FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"CARVEDILOL DIHYDROGEN 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:
The present invention relates to a new crystalline monohydrate phosphate salt of 1 -(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy) ethyl] amino]-propan-2-ol, (carvedilol phosphate monohydrate) of formula (1). 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 in solvents selected from acetonitrile, acetone and tetrahydrofuran and water.


HO P OH H
I H20
OH (1)
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. Carvedilol 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 (Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):21-994. PMID 12390947

The patent application 2005/0277689 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.
The patent application 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. This application provides the characterisation data such as X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC) and Thermo Gravimetric Analysis (TGA) for the claimed compounds.
The patent application WO2007/144900A2 claims the crystalline carvedilol dihydrogen phosphate sesquihydrate and provide the data for XRD, DSC and claims that the product is 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.
The present invention is directed to provide stable novel crystalline carvedilol dihydrogen phosphate monohydrate salt of formula I, which form subject matter of the present invention and sought patent protection. The invention also directed to convenient, robust and rugged process for the preparation of the subject matter of the present invention.
Summary of the invention:
Accordingly, the present invention discloses novel, stable crystalline carvedilol dihydrogen phosphate monohydrate, with high aqueous solubility. The invention further provides robust process for the preparation of monohydrate salt as it is very critical to maintain the moisture at 3.54 % (as per theory). Therefore, the invention
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provides efficient process for preparation of carvidilol phosphate having moisture content in the range of 3.30-3.8 %, which is corresponding to compound of the present invention, i.e., monohydrate salt of carvedilol dihydrogen phosphate. In yet anther aspect, the invention makes use of phosphate forming reagents, which has been added to public domain, in our-co-pending applications PCT/IN07/00333 as well as US11/923,352, such as phosphorous pentoxide, polyphosphoric acid, dipotassium hydrogen phosphate, ammonium dihydrogen ortho phosphate and sodium dihydrogen ortho phosphate.
Detailed description 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.
Accordingly, in a preferred embodiment, this invention provides novel crystalline carvedilol dihydrogen phosphate monohydrate and novel process as well as reagents for the preparation of phosphate salts of carvedilol with high yields and purity. The process of the present invention is simple to operate, high yielding and easily scalable to industrial production.
Thus, the process for preparation of carvedilol dihydrogen phosphate monohydrate according to the present invention comprising the steps of:
a. making slurry of carvedilol with acetonitrile, water or both;
b. generating a phosphate salt of the carvedilol using a suitable phosphate
forming agent selected from the group consisting of phosphoric acid,
phosphorous pentoxide, polyphosphoric acid, dipotassium hydrogen
phosphate, ammonium dihydrogen ortho phosphate or sodium dihydrogen
ortho phosphate at a temperature range of 25 to 55°C ;
c. isolating the carvedilol dihydrogen phosphate monohydrate salt from the
reaction mass by filtration.
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The carvedilol dihydrogen phosphate monohydrate thus obtained is dried till constant weight for 4-10 hours at 40-45°C under vacuum to obtain Carvedilol dihydrogen phosphate monohydrate having bound water content in the range of 3.3-3.8 %.
Further, the bound water content was removed by drying the material at 110°C under vacuum till the moisture content below 0.5%. The original moisture content was regained after about 10 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 dihydrate/hemihydrate/ sesqui hydrate form.
The compound of the invention is further characterized by its melting point, DSC, TGA, XRD, NMR, dissolution pattern etc.
The melting point of the carvedilol dihydrogen phosphate mono hydrate of the present invention is 148 to 154°C, which is distinct and different from the other known hydrated forms of carvedilol dihydrogen phosphate salts.
Moisture content by Karl Fischer indicates the range of 3.3-3.8%. The theoretical moisture content for carvedilol dihydrogen phosphate monohydrate is 3.54%
The DSC thermogram is shown in FIG. includes characteristic three peaks. The first one is an endothermic peak at an extrapolated onset temperature ranging 83.78 to 91.66 °C which is attributed to loss of one mole of water confirming product is monohydrate. Another peak is an exothermic peak at an extrapolated onset temperature ranging from 104.83 to 122.38 , corresponding to transition phase from hydrated to anhydrous phase. NMR of product shows
Another preferred embodiment of the present invention comprises preparation of phosphate salts of carvedilol which include all the above mentioned phosphate forming reagents and solvents in which carvedilol is soluble but not intended to limit, in any way, the scope of the present invention.
The Examples set forth below are illustrative of the present invention and are not intended
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to limit, in any way, the scope of the present in the invention.
EXAMPLES Example 1:
Preparation of Carvedilol dihydrogen Phosphate Hemihydrate
The reactor was charged with 135 ml acetonitrile, 15 g carvedilol and 16 ml water. The contents of the reaction mass were cooled to 0-5°C. Phosphorous pentoxide (2.7 g) was charged at 0-5°C. The temperature of the reaction mass was raised up to 40-45°C and maintained for 60 minutes. The contents were cooled to 0-5°C. The solid precipitate formed was stirred at 0-5°C, filtered to collect cake. The cake was washed with aqueous acetone and dried under vacuum to a constant weight to obtain the crystalline salt of carvedilol dihydrogen phosphate hemi hydrate salt. Yield: 18 g. (Theoretical yield-94.8 %) Purity- 99.7%, moisture content 1.6-2.0, melting point: 158 to 161°C
Example 2:
Preparation- Carvedilol dihydrogen Phosphate monohydrate
The reactor was charged with 15 g carvedilol dihydrohgen phosphate hemihydrate, 60 ml
acetone and 350 ml water. The contents were stirred for 48-72 hours at 25-30°C. Cooled
the reaction mass to 5-10°C and maintained for 1 hour and filtered to collect the cake.
The cake was washed with 30 ml water and dried under vacuum at 40-45°C to a constant
weight to obtain the salt of carvedilol dihydrogen phosphate salt monohydrate
Yield: 14 g (Theoretical yield- 88.5 %)
Purity- 99.6%.
Moisture content 3.3-3.8%,
Melting point 148-154°C
Example 3
Carvedilol (15 gm) was charged in to a reactor. To it was added acetonitrile (50ml) and
stirred for 10-20 minutes at 25-30 °C. To it was added dilute phosphoric acid (3.6 gm in
125 ml water) at 25-30 °C with constant stirring. Reaction mass was heated to 50-55°C
and maintained at this temperature for 1 hour. Cooled the reaction mass to 25-30 °C and
stirred for 24-48 hours. Cooled reaction mass to 5-10°C for 1 hour, filtered and washed
with 30 ml water, suck dried and dried under vacuum at 40-45°C till constant weight to
obtain carvedilol phosphate monohydrate.
Yield: 17 g (Theoretical yield- 89.5 %), Purity- 99.5%, moisture content
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3.4-3.8% melting point 148-154°C.
Example 4
Carvedilol (15 gm), water (240ml) and dipotassium hydrogen orthophosphate (6.5g) were charged in to a reactor and stirred for 10 minutes at 25-30 °C . Reaction mass was cooled to 5-10 °C. pH of the reaction mass adjusted to 4.5-5 with hydrochloric acid. The temperature was raised to 25-30 °C. Acetone (51ml) was added and stirred at 25-30 °C for 48 hrs-72 hrs. Reaction mass was cooled at 5-10°C for 1 hr, filtered and washed with water (30ml), suck dried and dried under vacuum at 40-45°C till constant weight to obtain carvedilol phosphate monohydrate.
Yield: 16.5 g (Theoretical yield- 86.9 %), Purity- 99.4%, moisture content 3.4 - 3.8% melting point 148-154°C.
Example 5
Carvedilol (15 gm), water (240ml) and polyphosphoric acid (3.7g) were charged in to a reactor and stirred for 10 minutes at 25-30 °C .Cool the reaction mass to 5-10 °C. The temperature was raised to 25-30 °C. Acetone (51ml) was added and stirred at 25-30 °C for 48 hrs-72 hrs. Reaction mass was cooled at 5-10°C for 1 hr, filtered and washed with water (30ml), suck dried and dried under vacuum at 40-45°C till constant weight to obtain carvedilol phosphate monohydrate.
Yield: 17.3 g (Theoretical yield- 91 %), Purity- 99.6%, moisture content 3.4 - 3.8%o melting point 148-154°C.
It is to be understood that the invention is not limited to the embodiments illustrated here in above and the right is reserved to the illustrated embodiments and all modifications coming within the scope of the following claims.
Dated this 23rd day of May, 2008

Dr. Gopakumar G. Nair Agent for the Applicant
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