FIELD OF THE INVENTION
The present invention relates to anhydrous crystalline form of carvedilol dihydrogen phosphate and process for the preparation of it.
BACKGROUND OF THE INVENTION
Carvedilol is chemically known as (±)-1-(9H-carbazol-4-yloxy)-3-[[2(2-methoxyphenoxy)ethyl]amino]-2-propanol having following structure (formula
1)-
Carvedilol is disclosed in US patent No. 4 503 067. Carvedilol is a nonselective p-adrenergic blocking agent with on blocking activity. It is used for treatment of hypertension, congestive heart failure and angina. Currently, carvedilol is synthesized as free base for incorporation in medication that is available commercially.
WO 2004/002419 discloses crystalline forns of carvedilol phosphate salts such as carvedilol dihydrogen phosphate, its hemihydrate and dihydrate which are characterized by PXRD, FT-IR and FT-Raman spectroscopic methods.
WO 2005/051383 discloses various crystalline forms of carvedilol salts such as mandelate, lactate, maleate, sulfate, glutarate and benzoate.
One of the most important physical properties of a pharmaceutical compound is its solubility in aqueous solution, particularly the solubility in gastric juices of a patient. Other important properties relate to the ease of processing the form
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into pharmaceutical dosages, such as the tendency of a powdered or granulated form to flow and the surface properties that determine whether crystals of the form will adhere to each other when compacted into a tablet.
The discovery of new forms and solvates of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. In light of the above, a need exists to develop different carvedilol forms which have greater aqueous solubility, chemical stability, sustained or prolonged drug or absorption levels.
SUMMARY OF THE INVENTION
The present invention provides novel anhydrous crystalline form designated as Form B of carvedilol dihydrogen phosphate and process for the preparation
of it.
DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffractogram for Form B of carvedilol dihydrogen
phosphate
Figure 2 is an FT-IR spectrum for Form B of carvedilol dihydrogen phosphate
Figure 3 shows the thermogravimetric analysis (TGA) results for Form B of
carvedilol dihydrogen phosphate
Figure 4 is Differential Scanning Calorimetry results for Form B of carvedilol
dihydrogen phosphate
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel anhydrous crystalline form of carvedilol dihydrogen phosphate referred to as Form B which is characterized by PXRD pattern with characteristic peaks at 6.96, 7.96, 9.13, 11.17, 11.36, 12.56, 12.9,
13.92, 14.33, 14.78, 15.39, 15.93, 16.22, 17.57, 18.20, 18.84, 19.67, 20.63,
20.92, 21.7, 22.16, 22.81, 23.08, 23.36, 23.99, 24.66, 25.05, 25.34, 25.44,
25.92, 27.0, 27.35, 27.81, 28.31, 29.4, 29.71 degrees two theta (figure 1).
The FT-IR spectrum of anhydrous crystalline form of carvedilol dihydrogen phosphate (Form B) has characteristic bands at about 3485, 3177, 2841,
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2396, 1607, 1504, 1455, 1410, 1330, 1253, 1220 cm -1 (figure 2). The Form B of the present invention is further characterized by thermogravimetric analysis over the temperature range of 35 to 200 °C (figure 3). The differential scanning calorimetry results are shown in figure 4.
In another aspect, the anhydrous crystalline form of carvedilol dihydrogen phosphate (Form B) of the present invention can be obtained by a process comprising:
(a) preparing a solution of carvedilol base in a suitable solvent,
(b) adding H3PO4 in acetic acid to a solution of step (a) and
(c) isolating the solid.
In step (a), the solvent is selected from ketone, lower alkanol, ester, chlorinated solvent, acetonitrile or mixture thereof. Examples of lower alkanol include those primary, secondary and tertiary alcohols having one to six carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and t-butanol. Ketone include acetone, 2-butanone and 4-methyl pentanone. Ester include ethyl acetate and butyl acetate. Chlorinated solvent include chloroform, dichloromethane and dichloroethane. Mixtures of all of these solvents are also contemplated.
The carvedilol base in a suitable solvent is heated in the range of temperature 40-70 °C, preferably at 55-60 °C. The ortho phosphoric acid is used preferably in anhydrous form to prepare the solution in acetic acid. After the addition of orthophosphoric acid in acetic acid to carvedilol base solution, the reaction mixture is cooled to 0-5 °C. The solid is collected by filtration and then dried.
The quantity of carvedilol base and ortho phosphoric acid is equivalent or slightly molar excess.
The effective amount of anhydrous crystalline form of carvedilol dihydrogen phosphate can be used to prepare pharmaceutical composition in association with one or more non toxic pharmaceutically acceptable carriers and/or diluents thereof, and if desired , other active ingredients, which may be administered orally, intravascularly, intraperitoneally, subcutaneously,
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intramuscularly or topically for the treatment of hypertension, congestive heart failure and angina in a mammal in need thereof.
The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and is not intended to limit the scope of the invention.
EXPERIMENTAL
The powder X-ray diffraction spectrum is measured using Philips (PAN alytical X'pert pro) difractogram (copper anti cathode) and expressed in terms of inter planar distance d, Bragg's angle 2 theta, intensity and relative intensity (expressed as a percentage of the most intense peak). The scanning parameters included: measurment range: 3-40 degrees two theta; continuous scan.
The FTIR spectra were obtained using a Perkin-Elmer, Spectrum-100
instrument.
The thermogravimetric analysis (TGA) was done using Perkin Elmer Pyris 1
TGA instrument.
Example 1: Preparation of anhydrous crystalline form of carvedilol dihydrogen phosphate (Form B)
A solution of carvedilol base (10 g) in acetone (250 mL) was heated at 55-60 °C and to that H3PO4 (2.65 g) in acetic acid was added. The reaction mixture was stirred for 15-30 minutes and then cooled to 0-5 °C. The solid was filtered, washed with acetone and dried. Yield: 8.5 g.
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We claim:
1. Anhydrous crystalline form of carvedilol dihydrogen phosphate having X-
ray diffraction pattern as shown in figure 1.
2. The compound according to claim 1 having PXRD pattern with
characteristics peaks at about 6.96, 7.96, 9.13, 11.17, 11.36, 12.56, 12.9,
13.92, 14.33, 14.78, 15.39, 15.93, 16.22, 17.57, 18.20, 18.84, 19.67,
20.63, 20.93, 21.7, 22.16, 22.81, 23.08, 23.36, 23.99, 24.66, 25.05, 25.34,
25.44, 25.94, 27.0, 27.35, 27.81, 28.31, 29.4, 29.71 degrees two theta.
3. A process for the preparation of compound of claim 1, which comprises of:

(a) preparing a solution of carvedilol base in a suitable solvent,
(b) adding H3PO4 in acetic acid to a solution of step (a) and
(c) isolating the solid.

4. A process according to claim 3 in which in step (a), the solvent is selected
from lower alkanol, ketone, ester, chlorinated solvent and acetonitrile.
5. A process according to claim 4 wherein the lower alkanol includes
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
butanol and mixtures thereof.
6. A process according to claim 4 wherein ketone includes acetone, 2-
butanone and 4-methyl pentanone.
7. A process according to claim 4 wherein ester includes ethyl acetate and
butyl acetate.
8. A process according to claim 4 wherein chlorinated solvent includes
chloroform, dichloromethane and dichloroethane.
9. A process according to claim 3, wherein in step (a), the solution is heated
at a temperatute of 40-70 °C, preferably at 55-60 °C.
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10. A process according to claim 3 wherein in step (b), the ortho phosphoric acid is preferably anhydrous.
The present invention provides novel anhydrous crystalline form designed as Form B of carvedilol dihydrogen phosphate and process for the preparation of it.