WO2010092589A2

WO2010092589A2 - Process for preparation of amorphous carvedilol phosphate

Info

Publication number: WO2010092589A2
Application number: PCT/IN2009/000301
Authority: WO
Inventors: Koundinya Jitendra; Kumar Rajiv; Rampal Ashok; Kumar Arvindbhai Patel Dharmesh
Original assignee: Alkem Laboratories Ltd.
Priority date: 2008-05-26
Filing date: 2009-05-26
Publication date: 2010-08-19
Also published as: WO2010092589A3

Abstract

The present invention relates to a process for the preparation of amorphous carvedilol phosphate comprising; adding carvedilol base or carvedilol phosphate to a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and optionally adding water; optionally, adding orthophosphoric acid or its diluted solution to the preceeding; and spray drying the solution thus obtained to afford amorphous carvedilol phosphate.

Description

TITLE:

PROCESS FOR PREPARATION OF AMORPHOUS CARVEDILOL PHOSPHATE

FIELD OF THE INVENTION:

The present invention relates to a process for preparation of amorphous carvedilol phosphate.

BACKGROUND OF THE INVENTION

Carvedilol, (±)-l-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy) ethyl] aminoJ-2- propanol, is a nonselective β-adrenergic blocker with α i- blocking activity. Carvedilol is a racemic mixture having the following structural formula (I):

(I)

Carvedilol is the active ingredient in COREG®, which is indicated for the treatment of congestive heart failure and for the management of hypertension. Since carvedilol is a multiple-action drug, its beta-blocking activity affects the response to certain nerve impulses in parts of the body. As a result, beta-blockers decrease the heart's need for blood and oxygen by reducing its workload. Carvedilol is also known to be a vasodilator resulting primarily from alpha-adrenoceptor blockade. The multiple actions of carvedilol are responsible for the antihypertensive efficacy of the drug and for its effectiveness in managing congestive heart failure.

Carvedilol contains an α-hydroxyl secondary amine functional group, which has a pKa of 7.8. Carvedilol exhibits predictable solubility behaviour in neutral or alkaline media, i.e. above a pH of 9.0, the solubility of carvedilol is relatively low (<lμg/mL). The solubility of carvedilol increases with decreasing pH and reaches a plateau near pH=5, i.e. where saturation solubility is about 23 μg/mL at pH=7 and about 100 μg/mL at pH=5 at room temperature. At lower pH values (i.e., at a pH of 1 to 4 in various buffer systems), solubility of carvedilol is limited by the solubility of its protonated form or its corresponding salt formed in-situ. The hydrochloride salt of carvedilol generated in situ in acidic medium, which simulates gastric fluid, is less soluble in such medium.

United States Patent No. 4,503,067 (O67 patent") discloses a class of carbazolyl-(4) - oxypropanolamine compounds, including carvedilol. The O67 patent also discloses the conversion of the compounds to their pharmacologically acceptable salts, by reacting the compound with "an equivalent amount of an inorganic or organic acid," such as -phosphoric acid. United States Publication No. 2005/0240027 and United States Publication No.2005/0277689 each disclose that carvedilol has "relatively low solubility" (<1 μg/mL) in alkaline media, and that its solubility increases with decreasing pH, up to about 100 μg/mL. These publications also disclose solid and crystalline forms of carvedilol salts, as well as solvates thereof.

There is a need of suitable chemical stable salt of carvedilol having good solubility profile. Many different salts of carvedilol are available but carvedilol phosphate seems the most suitable, solubility-wise. Various prior arts on carvedilol salts exists such as for example, United States Publication No.2007238774 claiming carvedilol dihydrogen phosphate hemihydrate, United States Patent No. 7268156 claiming a crystalline carvedilol dihydrogen phosphate hemihydrate, United States Publication No.20070259940 claiming a compound which is carvedilol phosphate, United States Publication No.2004198812 claiming a pseudo polymorphic form carvedilol dihydrogen Phosphate, PCT Application No. 2001/035958 claiming carvedilol methanesulfonate and the process of preparing it and PCT Application No. 2008002683 claiming an amorphous carvedilol dihydrogen phosphate as well as pure amorphous carvedilol phosphate free of any crystalline form.

In light of the above, a need exists to develop different carvedilol forms and/ or different compositions, respectively, which have greater aqueous solubility, chemical stability, sustained or prolonged drug or absorption levels (i.e., such as in neutral gastrointestinal tract pH regions, etc.). There also exists a need to develop methods of treatment for hypertension, congestive heart failure or angina, etc. which comprises administration of the aforementioned carvedilol phosphate salts and/or solvates thereof or corresponding pharmaceutical compositions, which contain such salts, and/or solvates.

