FIELD OF THE INVENTION
The present invention relates to a novel anhydrous crystalline form of carvedilol dihydrogen phosphate, referred to as Form A.
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 b-adrenergic blocking agent with a1blocking 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 carvedilol phosphate salts such as carvedilol dihydrogen phosphate and 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 into pharmaceutical dosages, such as the tendency of a powdered or granulated form
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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 a novel anhydrous crystalline form of carvedilol dihydrogen phosphate referred to as Form A having water content below 1.3%.
Further the present invention provides a process for the preparation of Form A that comprises of
(a) preparing a solution of carvedilol base in water miscible solvent,
(b) adding a solution of step (a) to aqueous H3PO4,
(c) adding mixture of step (b) to water and
(d) isolating the solid
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Figure 1 is an X-ray powder diffractogram for Form A of carvedilol dihydrogen
phosphate
Figure 2 is an FT-IR spectrum for Form A of carvedilol dihydrogen phosphate
Figure 3 shows the thermogravimetric analysis (TGA) results for Form A of
carvedilol dihydrogen phosphate
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, it has been found that carvedilol dihydrogen phosphate can be readily isolated as a novel anhydrous crystalline form referred to as Form A.
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In one aspect, the present invention provides a novel anhydrous crystalline carvedilol dihydrogen phosphate referred to as Form A is characterized by PXRD pattern with characteristic peaks at about 6.50, 7.06, 9.65, 12.99, 13.66, 14.97, 15.84, 17.69, 18.15, 18.44, 18.92, 19.58, 20.22, 20.94, 22.10, 23.10, 23.58, 24.53, 25.10, 27.51, 28.32 degrees two theta (figure 1).
The FT-IR spectrum of anhydrous carvedilol dihydrogen phosphate (Form A) of the present invention (figure 2) has characteristic bands at about 3224, 3071, 2841, 1625, 1604, 1587, 1505, 1454, 1442, 1346, 1332, 1252, 1218 cm-1 (figure 2).
The novel form of anhydrous of carvedilol dihydrogen phosphate designated as Form A is further characterized by weight loss in the range of about 0.4 % to 1.3 %, typically in the range of 0.7-1.0 % as measured by thermogravimetric analysis over the temperature range between about 25 °C and about 200 °C (figure 3).
In another aspect, the crystalline carvedilol dihydrogen phosphate (Form A) of the present invention can be obtained by process comprising:
(a) preparing a solution of carvedilol base in water miscible solvent,
(b) adding a solution of step (a) to aqueous H3PO4,
(c) adding mixture of step (b) to water and
(d) isolating the solid.
In step (a), the solvent is selected from dimethylformamide (DMF), tetrahydrofuran (THF), acetonitrile, diethylene glycol, dimethylacetamide, sulfolane or mixture thereof. The step (b) and step (c) can be performed at a temperature of 0-70 °C. The step (c) can be performed in reverse manner i.e water is added to mixture of step (b). The ratio of substrate to solvent in step (a) is from 1:0.1 to 1:10, preferably it is 1:1 to 1:3.
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The effective amount of Form A 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, intramuscularly or topically for the treatment of hypertension, congestive heart failure and angina in a mammal in need thereof.
The following examples are given for the purpose of illustrating the present invention but not intended to limit the scope of the invention as defined hereinabove and as claimed hereinbelow.
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.
EXAMPLES Example 1
A solution of carvedilol base (20 g) in DMF (40 mL) was prepared and to that one molar aqueous H3PO4 (3.4 mL) was added. This solution was then added to the cold water (120 mL). The reaction mixture was stirred for 5 to 10 minutes at 0-5 °C. The solid was filtered, washed with water and dried. Yield: 19 g. M.P.: 145-147 °C.
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Example 2
One molar aqueous H3PO4 (3.4 mL) was added to a solution of carvedilol base (20 g) in DMF (40 mL). This reaction mixture was stirred and slowly heated to 55-60 °C for 30 minutes. Water (120 mL) was added to the reaction mixture and then allowed to cool to 0-5 °C. Solid was filtered, washed with water and dried. Yield: 19 g. M.P.: 146-148 °C.
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WE CLAIM:
1. Anhydrous carvedilol dihydrogen phosphate.
2. The compound according to claim 1 having an X-ray diffraction pattern as
shown in figure 1.
3. The compound according to claim 2 having PXRD pattern with characteristics
peaks at about 6.50, 7.06, 9.65, 12.99, 13.66, 14.97, 15.84, 17.69, 18.15,
18.44, 18.92, 19.58, 20.22, 20.94, 22.10, 23.10, 23.58, 24.53, 25.10, 27.51,
28.32 degrees two theta.
4. The compound according to claim 1 having an infrared spectrum as shown in
figure 2.
5. The compound according to claim 4 having IR spectrum with characteristic
peaks at about 3224, 3071, 2841, 1625, 1604, 1587, 1505, 1454, 1442, 1346,
1332, 1252, 1218 cm1.
6. The compound of claim 1 in which water content is less than 1.3 % by weight.
7. A process for the preparation of compound of claim 1, which comprises of:
(a) preparing a solution of carvedilol base in water miscible solvent,
(b) adding a solution of step (a) to aqueous H3PO4,
(c) adding mixture of step (b) to water or adding water to mixture of
step (b) and
(d) isolating the solid.
8. A process according to claim 7 in which in step (a), the water miscible solvent
is selected from dimethylformamide (DMF), tetrahydrofuran (THF),
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acetonitrile, diethylene glycol, dimethylacetamide, sulfolane or mixtures thereof.
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9. A process according to claim 7 in which step (b) and step (c) are performed at
a temperature range of 0-70 °C.
10. A process according to claim 7 in which in step (a) the substrate solvent ratio
is from 1:0.1 to 1:10, preferably it is 1:1 to 1:3.

The present invention provides a novel anhydrous crystalline form of carvedilol dihydrogen phosphate referred to as Form A having water content below 1.3%. Further it provides a process for the preparation of Form A. The PXRD, FT-IR and TGA data has been provided.