Title of Invention

A NOVEL COST EFFECTIVE PROCESS FOR PRODUCTION OF CARVEDILOL PHOSPHATE

Abstract A novel cost effective process for the synthesis of phosphate salts of l-(9H-carbazol-4yloxy)-3-[[2-(2- methoxyphenoxy) ethyl] amino]-propan-2-ol, (carvedilol phosphate) of formula (II) with high yields and purity is disclosed. More particularly, the invention discloses a process for preparation of crystalline phosphate salts of carvedilol using various phosphonation reagents such as phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate, and Sodium Dihydrogen ortho phosphate in solvents selected from Acetonitrile, acetone and Tetrahydrofuran. The solvents used to prepare solvates of carvedilol dihydrogen phosphate are methanol, ethanol and isopropyl alcohol.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"A novel cost effective process for production of carvedilol phosphate"
2. APPLICANT (S)
(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 particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to a novel cost effective process for the synthesis of phosphate salts of l-(9H-carbazol-4yloxy)-3-[[2-(2- methoxyphenoxy) ethyl] amino]-propan-2-ol, (carvedilol phosphate) of formula (II) with high yields and purity. More particularly, the invention relates to a process for preparation of crystalline phosphate salts of carvedilol using various phosphonation reagents such as phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate, and Sodium Dihydrogen ortho phosphate in solvents selected from Acetonitrile, acetone and Tetrahydrofuran. The solvents used to prepare solvates of carvedilol dihydrogen phosphate are methanol, ethanol and isopropyl alcohol.

II
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 (I).

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, carvedilo 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 et al., 2002).
Carvedilol is synthesized as a racemic mixture of R (+) and S (-) enantiomers for incorporation in medication that is available commercially as a free base. The free base exhibits nonselective beta.-adrenoreceptor blocking activity by virtue of the S (-) enantiomer and also exhibits alpha.-adrenergic blocking activity by virtue of both R (+) and S(-) enantiomers.
Carvedilol contains an d- hydroxyl secondary amine functional group, which has a pKa pf 7.8. Carvedilol exhibits predictable solubility behavior in neutral or alkaline media, i.e. above pH of 9.0, the solubility of carvedilol is relatively low ( The presence of the d- hydroxyl secondary amine group in the carvedilol chemical structure confers a propensity upon the compound to chemically react with excipients normally included in a dosage form to aid manufacture, maintain quality, or enhances dissolution rate. For example, the d-hydroxyl secondary amine group of carvedilol can react with aldehydes or ester functional or ester functional groups residues associated with conventionally used excipients include ester, aldehyde and /or other chemical residue functional groups. This often results in marginal or unacceptable chemical stability upon storage.
The US patent 2005/0277689 Al describes the synthesis of carvedilol phosphate (II) by the treating carvedilol with o-phosphoric acid in acetone, acetone-water mixture to prepare crystalline salt and with methanol, isopropyl alcohol to prepare solvate of carvedilol phosphate.
The patent application 2005/0277689 Al describes the obtained carvedilol phosphate exhibits much higher aqueous solubility. This novel crystalline form 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.
In light of the foregoing, a salt, of carvedilol with greater aqueous solubility, chemical stability, etc. would offer many potential benefits for provision of medicinal products containing the drug carvedilol. Such benefits would include products with the ability to achieve desired or prolonged drug levels in a systemic system by sustaining absorption along the gastro-intestinal tract of mammals (i.e., such as humans), particularly in regions of neutral pH, where a drug, such as carvedilol, has minimal solubility.
The present invention is directed to provide another convenient and robust, rugged process for the preparation of carvedilol phosphate.
Summary of the invention:
Accordingly, the present invention discloses a novel process for production of carvedilol phosphate salts with high yields and purity. The phosphate salts of carvedilol which includes carvedilol dihydrogen phosphate and solvates of the dihydrogen phosphate salt of carvedilol. The process of the present invention involves the reaction of carvedilol with various phosphonation reagents such as phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium dihydrogen ortho phosphate, Sodium Dihydrogen ortho phosphate to prepare carvedilol phosphate.
This phosphonation reaction is carried out using solvents such as acetone, acetonitrile, tetrahydrofuran for the preparation of crystalline salt and methanol, ethanol, isopropyl alcohol for the preparation of solvates of carvedilol dihydrogen phosphate. The process of the present invention is simple to operate, high yielding and easily scalable to industrial production.
Detailed description of the invention:
While 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.


This invention provides a novel cost effective 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.
Accordingly, the process for preparation of carvedilol dihydrogen phosphate hemihydrate comprising the step of:
a) dissolving carvedilol free base in suitable solvent and water mixture;
b) phosphonating the carvedilol using suitable phosphonation agent selected from the group consisting of phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate or Sodium Dihydrogen ortho phosphate at a temperature range of 35 to 50°C for a period of 30 mins to 2 hrs; and
c) Isolating the carvedilol dihydrogen phosphate hemihydrate salt from the
reaction mass.
The phosphonation agent is selected from the group consisting of phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate or Sodium Dihydrogen ortho phosphate. The phosphonation reaction is carried out at a temperature range of 35 to 50°C for a period of 30 mins to 2 hrs.
The solvent suitable for preparation of carvedilol dihydrogen phosphate is a solvent in which carvedilol is soluble. The solvents suitable to prepare crystalline carvedilol dihydrogen phosphate are selected from acetone, tetrahydrofuran or acetonitrile, and to prepare solvates of carvedilol phosphates are selected from methanol, ethanol or isopropanol.
Thus, the phosphate salts of carvedilol which includes carvedilol dihydrogen phosphate and solvates of the dihydrogen phosphate salt of carvedilol.
The phosphonation reagent is used in 1:1 molar ratio with reference to the substrate, carvedilol. The phosphonation reaction is carried out preferably at a temperature of 45 to 50°C for 30 mins to 2 hrs to yield carvedilol dihydrogen phosphate salt.


The preferred embodiment of the present invention comprises preparation of phosphate salts of carvedilol which include all the above mentioned phosphonation reagents and solvents in which carvedilol is soluble but not intended to limit, in any way, the scope of the present invention.
In one embodiment, the invention provides a process for preparation of carvedilol dihydrogen phosphate dehydrate using phosphorous pentoxide in a reaction medium of acetone and water. The reaction is carried out at 35 to 50°C for a period of 30 mins to 2 hrs. The solid precipitated is stirred at 0- 5°C and then filtered. The collected solid is washed with aq. Acetone and dried under vacuum to obtain a constant weight.
In another embodiment, the invention provides a process for preparation of methanol solvate of carvedilol dihydrogen phosphate using phosphorous pentoxide in a reaction medium of methanol and water. The reaction is carried out at 35 to 50°C for a period of 30 mins to 2 hrs. The solid precipitated is stirred at 0- 5°C and then filtered. The collected solid is washed with aq. Acetone and dried under vacuum to obtain a constant weight.
In a similar manner, carvedilol dihydrogen phosphate hemihydrate and solvates of phosphate salts are prepared using different phosphonation reagents and various suitable organic solvents as described above. The Examples set forth below are illustrative of the present invention and are not intended to limit, in any way, the scope of the present in the invention.
EXAMPLES Example 1:
Preparation- Carvedilol Dihydrogen Phosphate Hemihydrate
The reactor was charged with 2520 ml acetone, 280 g carvedilol and 300 ml water. The contents of the reaction mass were cooled to 0-5°C. 50 g. phosphorous pentaoxide was charged at 0-5°C. The temperature of the reaction mass was raised up to 40-45°C and maintained for 60 mins. The contents were cooled to 0-5°C. The solid precipitate formed was stirred at 0-5°C, then 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 salt. Yield: 336 g..(Theoretical yield- 95 %) Purity-99.7%.
Example 2
Example 1 was reproduced by replacing acetone with acetonitrile to obtain crystalline salt
of carvedilol dihydrogen phosphate.
Example 3
Example 1 was reproduced by replacing acetone with Tetrahydrofuran to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 4
Example 1 was reproduced by replacing acetone with Isopropyl alcohol to obtain isopropanol solvate of the carvedilol dihydrogen phosphate.
Example 5
Example 1 was reproduced by replacing acetone with methanol to obtain the methanol
solvate of the carvedilol dihydrogen phosphate.
Example 6:
The reactor was charged 2520 ml. acetone, 280 g. carvedilol and 300 ml water. The contents of reaction mixture were cooled to 0-5°C. 50 g. polyphosphoric acid was charged at 0-5°C. The temperature of the reaction mass was raised up to 40-45°C and maintained for 60 mins. The contents of the reaction mass were cooled to 0-5°C. The solid precipitate formed was stirred at 0-5°C, then filtered to collect the cake and washed with aqueous acetone to obtain the crystalline salt of carvedilol dihydrogen phosphate salt. The cake was dried under vacuum to a constant weight. Yield: 330 g. (Theoretical yield- 93.3 %) purity 99.7%
Example 7
Example 6 was reproduced by replacing acetone with acetonitrile to obtain crystalline salt
of carvedilol dihydrogen phosphate.


Example 8
Example 6 was reproduced by replacing acetone with tetrahydrofuran to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 9
Example 6 was reproduced by replacing acetone with Isopropyl alcohol to obtain isopropanol solvate of the carvedilol dihydrogen phosphate.
Example 10
Example 6 was reproduced by replacing acetone with methanol to obtain methanol solvate of carvedilol dihydrogen phosphate
Example 11
The reactor was charged with 2520 ml acetone, 280 g. carvedilol, 300 ml. water and 50 g. Dipotasium Dihydrogen phosphate. The contents were cooled to 0-5°C. Adjust the pH of the reaction mass to 4.5-5 with HC1. The reaction temperature was raised up to 40-45°C and maintained for 60 mins. The contents of the reaction mass were cooled to 0-5°C. The solid precipitate formed was stirred at 0-5°C, then filtered to collect the cake and washed with aqueous acetone to obtain the crystalline salt of carvedilol dihydrogen phosphate salt. The cake was dried under vacuum to a constant weight. Yield: 334 g.(Theoretical yield-94.49%) Purity: 99.7%.
Example 12
Example 11 was reproduced by replacing acetone with acetonitrile to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 13
Example 11 was reproduced by replacing acetone with Tetrahydrofuran to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 14
Example 11 was reproduced by replacing acetone with Isopropyl alcohol to obtain isopropanol solvate of the carvedilol dihydrogen phosphate.


Example 15
Example 11 was reproduced by replacing acetone with Methanol to obtain methanol solvate of carvedilol dihydrogen phosphate.
Example 16
Example 11 was reproduced by replacing Dipotasium Dihydrogen phosphate with Ammonium Dihydrogen ortho phosphate in acetone to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 17
Example 16 was reproduced by replacing acetone with acetonitrile to obtain crystalline
salt of carvedilol dihydrogen phosphate.
Example 18
Example 16 was reproduced by replacing acetone with tetrahydrofuran to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 19
Example 16 was reproduced by replacing acetone with Isopropyl alcohol to obtain isopropanol solvate of carvedilol dihydrogen phosphate.
Example 20
Example 16 was reproduced by replacing acetone with methanol to obtain methanol solvate of carvedilol dihydrogen phosphate.
Example 21
Example 11 was reproduced by replacing Dipotasium Dihydrogen phosphate with Sodium Dihydrogen ortho phosphate to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 22
Example 21 was reproduced by replacing acetone with acetonitrile to obtain crystalline
salt of carvedilol dihydrogen phosphate.


