Claims:We Claim:
1. A process for the preparation of a stable and highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms, comprising:
a) providing a solution of Carvedilol in methanol solvent at reflux temperature of the solvent used;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment to obtain a filtrate;
c) cooling the solution obtained in step-(a) or step-(b) to a temperature of below about 20°C to cause crystallization; and
d) collecting the highly pure crystalline Form II of Carvedilol obtained in step-(c).

2. The process as claimed in claim 1, wherein the solution in step-(a) is prepared by dissolving Carvedilol (crude or pure) in methanol solvent at the reflux temperature of the solvent used; wherein the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about -5°C to about 20°C for at least 10 minutes; and wherein the collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

3. The process as claimed in claim 2, wherein the crystallization in step-(c) is accompanied by cooling the solution while stirring at a temperature of about 0°C to about 10°C for about 20 minutes to 5 hours.

4. A process for the preparation of a stable and highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms, comprising:
a) providing a solution of Carvedilol in ethyl acetate solvent at reflux temperature of the solvent used, wherein the quantity of ethyl acetate solvent required is at least about 8 volumes with respect to the quantity of Carvedilol used;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment to obtain a filtrate;
c) seeding the solution obtained in step-(a) or step-(b) with crystalline Form II of Carvedilol;
d) cooling the solution obtained in step-(c) to a temperature of below about 35°C to cause crystallization; and
e) collecting the highly pure crystalline Form II of Carvedilol obtained in step-(d).

5. The process as claimed in claim 4, wherein the amount of ethyl acetate solvent employed in step-(a) is about 8 volumes to about 12 volumes with respect to the quantity of Carvedilol used.

6. The process as claimed in claim 5, wherein the amount of ethyl acetate solvent employed in step-(a) is about 9 volumes to about 10 volumes, with respect to the quantity of Carvedilol used.

7. The process as claimed in claim 4, wherein the solution is step-(a) is prepared by dissolving Carvedilol (crude or pure) in ethyl acetate solvent at the reflux temperature of the solvent used; wherein the crystallization in step-(d) is accomplished by cooling the solution while stirring at a temperature of about 20°C to about 35°C for at least 30 minutes; and wherein the collection of the precipitated solid in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

8. The process as claimed in claim 7, wherein the crystallization in step-(d) is accomplished by cooling the solution while stirring at a temperature of about 25°C to about 30°C for about 45 minutes to about 5 hours.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved, consistently reproducible and commercially viable process for the production of highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms.

BACKGROUND OF THE INVENTION
U.S. Patent No. 4,503,067 discloses a variety of carbazolyl-(4)-oxypropanolamine derivatives, specifically Carvedilol, chemically named as (±)-1-(Carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol, and pharmaceutically acceptable salts thereof, processes for the preparation, pharmaceutical compositions, and method of use thereof. Carvedilol is represented by the following structural formula 1:

Carvedilol was approved by the USFDA for use in United States for the treatment of mild to severe chronic heart failure, left ventricular dysfunction following myocardial infarction in clinically stable patients and hypertension and it is sold under the trade name COREG®. It is orally administered as tablets containing 3.125 mg, 6.25 mg, 12.5 mg and 25 mg.
Various processes for the preparation of Carvedilol, and its intermediates, and pharmaceutically acceptable salts, are disclosed in U.S. Patent Nos. US 4,503,067, US 7,468,442 B2, US 7,705,163 B2; European Patent Nos. EP1142873B1, EP1756057B1; US Patent Application Publication No. US2003/0040485A1; PCT Publication Nos. WO2009115902A1, WO2009116069A2.
The synthesis of Carvedilol was first described in the U.S. Patent No. 4,503,067 (hereinafter referred to as the US‘067 patent). As per the process exemplified in Example 2 of the US’067 patent, Carvedilol is prepared by stirring a solution of 4-(2,3-Epoxypropoxy)-carbazole and 2-(2-methoxyphenoxy)-ethylamine in ethylene glycol dimethyl ether for 25 hours at 50°C, the resulting mixture is evaporated to dryness in a Rotavapor followed by trituration with diethyl ether, and finally recrystallized from ethyl acetate to produce Carvedilol as colorless crystals. The synthesis of Carvedilol is depicted in below scheme:

