FIELD OF THE INVENTION
The present invention relates to a novel crystalline form B of carvedilol dihydrogen
phosphate and to the 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 β-adrenergic blocking agent with α1 blocking activity while S(-) enantiomer
also has non-selective β-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,
amorphous salts, solvates thereof and 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.
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 (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 (GlaxoSmithKline) crystalline salt, anhydrous
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 anhydrous forms or solvates thereof arc
described.
The patent application US 2005/261,355 (SB Pharmco) covers carvedilol hydrobromide
monohydrate and anhydrous carvedilol hydrobromide.
The patent application US 2005/148,779 (GlaxoSmithKline) claims crystalline carvedilol
monocitrate monohydrate
To the organic chemist, the synthetic exploration of novel crystalline forms and/or solvates
thereof of a pharmaceutically active compound provides a possibility 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.
Thus, there exist a need exists to develop different carvedilol forms which have improved
characteristics. The present invention is directed to the same.

SUMMARY OF THE INVENTION
The present invention provides a novel crystalline form of carvedilol dihydrogen phosphate
refered to as Form B.
The present invention further provides a process for preparation of carvedilol dihydrogen
phosphate refered as Form B that comprises of:
(i) dissolving carvedilol base in aprotic polar solvent,
(ii) addition of phosphoric acid,
(iii) heating the solution,
(iv) adding water to hot solution,
(v) cooling, and
(vi) isolation.
DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffractogram (XRPD) for Form B of carvedilol dihydrogen
phosphate.
Figure 2 is an FT-IR spectrum for Form B of carvedilol dihydrogen phosphate.
Figure 3 is Differential Scanning Calorimetry (DSC) for Form B of carvedilol dihydrogen
phosphate.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides novel crystalline form of carvedilol dihydrogen
phosphate referred to as Form B which is identified by XRPD pattern as shown in figure 1.
The characteristic peaks of carvedilol dihydrogen phosphate referred to as Form B are as
shown in the table 1.

The crystalline Form B of carvedilol dihydrogen phosphate described herein is further
identified by FT-IR spectrum as shown in figure 2. The FT-IR spectrum of crystalline Form
B of carvedilol dihydrogen phosphate described herein has characteristic bands at 3406,
3330, 3062, 2397, 1942, 1902, 1625, 1603, 1587, 1505, 1471, 1454, 1441, 13961346, 1332,
1252,1218, 1180, 1125, 1098 cm-1.

The Form B of carvedilol dihydrogen phosphate of the present invention is further
characterized by differential scanning calorimetry which is shown in figure 3.
In an another aspect, the present invention provides process to obtain crystalline carvedilol
dihydrogen phosphate referred as Form B hereinabove that comprises of:
(i) dissolving carvedilol base in aprotic polar solvent
(ii) addition of phosphoric acid,
(iii) heating the solution,
(iv) adding water to hot solution,
(v) cooling, and
(vi) isolation.
In step (i), the carvedilol base is dissolved in polar aprotic solvent that is selected from
amides such as formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures
thereof. The preferred aprotic polar solvent is N,N-dimethyl formamide. The slurry of
carvedilol base in aprotic polar solvent is stirred at 25-30°C to get a clear solution.
The ortho phosphoric acid is added to the clear solution of carvedilol base in aprotic solvent
at 25-30°C. The ortho-phosphoric acid may be anhydrous or in the form of aqueoues
solution.
After the addition of orthophosphoric acid, the mixture of carvedilol base and phosphoric
acid in aprotic solvent is heated to the temperature in the range of 40-100 °C, preferably at
50-70 °C and most preferably at 55-60 °C.
The addition of water to the reaction mixture is performed at temperature in the range of 40-
100 °C, preferably at 50-70 °C and most preferably at 55-60 °C. The water addition is
carried out slowly over a period of 10 - 120 minutes.

After water addition the reaction mixture is slowly cooled to -5 to 30°C, preferably to 0-
10°C.
The crystalline solid that is separated is isolated by filtration and then dried.
The effective amount of crystalline carvedilol dihydrogen phosphate form B can be used to
prepare suitable formulation along with non toxic pharmaceutically acceptable carriers and/or
other active ingredients for the treatment of hypertension, congestive heart failure and
angina.
The following example is provided to illustrate the present invention and is not limit to 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.
Example: Preparation of crystalline form B of carvedilol dihydrogen phosphate
100 g of carvedilol base was added to 200 ml of N,N-dimethyl formamide and stirred to get
clear solution. The ortho-phosphoric acid was added in 5-10 minutes and slowly heated to
55-60°C followed by addition of water at 55-60°C. Mixture was stirred for 5-10 minutes and
then slowly cooled to 0-5°C. The solid was filtered, washed with water and dried. The yield
was 100 g. The crystalline solid melted at 156.1°C and had water 5.49% by KF.

WE CLAIM:
1. A novel crystalline form B of carvedilol dihydrogen phosphate having X-ray
diffraction pattern as shown in figure 1.
2. The crystalline form B of carvedilol dihydrogen phosphate according to claim 1
having X-ray diffraction pattern with characteristics peaks as shown in the table 1.
3. A novel crystalline form B of carvedilol dihydrogen phosphate according to claim 1
having FT-IR spectrum as shown in figure 2.
4. A novel crystalline form B of carvedilol dihydrogen phosphate according to claim 1
having DSC as shown in figure 3.
5. A process for the preparation of crystalline form B of carvedilol dihydrogen
phosphate according to claim 1 that comprises of:
(i) dissolving carvedilol base in aprotic polar solvent,
(ii) addition of phosphoric acid,
(iii) heating the solution,
(iv) adding water to hot solution,
(v) cooling, and
(vi) isolation of solid.
6. A process according to claim 5 wherein the aprotic solvent is selected from
formamide, N,N-dimethyl formamide, N-methylpyrrolidine and mixtures thereof,
preferably N,N-dimethyl formamide.
7. A process according to claim 5 wherein heating is carried out at temperature in the
range of 40-100 °C, preferably at 50-70 °C and most preferably at 55-60 °C.

8. A process according to claim 5 wherein water is added at temperature in the range of
40-100 °C, preferably at 50-70 °C and most preferably at 55-60 °C.
9. A process according to claim 5 wherein cooling is carried out at temperature in the
range of -5 to 30°C, preferably to 0-10°C.
10. A process according to claim 5 wherein the solid is isolated by filtration.

A novel crystalline form B of carvedilol dihydrogen phosphate having X-ray diffraction
pattern as shown in figure 1. A process for the preparation of crystalline form B of carvedilol
dihydrogen phosphate according to claim 1 that comprises dissolving carvedilol base in
aprotic polar solvent, addition of phosphoric acid, heating the solution, adding water to hot
solution, cooling, and isolation of solid.