TECHNICAL FIELD

The present invention relates to a novel method for drying to obtain amorphous
carvedilol dihydrogen phosphate.
BACK GROUND OF 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 (±)-1-(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 (3-adrenergic blocking agent with  blocking activity while S(-)
enantiomer also has non-selective p-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 or
amorphous salts and solvates thereof and also to their preparation.
The product patent US 4503067 assigned to 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 7056942 assigned to Teva, discloses crystalline carvedilol
hydrochloride hydrate.
The patent application US 2005/240027 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 2005/277689 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 2005/261355 assigned to SB Pharmco, covers carvedilol
hydrobromide monohydrate and carvedilol hydrobromide.
The patent application US 2005/148779 assigned to GlaxoSmithKline, claims
crystalline carvedilol monocitrate monohydrate.
The applicant has filed a patent application 119/KOL/2007 dated 31 January 2007
related to amorphous form of carvedilol dihydrogen phosphate and the process for
its preparation. The applicant has also filed another patent application
1152/KOL/2007 dated 21 august 2007 in Indian Patent Office related to stable
amorphous form of carvedilol dihydrogen phosphate and the process for its
preparation.
In case of carvedilol dihydrogen phosphate, the patent as well publication literature
lack in providing information on organic volatile impurities in amorphous carvedilol
dihydrogen phosphate, thereby indicating poor attention given for its control. The

synthetic chemists are well aware of the ICH guidelines that provide stringent
requirements for control organic volatile impurities.
The inventors prepared carvedilol dihydrogen phosphate by using methanol solvent
and found it to contain 10000-15000 ppm of methanol as OVI after drying under
reduced pressure at 60-65°C for 72 hours.
Thus, there exists a need to develop a method for drying of amorphous carvedilol
dihydrogen phosphate which has methanol content as per ICH guidelines in order to
qualify the stringent requirement laid down by the ICH guidelines. The present
invention is directed to the development of novel drying method of amorphous
carvedilol dihydrogen phosphate.
DESCRIPTION OF THE DRAWINGS
Figure 1: PXRD of amorphous form of carvedilol dihydrogen phosphate.
Figure 2: FT-IR spectrum of amorphous form of carvedilol dihydrogen
phosphate.
SUMMARY OF THE INVENTION
The present invention provides a novel method to obtain amorphous carvedilol
dihydrogen phosphate having methanol content less than 2000 ppm. The drying of
carvedilol dihydrogen phosphate is carried out at 55-60°C initially at atmospheric
pressure for 5-7 hours then at pressure in the range 300-350 mm Hg for 5-7 hours
and finally under at pressure in the range 740-760 mm Hg for 10-15 hours.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel method for drying of carvedilol dihydrogen
phosphate to obtain amorphous carvedilol dihydrogen phosphate having methanol
content less than 2000 ppm. The drying of carvedilol dihydrogen phosphate is
carried out in a stepwise manner that comprises of:
i) heating at atmospheric pressure,

ii) heating at partially reduced pressure, and
iii) heating at pressure 740-760 mm Hg.
The heating in step (i) and step (ii) is carried out at 40-70°C, preferably at 55-
60°C and for the period of 3-20 hours, preferably 5-7 hours. In step (i) the door of
oven is kept open and thus the drying is carried out at atmospheiic pressure.
During second step of drying, the door of oven is closed and pressure in the
range 300-350 mm Hg is applied. In third step, pressure in the range 740-760
mm Hg is applied and drying is carried out at 40-70°C, preferably at 55-60°C for
10-15 hours.
The amorphous form of carvedilol dihydrogen phosphate of the present invention is
characterized by X-ray diffractogram as shown in figure 1 and FT-IR spectrum as
shown in figure 2.
The following example is provided only to illustrate the present invention and should
not be considered as limit to the scope of the invention.
EXPERIMENTAL
Example 1
Preparation of amorphous carvedilol dihydrogen phosphate having methanol
content less than 2000 ppm.
Mixture of 100 g of carvedilol base and 2000 ml methanol was heated at 50-55°C to
get clear solution. To the solution, 27.4 g of 88% ortho phosphoiic acid was added
dropwise. To the solution, 5 g of PVPK-30 (polyvinyl prrrolidone K-30) was added.
The solvent was distilled off under reduced pressure. Residual solid was scratched
to get 120 g of free flowing solid.
Solid obtained above was taken in a drying tray and kept in an oven. Temperature
was raised to 55-60°C and maintained for 3 hours keeping the door open. Then door
was closed, pressure was adjusted to 300-350 mm Hg and drying was continued at

55-60°C for 4 hours. The pressure was adjusted to 740-760 mm Hg and drying was
continued at 55-60°C for further15 hours. The dried product was unloaded, weight
was 120 g and methanol content was 1212 ppm (parts par million).
Example 2
Preparation of amorphous carvedilol dihydrogen phosphate by conventional
drying method.
Mixture of 100 g of carvedilol base and 2000 ml methanol was heated at 50-60°C to
get clear solution. To the solution, 27.4 g of 88% ortho phosphoiic acid was added
dropwise. To the solution, 5 g of PVPK-30 (polyvinyl prrrolidone K-30) was added.
The solvent was distilled off under reduced pressure. Residual solid was scratched
to get 120 g of free flowing solid.
Solid obtained above was taken in a drying tray and kept in an oven. Dried at 60-
65°C for 72 hours at 740-760 mm Hg. The dried product was unloaded, weight was
120 g and methanol content was 12976 ppm (parts par million).

We Claim:
1. A novel method for drying to obtain amorphous carvedilol dihydrogen
phosphate having solvent content less than 2000 ppm that comprises of:
i) heating carvedilol dihydrogen phosphate initially at atmospheric
pressure,
ii) heating carvedilol dihydrogen phosphate of step (i) at partially
reduced pressure 300-350 mm Hg, and
iii) heating carvedilol dihydrogen phosphate of step (ii) at pressure
740-760 mm Hg.
2. Method according to claim 1 wherein the solvent is MeOH.
3. Method according to claim 1 wherein each step is carried out for the period of
3-20 hours, preferably 5-7 hours.
4. The Method according to claim 1 wherein temperature in each step is 40-
70°C, preferably at 55-60°C.
5. The amorphous carvedilol dihydrogen phosphate having PXRD as shown in
figure 1 that is obtained according to process of claim 1.