Field of the Invention:

The present invention relates to a novel process for the preparation of crystalline l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide and its pharmaceutical composition.

Background of the invention:

1 -(3-hydroxypropyl)-5-[(2R)-( {2-[2-[2-(2,2,2-trifluoro ethoxy) phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide is generally known as Silodosin with an empirical formula of C25H32F3N3O4 and a molecular weight of 495.53 and having the following structural formula-1.

Silodosin is commerically available as a capsule for oral administration (RAPAFLO®, marketted by Watson). Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).

The pharmaceutical compositions comprising, l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-l//-indole-7-carboxamide, and its pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof as an active ingredient, are known in the prior-art.

In US 5387603 patent, which discloses indoline compounds including l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]sthyl}amino)propyl]-2,3-dihydro-l//-indole-7-carboxamide, several dosage fonns are exemplified as an oral solid formulation. It is also reported therein as a general description that such dosage forms may be prepared by formulating indoline compounds according to conventional formulation procedures. However, US 5387603 has not disclosed a specific formulation
comprising,l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide as an active ingredient.

In US Patent application 2004072851, which discloses a medicament comprising, as an active ingredient, an [alpha] 1-AR blocking agent including l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]etbyl}amino)propyl]-2,3-dihydro-l/f-indole-7-carboxamide for treating lower urinary tract disorders, several dosage forms are exemplified as an oral solid formulation. It is also reported that such dosage forms may be prepared using ordinary pharmaceutical additives according to conventional formulation procedures. However, US2004072851A1 has not disclosed a specific pharmaceutical composition comprising, l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-triiluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamideas an active ingredient.

As per the available literature, l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-ndole-7-carboxamide is relatively unstable when exposed to light. Admixing some kind of pharmaceutical additives with 1 -(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl}amino)propyl]-2,3-dihydro-li/-indole-7-carboxamide results in incompatibility and yields degradation products. For example, compatibility between l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-l//-indole-7-carboxamide and lactose, were most popularly used as a filler, which is not recommended, and use of lactose as a filler gives undesirable dissolution properties and unsatisfactory hardness of tablets. Moreover, l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide has a potent adhesive property, and in the case of preparing a tablet or capsule, use of a lubricant is inevitable. On the contrary, the addition of such lubricants causes the problem of delaying in dissolution time. Accordingly, it is extremely difficult to prepare practically usable solid oral dosage form pharmaceuticals comprising, l-(3-hydroxypropyl)-5-[(2^)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-l/f-indole-7-carboxamide, its prodrug, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof as an active ingredient, by conventional formulation methods.

In US Patent application 20060142374 discloses the medicament of crystalline form a of the compound of formula-1 and process for the preparation of crystalline forms of the compound of formula-1.
In US Patent application 2006018959 discloses the dissolution of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide wherein the said oral solid dosage form has 85% dissolution time, which is not more than 60 minutes in a dissolution test according to method 2 (paddle method) of Japanese pharmacopoeia in a condition using water as a dissolution medium with 50 rpm paddle speed.

In the present invention our inventor carried the dissolution of l-(3-hydroxy propyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide by using method-1 (Basket method) according to United States of Pharmacopoeia in a condition using the 0.0IN HC1 as dissolution medium, with a basket speed of 100 rpm wherein, 85% drug release with in 60 minutes.

It has been reported in prior-art that the crystalline a-form of /-(3-hydroxy propyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl} amino)propyl]-2,3-dihydro-lH-indole-7 -carboxamide is more stable form and P-crystalline form is comparitively less stable. In the present invention, the most preferable polymorph used for the preparation of pharmaceutical formulation is a-crystalline form.

The present invention discloses the novel process for the preparation of stable p-crystalline form of /-(3-hydroxy propyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy] ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide from its crude. Without being bound by any particular theory, it would appear by the data gathered and presented herein that the "initial burst release" at 5 min of silodosin formulation of the present invention has better dissolution profile, which inturns gives a better therapeutic effect. Such stable oral dosage form of silodosin, prepared as herein described, can be used for the treatment of the signs and symptoms of benign prostatic hyperplasia.