Despite various processes disclosed in the prior art for the preparation of carvedilol phosphate salt thereof, still there is a need for a process which can give carvedilol phosphate thereof in high purity and yield. It has been found that crystalline forms are less readily soluble than amorphous form, which may cause problems in the bioavailability of carvedilol phosphate in the body. There is therefore, a need for a form of carvedilol phosphate having limited crystallinity with improved process and formulation characteristics. OBJECT OF THE INVENTION

It is the object of the invention to provide a process for the preparation of amorphous carvedilol phosphate.

It is further the object of the invention to provide a process for the preparation of amorphous carvedilol phosphate in high yields and purity, suitable for large-scale manufacturing, which helps to overcome some of the deficiencies of the prior art and in other forms of carvedilol phosphate.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, a process for the preparation of amorphous carvedilol phosphate is provided.

According to another aspect of the present invention, a process for the preparation of amorphous carvedilol phosphate in high yields and purity, suitable for large-scale manufacturing is provided.

Accordingly, the present invention provides a process for the preparation of amorphous carvedilol phosphate comprising; adding carvedilol base or carvedilol phosphate to a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and optionally adding water; optionally, adding orthophosphoric acid or its diluted solution; and spray drying the obtained solution to afford amorphous carvedilol phosphate.

In one aspect of the present invention, the process comprises adding carvedilol phosphate in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and adding water; and spray drying the obtained solution to afford amorphous carvedilol phosphate.

According ,to another aspect of the present invention, the process comprises adding carvedilol base in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof; adding orthophosphoric acid or its diluted solution; and spray drying the obtained solution to afford amorphous carvedilol phosphate.

There is also provided a process for the preparation of amorphous carvedilol phosphate wherein the water miscible cyclic ether(s) used in the process is selected from the group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane and the like and mixtures thereof.

There is also provided a process for the preparation of amorphous carvedilol phosphate wherein the aliphatic nitrile(s) used in the process is selected from the group comprising acetonitrile, propanenitrile and the like and mixtures thereof.

The invention can be summarized as follows:

A. A process for the preparation of amorphous carvedilol phosphate comprising;

(a) adding carvedilol base or carvedilol phosphate to a solvent consisting of water miscible cyclic ether (s) or aliphatic nitrile(s) or a mixture thereof and optionally adding water;

(b) optionally, adding orthophosphoric acid or its diluted solution to (a); and

(c) spray drying the solution obtained in (a) or (b) to afford amorphous carvedilol phosphate. B. The process according to A above, comprising:

(a) adding carvedilol phosphate in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and adding water;

(b) spray drying the solution obtained in (a) to afford amorphous carvedilol phosphate.

C. The process according to A above, comprising:

(a) adding carvedilol base in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof;

(b) adding orthophosphoric acid or its diluted solution to (a) to obtain a solution;

(c) spray drying the solution obtained in (b) to afford amorphous carvedilol phosphate.

D. The process according to A above, wherein the water miscible cyclic ether(s) is selected from the group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane and the like and mixtures thereof.

E. The process according to A above, wherein the aliphatic nitrile(s) is selected from the group comprising acetonitrile, propanenitrile and the like and mixtures thereof

F. The process according to A above, wherein the carvedilol phosphate includes carvedilol phosphate, carvedilol hydrogen phosphate and carvedilol dihydrogen phosphate. G. The process according to A above, wherein the spray drying is carried out with an inlet temperature of about 80⁰C to about 120⁰C and an outlet temperature of about 30⁰C to about 110⁰C.

H. The process according to A above, wherein the purity of the amorphous carvedilol phosphate obtained is more than about 99%.

I. The process according to A above, wherein the amorphous carvedilol phosphate has a moisture content of less than about 5% by weight.

J. The process according to A above, wherein the amorphous carvedilol phosphate has a particle size of less than about 20 micron.

BRIEF DESCRIPTION OF DRAWINGS

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein:

Figure 1 is a XRPD for amorphous carvedilol phosphate prepared by the process of the present invention.

Coirtβ

PasftBr>PTh*3

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/ or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

The term "carvedilol phosphate" as used herein, in the specification includes carvedilol phosphate, carvedilol hydrogen phosphate and carvedilol dihydrogen phosphate as given below.

Formula Ia: Carvedilol phosphate

Formula Ib: Carvedilol hydrogen phosphate

Formula Ic: Carvedilol dihydrogen phosphate Major advantages of the process of the present invention as compared to the prior arts processes are: (i) the product obtained by the process of the invention is free from residual solvents; (ii) the operations are less time consuming; (iϋ) the operations are easy to handle on large scale.

The present invention relates to a process for the preparation of amorphous (±)-l-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy) ethyl] amino]-2- propanol phosphate salt i.e. amorphous carvedilol phosphate salt.

The present invention also relates to pharmaceutical compositions which contain amorphous carvedilol phosphate salts and/ or solvates thereof.

The present invention further relates to a method of treating hypertension, congestive heart failure and angina, which comprises administering to a subject in need thereof an effective amount of amorphous carvedilol phosphate salt (or a pharmaceutical composition).

Surprisingly, we have found that by using a unique solvent system for dissolving carvedilol phosphate and spray drying technique the resultant solution, we were able to produce pharmaceutical grade amorphous form of carvedilol phosphate in an efficient manner with a yield and purity higher than the prior art processes. This amorphous form of carvedilol phosphate exhibited much higher aqueous solubility than the corresponding free base or other prepared crystalline salts of carvedilol, such as the hydrochloride salt. This amorphous form also has potential to improve the stability of carvedilol phosphate 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.

Accordingly, the present invention provides a process for the preparation of amorphous carvedilol phosphate comprising; adding carvedilol base or carvedilol phosphate to a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and optionally adding water; optionally, adding orthophosphoric acid or its diluted solution and then spray drying the obtained solution to afford amorphous carvedilol phosphate.

In one embodiment of the present invention, the process comprises adding carvedilol phosphate in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and adding water; and spray drying the obtained solution to afford amorphous carvedilol phosphate.

In another embodiment of the present invention, the process comprises adding carvedilol base in a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof; adding orthophosphoric acid or its diluted solution; and spray drying the obtained solution to afford amorphous carvedilol phosphate.

The solvent used in process of the present invention is used for dissolving carvedilol phosphate before its removal by spray drying in order to afford amorphous carvedilol phosphate. The solvent may be selected from water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof. The water miscible cyclic ether(s) used in the process is selected from the group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane and the like and mixtures thereof. The aliphatic nitrile(s) used in the process is selected from the group comprising acetonitrile, propanenitrile and the like and mixtures thereof. Preferred solvents are tetrahydrofuran or acetonitrile or mixtures thereof.

In an embodiment of the present invention, carvedilol phosphate was dissolved in tetrahydrofuran or acetonitrile /water at 30 -50 ⁰C and the solution was cooled to 30-35⁰C. Then the solution was spray dried with air flow (feeding speed 200 ml/ hours) at inlet temperature about 50-120 ⁰C and out let temperature maintained at 30-50⁰C.

In another embodiment of the present invention, carvedilol was dissolved in tetrahydrofuran or acetonitrile at 40-45⁰C; diluted orthophosphoric acid solution was added; pH of solution was maintained at 2.8-3.8 and solution was cooled to 30-35⁰C. Then the solution was spray dried with air flow (feeding speed 200 ml/ hours) at inlet temperature 65-100 ⁰C and out let temperature maintained at 37-55°C to afford amorphous carvedilol phosphate.

Spray drying broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture. In a typical spray drying apparatus, there is a strong driving force for evaporation of solvent from the droplets, which may be provided by providing a drying gas. Spray drying processes and equipment are described in Perry's Chemical Engineer's Handbook, pp. 20-54 to 20-57 (6th ed. 19S4) and Remington: The Science and Practice of Pharmacy, 19th ed., vol. II, pg. 1627, which are herein incorporated by reference. By way of non -limiting example only, the typical spray drying apparatus comprises a drying chamber, atomizing means for atomizing a solvent-containing feed into the drying chamber, a source of drying gas that flows into the drying chamber to remove solvent from the atomized-solvent-containing feed, an outlet for the products of drying, and product collection means located downstream of the drying chamber. Examples of such apparatuses include Model LSD - 48 (Jay Instrument & System Pvt. Ltd. Mumbai, India). Typically, the product collection means includes a cyclone connected to the drying apparatus. In the cyclone, the particles produced during spray drying are separated from the drying gas and evaporated solvent, allowing the particles to be collected. A filter may also be used to separate and collect the particles produced by spray drying.

Spray drying can be carried out with an inlet temperature of about 50⁰C to about 160⁰C and an outlet temperature of below about 120⁰C. It is preferred that the spray drying is carried out with an inlet temperature of about 80⁰C to about 120⁰C and an outlet temperature of about 30⁰C to about 110⁰C.

In the process of the invention where carvedilol base is used, orthophosphoric acid is used to convert the carvedilol base into carvedilol phosphate. Orthophosphoric acid may be used as such or more preferably it may be used in its diluted form. The orthophosphoric acid can be generally diluted up to 500 times by water. The orthophosphoric acid may be diluted to provide 1 mol phosphoric acid to react with 1 mol of carvedilol to ^prepare carvedilol phosphate. The orthophosphoric acid may be diluted to provide 2 mol phosphoric acid to react with 1 mol of carvedilol to prepare carvedilol hydrogen phosphate. The orthophosphoric acid may be diluted to provide 3 mol phosphoric acid to react with 1 mol of carvedilol to prepare carvedilol dihydrogen phosphate.

The present invention provides a process for the preparation of amorphous carvedilol phosphate in high yields and purity and which is suitable for large-scale manufacturing. The process of the present invention provides amorphous carvedilol phosphate with purity of at least about 99%.

The amorphous form of carvedilol phosphate of the invention has a moisture content between about 0.5 and about 7.5%, more preferably between about 0.5 and about 5% by weight, even more preferably less than about 5%. As used herein, the term "water content" refers to the content of water based upon the Loss on Drying method (the "LOD" method) as described in UPS 29-NF 24, official August 1, 2006, Physical Test and Determinations, <731> LOSS ON DRYING or in Pharmacopeial Forum, Vol. 24, No. 1, p. 5438 (Jan - Feb 1998), the Karl Fisher assay for determining water content or thermogravimetric analysis (TGA). The moisture content of the present invention may be measured on Mettler DL-35 instrument using Karl-Fisher reagent.

The present invention provides in one aspect, a process for the preparation of amorphous carvedilol phosphate with particle size less than 20 micron.

The following example illustrates the preparation of amorphous form of carvedilol dihydrogen phosphate is not to be construed as limiting the scope of the invention in any manner.

EXAMPLE l

Carvedilol phosphate (40 gm) was dissolved in 10 volume THF and water mixture (90:10) at 40-45 ⁰C and solution was cooled to 30- 35°C. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) at inlet temperature 65-100 ⁰C and outlet temperature maintained at 40-50⁰C. Yield: 37.5% of Amorphous Carvedilol phosphate; purity: 99.9% EXAMPLE 2

Carvedilol phosphate (40 gm) was dissolved in 13 volume acetonitrile and water mixture (70:30) at 40-45 ⁰C and solution was cooled to 30-35⁰C. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) -at inlet temperature 82-100 ⁰C and outlet temperature maintained at 40-50⁰C. Yield: 37.5% of Amorphous Carvedilol phosphate; purity: 99.9%

EXAMPLE S

Carvedilol phosphate (100 gm) was dissolved in 13 volume of acetonitrile and water mixture (70:30) at 40 -45 ⁰C and solution cooled to 30-35⁰C. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) at inlet temperature 82-90 ⁰C and outlet temperature maintained at 37-55°C. Yield: 42 % of Amorphous Carvedilol phosphate; purity: 99.89%

EXAMPLE 4

Carvedilol phosphate (2.8 kgs) was dissolved in 13 volume of acetonitrile and water mixture (70:30) at 40 -45 ⁰C and solution cooled to 30-35⁰C. Then the solution was spray dried with air flow

(feeding speed 5.0 lit / hours) at inlet temperature 110-115⁰C and outlet temperature maintained at 50 -60⁰C.

Yield: 1.8 kg (64 % w/w) of Amorphous carvedilol phosphate; purity: 99.93%

EXAMPLE 5 Process for preparation of amorphous carvedilol phosphate from earvedilol base

Carvedilol (50 gm) was dissolved in acetonitrile (455 mL) at 65-75 °C, added o-phosphoric acid (85 %) solution (14.2 gm in 195 mL water), pH of solution was maintained at 2.8-3.8 and solution cooled to 30-35⁰C. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) at inlet temperature 82-115 ⁰C and out let temperature maintained at 37-55°C. Yield: 40 % of Amorphous carvedilol phosphate; purity: 99.80%

EXAMPLE 6

Process for preparation of amorphous carvedilol phosphate from carvedilol base

Carvedilol (50 gm) was dissolved in THF (450 mL) at 40-45⁰C, added o-ρhosphoric acid (85 %) solution (14.2 gm in 50 mLwater), pH of solution was maintained at 2.8-3.8 and solution was cooled to 30- 35°C. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) at inlet temperature 65-100 ⁰C and out let temperature maintained at 37-55°C. Yield: 50 % of Amorphous carvedilol phosphate; purity: 99.83%

EXAMPLE 7

Process for preparation of amorphous carvedilol phosphate from carvedilol base

Carvedilol (50 gm) was dissolved in mixture of THF (250 mL) and acetonitrile (250 mL) at 30-35 ⁰C, added o-phosphoric acid (85 %) solution (14.2 gm in 100 mLwater), pH of solution was maintained at 2.8-3.8. Then the solution was spray dried with air flow (feeding speed 200 ml / hours) at inlet temperature 65-100 ⁰C and out let temperature maintained at 37-55°C. Yield: 40 % of Amorphous carvedilol phosphate; purity: 99.76%

EXAMPLE 8

Process for the preparation of amorphous Carvedilol phosphate from carvedilol base

To the mixture of 25.0 g Carvedilol and 230.0 ml acetonitrile, the solution of 2 A g phosphoric acid in 98.0 ml water is added. The reaction mass was heated to 45-50⁰C and maintained at the same temperature for 2 hrs. Then the reaction mass was cooled to 25- 30^cC. The solution was spray dried with air flow (feeding speed 0.3 lit/ hour) at inlet temperature 110-115⁰C and outlet temperature maintained at 60-65⁰C. Yield: 46% of Amorphous Carvedilol phosphate; purity: 99.85%

EXAMPLE 9

Process for the preparation of amorphous Carvedilol hydrogen phosphate from carvedilol base

To the mixture of 25.0 g Carvedilol and 230.0 ml acetonitrile, the solution of 3.6 g phosphoric acid in 98.0 ml water was added. The reaction mass was heated to 45-50⁰C and maintained at the same temperature for 2 hrs. The reaction mass was then cooled to 25- 30⁰C. The solution was spray dried with air flow (feeding speed 0.5 lit/hour) at inlet temperature 110-115⁰C and outlet temperature maintained at 50-60⁰C Yield: 45% g of Amorphous carvedilol phosphate; purity: 99.88%

EXAMPLE IO

To the mixture of 25.0 g Carvedilol and 230.0 ml acetonitrile, the solution of 7.2 g phosphoric acid in 98.0 ml water was added. The reaction mass was heated to 45-50⁰C and maintained at the same temperature for 2 hrs. The reaction mass was then cooled to 25- 30⁰C. The solution was spray dried with air flow (feeding speed 0.5 lit/ hour) at inlet temperature 110-115⁰C and outlet temperature maintained at 55-60⁰C. Yield: 64.5% of Amorphous Carvedilol phosphate; purity: 99.91%

EXAMPLE Il

To the mixture of 25.0 g Carvedilol and 225.0 ml THF, the solution of 2.4 g phosphoric acid in 25.0 ml water was added. The reaction mass was heated to 45-50⁰C and maintained at the same temperature for 2 hrs. The reaction mass was then cooled to 25- 30⁰C. The solution was spray dried with air flow (feeding speed 0.15 lit/ hour) at inlet temperature 65-100⁰C and out let temperature maintained at 40-55⁰C. Yield: 43 % of Amorphous carvedilol phosphate; purity: 99.78% Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Claims

Claims:

1. A process for the preparation of amorphous carvedilol phosphate comprising;

(a) adding carvedilol base or carvedilol phosphate to a solvent consisting of water miscible cyclic ether(s) or aliphatic nitrile(s) or a mixture thereof and optionally adding water;

(b) optionally, adding orthophosphoric acid or its diluted solution to (a); and

(c) spray drying the solution obtained in (a) or (b) to afford amorphous carvedilol phosphate.

2. The process as claimed in claim 1, comprising:

3. The process as claimed in claim 1, comprising:

4. The process as claimed in claim 1, wherein the water miscible cyclic ether(s) is selected from the group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane and the like and mixtures thereof.

5. The process as claimed in claim 1, wherein the aliphatic nitrile(s) is selected from the group comprising acetonitrile, propanenitrile and the like and mixtures thereof

6. A process as claimed in claim 1, wherein the carvedilol phosphate includes carvedilol phosphate, carvedilol hydrogen phosphate and carvedilol dihydrogen phosphate.

7. A process as claimed in claim 1, wherein the spray drying is carried out with an inlet temperature of about 80⁰C to about 120⁰C and an outlet temperature of about 30⁰C to about 110⁰C.

8. A process as claimed in claim 1, wherein the purity of the amorphous carvedilol phosphate obtained is more than about 99%.

9. A process as claimed in claim 1, wherein the amorphous carvedilol phosphate has a moisture content of less than about 5% by weight.

10. A process as claimed in claim 1, wherein the amorphous carvedilol phosphate has a particle size of less than about 20 micron.