Carvedilol is known to exhibit polymorphism and various crystalline forms and processes for their preparation are apparently disclosed in US Patent Nos. US 6,730,326 B2, US 8,058,453 B2, US Patent Publication Nos. US 2004/152756 A1, US 2009/163721 A1, European Patent Publication No. EP 1655285 A1 and PCT Patent Publication Nos. WO2002/000216A1, WO 2005/021504 A2, WO 2006/135757 A1.
US Patent No. US 6,730,326 B2 (hereinafter referred to as the US’326 patent) discloses two crystalline forms of Carvedilol namely Form I and Form II and a process for the preparation of Form I. Further, the US’326 patent teaches that, when Carvedilol was originally produced as per the process disclosed in EP0004920 (US equivalent No. US4503067), the crystalline form was Form II.
However, the processes exemplified in the US’067 patent suffer from several disadvantages such as lack of consistency in producing pure crystalline Form II of Carvedilol essentially free of other polymorphic forms, and lack of disclosure of the actual quantities of raw materials and solvents that are required for producing crystalline Form II of Carvedilol.
According to the US’326 patent, the crystalline Form I of Carvedilol is characterized by an XRPD pattern having characteristic 2-theta peaks at about 9.5, 10.8, 12.0, 14.6, 19.6, 21.5 and 22.3 degrees; an infrared absorption spectrum having IR stretching vibration at 3451 cm-1; and a melting point at about 123-126°C.
According to the US’326 patent, the crystalline Form II of Carvedilol is characterized by an XRPD pattern having characteristic 2-theta peaks at 5.9, 14.9, 17.6, 18.5 and 24.4 degrees; an infrared absorption spectrum having IR stretching vibration at 3345 cm-1; and a melting point at about 114-115°C.
US Publication No. US 2004/152756 A1 (hereinafter referred to as the US’756 publication) discloses a crystalline Form III of Carvedilol, and its process for the preparation, which is characterized by XRPD pattern having characteristic 2-theta peaks at about 8.4, 17.4 and 22.0 degrees; and a melting point at about 92-95°C.
US Publication No. US 2009/163721 A1 (hereinafter referred to as the US’721 publication) discloses crystalline Form VI of Carvedilol (crystalline solid or solvate), and its process for the preparation. According to the US’721 publication, the crystalline Form VI of Carvedilol (crystalline solid or solvate) is characterized by an XRPD pattern having characteristic 2-theta peaks at 5.8, 6.5, 7.3, 10.7, 11.1, 11.5, 13.1, 13.7, 16.0, 16.8, 17.7, 18.5, 23.0 and 30.5 ± 0.2 degrees; an FTIR spectrum with peaks at about 613, 740, 994, 1125, 1228, 1257, 1441, 1508, 1737, 2840, 3281, 3389, and 3470 cm-1; and a DSC thermogram with endothermic peaks at about 74°C and 112°C.
PCT Publication No. WO 2002/000216 A1 (hereinafter referred to as the WO’216 publication) discloses crystalline Form III, Form IV and Form V of Carvedilol, process for the preparation thereof, and characterizes them by XRPD pattern and DTG thermal profile.
According to the WO’216 publication, the crystalline Form III of Carvedilol is characterized by XRPD 2-theta peaks at about 8.4, 17.4 and 22.0 ± 0.2 degrees; crystalline Form IV of Carvedilol is characterized by XRPD 2-theta peaks at about 11.9, 14.2, 18.3, 19.2, 21.7 and 24.2 ± 0.2 degrees; and crystalline Form V of Carvedilol is characterized by XRPD 2-theta peaks at about 4.1, 10.3 and 10.7 ± 0.2 degrees.
PCT Publication No. WO 2005/021504 A1 (hereinafter referred to as the WO’504 publication) discloses the crystalline Form VII and Form IX of Carvedilol, process for the preparation and characterizes by XRPD pattern, DSC curve and FT-IR spectrum.
According to WO’504 publication, crystalline Form VII of Carvedilol is characterized by XRPD 2-theta peaks at 6.42, 6.78, 10.94, 11.58, 12.90, 13.62, 16.79, 17.51, 17.90, 18.81, 19.42, 20.83, 21.19, 21.93, 23.30, 24.49, 25.27, 26.09, 27.20, 29.21 ± 0.1 degrees; IR spectrum having most characteristic absorption bands at 3469.2 cm-1, 3278.1 cm-1, 2871.2 cm-1, 1123.6 cm-1, 1095.8 cm-1, 745.0 cm-1, 722.9 cm-1; and melting point at about 68.8-72.4°C.
Further, crystalline Form IX of Carvedilol is characterized by XRPD 2-theta peaks at 6.16, 6.46, 8.39, 10.88, 11.39, 12.35, 12.98, 13.62, 14.72, 16.86, 17.42, 18.26, 19.28, 19.58, 21.88, 23.15, 24.61, 25.58, 26.06, 27.40, 27.63, 29.01, 29.55 ± 0.1 degrees; IR spectrum, with most characteristic absorption bands at 3568.0 cm-1, 3339.1 cm-1, 3287.9 cm-1, 2942.9 cm-1, 2896.1 cm-1, 1349.9 cm-1, 1307.9 cm-1, 1288.4 cm-1, 1104.0 cm-1, 997.2 cm-1, 737.1 cm-1; and melting point at about 94.5-96.2°C.
PCT Publication No. WO 2006/135757 A1 (hereinafter referred to as the WO’757 publication) discloses the crystalline Form of Carvedilol, process for the preparation, and characterizes the crystalline form by XRPD, DSC and TGA. According to the WO’757 publication, crystalline For of Carvedilol is characterized by XRPD 2-theta peaks at 4.3, 10.6, 11.1, 15.6, and 21.2 ± 0.2 degrees; and DSC thermogram with endothermic peaks at about 60°C and 113°C.
However, the processes described in the aforementioned prior art have failed to consistently produce pure crystalline Form II of Carvedilol essentially free of other polymorphic forms. The prior art processes suffer from several disadvantages such as lack of reproducibility, formation of mixture of crystalline forms, formation of different and undesired crystalline forms.
A need still remains for simple, cost effective, consistently reproducible and environmentally friendly processes for preparing highly pure crystalline Form II of Carvedilol which is essentially free of other crystalline forms.

SUMMARY OF THE INVENTION
The present inventors have found that stable and highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms can be consistently produced by a process comprising providing a clear solution of Carvedilol in methanol solvent at reflux temperature of the solvent, optionally subjecting the clear solution to carbon treatment, cooling the resulting solution at a temperature of below about 20°C to cause crystallization, stirring the resulting mass at the same temperature, and then collecting the highly pure crystalline Form II of Carvedilol by filtration or centrifugation, followed by drying the material.
In another aspect, provided herein is a cost effective and consistently reproducible process for the preparation of highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms by providing a clear solution of Carvedilol in ethyl acetate solvent at reflux temperature of the solvent, wherein the quantity of ethyl acetate solvent employed is at least about 8 volumes, preferably about 8 volumes to about 12 volumes, with respect to the quantity of Carvedilol used (i.e., about 8 ml to about 12 ml per 1 gm of Carvedilol), seeding the resulting solution followed by cooling at a temperature of below about 35°C to cause crystallization, stirring the resulting mass at the same temperature, and then collecting the highly pure crystalline Form II of Carvedilol by filtration or centrifugation, followed by drying the material.
Provided herein is a simple, cost effective and consistently reproducible processes for the preparation of highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms.
In another aspect, provided herein is a pharmaceutical composition comprising highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms made by the processes disclosed herein, and one or more pharmaceutically acceptable excipients.
In still further aspect, encompassed herein is a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms made by the processes disclosed herein with one or more pharmaceutically acceptable excipients.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
The term “crystalline Form II of Carvedilol”, otherwise called “Carvedilol crystalline Form II”, as used herein is intended to mean the crystalline Form II of Carvedilol as originally disclosed in the U.S. Patent No. 6,730,326.
In one embodiment, the crystalline Form II of Carvedilol essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 14.88, 17.57, 18.51 and 24.35 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 3345, 2923, 1630, 1607, 1589, 1504, 1450, 1403, 1255, 1217, 1176, 1156, 1099, 1021, 956, 751 and 723 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 114.26°C and a sharp endotherm peak at about 117.21°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form II of Carvedilol obtained by the processes disclosed herein is essentially free from other solid state forms of Carvedilol detectable by the spectral methods typically used, e.g., Powder X-ray diffraction.
The term “crystalline Form II of Carvedilol essentially free of other crystalline forms” means that no other polymorphic forms of Carvedilol can be detected within the limits of a powder X-ray diffractometer. The term “other polymorphic forms of Carvedilol” is intended to mean the polymorphic forms of Carvedilol other than crystalline Form II.
The process disclosed herein above advantageously produces the crystalline Form II of Carvedilol with high chemical and polymorphic purity.
The highly pure crystalline Form II of Carvedilol obtained by the process disclosed herein has chemical purity of greater than about 99.5%, specifically greater than about 99.7%, and most specifically greater than about 99.9% as measured by HPLC.
Unless otherwise specified, the term “crude or impure form of Carvedilol” refers to any form of Carvedilol having purity less than 99.5% as measured by HPLC.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of crystalline Form II of Carvedilol.
Figure 2 is a characteristic infra-red (IR) spectrum of crystalline Form II of Carvedilol.
Figure 3 is a characteristic Differential Scanning Calorimetric (DSC) thermogram of crystalline Form II of Carvedilol.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms, comprising:
a) providing a solution of Carvedilol in methanol solvent at reflux temperature of the solvent used;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment to obtain a filtrate;
c) cooling the solution obtained in step-(a) or step-(b) to a temperature of below about 20°C to cause crystallization; and
d) collecting the highly pure crystalline Form II of Carvedilol obtained in step-(c).
Step-(a) of providing a solution of Carvedilol includes dissolving Carvedilol (crude or pure) in methanol solvent at the reflux temperature of the solvent used.
The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the reflux temperature for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Carvedilol by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the crystallization in step-(c) is accomplished by cooling the solution while stirring at a temperature of about -5°C to about 20°C for at least 10 minutes, more specifically at a temperature of about 0°C to about 10°C for about 20 minutes to about 5 hours, and most specifically at a temperature of about 0°C to about 5°C for about 45 minutes to about 2 hours.
The collection of the precipitated solid in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the highly pure crystalline Form II of Carvedilol, obtained by the process described herein, remains in the same crystalline form and is found to be stable.
According to another aspect, there is provided a process for the preparation of a stable and highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms, comprising:
a) providing a solution of Carvedilol in ethyl acetate solvent at reflux temperature of the solvent used, wherein the quantity of ethyl acetate solvent required is at least about 8 volumes with respect to the quantity of Carvedilol used;
b) optionally, subjecting the solution obtained in step-(a) to carbon treatment to obtain a filtrate;
c) seeding the solution obtained in step-(a) or step-(b) with crystalline Form II of Carvedilol;
d) cooling the solution obtained in step-(c) to a temperature of below about 35°C to cause crystallization; and
e) collecting the highly pure crystalline Form II of Carvedilol obtained in step-(d).
The present inventors have found that the amount of ethyl acetate solvent with respect to the quantity of Carvedilol employed is critical in order to consistently produce the highly pure crystalline Form II of Carvedilol essentially free of other crystalline forms.
In one embodiment, the amount of ethyl acetate solvent employed in step-(a) is about 8 volumes to about 12 volumes, most specifically about 9 volumes to about 10 volumes, with respect to the quantity of Carvedilol used.
Step-(a) of providing a solution of Carvedilol includes dissolving Carvedilol (crude or pure) in ethyl acetate solvent at the reflux temperature of the solvent used. After complete dissolution of Carvedilol, the resulting solution is stirred at the reflux temperature for at least 10 minutes, and specifically for about 10 minutes to about 30 minutes.
The carbon treatment in step-(b) is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at the reflux temperature for at least 5 minutes, specifically for about 10 minutes to about 30 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Carvedilol by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
The seeding in step-(c) is carried out by adding the solution to the seeding material of crystalline Form II of Carvedilol, wherein the seeding material can be prepared by the process described hereinabove, for example, as per the process exemplified in Example 1 disclosed hereinafter.
In one embodiment, the crystallization in step-(d) is accomplished by cooling the solution while stirring at a temperature of about 20°C to about 35°C for at least 30 minutes, and more specifically at a temperature of about 25°C to about 30°C for about 45 minutes to about 5 hours.
The collection of the precipitated solid in step-(e) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
In one embodiment, the highly pure crystalline Form II of Carvedilol, obtained by the process described herein, remains in the same crystalline form and is found to be stable.
In one embodiment, the crystalline Form II of Carvedilol essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 5.87, 14.88, 17.57, 18.51 and 24.35 ± 0.2 degrees substantially in accordance with Figure 1; and/or an infra red (FT-IR) spectrum having main bands at about 3345, 2923, 1630, 1607, 1589, 1504, 1450, 1403, 1255, 1217, 1176, 1156, 1099, 1021, 956, 751 and 723 cm-1 ± 5 cm-1 substantially in accordance with Figure 2; and/or a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 114.26°C and a sharp endotherm peak at about 117.21°C substantially in accordance with Figure 3.
In another embodiment, the highly pure crystalline Form II of Carvedilol obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta peaks at about 11.70, 13.04, 15.24, 16.52, 17.06, 20.38 and 21.11 ± 0.2 degrees substantially in accordance with Figure 1.
The highly pure crystalline Form II of Carvedilol obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 80°C, and most preferably at about 50°C to about 65°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 30 hours, and more preferably about 20 to 24 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
Unless otherwise specified, the Carvedilol as used herein as starting material can be obtained by the processes known in the prior art, for example, as per the processes described in the U.S. Patent No. 4,503,067.
The stable and highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form II of Carvedilol obtained by the processes disclosed herein exhibits properties making it suitable for formulating Carvedilol.
Further encompassed herein is the use of the highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In one embodiment, the highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 150 microns, specifically about 1 micron to about 120 microns, and most specifically about 4 microns to about 100 microns.
In another embodiment, the highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D50 particle size of less than or equal to about 100 microns, specifically about 1 micron to about 80 microns, and most specifically about 4 microns to about 60 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form II of Carvedilol obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, troches, sachets, suspensions, powders, lozenges, elixirs and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 1-2 mg of sample was powdered with 300-400mg of KBr. The spectra were recorded in transmission mode ranging from 4000 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 150°C.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of pure crystalline Form II of Carvedilol
Methanol (150 ml) was added to crude Carvedilol (30 g, Purity by HPLC: 99.2%) at 25-30°C and the resulting suspension was heated to reflux temperature to form a clear solution, and then stirred for 10 to 20 minutes at reflux temperature. Carbon powder (3 g) was added to the resulting solution at reflux temperature and then stirred for 10 minutes at the same temperature. The reaction mixture was filtered through charcoal bed and washed the bed with methanol (15 ml). The resulting filtrate was cooled to 0-5°C, followed by stirring the mass for 1 hour at the same temperature. The separated solid was filtered, washed the solid with chilled methanol (30 ml) and then dried the material at 55-60°C for 4 to 5 hours to produce 23 g of pure crystalline Form II of Carvedilol (Purity by HPLC: 99.9%).

Example 2
Preparation of pure crystalline Form II of Carvedilol
Ethyl acetate (390 ml) was added to crude Carvedilol (43 g, Purity by HPLC: 99.2%) at 25-30°C and the resulting suspension was heated to reflux temperature and maintained for 10 to 15 minutes at the same temperature. The resulting solution was slowly added to seeding sample of crystalline Form II of Carvedilol (1 g). The resulting mass was cooled to 30-32°C and maintained for 1 hour at the same temperature. The separated solid was filtered, washed the solid with ethyl acetate (40 ml) and then dried the material at 60-65°C for 8 to 10 hours to produce 40 g of pure crystalline Form II of Carvedilol (Purity by HPLC: 99.9%).

Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term “pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable, and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
The term “pharmaceutical composition” is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “therapeutically effective amount” as used herein means the amount of a compound that, when administered to a mammal for treating a state, disorder or condition, is sufficient to effect such treatment. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
The term “delivering” as used herein means providing a therapeutically effective amount of an active ingredient to a particular location within a host causing a therapeutically effective blood concentration of the active ingredient at the particular location. This can be accomplished, e.g., by topical, local or by systemic administration of the active ingredient to the host, e.g., human, animal, etc.
The term “buffering agent” as used herein is intended to mean a compound used to resist a change in pH upon dilution or addition of acid of alkali. Such compounds include, by way of example and without limitation, potassium metaphosphate, potassium phosphate, monobasic sodium acetate and sodium citrate anhydrous and dihydrate and other such materials known to those of ordinary skill in the art.
The term “sweetening agent” as used herein is intended to mean a compound used to impart sweetness to a formulation. Such compounds include, by way of example and without limitation, aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose and other such materials known to those of ordinary skill in the art.
The term “binders” as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Such compounds include, by way of example and without limitation, acacia, alginic acid, tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, pregelatinized starch, starch, polyethylene glycol, guar gum, polysaccharide, bentonites, sugars, invert sugars, poloxamers, collagen, albumin, celluloses in non-aqueous solvents, polypropylene glycol, polyoxyethylene-polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, polyethylene oxide, microcrystalline cellulose, combinations thereof and other material known to those of ordinary skill in the art.
The term “diluents” or “filler” as used herein is intended to mean inert substances used as fillers to create the desired bulk, flow properties, and compression characteristics in the preparation of solid dosage formulations. Such compounds include, by way of example and without limitation, dibasic calcium phosphate, kaolin, sucrose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sorbitol, starch, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “glidant” as used herein is intended to mean agents used in solid dosage formulations to improve flow-properties during tablet compression and to produce an anti-caking effect. Such compounds include, by way of example and without limitation, colloidal silica, calcium silicate, magnesium silicate, silicon hydrogel, cornstarch, talc, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “lubricant” as used herein is intended to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, by way of example and without limitation, calcium stearate, magnesium stearate, mineral oil, stearic acid, zinc stearate, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “disintegrant” as used herein is intended to mean a compound used in solid dosage formulations to promote the disruption of the solid mass into smaller particles which are more readily dispersed or dissolved. Exemplary disintegrants include, by way of example and without limitation, starches such as corn starch, potato starch, pregelatinized, sweeteners, clays, such as bentonite, microcrystalline cellulose, carsium, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, tragacanth, combinations thereof and other such materials known to those of ordinary skill in the art.
The term “wetting agent” as used herein is intended to mean a compound used to aid in attaining intimate contact between solid particles and liquids. Exemplary wetting agents include, by way of example and without limitation, gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxylpropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP).
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.