Summary of the Invention:

In aspect of the present invention relates to the novel process for the preparation of stable crystalline β form of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoro ethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide.

In another aspect of the present invention relates to an oral solid dosage form of 1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)-propyl]-2,3-dihydro-lH-indole-7-carboxamide and process for its preparation thereof, wherein the said oral solid dosage form has 85% drug release with in 60 minutes time by using USP apparatus 1 (basket) at 100 rpm in dissolution medium as 0.0IN HC1.

In another aspect of the present invention relates to the pharmaceutical composition of oral solid dosage form of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)-propyl]-2,3-dihydro-lH-indole-7-carboxamide.

In another aspect of the present invention relates to the process for the preparation of oral solid dosage form of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoro ethoxy)phenoxy] ethyl} amino)-propyl]-2,3 -dihydro-1 H-indole-7-carboxamide.

In another aspect of the present invention relates to a solid oral dosage form comprising silodosin or its salts having an initial burst release of about 65% in 0.01 N Hcl, 100 RPM, USP apparatus-I (Basket), 900 ml in about 5 minutes.

In another aspect of the present invention relates to a solid oral dosage form comprising silodosin or its salts prepared by a direct compression technique.

In an aspect of the present invention relates to a pharmaceutical formulation exhibiting storage stability at a temperature of about 40 °C and a relative humidity of about 75% for a period of at least 3 months, and contains not more than 2% w/w total impurities (based on total weight of the formulation) formed upon storage.

In yet another aspect, the pharmaceutical formulation of present invention is stable at accelerated conditions for a period of at least 3 months. The formulations of were stored at about 40°C temperature and a relative humidity of about 75% after packing into Alu-Alu blister packs and/or HDPE containers.

Brief Description of the Drawings:

Figure-1: Illustrates an XRPD pattern for the crystalline β form of the compound of formula-1.

Figure-2: Illustrates ccomparative dissolution diagram of RAPAFLO® capsules 8mg (Innovator product) with Compound of formula-1 capsule 8mg (Test product). Figure-3: Illustrates comparative dissolution diagram of RAPAFLO® capsules 8mg (Innovator product) with Compound of formula-1 capsule 4rng (Test product).

Detailed Description of the Invention:

The present invention relates to a novel process for the preparation of crystalline l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide compound of formula-1 and its pharmaceutical composition. Hereinafter formula-1 is also referred as silodosin or its salt. Further, silodosin exists in different polymorphic forms are well known in the art. In the present invention, the most preferable polymorph used for the preparation of pharmaceutical formulation is a-crystalline form.

B.y "salt" or "pharmaceutically acceptable salt", it is meant those salts and esters which are, within the scope of sound medical judgment, suitable for oral use for humans to commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, and bisulphate. Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts. The term "pharmaceutically acceptable" as used in connection with components includes those components approved by a governmental regulatory agency or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, such as humans.

The process for the preparation of compound of formula-1 was disclosed in the US 5387603, herein after included as the reference.

In an aspect of the present invention is to provide a process for the preparation of stable crystalline β form of the compound of formula-1, comprises of following steps;

a) Dissolving the compound of formula-1 in methyl isobutyl ketone,
b) heating and stirring the reaction mixture,
c) filtering the obtained reaction mixture,
d) slowly cooling the reaction mixture,
e) stirring the reaction mixture,
f) filtering the reaction mixture and washing with methyl isobutyl ketone,
g) drying the solid to get β form of indoline compound of formula-1.

The present crystalline β form of compound of formula-1 is more stable under the following conditions:

a) pressure up to ten tons,
b) at a temperature of 60°C for 24 hours,
c) under UV light for 24 hours, and
d) in presence of moisture, confirmed by the fact that there is no change in the PXRD pattern under these conditions.

In US application 2006/0142374 Al discloses a process for the preparation of crystalline P form of the compound of formula-1 using alcohol solvents. Wherein crude crystals are dissolved in appropriate amount of methanol or ethanol under heating, adding a non polar solvent like petroleum ether and stirring vigorously to precipitate the crystals forcibly and suddenly. It has a manufacturing issue in industrial preparation and it may be difficult to get consistent quality of the crystal.

The present invention relates to an improved process for the preparation of crystalline P form of the compound of formula-1 by using single solvent.

The term "pharmaceutical formulation" (synonymously, "pharmaceutical composition") is used herein to refer to a pharmaceutical preparation intended for oral administration for the treatment of the signs and symptoms of benign prostatic hyperplasia of a subject in need thereof.

The term "solid oral dosage form" (synonymously, "dosage form") is used herein to refer to a pharmaceutical preparation intended for oral administration, includes such dosage forms as tablets, capsules, minitablets, pellets, granules, powders & spheroids. Preferably, solid oral dosage form is in the form of a tablet or a capsule.

Direct compression is the preferred technique since it is considered that fewer chemical stability problems are associated with this technique in comparison with the wet granulation process as moisture is considered to be a primary cause of instability in tablet dosage forms. In addition to the advantage of improved active ingredient stability, the use of direct compression makes it unnecessary to use applied heat to dry the damp granule. Other benefits associated with direct compression are related to particle size uniformity. This invention therefore is directed towards a direct compression pharmaceutical formulation of an active pharmaceutical ingredient.

In an aspect of the present invention relates to an oral solid composition of l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl} amino) propyl]-2,3-dihydro-lH-indole-7-carboxamide, wherein the said oral solid dosage form has 85% drug release with in 60 minutes time by using USP apparatus 1 (basket) at 100 rpm in 0.01N HC1.

In another aspect of the present invention is to provide the pharmaceutical composition comprising:

a) Crystalline form of Silodosin,
b) at least one diluent,
c) at least one disintegrant,
d) at least one surfactant,
e) and at least one lubricant.

The diluents are generally used to increase the bulk of the tablet or capsule, the diluent preferred in the present formulation are Mannitol and/or dicalcium phosphate. Preferably mannitol.

Disintegrants are included in the tablet or capsule formulations to promote the breakup of the tablet or capsule into smaller fragments thereby increasing the available surface area and promoting a more rapid dissolution of the active ingredient. This will enhance the bio availability of the active pharmaceutical ingredients. The various dinintegrants include starch, low-substituted hydroxyethylcellulose, and partially pregelatinized starch but the preferable one is pregelatinized starch.

Surfactants are included to improve the drug release rate. The improved release rate is often associated with the effect of surfactant increasing the hydrophilicity of the dosage form thereby promoting the drug dissolution. Various surfactants include polyethylene glycol, polyoxyethylene, sodium lauryl sulphate, polyoxypropylene glycol and triethylcitrate, docusate sodium. Preferable surfactant is sodium lauryl sulphate.

Lubricants are used in the tablet or capsule formulation to reduce the friction during the compression and capsule filling operations. Lubricants include stearic acid (calcium stearate and magnesium stearate), sodium steryl fumerate, vegetable oils(corn oil), mineral oils, polyethylene glycol, inorganic salts(such as sodium chloride), and polyvinyl alcohols. Preferred lubricant is magnesium stearate or steric acid; most preferably magnesium sterate.

In an another aspect of the present invention relates to the process for the preparation of oral solid dosage form of l-(3-hydroxypropyl)-5-[(2i?)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl} amino)propy 1] -2,3-dihydro-1H-indole-7-carboxamide comprises of the following steps:

a) Sifting all excipients,

b) mixing l-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethyl}amino)propyl]-2,3-dihydro-lH-indole-7-carboxamide with mannitol, pregelatinized starch and sodium lauryl sulphate,

c) lubricating the above mixture with magnesium stearate,

d) filling the above mixture into a capsule shell.