Example 23
Example 21 was reproduced by replacing acetone with tetrahydrofuran to obtain crystalline salt of carvedilol dihydrogen phosphate.
Example 24
Example 21 was reproduced by replacing acetone with Isopropyl alcohol to obtain isopropanol solvate of carvedilol dihydrogen phosphate.
Example 25
Example 21 was reproduced by replacing acetone with methanol to obtain methanol
solvate of carvedilol dihydrogen phosphate.
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.


We claim,
1. A novel cost effective process for preparation of carvedilol dihydrogen phosphate hemihydrate comprising the step of:
a) dissolving carvedilol free base in suitable solvent and water mixture;
b) phosphonating the carvedilol using suitable phosphonation agent selected from the group consisting of phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate or Sodium Dihydrogen ortho phosphate at a temperature range of 35 to 50°C for a period of 30 mins to 2 hrs to obtain carvedilol dihydrogen phosphate salt; and
c) isolating the carvedilol dihydrogen phosphate hemihydrate salt from the
reaction mass.
2. The process as claimed in claim 1, wherein, the phosphonation agent used in the preparation of salt is phosphorus pentoxide.
3. The process as claimed in claim 1, wherein, the phosphonation agent used in the preparation of salt is polyphosphoric acid.
4. The process as claimed in claim 1, wherein, the phosphonation agent used in the preparation of salt is dipotasium hydrogen phosphate and hydrochloric acid.
5. The process as claimed in claim 1, wherein, the phosphonation agent used in the preparation of salt is ammonium Dihydrogen ortho phosphate and hydrochloric acid.
6. The process as claimed in claim 1, wherein, the phosphonation agent used in the preparation of salt is Sodium Dihydrogen ortho phosphate and hydrochloric acid.
7. The process as claimed in claims 1 to 6, wherein, said solvent used in the salt preparation is acetonitrile.


8. The process as claimed in claims 1 to 6, wherein, said solvent used in the salt preparation Tetrahydrofuran.
9. The process as claimed in claims 1 to 6, wherein, said solvent used in the salt preparation in acetone.
10. A novel cost effective process for preparation of solvates of carvedilol dihydrogen phosphate comprising the step of:
i) dissolving carvedilol in solvent and water mixture;
ii) phosphonating the carvedilol using suitable phosphonation agent selected from the group consisting of phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate or Sodium Dihydrogen ortho phosphate at a temperature range of 35 to 50°C for a period of 30 mins to 2 hrs to obtain carvedilol dihydrogen phosphate salt; and
iii) isolating the solvate of carvedilol dihydrogen phosphate from the reaction mass.
11. The process as claimed in claim 10, wherein, the phosphonation agent used in the preparation of salt is phosphorus pentoxide.
12. The process as claimed in claim 10, wherein, the phosphonation agent used in the preparation of salt is polyphosphoric acid.
13. The process as claimed in claim 10, wherein, the phosphonation agent used in the preparation of salt is dipotasium hydrogen phosphate and hydrochloric acid.
14. The process as claimed in claim 10, wherein, the phosphonation agent used in the preparation of salt is ammonium Dihydrogen ortho phosphate and hydrochloric acid.


15. The process as claimed in claim 10, wherein, the phosphonation agent used in the preparation of salt is Sodium Dihydrogen ortho phosphate and hydrochloric acid.
16. The process as claimed in claims 10 to 15, wherein, the solvent used in solvate preparation is carried out in methanol.
17. The process as claimed in claims 10 to 15, wherein, solvate preparation is carried out in ethanol.
18. The process as claimed in claims 10 to 15, wherein, solvate preparation is carried out in Isopropyl alcohol.
19. The process as claimed in any of the preceding claims, wherein carvedilol phosphate is isolated with impurity below detection limit.





ABSTRACT:
A novel cost effective process for the synthesis of phosphate salts of l-(9H-carbazol-4yloxy)-3-[[2-(2- methoxyphenoxy) ethyl] amino]-propan-2-ol, (carvedilol phosphate) of formula (II) with high yields and purity is disclosed. More particularly, the invention discloses a process for preparation of crystalline phosphate salts of carvedilol using various phosphonation reagents such as phosphorous pentoxide, polyphosphoric acid, Dipotasium hydrogen phosphate, Ammonium Dihydrogen ortho phosphate, and Sodium Dihydrogen ortho phosphate in solvents selected from Acetonitrile, acetone and Tetrahydrofuran. The solvents used to prepare solvates of carvedilol dihydrogen phosphate are methanol, ethanol and isopropyl alcohol.


