FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR PREPARATION OF CARVEDILOL PHOSPHATE
MONOHYDRATE"
2. APPLICANT:
(a) NAME. WANBURY LIMITED


(b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: B-Wing, 10th Floor, BSEL Tech Park, Sector 30 A, Plot No.39/5 & 39/5A, Opp. Vashi Railway Station, Navi- Mumbai- 400 703, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.


Technical field of Invention:
The present invention relates to a novel process for preparation of crystalline monohydrate phosphate salt of l-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl] amino]-propan-2-ol, (carvedilol phosphate monohydrate) of formula (I). Further, the invention relates to a process for preparation of monohydrate salt of carvedilol using various phosphate forming reagents such as phosphoric acid, phosphorous pentoxide, polyphosphoric acid, dipotassium hydrogen phosphate, ammonium dihydrogen ortho phosphate and sodium dihydrogen ortho phosphate.

Background of invention:
Carvedilol, the first beta blocker labeled in the United States for the treatment of heart failure, has been shown to improve left ventricular ejection fraction and may reduce mortality. Carvedilol is chemically known as l-(9H-carbazol-4yloxy)-3-[[2-(2-methoxyphenoxy)-ethyl] amino]-propan-2-ol, which has the following structure (II).

Carvedilol is disclosed in U.S. Pat. No. 4,503,067 to Wiedemann et al and is indicated in the management of congestive heart failure (CHF), as an adjunct to conventional treatments (ACE inhibitors and diuretics). Currently, carvedilol is used for treating patients suffering with hypertension, congestive heart failure and angina. The use of carvedilol has been shown to provide additional morbidity and mortality benefits in CHF by Packer M, Fowler MB, Roecker EB, et al. titled Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective

randomized cumulative survival (COPERNICUS) study published in Circulation. 2002; 106( 17):2194-9. PMID 12390947.
The patent application US2005/0277689 Al describes novel crystalline forms of carvedilol phosphate which exhibits much higher aqueous solubility. These novel crystalline forms also has potential to improve the stability of carvedilol in formulations due to the fact that the secondary amine functional group attached to the carvedilol core structure, a moiety pivotal to degradation processes, is protonated as a salt. The patent application describes crystalline carvedilol dihydrogen phosphate, carvedilol hydrogen phosphate, solvates and preparation of said compounds.
PCT publication WO2008002683A2 describes amorphous Carvedilol phosphate, amorphous Carvedilol hydrogen phosphate, amorphous Carvedilol dihydrogen phosphate, crystalline carvedilol dihydrogen phosphate as well as process for preparation of the same.
WO2007/144900 A2 claims the crystalline carvedilol dihydrogen phosphate sesquihydrate having moisture content between 4 to 7 preferably to 4.5 to 6.0 %.
US7268156 provides carvedilol phosphate hemihydrate and pharmaceutical composition comprising the same for treating hypertension, congestive heart failure.
In our earlier application nol094/MUM/2008 filed on 23.05.2008, we have disclosed novel crystalline carvedilol hydrogen phosphate monohydrate and the process for preparation thereof. The process disclosed in our earlier application comprises reacting carvedilol free base in water with various phosphate forming agents and isolating said carvedilol phosphate monohydrate via carvedilol phosphate hemihydrate from the reaction mass. In another process variant, monohydrate is prepared directly from carvedilol base in water.
The current invention is directed to an alternate convenient, robust and rugged process for the preparation of crystalline carvedilol phosphate monohydrate via carvedilol phosphate