In another aspect of the present invention relates to a solid oral dosage form comprising silodosin or its salts having an initial burst release of about 65% in 0.01 N Hcl, 100 rpm, USP apparatus-I (Basket), 900 ml in about 5 minutes.

Wherein "Initial burst release" refers to the release of a active pharmaceutical ingredient from the pharmaceutical formulation in the first 5 minutes.

In another aspect of the present invention relates to a solid oral dosage form comprising silodosin or its salts prepared by a direct compression technique comprising: (a) sifting active pharmaceutical ingredient, surfactant & disintegrant (b) blend the step (a) material in an octagonal blender, (c) lubricating the step (b) with lubricant (d) fill the resultant mixture of step (c) into a capsules or optionally compressed into a tablets.

According to the invention there is provided a solid oral dosage form comprising silodosin and a pharmaceutically acceptable carrier, of which are in finely divided form, wherein the final blend has a poured bulk density of about 0.40 to about 0.65 g/ml, preferably about 0.45 to about 0.60 g/ml.

In an aspect of the present invention relates to a pharmaceutical formulation exhibiting storage stability at a temperature of about 40 °C and a relative humidity of about 75% for a period of at least 3 months, and contains not more than 2% w/w total impurities (based on total weight of the formulation) formed upon storage.

In yet another aspect, the pharmaceutical formulation of present invention is stable at accelerated conditions for a period of at least 3 months.

For the pharmaceutical formulation being referred to as "stable" in the context of present invention, the formulation should contain not more than 2% w/w total impurities (based on total weight of the formulation) formed upon storage at accelerated conditions (i.e., at a temperature of about 40°C and relative humidity of about 75%) for a period of at least 3 months. As described herein, the pharmaceutical formulation, before being stored at accelerated conditions, contains less than about 0.5% w/w of total impurities related to silodosin. Impurity levels above 2% w/w would be unacceptable for a number of reasons, including reduced activity and/or shelf life. In an embodiment, the pharmaceutical formulation of present invention contains not more than 1.0% w/w "dehydro impurity" formed upon similar storage for a period of 3 months.

The compound of formula-1 obtained according to the process of the present invention as described above, may contain the impurity less than about 0.1 % at 1.28 RRT, as determined by HPLC. The said impurity may have the following structure:

Related substances of the compound of formula-1 and its pharmaceutically acceptable salts were measured by High Performance Liquid Chromatography (HPLC) using the following conditions.
Apparatus: A liquid chromatograph is equipped with variable wavelength UV-Detector; Column: Unison C8, 150 x 4.6 mm, 5μ or equivalent; Flow rate: 1.0 mL /min, wave length: 225 nm, Temperature: 25°C; Injection volume: 10μL; Run time: 47 minutes; Elution: Gradient, Diluent: Water: Acetonitrile (50:50)v/v, Buffer: Weigh accurately about 2.72g potassium dihydrogenortho phosphate and l.0g 1-octane sulphonic acid sodium salt anhydrous in 1000ml of water and adjust pH to 3.0 with ortho phosphoric acid. Filter this solution through 0.45 μm Nylon membrane filter paper and sonicate to degas it. Mobile Phase-A: Buffer; Mobile Phase-B: Acetonitrile: Methanol (80:20)v/v,

The functions and advantages of the present invention will be explicable from the examples mentioned in the below table. The following examples are intended to illustrate the benefits of the present invention, but do not exemplify the full scope of the invention.

Examples:
Example 1: Preparation of crystalline β form of the compound of formula-1
Methyl isobutyl ketone (1000 ml) was added to the compound of formula-1 (100 g) and heated to 70-75°C. Stirred the reaction mixture for 10-15 min at 70-75°C and filtered the reaction mixture through the hyflow bed. The obtained filtrate was slowly cooled to 25-30°C for 3-5 hrs and then stirred the reaction mixture for 3-4 hrs at 25-30°C. Filtered the obtained solid, washed the wet compound with methyl isobutyl ketone to get the crystalline p form of the compound of formula-1. Yield: 60-65 grams.

Purity by HPLC: 99.8%, Impurity at 1.28 RRT: 0.06%

Example-2: Silodosin compositions

Table 1

Manufacturing Process:
Sifting of Ingredients:

Table: 2

The above materials were sifted separately in a double lined poly bags.
a) Silodosin & sodium lauryl sulphate were sifted in a poly bag & mixed for 2 min.
b) To the above blend pregelatinised starch was added and mixed for 3 min.
c) To the above blend, Mannitol (partial amount) was added and mixed for 3 min.
d) To the above blend, remaining quantity of Mannitol was added into blender and mixed for 20min.
e) Magnesium stearate was mixed with preblended granules in a Poly bag and loaded into the Octagonal blender and mixed for 5 minutes.

f) Resultant blend of step 5 was filled into capsules.

Dissolution Method:
In vitro dissolution studies on silodosin capsules are carried out using USP apparatus 1 (basket) at 100 rpm in 900ml of 0.0 IN HC1 as a dissolution medium maintained at a temperature of 37±0.5°c, aliquot was withdrawn at the specified time intervals and assayed spectrophotometrically, wherein 85% dissolution profile is obtained in not more than 60 minutes.

TabIe-3: Comparative dissolution profile of RAPAFLO ©capsules Vs Example-2:
Table-3

Example-3: Silodosin compositions
Table-4

Manufacturing Process:
Manufacturing process is same as Example-2

Table-5: Comparative dissolution profile of RAPAFLO® capsules 8mg Vs Silodosin capsules 4mg
Table-5

Stability data:
The formulations of Examples 2 & 3 were stored at about 40°C temperature and a relative humidity of about 75% after packing into Alu-Alu blister packs and/or HDPE containers. For three months at monthly intervals, the formulations were analyzed for impurities and an assay of silodosin was performed. The results of this stability study are tabulated below.

Table:6

We claim:

1. A method for the preparation of stable crystalline β form of the compound of formula-1, comprises of:

a) Dissolving the compound of formula-1 in methyl isobutyl ketone,

b) heating and stirring the reaction mixture,

c) filtering the obtained reaction mixture,

d) slowly cooling the reaction mixture,

e) stirring the reaction mixture,

f) filtering the reaction mixture and washing with methyl isobutyl ketone, drying the solid to get P form of indoline compound of formula-1.

2. A solid oral dosage form comprising silodosin or its salts prepared by a direct compression technique.

3. A solid oral dosage form according to claim 2, wherein a dosage form comprising silodosin or its salts, mannitol, sodium lauryl sulfate, pregelatinized starch, & magnesium stearate.

4. A solid oral dosage form comprising silodosin or its salts having an initial burst release of about 65% in 0.01 N HC1, 100 RPM, USP apparatus-I (Basket), 900 ml in about 5 minutes.

5. A solid oral dosage form comprising silodosin or its salts having a bulk density of the final blend is about 0.45 gm/ml to about 0.6gm/ml.

6. A solid oral dosage form of claim 2, which contains not more than 2% w/w total impurities (based on total weight of the formulation), formed upon storage at a temperature of about 40°C and a relative humidity of about 75% for a period of at least 3 months.

7. A solid oral dosage form according to the preceding claims, wherein a dosage form is in the form of a capsule, tablets, pellets or mini tablets.

8. A solid oral dosage form according to claim 7, wherein a dosage form is in the form of a capsule.

9. A solid oral dosage form of silodosin or its salt comprising:

(a) Sifting silodosin, sodium lauryl sulfate, pregelatinized starch, mannitol,
(b) blending the step (a) material in a octagonal blender,
(c) lubricating the step (b) with magnesium stearate,
(d) filling the resultant mixture of step (c) into a capsules or optionally compressed into a tablets.