Documents:

929-MUM-2007-ABSTRACT(17-5-2007).pdf

929-MUM-2007-ABSTRACT(GRANTED)-(15-9-2011).pdf

929-mum-2007-abstract.doc

929-mum-2007-abstract.pdf

929-MUM-2007-CANCELLED PAGES(14-6-2011).pdf

929-MUM-2007-CLAIMS(AMENDED)-(14-6-2011).pdf

929-MUM-2007-CLAIMS(AMENDED)-(17-3-2011).pdf

929-MUM-2007-CLAIMS(AMENDED)-(26-2-2010).pdf

929-MUM-2007-CLAIMS(GRANTED)-(15-9-2011).pdf

929-MUM-2007-CLAIMS(MARKED COPY)-(14-6-2011).pdf

929-MUM-2007-CLAIMS(MARKED COPY)-(17-3-2011).pdf

929-mum-2007-claims.doc

929-mum-2007-claims.pdf

929-MUM-2007-CORRESPONDENCE(14-6-2011).pdf

929-mum-2007-correspondence(4-6-2007).pdf

929-MUM-2007-CORRESPONDENCE(IPO)-(20-9-2011).pdf

929-mum-2007-correspondence-received.pdf

929-mum-2007-description (complete).pdf

929-MUM-2007-DESCRIPTION(GRANTED)-(15-9-2011).pdf

929-mum-2007-form 1(4-6-2007).pdf

929-mum-2007-form 18(4-6-2007).pdf

929-MUM-2007-FORM 2(GRANTED)-(15-9-2011).pdf

929-MUM-2007-FORM 2(TITLE PAGE)-(17-5-2007).pdf

929-MUM-2007-FORM 2(TITLE PAGE)-(GRANTED)-(15-9-2011).pdf

929-MUM-2007-FORM 3(17-5-2007).pdf

929-MUM-2007-FORM 3(26-2-2010).pdf

929-mum-2007-form 9(4-6-2007).pdf

929-mum-2007-form-1.pdf

929-mum-2007-form-2.doc

929-mum-2007-form-2.pdf

929-mum-2007-form-26.pdf

929-mum-2007-form-3.pdf

929-MUM-2007-REPLY TO EXAMINATION REPORT(26-2-2010).pdf

929-MUM-2007-REPLY TO HEARING(17-3-2011).pdf

929-MUM-2007-SPECIFICATION(AMENDED)-(14-6-2011).pdf

929-MUM-2007-WO INTERNATIONAL PUBLICATION REPORT(17-5-2007).pdf


Patent Number 248966
Indian Patent Application Number 929/MUM/2007
PG Journal Number 38/2011
Publication Date 23-Sep-2011
Grant Date 15-Sep-2011
Date of Filing 17-May-2007
Name of Patentee WANBURY LIMITED
Applicant Address B-WING, 10TH FLOOR, BSEL TECH PARK, SECTOR 30 A, PLOT NO.39/5 & 39/5A, OPP VASHI RAILWAY STATION, NAVI-MUMBAI 400703
Inventors:
# Inventor's Name Inventor's Address
1 SANGANBHATLA SHANKAR 402, PLOT NO.51, SECTOR-12 B, KOPARKHAIRANE, NAVI MUMBAI 400709
2 SURYAVANSHI JITENDRA PANDURANG N.A.16, B.M.C. COLONY, KHARDEO NAGAR, CHEMBUR (E), MUMBAI 400071
3 ZAHID ALAM SAYYED 31, PAARIJAAT COLONY, SUDARSHAN NAGAR, CHINCHWAD, PUNE 413033
PCT International Classification Number C07D209/88
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA