WO2013072935A2

WO2013072935A2 - Process for the preparation of silodosin

Info

Publication number: WO2013072935A2
Application number: PCT/IN2012/000670
Authority: WO
Inventors: Ashok Prasad; Shriprakash Dhar DWIVEDI; Niraj Kumar Shyamlal SHAH; Jitesh Amratlal DESAI
Original assignee: Cadila Healthcare Limited
Priority date: 2011-10-10
Filing date: 2012-10-10
Publication date: 2013-05-23
Also published as: WO2013072935A3

Abstract

The invention relates to a process for preparing silodosin. The invention relates to the preparation of substantially pure silodosin. The invention also relates to silodosin solid particles, wherein 90 volume-percent of the particles (D₉₀) are less than 10 microns and a process for achieving the particle size (D₉₀) less than 10 microns. The invention also relates to pharmaceutical compositions of silodosin comprising 90 volume-percent of the particles (D₉₀) less than 10 microns.

Description

PROCESS FOR THE PREPARATION OF SILODOSIN

FIELD OF THE INVENTION

The present invention relates to a process for preparing silodosin. The invention relates to the preparation of substantially pure silodosin. The invention also relates to silodosin solid particles, wherein 90 volume-percent of the particles (D90) are less than 10 microns and a process for achieving the particle size (D90) less than 10 microns. The invention also relates to pharmaceutical compositions of silodosin comprising 90 volume-percent of the particles (D90) less than 10 microns.

BACKGROUND OF THE INVENTION

Silodosin, l -(3-Hydroxypropyl)-5-[(2tf)-2-({2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide of Formula (I) is an indoline antidysuric which has a selectively inhibitory effect against urethra smooth muscle constriction, and decreases urethra internal pressure without great influence on blood pressure.

U.S. Patent No. 5,387,603 discloses the process for the preparation of silodosin and salts thereof with a pharmaceutically acceptable acid and their therapeutic use.

U.S. Patent No. 7,834, 193 B2 discloses the process for preparing silodosin via formation of oxalate salt of compound of Formula (la) as shown below:

(la) U.S. Patent Pub. No. 2006/0142374 A l discloses three polymorphic forms of silodosin namely crystal form a, crystal form β and crystal form □, which are characterized by X PD and process for the preparation of crystal forms thereof.

PCT Pub. No. WO201 1030356 A2 discloses process for preparing silodosin using novel intermediates unlike the prior art processes.

PCT Pub. No. WO201 1 101864 A l discloses process for preparing 2-[2-(2,2,2- trifluoroethoxy) phenoxy]ethanol being useful intermediate in the synthesis of silodosin.

Hence, there is still a need for an alternative process for preparing silodosin. In particular, there is a need for improved process at the hydrogenation step to achieve highly pure silodosin.

SUMMARY OF THE INVENTION

In one general aspect, the present invention provides a solid state form of (R)-

5-(2-(pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- carbonitrile of Formula (S2).

In another general aspect, the solid state form of (R)-5-(2-(pivaloyloxy (2-(2- (2,2,2-trifluoro ethoxy)phenoxy)ethyl)amino) propyl)indoline-7-carbonitrile of Formula (S2) is characterized by XRD and DSC.

In another general aspect, there is provided a process for preparing solid state form of (R)-5-(2-(pivaloyloxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile of Formula (S2), the process comprising:

i) treating (R)- l-acetyl-5-(2-(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-carbonitrile of Formula (S) in a suitable solvent in presence of a protecting agent to obtain (R)-l-acetyl-5-(2- (pivaloyloxy(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyI)amino)propyl)indoline-7- carbonitrile of Formula (S I ); ii) treating (R)-l-acetyl-5-(2-(pivaloyloxy(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino) propyl) indoline-7-carbonitrile of Formula (SI) in a suitable solvent in presence of a base to obtain solid state form of (R)-5-(2- (pivaloyl oxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7- carbonitrile of Formula (S2).

In another general aspect, there is provided use of solid state form of (R)-5-(2- (pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- carbonitrile of Formula (S2) in the preparation of silodosin of Formula (I).

In another general aspect, there is provided an improved process of preparing silodosin of Formul

the process comprising:

i) treating (R)-l-(3-R'-(oxy)propyl)-5-(2-(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethylamino) propyl) indoline-7-carboxamideof compound of Formula (A)

(wherein R' is a hydroxy protecting group selected from benzyl, benzoyl, trityl, t-butyl, f-butyl dimethylsilyl (TBDMS), -butyldiphenylsilyl (TBDP), pivaloyl)

in a suitable solvent in presence of a metal hydrogenation catalyst and one or more acids;

ii) isolating silodosin of Formula (I).

In another general aspect, there is provided substantially pure silodosin of Formula (I) and its pharmaceutically acceptable salts thereof. In another general aspect, there is provided silodosin substantially free of impurity X at RRT 0.87 to 0.90.

In another general aspect, there is provided a process for preparing silodosin substantially free of impurity X at RRT 0.87 to 0.90.

In another general aspect, there is provided a pharmaceutical compositions comprising silodosin substantially free of impurity X at RRT 0.87 to 0.90 and use of said composition for treating dysuria.

In another general aspect, there is provided silodosin having 90 volume-percent of the particles (D90) less than 10 microns.

, In another general aspect, there is provided silodosin having 90 volume-percent of the particles (D90) less than 5 microns.

In another general aspect, there is provided a process for preparing silodosin having 90 volume-percent of the particles (D₉o) less than 10 microns.

In another general aspect, there is provided a pharmaceutical composition comprising silodosin having a (D90) particle size less than 10 microns and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTIO OF THE ACCOMPANYING DRAWINGS FIG. 1 is a characteristic powder X-ray diffraction (XRD) pattern of (R)-5-(2- (pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- carbonitrile of Formula (S2).

FIG. 2 is a characteristic differential scanning calorimetry (DSC) of (R)-5-(2- (pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- carbonitrile of Formula (S2).

DETAILED DESCRIPTION OF THE INVENTION

The term 'substantially pure' referred in the present specification relates to silodosin of Formula (I) or a process for preparation thereof, in which silodosin has a purity of about 99% to about 99.99% and all impurities in an amount of less than about 0.15% as measured by HPLC. Specifically, silodosin as disclosed herein contains less than about 0.1 %, more specifically less than about 0.05%, still more specifically less than about 0.01% of all impurities.

An embodiment of the present invention provides a solid state form of (R)-5-(2-

(pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- , carbonitrile of Formula (S2).

A solid state form of (R)-5-(2 (pivaloyloxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino) propyl)indoline-7-carbonitrile of Formula (S2) is characterized by one or more of the following properties:

i) a powder X-ray diffraction pattern having peaks at about 9.8, 12.2, 14.0, 15.1, 16.5, 17.0, 18.0, 19.9, 21 .0 23.5 and 24.6 ±0.2 degrees 2-theta substantially as depicted in

FIG. l ;

ii) having a single endotherm peak in DSC at about 93.9°C ±3 degrees substantially as depicted in FIG.2;

iii) an 1R spectrum having absorption bands at about 3344, 2978, 2204, 1666, 1595, 1398, 1255, 1 166, 1047, 983, 860, 742, 601 and 516 ± 2 cm^"1.

In another general aspect, there is provided a process for preparing solid state form of (R)-5-(2-(pivaloyl oxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile of Formula (S2),

the process comprising:

i) treating (R)- l-acetyl-5-(2-(2-(2 -(2,2,2- trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-carbonitrile of Formula (S) in presence of a protecting agent to obtain (R)- 1 -acetyl-5-(2-(pivaloyloxy(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile of Formula (SI); ii) treating (R)-l-acetyl-5-(2-(pivaloyloxy(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino) propyl)indoline-7-carbonitrile of Formula (S I ) in a suitable solvent in presence of a base to obtain solid state form of (R)-5-(2- (pivaloyl oxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7- carbonitrile of Formula (S2). The suitable solvent for step (i) may be selected from one or more of C1 -C5 alcohols, esters, ethers, halogenated solvent, aromatic hydrocarbons, water or a mixture thereof, preferably methylene dichloride (MDC).

The protecting agent for step (i) may be selected from NH-protecting agents, specifically carbobenzyloxy (Cbz), butyloxycarbonyl (BOC), acetyl, benzoyy, benzyl, p-methoyxy phenyl, tosyl, carbamate, preferably butyloxycarbonyl (BOC).

The suitable solvent for step (ii) may be selected from one or more of C1 -C5 alcohols, esters, ethers, nitriles, tetrahydrofuran (THF), water, halogenated solvents, dimethylformamide, dimethyl sulfoxide, sulfolane, or a mixture thereof, preferably ethanol.

The base used at step (ii) may be selected from one or more of alkali or alkaline earth metal hydroxides, alkoxides, carbonates or bicarbonates or an organic base. The base may be selected from one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium teri-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine, dimethyl amine, diisopropylethylamine, diisopropylmethyl amine, pyridine, piperidine, morpholine and N-methyl piperidine; preferably sodium hydroxide.

In a general aspect, (R)-l-acetyl-5-(2-(2-(2-(2,2,2-trifluoroethoxy)phenoxy) ethylamino)propyl) indoline-7-carbonitrile of Formula (S) being used in the preparation of a solid state form of (R)-5-(2-(pivaloyl oxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7-carbonitrile of Formula (S2) may be prepared as per the process disclosed in U.S. Patent No. 5,387,603.

In another general aspect, there is provided an improved process of preparing silodosin of Formula (I), the process comprising:

(wherein R' is a hydroxy protecting group selected from benzyl, benzoyl, trityl, t-butyl, i-butyl dimethylsilyl (TBDMS), i-butyldiphenylsilyl (TBDP), pivaloyl)

in a suitable solvent in presence of a metal hydrogenation catalyst and one or more acids

ii) isolating silodosin of Formula (I).

The suitable solvent for step (i) is selected from one or more C1 -C5 alcohols, esters, ethers, water or a mixture thereof, preferably ethanol and water.

The suitable hydrogenation catalyst for step (ii) is selected from nickel, platinum, palladium, ruthenium, rhodium, osmium, and iridium; and exposing the combination of solution and metal catalyst to hydrogen gas, or without hydrogen gas.

The ratio of weight of metal to the weight of compound of Formula (A) is about 0.007: 1 to 1 : 1 respectively, especially about 0.005: 1 ; exposing the combination of solution and metal catalyst to hydrogen gas at a pressure between about 1 and about 10 Atm and a temperature between about 40°C to 100°C.

The acid for step (i) is selected from mineral acid or organic acid such as hydrochloric acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, acetic acid, formic acid; preferably methane sulfonic acid.

The ratio of acid with respect to compound of Formula (A) is about 1 :3 respectively; the preferred ratio is 1 : 1.

The suitable solvent for isolation of silodosin of Formula (I) in step (ii) may be selected from C1 -C5 alcohols, ketones, esters, ethers, amides, sulfolane, nitriles, preferably methyl ethyl ketone.

In a general aspect, (R)-l-(3-R'-(oxy)propyl)-5-(2-(2-(2-(2,2,2- trifluoroethoxy)phenoxy) ethyl amino) propyl) indoline-7-carboxamideof compound of Formula (A) may be prepared using solid state of (R)-5-(2-(pivaloyl oxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7-carbonitrile of Formula (S2) as per the process disclosed in U.S. Patent No. 5,387,603. In another general aspect, there is provided substantially pure silodosin of Formula (I)

In another general aspect, there is provided substantially pure silodosin of Formula (I) having purity greater than 99.9% and all impurities less than 0.1%.

In another general aspect, there is provided highly pure silodosin of Formula (I) substantially free of impurity X at RRT 0.87 to 0.90.

The 'impurity X' at RRT 0.87 to 0.90 is l-(3-Hydroxypropyl)-5-[(2i?)-2-({2-[2- (2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]- lH-indole-7-carboxamide as shown below

The 'impurity X' has molecular mass of 494.7.

As used herein, "highly pure silodosin of Formula (I) substantially free of impurity X at RRT 0.87 to 0.90" refers to silodosin or a process for preparation thereof, in which silodosin has a purity of about 99% to about 99.99% and further comprising impurity X at RRT 0.87 to 0.90 in an amount of less than about 0.15% as measured by HPLC. Specifically, silodosin as disclosed herein contains less than about 0.1%, more specifically less than about 0.05%, still more specifically less than about 0.01% of impurity X, and most specifically is essentially free of impurity X.

In another general aspect, there is provided silodosin of Formula (I) having a total purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater. than about 99.99% as measured by HPLC.

In another general aspect, there is provided a process for preparing highly pure silodosin of Formula (I)

substantially free of impurity X at RRT 0.87 to 0.90 having molecular mass of 494.2, the process comprising:

i) treating silodosin Formula (1) in a suitable solvent;

ii) isolating highly pure silodosin of Formula (I).

The suitable solvent for step (i) may be selected from one or more of hydrocarbons, nitriles, amides, alcohols, ketones, halogenated solvent, ester selected from toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C 1 -C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate or mixture thereof, preferably methyl ethyl ketone.

In another general aspect, there is provided a particle size of silodosin of Formula (I).

In another general aspect, there is provided silodosin having an average particle size in the range of 5 to 300 microns, preferably 20 to 150 microns, more preferably 50 to 100 microns. The term "average particle size" or "particle size" as used herein refers to the volume mean diameter of particles.

In another general aspect, there is provided silodosin having particle size in terms of D 0 less than about 10 microns.

In another general aspect, there is provided silodosin having particle size in terms of D90 less than about 8 microns.

In another general aspect, there is provided silodosin having particle size in terms of D90 less than about 5 microns.

In another general aspect, there is provided a process for the preparation of silodosin having a D90 particle size less than 10 microns.

The process for obtaining silodosin having D90 particle size less than 10 microns may comprise a mechanical process, which includes any one or more of cutting, chipping, crushing, 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.

In another aspect, there is provided a process for the preparation of silodosin having a D 0 particle size less than 10 microns, the process comprising;

a) subjecting silodosin to jet mill under specific grinding pressure and feeding pressure; b) isolating silodosin having a D90 particle size less than 10 microns.

The grinding pressure in jet mill for step a) is about 7 Kg, preferably 4 Kg The feeding pressure in jet mill for step a) is about 4 Kg, preferably 2 Kg.

Silodosin obtained by the process described hereinabove is stable, consistently reproducible and has good flow properties, and which is particularly suitable for bulk preparation and handling, and so, silodosin particles having D90 particle size less than 10 microns is suitable for formulating silodosin.

In another general aspect, there is provided a pharmaceutical composition comprising silodosin having D90 particle size less than 10 microns, and one or more pharmaceutically acceptable excipients.

The process for preparation of soild state form of (R)-5-(2-(pivaloyloxy(2-(2- (2,2,2-trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7-carbonitrile of Formula (S2) as per the present invention is shown in below scheme- 1

Sc eme-1

The present invention is further illustrated by the following example which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Example -1:

Preparation of solid state form of (R)-5-(2-(pivaloyloxy (2-(2-(2,2,2- trifluoroethoxy)phenoxy) ethyI)amino) propyl)indoline-7-carbonitrile of Formula (S2)

(R)- 1 -acetyI-5-(2-_t(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-carbonitrile of Formula (S) (100 g) and MDC (300 ml) was added at 30-35°C and stirred for 40 minutes. Layers were separated and water (500 ml) was added to MDC layer and stirred for 40 minutes. MDC layer was distilled our under vacuum below 45°C and reaction mass was cooled to 20°C. Solution. of Di-t-butyl dicarbonate (BOC) and Dichloromethane was added and temperature was raised to 40°C. The reaction mass was stirred for 3 hours. MDC was distilled out under vacuum and the residue i.e. compound of Formula (S I ) was treated with ethanol (600 ml) and sodium hydroxide (145 g) at 35°C and stirred for 20 minutes. The temperature was raised to 40°C and stirred for 3 hours. The reaction mass was treated with water ( 1 00 ml) and stirred for 20 minutes. The reaction mass was filtered and washed with water (200 ml) afforded solid state form of (R)-5-(2-(pivaloyloxy (2- (2-(2,2,2-trifluoroethoxy) phenoxy) ethyl)amino) propyl)indoline-7-carbonitrile of Formula (S2).

Example -2:

Preparation of silodosin of Formula (I)

(R)-l -(3-(benzoyloxypropyl)-5-(2-(2-(2-(2,2,2-trifluoroethoxy) phenoxy) ethylamino)propyl) indo line-7-carboxamide of Formula (A) ( 1.0 Kg), ethanol (10.0 L), methane sulfonic acid ( 1.0 L) and water ( 1.0 L) were added into autoclave cell at 30°C to 35°C followed by the addition of 10% Pd/C (0.05 Kg) with nitrogen 2 kg pressure and pressure was released. To the reaction mass, H₂ pressure (5 Kg) was applied and raised to 7 Kg and maintained for 3.0 hours at 30°C to 35°C. The reaction mass was cooled and washed with ethanol (2 x 0.50 L), followed by the addition of water (10.0 L) and ethyl acetate (2.0 L) and the reaction mass was stirred for 30.0 min. The layers were separated followed by the addition of dichloromethane (2.0 L) to the aqueous layer and pH of reaction mass was adjusted between 8.0 to 9.0 by sodium carbonate solution at 30°C and the reaction mass was stirred for 30 minutes . Ethyl acetate (4.0 L) was added followed by layer separation. Further, methyl ethyl ketone (0.8L) was added and cooled to 15°C to 20°C and stirred for 30 minutes and washed with MTBE (2 x 0.50 L)

Π afforded silodosin substantially free of impurity X at RRT 0.87 to 0.90 (Purity greater than 99.9% by HPLC).

The product was jet milled with a grinding pressure of 4 Kg and feeding pressure of 2 Kg to afford silodosin particles having a (D90) particle size less than 8 microns.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

We claim:

A process for rmula (I),

(i) comprising:

i) treating (R)-l -(3-R'-(oxy)propyl)-5-(2-(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethylamino) propyl) indoline-7-carboxamideof compound of F

wherein R' is a hydroxy protecting group selected from benzyl, benzoyl, trityl, t- butyl, /-butyl dimethyisilyl (TBDMS), /-butyldiphenylsilyl (TBDP), pivaloyl, in a suitable solvent in the presence of a metal hydrogenation catalyst and one or more acids; and

ii) isolating the silodosin of Formula (1).

The process as claimed in claim 1 , wherein the solvent comprises one or more of Ci-C₅ alcohols, esters, ethers, water and mixtures thereof.

The process as claimed in claim 1 , wherein the metal hydrogenation catalyst is selected from nickel, platinum, palladium, ruthenium, rhodium, osmium, and iridium; and exposing the combination of solution and catalyst to hydrogen gas, or without hydrogen gas.

The process as claimed in claim 1 , wherein the ratio of weight of metal to the weight of compound of Formula (A) is about 0.007: 1 to 1 : 1.

The process as claimed in claim 3, wherein the combination of solution and metal catalyst to hydrogen gas is exposed at a pressure between about 1 to 10 atm and a temperature of about 40°C to 100°C.

6. The process as claimed in claim 1, wherein the acid comprises one or more of hydrochloric acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, acetic acid, and formic acid.

7. The process as claimed in claim 1, wherein the ratio of acid with respect to the compound of Formula (A) is about 1 :3.

8. A solid state form of (R)-5-(2-(pivaloyloxy (2-(2-(2,2,2-trifluoroethoxy)

phenoxy) ethyl) amino)

propyl)indoline-7-carbonitrile of Formula (S2)

which is characterized by one or more of the following properties:

i) a powder X-ray diffraction pattern having peaks at about 9.8, 12.2, 14.0, 15.1 , 16.5, 17.0, 18.0; 19.9, 21.0 23.5 and 24.6 ±0.2 degrees 2-theta substantially as depicted in FIG.1 ;

ii) having a single endotherm peak in DSC at about 93.9°C ±3 degrees substantially as depicted in FIG.2; or

iii) an IR spectrum having absorption bands at about 3344, 2978, 2204, 1666, 1595, 1398, 1255, 1 166, 1047, 983, 860, 742, 601 and 516 ± 2 cm^"1.

9. A process for preparing a solid state form of (R)-5-(2-(pivaloyl oxy (2-(2-(2,2,2- trifluoro ethoxy)phenoxy)ethyl)amino)propyl)indoline-7-carbonitrile of Formula (S2),

the process comprising: i) treating (R)- 1 -acetyl-5-(2-(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-carbonitrile of Formula (S) in the presence of a protecting agent to obtain (R)-l -acetyl-5-(2-(pivaloyl oxy(2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl)amino)propyl)indoline-7- carbonitrile of Formula (S I ); and

ii) treating the (R)-l -acetyl-5-(2-(pivaloyloxy(2-(2-(2,2,2- trifluoroethoxy)phenoxy)ethyl)amino) propyl)indoline-7-carbonitrile of Formula (S I) in a suitable solvent in the presence of a base to obtain the solid state form of (R)-5-(2-(pivaloyl oxy (2-(2-(2,2,2-trifluoroethoxy)phenoxy)ethyl) amino) propyl) indoline-7-carbonitrile of Formula (S2).

10. The process as claimed in claim 9, wherein the solvent comprises one or more of C 1 -C5 alcohols, esters, ethers, halogenated solvent, aromatic hydrocarbons, water and mixtures thereof.

1 1. The process as claimed in claim 9, wherein the protecting agent is a NH- protecting agent.

12. The process as claimed in claim 1 1 , wherein the NH-protecting agent comprises one or more of carbobenzyloxy (Cbz), butyloxycarbonyl (BOC), acetyl, benzoyy, benzyl, p-methoyxy phenyl, tosyl, and carbamate.

13. The process as claimed in claim 9, wherein the base comprises one or more of alkali or alkaline earth metal hydroxides, alkoxides, carbonates, bicarbonates or an organic base.

14. The process as claimed in claim 13, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert- butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethyl amine, diisopropyl amine, dimethyl amine, diisopropylethylamine, diisopropylmethyl amine, pyridine, piperidine, morpholine and N-methyl piperidine.

Silodosin, which is substantially free of l -(3-Hydroxypropyl)-5-[(2R)-2-({2-[2- (2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]- 1 H-indole-7-carboxamide, impurity-

A process for preparing silodosin substantially free of l -(3-Hydroxypropyl)-5- [(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]- lH-indole-7- carboxamide, impurity-X at RT 0.87 to 0.90,

comprising:

i) treating silodosin in a suitable solvent; and

ii) isolating the highly pure silodosin.

17. The process as claimed in claim 16, wherein the solvent comprises one or more of hydrocarbons, nitriles, amides, alcohols, ketones, halogenated solvents, and esters.

18. The process as claimed in claim 17, wherein the solvent comprises one or more of toluene, xylene, ethylbenzene dimethyl formamide, dimethyl acetamide, acetonitrile, C 1 -C4 straight chain or branched alcohols, acetone, methyl isobutyl ketone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, butyl acetate, and mixtures thereof.

19. Silodosin having a total purity of greater than about 99%, as measured by HPLC. 20. Silodosin as claimed in claim 19 having a total purity of greater than about 99.5% as measured by HPLC.

21. Silodosin as claimed in claim 19 having a total purity of greater than about 99.98% as measured by HPLC.

22. Silodosin having a particle size in terms of D90 less than about 10 microns.

23. Silodosin as claimed in claim 22 having a particle size in terms of D90 less than about 5 microns.

24. A process for preparing silodosin having a (D90) particle size less than 10 microns,

the process comprising:

a) subjecting silodosin to a jet mill under specific grinding pressure and feeding pressure; b) isolating silodosin having a (D₉o) particle size less than 10 microns.

25. The process as claimed in claim 24, wherein the grinding pressure is about 7 Kg.

26. The process as claimed in claim 24, wherein the feeding pressure is about 4 Kg.