Abstract:
The present invention disclosed 1-(Carbazol-4-Yloxy-3-(2-(0-methoxyphenoxy) ethyl) amino)-2-propanol phosphate sesquihydrate (Carvedilol dihydrogenphosphate sesquihydrate), methods of preparing the sesquithydrate by adding phosphoric acid to a suspension of Carvedilol in water or an organic solvent or a mixture of water and organic solvent followed by isolating the product directly or by adding an organic solvent.
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BACKGROUND OF THE INVENTION
Field of the Invention:
The present invention relates to new crystalline forms of carvedilol and pharmaceutical compositions thereof, as well as processes for its preparation and manufacture. Description of the Related Art:
Carvedilol, 1 -(Carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy) ethyl]amino]-2-propanol (CAS Registry No. 72956-09-3), has the formula as given below:
Carvedilol as a free base is used for treatment of hypertension, congestive heart failure and angina. The currently commercially available carvedilol product is a conventional, tablet prescribed as a twice-a-day medication.
U.S. Patent No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds and salts thereof with pharmacologically acceptable acids. The patent discloses the conversion of carbazolyl-(4)-oxypropanolamine compounds into their pharmacologically acceptable salts, by reacting with an equivalent amount of an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, acetic acid, citric acid, maleic acid or benzoic acid in an organic solvent.
International Application publication number WO 2004/002419 discloses and designates the following forms of carvedilol, pharmaceutical compositions thereof and methods of
using the same to treat cardiovascular diseases including hypertension, congestive heart failure and angina:
Carvedilol dihydrogen phosphate hemihydrate Form-I
Carvedilol dihydrogen phosphate dihydrate Form-II
Carvedilol dihydrogen phosphate methanol solvate Form-Ill
Carvedilol dihydrogen phosphate dihydrate Form-IV
Carvedilol dihydrogen phosphate Form-V
Carvedilol hydrogen phosphate Form-VI
The WO 2004/002419 application further characterizes (XRD, thermal analysis, FT- Raman spectrums) crystalline forms of carvedilol phosphate salt. The processes disclosed for preparation of carvedilol dihydrogen phosphate hemihydrate (Form-I) involve the addition of phosphoric acid to the solution of carvedilol in acetone-water, followed by isolation and drying under vacuum. The processes disclosed for preparation of carvedilol dihydrogen phosphate dihydrate involve the slurrying of the Form-I with an acetone/water mixture between 10 and 30 oC for several days, and for the preparation of carvedilol dihydrogen phosphate methanol solvate (Form-Ill) by slurring Form-I in methanol between 10 and 30 oC for several days. The application further discloses that the carvedilol dihydrogen phosphate displays higher solubility when compared to the free base of carvedilol.
International Application publication number WO 2005/051383 discloses several crystalline carvedilol salts selected from mandelate, lactate, maleate, sulfate, glutarate, mesylate, phosphate, citrate, hydrobromide, oxalate, hydrochloride, benzoate as solvates and anhydrous forms. The application further discloses pharmaceutical compositions containing the above salts, anhydrous forms or solvates thereof, and methods of using the compound in the treatment of certain disease in mammals.
It has now been shown that a novel crystalline form of carvedilol phosphate (i.e., carvedilol dihydrogen phosphate salt) can be isolated as pure crystalline, sesquihydrate, which is found to be more stable.
SUMMARY AND OBJECTS OF THE INVENTION
It is a principle object of the present invention to provide a novel crystalline form of carvedilol as carvedilol dihydrogen phosphate sesquihydrate.
It is another object of the present invention to provide a method for preparing crystalline carvedilol dihydrogen phosphate sesquihydrate.
It is still another object of the present invention to provide a preparation containing stable crystalline carvedilol dihydrogen phosphate sesquihydrate.
Briefly described, those and other objects and advantages of the present invention are accomplished, as embodied and fully described herein, by crystalline carvedilol dihydrogen phosphate sesquihydrate having the formula:
The carvedilol is characterized by an x-ray powder diffraction pattern having peaks at about 5.83 (±) 0.2, 6.46 (±) 0.2, 6.78 (±) 0.2, 14.39 (±) 0.2, 15.11 (±) 0.2, 16.21 (±) 0.2, 17.26 (±) 0.2, 18.00 (±) 0.2, 19.01 (±) 0.2, 20.46 (±) 0.2, 20.97 (±) 0.2, 21.81 (±) 0.2, 24.45 (±) 0.2, and 26.11 (±) 0.2 two-theta. The carvedilol is also characterized by a differential scanning calorimetry thermogram having a peak at about 105° C to about 120° C and 156° C (±) 0.1%, and by a water content of between about 4.0 to 7.0 % w/w. The aforementioned objects and advantages of the present invention are also accomplished, as embodied and fully described herein, by a process for preparing carvedilol dihydrogen phosphate sesquihydrate by suspending carvedilol in one of water, water miscible solvents, and a mixture of water and water miscible organic solvents; reacting the suspension with phosphoric acid to form a solution; adding a solvent to the solution; and isolating the product. The water miscible organic solvent may be ethanol, n-propyl alcohol, isopropyl alcohol, acetone, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethoxy ethane and mixtures thereof. The solvent may be water, ethanol, n-propyl alcohol, isopropyl alcohol, acetone, acetonitrile, dioxane, tetrahydrofuran, ethyl acetate, isopropyl acetate, dimethoxy ethane and mixtures thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an FT-IR spectrum for carvedilol phosphate sesquihydrate according to a preferred embodiment of the present invention;
FIG. 2 is and X-ray powder diffractogram for the carvedilol phosphate sesquihydrate of FIG. 1 and
FIG. 3 is a DSC curve for the carvedilol phosphate sesquihydrate of FIG. 1.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Several preferred embodiments of the present invention are described for illustrative purposes, it being understood that the invention may be embodied in other forms not specifically shown in the drawings.
Thus, in accordance with the present invention, a novel crystalline carvedilol dihydrogen phosphate sesquihydrate and process for preparing the carvedilol phosphate sesquihydrate is provided.
The novel crystalline carvedilol dihydrogen phosphate sesquihydrate according to the present invention is the compound of formula (I):
(jj MeO ^^ HO-p-OH t.sHjO
I *
OH
(I)