using seed crystal of carvedilol phosphate monohydrate which forms the subject matter of the present invention and soughts patent protection.
Disclosure of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
The present invention discloses a convenient, robust and rugged process for the preparation of crystalline carvedilol phosphate monohydrate without going into hemihydrate form, using seed crystal of carvedilol phosphate monohydrate.
In preferred embodiment, the invention provides a process for preparation of carvedilol dihydrogen phosphate monohydrate which comprises the following steps of:
a. making solution of carvedilol in organic solvent;
b. adding solution of phosphate generating agent in organic solvent to the solution in
step (a) followed by heating the reaction mass to a temperature of 55 to 60°C to obtain
carvedilol phosphate;
c. adding water followed by organic solvent to the contents of step (b); maintaining
at temperature of 55 to 60C for 3 hrs;
d. maintaining reaction mass of step (c), at 25 - 35 °C for 24 hrs;
e. seeding the cooled reaction mass with carvedilol dihydrogen phosphate
monohydrate followed by distilling the organic solvent to obtain precipitate; and
f. isolating the precipitate, carvedilol dihydrogen phosphate monohydrate from the
chilled reaction mass by filtration.
The preferred embodiment of the present invention comprises preparation of phosphate salt of carvedilol phosphate monohydrate which includes phosphate forming reagents selected from the group consisting of phosphoric acid, phosphorous pentoxide, polyphosphoric acid, dipotassium hydrogen phosphate, ammonium dihydrogen ortho phosphate or sodium dihydrogen ortho phosphate and the organic solvents in which carvedilol is soluble but not intended to limit, in any way, the scope of the present invention.

The carvedilol dihydrogen phosphate monohydrate thus obtained is dried till constant weight for 4-10 hours at 55-60°C under vacuum to obtain Carvedilol dihydrogen phosphate monohydrate having bound water content in the range of 3.0-4.0 %.
Further, the bound water content was removed by drying the material at 110°C till the moisture content below 0.5%. The original moisture content was regained after about 10-15 hours when exposed to 75% relative humidity at 37°C (in air). This confirms that the monohydrate salt of carvedilol dihydrogen phosphate is stable and do not convert into any other forms like dihydrate/hemihydrate.
Moisture content by Karl Fischer method indicates the range of 3.0-4.0%, the theoretical moisture content for carvedilol dihydrogen phosphate monohydrate is 3.54%.
In another embodiment, the compound of the invention is further characterized by its XRD, DSC, IR and NMR, the values of which are matched with XRD, DSC, IR and NMR of the crystalline salt of carvedilol hydrogen phosphate monohydrate of our earlier application.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Examples:
Example 1:
Preparation of carvedilol phosphate monohydrate
Acetone (900ml) followed by Carvedilol base (100 gm) was charged at a temperature of
o
30-35 C into neat and dry 4 neck R.B.flask fitted with reflux condenser and thermometer pocket. The solution was heated upto 40- 45 C to obtain clear solution. A solution of phosphoric acid (33gm) in acetone (100ml) was added drop wise at a temperature of 40-
o
45 C in about 2 hrs. 20 ml of water was added to the reaction mass (water addition at this

step is also crucial. Change in quantity will give hemihydrate) and heated the reaction
o o
mass to 55-60 C and was maintained at 55-60 C for 5 to 6 hrs. The reaction mass was
o
cooled to 25-30 C slowly in about 2 to 3 hrs and stirred for 24 hrs at the same temperature, filtered the solid, washed with mixture of acetone (200ml) and water(200ml) and suck dried to obtain wet cake.
The wet cake was transferred into 4 necked RB flask with reflux condenser and thermometer pocket and charged with water (1400ml) and heated the reaction mass to 55-60 C in 30 min and maintained the temperature for 90 mins. Acetone (830ml) was added
o
in 30 min at 55-60 C and maintained at the same temperature for 90 mins. The reaction mass was cooled to 25 to 30 C in 45 to 60 mins. The reaction mass was seeded with 0.5 gm pure Carvedilol phosphate Monohydrate and maintained at 25-30 C for 24 hrs. Acetone was distilled out under vacuum between 45-50 C till precipitation observed. The
o o
reaction mass was cooled gradually to 25-30 C over 60 min and chilled between 0-5 C
and maintained for 120 min. The reaction mass filtered and washed with mixture of
acetone (50ml) and water (50ml) and dried the product under vacuum at 55-60 C forlO
hrs.
Moisture content (3.59)
Dry wt - 98 gm
Purity: 99.9 %
Partial size:
1. dl0 = 4.706
2. d50 = 22.329
3. d90 = 73.504