Title of Invention

A PROCESS FOR PREPARING BICALUTAMIDE POLYMORPH

Abstract The invention provides crystalline form of bicalutamide and amorphous bicalutamide. The invention also provides methods for their preparation and pharmaceutical compositions containing the new forms of bicalutamide.
Full Text The present invention provides a bicalutamide crystalline form and amorphous bicalutamide. The present invention also provides methods of preparing these forms.
BACKGROUND OF THE INVENTION
Bicalutamide which is known by the chemical name N-[4-cyano-3-(trifluoro-methyl) phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methylpropanamide is used for treatment of prostate cancer which is described in US 4636505. Various methods of synthesis of bicalutamide are disclosed in US 6479692, WO 01/00608, US patent application No.2002/0086902.
In all the prior art documents bicalutamide is crystallized from ethyl acetate/petroleum ether. Bicalutamide crystallized from ethyl acetate/petroleum ether does not produce well defined, stable polymorphic form. A well-defined crystalline form of bicalutamide is synthesized and characterized. According to the present invention, the new crystalline form is found to be obtainable in pure form and stable and consistently reproducible.
Prior art does not disclose amorphous form of bicalutamide and also, processes described in the prior art does not produce amorphous form of bicalutamide. The amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form. For some therapeutic indications one bioavailability pattern may be favored over another. According to the present invention amorphous form of bicalutamide with good dissolution characteristics is synthesized.
Thus, the object of present invention is to provide a stable, pure, consistently obtainable crystalline form of bicalutamide methods for preparing bicalutamide crystalline form and pharmaceutical formulations containing bicalutamide crystalline form.
Another object of the present invention is to provide a stable amorphous bicalutamide and converting the bicalutamide crystalline form into amorphous form of bicalutamide.

SUMMARY OF THE INVENTION
The present invention provides N-[4-cyano-3"(trifluoromethyl) phenyl]-3-[(4-fluoro- phenyl) sulfonyl]-2-hydroxy-2-methylpropanamlde crystalline form(hereinafter referred to as bicalutamide crystalline form) having a typical x-ray diffraction pattern of Fig.1. The significant reflections of the bicalutamide crystalline form are shown in Table 1 wherein d represents the interplanar spacing and I/I1 represents the relative intensities expressed as a percentage of most intense reflection.
Another feature of the Invention is to provide a method of preparing bicalutamide crystalline form which comprises:
i) dissolving bicalutamide obtained by a known method in a suitable
solvent,
ii) maintaining the solution obtained in step(i) at 0-40°C for about 5 to 36
hours, optionally seeded with bicalutamide crystalline form,
iii) filtering and drying the crystals formed to give bicalutamide crystalline
form, wherein suitable solvents include C1-C3 alcohol, CrCe ketone or mixture thereof. Preferred alcohols are ethanol, isopropyl alcohol and preferred ketone is acetone.
Another feature of the invention is to provide a pharmaceutical composition comprising the bicalutamide crystalline form.
Another feature of the invention is to provide amorphous form of bicalutamide (hereinafter referred to as amorphous bicalutamide) which is characterized by broad x-ray diffraction maxima at about 10.0 to 35.0 degrees 2G. The typical x-ray diffractogram is shown in figure 2.
Another feature of the invention is to provide a process for preparation of
amorphous bicalutamide, which comprises:
i) heating bicalutamide to melt,
ii) cooling the mass to 25-35°C,
iii) crushing the flakes formed in step(ii) to give amorphous bicalutamide
wherein bicalutamide used in step(l) is either bicalutamide obtained by a known
method or bicalutamide crystalline form.

