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
"Novel Polymorphs of Carvedilol Phosphate"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies Act 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

Novel Polymorphs of Carvedilol Phosphate
TECHNICAL FIELD
The present invention relates to novel polymorphs of (+/-)-1- (carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanoldihydrogen phosphate, which has formula (I) and process for producing the same.

Formula (I)
BACKGROUND OF INVENTION
US 4,503,067 discloses (+/-)-l-(carbazol-4-yloxy)- 3- [[2 -(o-methoxy phenoxy)ethyl] amino]-2-propanol known as Carvedilol and its pharmaceutically acceptable salts and a process for producing the same. In the racemic form of Carvedilol, the S(-) enantiomer exhibits nonselective b-adrenoreceptor blocking activity and both R(+) and S(-) enantiomer exhibits a-adrenergic blocking activity. This unique activity exhibited by racemic carvedilol is effective against mixed venous and arterial vasodilation and non-cardioselective beta-adrenergic blockade. Carvedilol is also used for the treatment of hypertension, congestive heart failure and angina.
WO2004002419 discloses that carvedilol has a pKa of 7.8 with a low solubility (< lmg/ml) above pH of 9. The solubility of carvedilol increases with decreasing pH and reaches a plateau near pH 5 (23 mg/ml at pH= 7 and 100 mg/ml
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at pH = 5 at room temperature). At lower pH the solubility of carvedilol is limited by solubility of its protonated form or its corresponding salt formed in situ. This patent application also discloses that a salt and/or novel crystalline form 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.
In light of better solubility and chemical stability of salt of Carvedilol, WO2004002419 discloses crystalline carvedilol phosphate and their corresponding solvates. This application also discloses that the crystalline form of carvedilol phosphate salt (i.e. such as carvedilol dihydrogen phosphate and/or carvedilol hydrogen phosphate, etc. ) can be isolated as a pure, crystalline solid, which exhibits much higher aqueous solubility than the corresponding free base or other prepared crystalline salts of carvedilol, such as the hydrochloride salt. The 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
The drawback of the process disclosed in the patent application is the lack of different solvent or solvent combinations for obtaining Carvedilol phosphate. The use of similar solvent systems for getting different forms can lead to contamination of forms but use of different solvent or solvent combination can lead to novel and pure polymorphic forms.
Polymorphism is the ability of the compound to exhibit more than one orientation or conformation of molecule within the crystal lattice. Many organic compounds including active pharmaceutical ingredients (APIs) exhibit polymorphism. Drug substance existing in various polymorphic forms, differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties thus affecting dissolution, bioavailability and handling
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characteristics of the substance. Rate of dissolution of an API in patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally administrated API can reach the patient's bloodstream. Flowability affects the ease with which the material is handled while processing a pharmaceutical product.
Knowledge of existence of different crystal phases and their overall physical and chemical behaviour is required for selection of polymorphic form to be used in the preparation of final dosage form. Towards this end, investigation of crystal polymorphism is an essential step in pharmaceutical research due to the influence of solid state properties on dosage form.
WO2004002419 discloses six polymorphic forms of carvedilol phosphate, namely carvedilol dihydrogen phosphate hemihydrate (Form I), carvedilol dihydrogen phosphate dihydrate (Form II and Form IV), carvedilol dihydrogen phosphate methanol solvate (Form III), carvedilol dihydrogen phosphate (Form V) and carvedilol hydrogen phosphate (Form VI). Form I and Form VI are obtained using aqueous acetone. Other polymorphic forms are obtained by solution phase transformation of crystalline Form I. Form I is obtained by dissolving carvedilol in aqueous acetone followed by the addition of aqueous phosphoric acid. To this solution seeds of carvedilol dihydrogen phosphate are added to get Form I of Carvedilol dihydrogen phosphate. Form II, Form III and Form V are obtained by solution phase transformation of Form I in acetone/water, methanol and water respectively. Form IV is obtained by following a process where carvedilol dihydrogen phosphate is dissolved in acetone/water mixture and acetone is removed under vacuum. Form VI is obtained by following process which is similar to the process for obtaining Carvedilol dihydrogen phosphate Form I.
WO2005051383 discloses various salts of carvedilol such as carvedilol phosphate, carvedilol HBr, carvedilol citrate, carvedilol mandelate, carvedilol lactate, carvedilol maleate, carvedilol sulfate, carvedilol glutarate, carvedilol benzoate characterized by XRPD, FT-IR and FT-Raman.
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The discovery of new polymorphs with same or better pharmaceutical equivalence and bioequivalence as that of the existing polymorphs provide an opportunity to improve the performance characteristic of the pharmaceutical product.
All the polymorphic forms reported in the prior art are crystalline in nature. It is known that the amorphous form of drug substance exhibits different dissolution characteristic. When the difference in the solubilities of various polymorphs is sufficiently large, it may alter the in vivo dissolution of the drug product and hence the bioavailability of the drug product. Amorphous forms can have solubilities several hundred times than that of the crystalline counterparts.
There is still a need to develop improved polymorphic forms of Carvedilol phosphate. Surprisingly in our polymorphic study we have found a novel crystalline polymorphic form of Carvedilol phosphate and novel amorphous Carvedilol phosphate.
OBJECT OF THE INVENTION
It is the object of the present invention to provide novel crystalline form of Carvedilol phosphate and process for preparing the same.
Yet another object of the present invention is to provide a novel amorphous Carvedilol phosphate and process for preparing the same.
SUMMARY OF THE INVENTION
According to the present invention there is provided a novel crystalline form of Carvedilol phosphate (Form VII) characterized by the X-ray powder diffraction pattern having peaks at about 2-theta. 4.63, 7.65, 8.89, 11.72, 13.48, 15.81, 16.50, 18.32, 18.91, 19.54, 20.21, 21.00, 21.75, 22.42, 23.00, 23.60, 25.29, 26.33, 26.91, 28.74, 30.17, 39.28, 43.08 ± 0.2 degrees.
According to one aspect of the present invention there is provided a process for the preparation of Carvedilol phosphate (Form VII).
According to another aspect of the present invention there is provided a novel amorphous form of Carvedilol phosphate.
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According to yet another aspect of the present invention there is provided a process for the preparation of amorphous Carvedilol phosphate.
The present invention also relates to a pharmaceutical composition containing novel crystalline form of Carvedilol phosphate and/or novel amorphous Carvedilol phosphate.
Further the present invention also relates to method of treatment of hypertension, congestive heart failure and angina using the novel crystalline form of Carvedilol phosphate and/or novel amorphous Carvedilol phosphate.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: X Ray powder diffraction pattern of Carvedilol phosphate (Form VII). Figure 2: X Ray powder diffraction pattern of Amorphous Carvedilol phosphate.
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.
According to the present invention there is provided a novel crystalline form viz., Form VII of Carvedilol phosphate and novel amorphous Carvedilol phosphate and a process for manufacturing the same.
The process to make the crystalline form VII of Carvedilol phosphate comprises of following steps,
a. Dissolving Carvedilol in a solubilizing solvent;
b. Adding required quantity of phosphoric acid;
c. Stirring the suspension for several hours;
d. Isolating the separated product; and
e. Drying the isolated product.
The solubilizing solvent may be selected from aliphatic cyclic ethers. The aliphatic cyclic ethers may be selected from a group consisting of tetrahydrofuran (THF), 1,4-dioxane or a mixture thereof preferably 1,4-dioxane. The required quantity of phosphoric acid is added in the form of a solid or an aqueous solution.
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The separated solid is isolated by filtration process followed by drying to get Form VII.
Another process to make Carvedilol Phosphate Form VII comprises of following steps,
1. Suspending amorphous Carvedilol phosphate in a solvent;
2. Stirring the suspension for several hours;
3. Isolating the separated product; and
4. Drying the isolated product.
The solvent for suspending amorphous Carvedilol may be selected from aliphatic cyclic ethers. The aliphatic cyclic ethers may be selected from a group of THF or 1,4-Dioxane or mixture thereof preferably 1,4-Dioxane.
The XRPD of Form VII of Carvedilol Phosphate [Figure 1] exhibit following peaks:

Pos. [°2Th.] Rel. Int. [%]
4.63 26.16
7.65 16.30
8.89 31.31
11.72 19.39
13.48 21.50
15.81 37.22
16.50 23.59
18.32 35.43
18.91 18.20
19.54 42.46
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20.21 24.18
21.00 35.66
21.75 16.81
22.42 78.22
23.00 100
23.60 98.54
25.29 19.43
26.33 31.33
26.91 24.60
28.74 20.97
30.17 14.30
39.28 3.36
43.08 2.58
The process to make the amorphous Carvedilol phosphate comprises of following steps,
1. Dissolving Carvedilol in a solubilizing solvent;
2. Adding required quantity of phosphoric acid;
3. Precipitating the carvedilol phosphate by adding antisolvent;
4. Decanting the supernatant and adding fresh antisolvent;
5. Stirring the suspension for several hours; and
6. Isolating the product and drying.
The XRPD of amorphous Form of Carvedilol phosphate is shown in Fig.2
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Solubilizing solvent may be selected from a group consisting of alcohols. ketones, esters, nitriles or mixtures thereof. The alcohol may be selected from Cr C4 alcohol or a mixture thereof, preferably methanol, ethanol, 1-propanol, 2-propanol (IPA) more preferably methanol. The ketones may be selected from acetone, 2-butanone, diethyl ketone or mixtures thereof, preferably acetone. The ester may be selected from methyl acetate, ethyl acetate or mixtures thereof, preferably ethyl acetate. The nitrile can be acetonitrile.
The antisolvents may be selected from a group consisting of aliphatic ethers, aliphatic hydrocarbons or a mixture thereof. Aliphatic ethers may be selected from Diethyl ether (DEE), Diisopropyl ether (DIPE), Methyl t-butyl ether (MTBE), Tetrahydrofuran (THF), 1,4-Dioxane or mixtures thereof preferably DIPE. An aliphatic hydrocarbon may be selected from pentane, hexane, heptane or mixtures thereof, preferably hexane.
The crystallization process hitherto described to prepare the novel polymorph consists of dissolving Carvedilol phosphate in the selected solvent either with or without heating, preferably with heating at or near boiling point of the solvent. The resultant solution is cooled to -5°C to 30°C for several hours to regenerate the solid. The precipitated solids are isolated and dried at a temperature between about ambient to 65°C.
The solvent and antisolvent combination described to prepare amorphous Carvedilol phosphate consists of dissolving Carvedilol phosphate in a solubilizing solvent. The dissolution may be carried out at room temperature or under reflux condition. Antisolvent is added to the resulting solution under warm condition to regenerate the Carvedilol phosphate. The antisolvent addition is generally carried out at room temperature or at 35-55°C. The precipitated solid is isolated and dried at a temperature of about ambient temperature to 65°C.
The novel polymorphs of Carvedilol Phosphate are characterized by X-ray powder diffraction. X-ray powder diffraction pattern has been obtained on Xpert'PRO, Panalytical, diffractometer equipped with accelerator detector using Copper Ka(X= 1.5406 A) radiation with scanning range between 4-50 20 at scanning speed of 2°/min.
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The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
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EXAMPLES
Form VII
Example 1
2.5g of Carvedilol was dissolved in 50 ml 1,4-Dioxane at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.68g o-phosphoric acid (85%) solution was added dropwise. The sticky material was obtained which was stirred at the same temperature for 3 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get Form VII.
Example 2
2.5g of Carvedilol was dissolved in 50 ml THF at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.68g o-phosphoric acid (85%) solution was added dropwise. The sticky material was obtained which was stirred at the same temperature for 3 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get Form VII.
Example 3
2.5g of Carvedilol was dissolved in 50 ml 1,4-Dioxane at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.6g o-phosphoric acid was added. The sticky material was obtained which was stirred at the same temperature for 3 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get Form VII.
Example 4
2.5g of Carvedilol was dissolved in 50 ml THF at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.6g o-phosphoric acid was added. The sticky material was obtained which was stirred at the same
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temperature for 3 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get Form VII.
Example 5
2.5g of Amorphous Carvedilol phosphate was suspended in 50 ml THF at room temperature. The suspension was stirred at the same temperature for 3 hours. The solid was isolated by filtration and dried at 65°C to get Form VII.
Example 6
2.5g of Amorphous Carvedilol phosphate was suspended in 50 ml 1,4-Dioxane at room temperature. The suspension was stirred at the same temperature for 3 hours. The solid was isolated by filtration and dried at 65°C to get Form VII.
Amorphous Form
Example 7
2 g of Carvedilol was dissolved in 20 ml Methanol at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml Diisopropyl ether (DIPE) was added. The sticky material was obtained from which the solvent is separated by decantation. A fresh 135ml DIPE was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 8
2 g of Carvedilol was dissolved in 20 ml Ethanol at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml DIPE was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml DIPE was added
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and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65 °C to get amorphous form.
Example 9
2 g of Carvedilol was dissolved in 20 ml Ethanol at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml hexane was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml hexane was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65 °C to get amorphous form.
Example 10
2 g of Carvedilol was dissolved in 20 ml Ethyl acetate at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml Diisopropyl ether (DIPE) was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml DIPE was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 11
2 g of Carvedilol was dissolved in 20 ml Ethyl acetate at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml hexane was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml hexane was added and the suspension was stirred for 24 hours. The sticky solid converts to free
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flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 12
2 g of Carvedilol was dissolved in 20 ml Acetone at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml DIPE was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml DIPE was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 13
2 g of Carvedilol was dissolved in 20 ml Acetone at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml Hexane was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml Hexane was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 14
2 g of Carvedilol was dissolved in 20 ml MDC at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml DIPE was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml DIPE was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid
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on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 15
2 g of Carvedilol was dissolved in 20 ml MDC at room temperature. The solution was filtered to remove any insoluble material. To this solution 0.5 g o-phosphoric acid (85%) solution was added dropwise. After complete addition of phosphoric acid 135 ml hexane was added. The sticky material was obtained from which the solvent was separated by decantation. A fresh 135ml hexane was added and the suspension was stirred for 24 hours. The sticky solid converts to free flowing solid on stirring, which was isolated by filtration and dried at 65°C to get amorphous form.
Example 16
20g of Carvedilol phosphate was dissolved in 200 ml water at room temperature.
The solution was lyophilized for 48 hours to get amorphous Form of Carvedilol
phosphate.
Example 17
Carvedilol phosphate is dissolved in water at a temperature range of 30-40 °C. Concentration of Carvedilol phosphate used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C.
Example 18
Carvedilol phosphate is dissolved in acetone at a temperature range of 30-40 °C. Concentration of Carvedilol Phosphate used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C.
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Example 19
Carvedilol Phosphate is dissolved in Methanol at a temperature range of 30-40 °C. Concentration of Carvedilol Phosphate used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C.
Example 20
Carvedilol Phosphate is dissolved in MDC at a temperature range of 30-40 °C. Concentration of Carvedilol Phosphate used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C.
Example 21
Carvedilol Phosphate is dissolved in Ethyl acetate at a temperature range of 30-
40 °C . Concentration of Carvedilol Phosphate used for spray drying is about 10 % weight/volume. Spray drying is carried out at the inlet temperature 120° C and outlet temperature 65°C.
Dated this 30th day of March, 2007

Dr K G Rajendran
Head-Knowledge Cell
USV Limited
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