliphatic ketone, and water miscible cyclic and
acyclic ethers, cyclic and acyclic amides and nitriles.
The examples of lower alkanol include methanol, ethanol, n-propanol and isopropanol.
Dihydroxy solvent such as ethylene glycol and diethylene glycol can also be used. The
examples of aliphatic ketone include those acetone. 2-butanone and 4-methyl pentanone.
The examples of cyclic ethers include tetrahydrofuran and 1,4-dioxane. The examples of
cyclic and acyclic amides include formamide, acetamide, propanamide and 2-methyl
pyrrolidinone.The examples of nitrile solvents include acetonitrile and propionitrile.
Other polar aptotic solvents like diethylene glycol dimethyl ether, dimethyl sulfoxide,
sulfolane can also be useful.solvents. The process may also be carried out by using one or
two solvents.
The preferred suitable solvent is lower alkanol such as methanol, ethanol, propanol and
isopropanol and the most preferred solvent is methanol or ethanol.
In either of the process variety of the compounds can be used as stabiliser such as
polyvinyl prrrolidone K-30 (PVPK K-30); 5% Eudragit RSPO. 5%Klucef EXF, 5%
Polyethylene glycol-6000 (5% PEG-6000). 5% Polyethylene glycol-4000 (5% PEG-
4000), 5% Ethyl cellulose, 5% Hydroxypropyl methyl cellulose (HPFC E-5) and the like.
The quantity of stabiliser can be used in the range 0.01 to 0.1 weight by weight, most
preferably 0.05 times weight by weight with respect to carvedilol base or
amorphous/crystalline carvedilol dihydrogen phosphate. Stabiliser can added to the
solution at temperature 0-250°C. preferably at 50-75°C. most preferably at 50-55°C.
The removal ot the solvent before isolation of solid in either of the processes described
above is accomplished by techniques which include distillation at atmospheric pressure,
distillation under reduced pressure, evaporation, spray drying, freeze drying and agitation
thin film evaporation. Moreover, the product obtained may be further dried to achieve the
desired moisture values or desired residual solvent values because of the higher glass
transition temperature which is in the range of 70-176 °C, preferably is in the range of 80-
90°C.
The thermodynamically stable forms are always preferred for the formulation because of
their advantages. Due to high thermodynamic stability the stable amorphous form of
carvedilol dihydrogen phosphate of the present invetion is useful for pharmaceutical
formulation. The effective amount of stable amorphous form of carvedilol dihydrogen
phosphate can be used to prepare pharmaceutical composition in association with one or
more non toxic pharmaceutically acceptable carriers and/or diluents thereof, and if
desired . other active ingredients, which may be administered orally, intravascularly,
intraperitoneally, subcutaneously, intramuscularly or topically for the treatment of
hypertension, congestive heart failure and angina in a mammal in need thereof.
The present invention is illustrated by the following representative examples and are not
intended to limit the scope of the invention.
EXAMPLES
The powder X-ray diffraction spectrum is measured using Philips (PAN alytical X'pert
pro) difractogram (copper anti cathode) and expressed in terms of inter planar distance d,
Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the
most intense peak). The scanning parameters included: measurment range: 3-40 degrees
two theta; continuous scan.
The FTIR spectra were obtained using a Perkin-Elmer. Spectrum-100 instrument.
The thermogravimetric analysis (TGA) was done using Perkin Elmer Pyris 1 TGA
instrument.
Preparation of stable amorphous carvedilol dihydrogen phosphate with stabilser.
Example 1: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% PVPK-30 as stabiliser.
Mixture of 100 g of carvedilol base and 2000 ml methanol was heated at 50-55°C to get
clear solution. To the solution, 274 g of 88% ortho phosphoric acid was added dropwise.
To the solution. 5 g of PVPK-30 was added . The solvent was distilled off under reduced
pressure. Residual solid was scratched to get 120 g of free flowing stable amorphous
solid.
Example 2: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% Eudragit RSPO as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution, 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution, 0.5 g of 5%Eudragit RSPO was added . The solvent was distilled off
under reduced pressure. Residual solid was scratched to get 119 g of free flowing stable
amorphous solid.
Example 3: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% Klucef EXF as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution. 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution. 0.5 g of 5% Klucef EXF was added . The solvent was distilled off under
reduced pressure. Residual solid was scratched to get 122 g of free flowing stable
amorphous solid.
Example 4: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% PEG-6000 as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution, 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution, 0.5 g of 5% PEG-6000 was added . The solvent was distilled off under
reduced pressure. Residual solid was scratched to get 117 g of free flowing stable
amorphous solid.
Example 5: Preparation of stable amorphous carvedilol dihytlrogen phosphate
using 5% ethyl cellulose as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution, 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution. 0.5 g of 5% ethyl cellulose was added . The solvent was distilled off
under reduced pressure. Residual solid was scratched to get 120 g of free flowing stable
amorphous solid.
Example 6: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% PEG-4000 as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution, 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution, 0.5 g of 5% PEG-4000 was added . The solvent was distilled off under
reduced pressure. Residual solid was scratched to get 121 g of free flowing stable
amorphous solid.
Example 7: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% HPMC E-5 as stabiliser.
Mixture of 10 g of carvedilol base and 200 ml methanol was heated at 50-55°C to get
clear solution. To the solution. 2.74 g of 88% ortho phosphoric acid was added dropwise.
To the solution. 0.5 g of 5% HPMC E-5was added . The solvent was distilled off under
reduced pressure. Residual solid was scratched to get 118 g of free flowing stable
amorphous solid.
Example 8: Preparation of stable amorphous carvedilol dihydrogen phosphate using
spray dryer.
Carvedilol base (10 g) was dissolved in methanol (500 mL). To the solution, ortho
phosphoric acid (2.9 g, 88 % aqueous solution,) was added. The solution was subjected to
spray drying to afford 5 g of stable amorphous carvedilol dihydrogen phosphate melting
at 62-63 °C having 4.1% moisture content.
Example 9: Conversion of crystalline carvedilol dihydrogen phosphate into stable
amorphous carvedilol dihydrogen phosphate.
Crystalline carvedilol dihydrogen phosphate (10 g) was dissolved in methanol (750 ml)
and the solution was spray dried to afford 4.7 g of stable amorphous carvedilol
dihydrogen phosphate.
Example 10: Preparation of stable amorphous carvedilol dihydrogen phosphate 5%
PVPK-30 as stabiliser.
Mixture of 10 g of stable amorphous carvedilol dihydrogen phosphate obtained in
example 8 and 200 ml methanol was heated at 50-55°C to get clear solution. To the
solution, 2.74 g of 88% ortho phosphoric acid was added dropwise. To the solution, 0.5 g
of 5% PVPK-30 was added. The solvent was distilled off under reduced pressure.
Residual solid was scratched to get 9.2 g of free flowing stable amorphous solid.
Example 11: Preparation of stable amorphous carvedilol dihydrogen phosphate
using 5% PVPK-30 as stabiliser.
Mixture of 10 g of crystalline carvedilol dihydrogen phosphate hemihydrate and 200 ml
methanol was heated at 50-55°C to get clear solution,. To the solution, 2.74 g of 88%
ortho phosphoric acid was added dropwise. To the solution, 0.5 g of 5% PVPK-30 was
added . The solvent was distilled off under reduced pressure. Residual solid was
scratched to get 9.1 g of free flowing stable amorphous solid.
We claim:
1. A process for the preparation of stable amorphous form of carvedilol dihydrogen
phosphate comprising of:
(a) preparation of a solution of carvedilol base in a suitable solvent or mixture
of solvents.
(b) addition of ortho phosphoric acid.
(c) removal of solvent, and
(d) isolation of solid.
2. A process for the preparation of stable amorphous form of carvedilol dihydrogen
phosphate comprising of:
(a) preparation of a solution of stable amorphous or crystalline carvedilol
dihydrogen phosphate in a suitable solvent or mixture of solvents,
(b) addition of stabiliser.
(c) removal of solvent, and
(d) isolation of solid.
3. A process according to claim 1 wherein phosphoric acid is added to the solution
of carvedilol base in a suitable solvent at a temperature 0-50 °C. preferably at 25-
30 °C.
4. A process according to claim 1 wherein the quantity of carvedilol base and
phosphoric acid may be molar equivalent or ortho phosphoric acid may be in
slight molar excess.
5. A process according to claim 1 and/or claim 2 wherein suitable solvent includes
any protic or aprotic polar solvent or mixture of solvents selected from lower
alkanols such as methanol, ethanol, n-propanol and isopropanol; lower aliphatic
ketones such as acetone. 2-butanone and 4-methyl pentanone; water miscible
cyclic and acyclic ethers such as tetrahydrofuran, 1,4-dioxane and diethylene
glycol dimethyl ether; cyclic and acyclic amides such as formamide, acetamide,
propanamide and 2-methyl pyrrolidinone; aliphatic nitirles such as acetonitrile
and propionitrile. dimethyl sulfoxide, and sulfolane and mixtures thereof.
6. A process according to claim 5 wherein the most preferred solvent is methanol.
7. A process according to claim 1 and/or claim 2 wherein the stabiliser is selected
from a group of polyvinyl prrrolidone K-30 (PVPK K-30); 5% Eudragit RSPO,
5%Klucef EXF, 5% Polyethylene glycol-6000 (5% PEG-6000), 5% Polyethylene
glycol-4000 (5% PEG-4000). 5% Ethyl cellulose. 5% Hydroxypropyl methyl
cellulose (HPFC E-5).
8. A process according to claim 1 and/or claim 2 wherein the quantity of stabiliser
with respect to the quantity of carvedilol base or amorphous/crystalline carvedilol
dihydrogen phosphate, is in the range 0.01 to 0.1 weight by weight, most
preferably 0.05 times weight by weight.
9. A process according to claim 1 and/or claim 2 wherein the stabiliser is added to
the solution at temperature in the range 0-250°C. preferably at 50-75°C, most
preferably at 50-55°C.
10. A process according to claim 1 and/or claim 2 wherein removal of the solvent
before isolation of solid is accomplished by techniques such as distillation at
atmospheric pressure, distillation under reduced pressure, evaporation, spray
drying, freeze drying and agitation thin film evaporation.
11. A novel stable amorphous form of carvedilol dihydrogen phosphate having glass
transition temperature of 50°C-176°C.
12. The compound according to claim 11 having glass transition temperature of 80-
90°C.
13. The compound according to claim 11 having an X-ray diffraction pattern as
shown in figure 1.
14. The compound according to claim 11 having an FT-Infra Red spectrum as shown
in figure 2.
15. The compound according to claim 11 having an Differential Scanning
Calorimetry as shown in figure 3.
16. The compound according to claim 1 having Thermal Gravimetric Analysis as
shown in figure 4.

The present invention provides a novel stable amorphous form of carvedilol dihydrogen
phosphate and the process for its preparation that involves reaction of carvedilol base
with ortho phosphoric acid in the presence of stabilizer in a suitable solvent or mixture of
solvents followed by concentration and isolation. An alternate process for preparation of
stable amorphous form of carvedilol dihydrogen phosphate involves addition of stabiliser
to the solution of stable amorphous or crystalline carvedilol dihydrogen phosphate in a
suitable solvent or mixture of solvents followed by concentration and isolation. The novel
stable amorphous form of carvedilol dihydrogen phosphate is highly stable.