Another feature of the present invention is to provide an alternative method of
preparing amorphous bicalutamide, which comprises:
i) mixing bicalutamide and suitable solvent in a suitable proportion,
ii) slurring for about 1 to 5 hours,
iii) drying to give amorphous bicalutamide,
wherein suitable solvents include C1-C3 alcohol or CrCe ketone.
Bicalutamide used in step (i) is either bicalutamide obtained by a known method or bicalutamide crystalline form. Preferred alcohols are ethanol, isopropyl alcohol and preferred ketone is acetone.
The term "suitable proportion" implies that the weight/volume ratio of bicalutamide to the solvent is 1:2 to 1:8.
Another feature of the invention is to provide a pharmaceutical composition comprising the amorphous bicalutamide.
BRIEF DESCRIPTION OF THE DRAW/NGS Figure 1 is a powder x-ray diffractogram of bicalutamide crystalline form.
Figure 2 is a powder x-ray diffractogram of amorphous bicalutamide.
x-ray diffraction patterns were measured on a Siemens D-5000 diffractometer with CuKr radiation.
DETAILED DESCRIPTION OF THE INVENTION
Bicalutamide crystalline form
The present invention provides N-[4-cyano-3-(trifluoromethyl) phenyl]-3"[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methylpropanamide crystalline form (bicalutamide crystalline form) having a typical x-ray diffraction pattern of Fig.1. The significant reflections of the bicalutamide crystalline form are shown in Table 1 wherein d represents the interplanar spacing and I/I1 represents the relative intensities expressed as a percentage of most intense reflection.
Another feature of the invention is to provide a method of preparing crystalline form of bicalutamide.

Thus, bicalutamide obtained from a known method is dissolved in a suitable solvent. Suitable solvents include C1-C3 alcohol or CrCe ketones, preferred alcohols being ethanol, isopropyl alcohol and preferred ketones being acetone. The solution uutained is maintained at 0-40°C for about 5 to 36 hours. Preferably, the solution is maintained at 20-35°C for about 20-25 hours. During maintenance the solution may be seeded with bicalutamide crystalline form. The crystals formed are then filtered and dried to give bicalutamide crystalline form.
Amorphous bicalutamide
Another feature of the invention is to provide amorphous bicalutamide, which is characterized by broad x-ray diffraction maxima at about 10.0 to 35.0 degrees 29. The typical x-ray diffractogram is shown in figure 2.
Another feature of the invention is to provide a process for preparation of amorphous bicalutamide.
Thus, bicalutamide obtained by a known process or bicalutamide crystalline form is heated to about 195-200°C to melt and then the mass is cooled gradually to 25-35°C to form flakes. The flakes are crushed to give amorphous bicalutamide.
Another feature of the present Invention is to provide an alternative method of preparing amorphous bicalutamide.
Thus, bicalutamide obtained by a known process or bicalutamide crystalline form is mixed with a suitable solvent in a suitable proportion. Suitable solvents include C1-C3 alcohol, CrCe ketones, and preferable alcohols being ethanol, isopropyl alcohol and preferable ketone being acetone. Suitable proportion implies that the weight/volume ratio of bicalutamide to the solvent is 1:2 to 1:8. The contents are slurried for about 1 to 5 hours and then dried to form amorphous bicalutamide. The drying can be of vacuum drying or spray drying.
Another feature of the invention is to provide a pharmaceutical composition comprising bicalutamide crystalline form.
Another feature of the invention is to provide a pharmaceutical composition comprising amorphous bicalutamide.

The compositions containing bicalutamide crystalline form or amorphous bicalutamide may be in a form suitable for oral dosage as a tablet, capsule, suspension, ointment, lotion. Any conventional technique may be used for the preparation of pharmaceutical formulation according to the invention. Examples of suitable diluents include lactose, micro crystalline cellulose, starch, mannitol. Examples of binders include polyvinyl pyrrolidone, hydroxy propyl cellulose, hydroxy propyl methylcellulose, methyl hydroxy propyl cellulose. Examples of suitable disintigrants include sodium starch glycollate, crospovidone, croscarmellose sodium. Examples of lubricants include magnesium stearate, zinc stearate, calcium stearate.

The following nonlimiting examples illustrate the inventors preferred methods for preparing the compounds of the invention.

EXAMPLES
Example-1 m-Chloroperbenzoic acid (3 gm of 85% strength) was added in portion to a stirred sniijtion of N- [4-cyano-3"(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methylpropanamide (2.7 gm) in methylene dichloride(450 ml). The reaction mixture is stirred at room temperature for 16 hours and then washed with saturated sodium sulfite solution (100 ml), aqueous sodium carbonate solution and brine and dried with Na2S04. The solid obtained on removal of solvent was crystallized from ethyl acetate and petroleum ether (bp 60-80°C) to give 2.5 gm of bicalutamide.
Example-2 Bicalutamide (10 gm) obtained by the process described in example 1 was dissolved in acetone (50 ml) and the solution was stirred at 25-30°C for 24 hours. The crystals formed were filtered and dried under vacuum to give 8.8 gm of bicalutamide crystalline form.
Example-3 Crystalline form of bicalutamide (5 gm) by the process described in example 1, was heated to melt and the resulting transparent flake was crushed to give white powder of the amorphous bicalutamide in near quantitative yield.
Example-4 Bicalutamide crystalline form (5 gm) obtained by the process described in example 2, was slurried in acetone (25 ml) for 2 hours and dried in vacuum to give white powder amorphous form of bicalutamide in near quantitative yield.
Example-5 Amorphous bicalutamide (5 gm) obtained by the process described in example 1 was clurried in ethanol (30 ml) for 3 hours and spray dried to give white amorphous bicalutamide in near quantitative yield.
Example-6 Example-2 was repeated by seeding the contents with bicalutamide crystalline form during stirring at 25 to 30°C after 12 hours to give 9.2 gm of bicalutamide crystalline form.



We claim ,
1) A method of preparing bicalutamide, which process comprises: A)
i) dissolving bicalutamide obtained by known method in a suitaWe^lygn
ii) maintaining the solution obtained in step(i) at 0-40°C for about 5 to 36
hours, optionally seeded with bicalutamide crystalline form,
iii) filtering and drying the crystals formed to obtain bicalutamide in
crystalline form, characterized by a powder x-ray diffraction pattern having characteristic interpianar spacings shown in table 1,
wherein suitable solvents include d-Cs alcohol, C^Ce ketone. ;)
B) i) heating either (a) bicalutamide obtained by a known process o
^ (b)bicaiutamide crystalline form to melt,
ii) cooling the mass to 25"35°C and
iii) crushing the flakes formed in step(ii) to obtain bicalutamide in
amorphous forrn.
^ (or) " ' " v^W--'^^'^
y C) i) mixing bicalutamide and suitable solvent in a suitable
^ proportion,
ii) slurring for about 1 to 5 hours and
iii) drying to obtain bicalutamide in amorphous form,
wherein suitable solvents include d-Ca alcohol, d-Ce ketone.
2) The method according to claim 1, wherein suitable solvent in (A) is ethanol. ^
Z) The method according to claim 1, wherein suitable solvent in (A) is acetone. ^
4) The method according to claim 1, wherein the solution in (A) is maintained at 2 30°C for 20-25 hours in step (ii).
5) The method according to claim 1, wherein the solution in (A) is seeded with bicalutamide crystalline form.
6) The method according to claim 1, wherein the solvent in (C) is ethanol. ^
7) The method according to claim 1, wherein the solvent in (C) is acetone. --
8) The method according to claim 1, wherein the slurry in (C) is spray dried.
9) The method according to claim 1, wherein the slurry in (C) is vacuum dried. ^


Documents:

711-chenp-2003 description (complete) granted.pdf

711-chenp-2003 form 19.pdf

711-chenp-2003 form 4.pdf

711-chenp-2003-abstract.pdf

711-chenp-2003-claims.pdf

711-chenp-2003-correspondnece-others.pdf

711-chenp-2003-correspondnece-po.pdf

711-chenp-2003-description(complete).pdf

711-chenp-2003-drawings.pdf

711-chenp-2003-form 1.pdf

711-chenp-2003-form 3.pdf

711-chenp-2003-form 5.pdf

711-chenp-2003-others.pdf


Patent Number 194055
Indian Patent Application Number 711/CHENP/2003
PG Journal Number 20/2006
Publication Date 19-May-2006
Grant Date 19-Dec-2005
Date of Filing 12-May-2003
Name of Patentee M/S. HETERO DRUGS LIMITED
Applicant Address HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 PARTHASARADHI REDDY HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
2 RATHNAKAR REDDY, KURA HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
3 RAJI REDDY, RAPOLU HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
4 NARASA REDDY, ATTUNURI HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
5 NARASA REDDY, BOLLA HETERO DRUGS LIMITED (R & D), PLOT NO.B-80 & 81, A.P.I.E, BALANAGAR, HYDERABAD-500 018, ANDHRA PRADESH, INDIA
PCT International Classification Number C07C255/49
PCT International Application Number PCT/IN03/00035
PCT International Filing date 2003-02-21
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA