DESC:Field of the invention
The present invention relates to a novel and improved purification process of fluticasone furoate. The present invention also relates to pharmaceutical compositions comprising said fluticasone furoate and its use in the medicine.

Background of the invention
Inhalers are well known devices for administering pharmaceutically active materials to the respiratory tract by inhalation. Such active materials commonly delivered by inhalation include bronchodilators such as ß2 agonists and anticholinergics, corticosteroids, anti-allergics and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.

Fluticasone furoate, is first described by U.S. Pat. No. 7,101,866 B2 and sold under the brand name Veramyst among others. It is a corticosteroid acting as a potent anti-inflammatory for the treatment of non-allergic and allergic rhinitis administered by a nasal spray. It is also available as an inhaled corticosteroid to help prevent and control symptoms of asthma and chronic obstructive pulmonary disease (COPD). It is derived from cortisol. Unlike fluticasone propionate, which is only approved for children four years and older, fluticasone furoate nasal spray is indicated for the treatment of the symptoms of seasonal and perennial allergic rhinitis in patients aged 2 years and older.

It has the chemical name (6a,11ß,16a,17a)-6,9-difluoro-17{[(fluoro-methyl)thio]carbonyl}-11-hydroxy-16-methyl-3-oxoandrosta-1,4-dien-17-yl 2furancarboxylate and the following chemical structure:

Formula I
Two widely used systems for the administration of drugs to the airways through the inhalation route are the dry powder inhalers (DPIs) comprising micronized drug particles as dry powder usually admixed with coarser excipient particles of pharmacologically inert materials such as lactose, and the pressurized metered - dose inhalers (PMDIs ) which may comprise a liquefied propellant to expel droplets containing micronized drug particles of the pharmaceutical product to the respiratory tract as an aerosol. PMDI formulations are generally characterised as solution formulations or suspension formulations. Both types of products are used to treat lung diseases characterized by obstruction of airflow and shortness of breath, including asthma and chronic obstructive pulmonary disease (COPD), as well as respiratory infections and cystic fibrosis. The inhalation route offers further potential for systemic drug delivery.

The efficiency of an aerosol device is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterised by their mass median aerodynamic diameter (MMAD).

Many of the factors relevant to the MMAD of particles are relevant to droplets and the additional factors of rate of solvent evaporation, and surface tension are also important.

In suspension formulations, particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation. However, if the suspended drug has the slightest solubility in propellant, a process known as Ostwald Ripening can lead to particle size growth. Also, particles may have tendency to aggregate, or adhere to parts of the MDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particularly severe for potent drugs (including fluticasone propionate) which need to be formulated in low doses.

Solution formulations do not suffer from these disadvantages, but suffer from different ones in that particle or droplet size is both a function of rate of evaporation of the propellant from the formulation, and of the time between release of formulation from canister and the moment of inhalation. Thus, it may be subject to considerable variability and is generally hard to control.

Besides its impact on the therapeutic profile of a drug, the size of aerosol particles has an important impact on the side effect profile of a drug. For example, it is well known that the orthopharynx deposition of aerosol formulations of steroids can result in side effects such as candidiasis of mouth and throat. Accordingly, throat deposition of such aerosol formulations is generally to be avoided. Furthermore, a higher systemic exposure to the aerosol particles due to deep lung penetration can enhance the undesired systemic effects of certain drugs. For example, the systemic exposure to certain steroids can produce side effects on bone metabolism and growth.

For drug substances used in MDIs or DPIs, particle size distribution (PSD), moisture content, bulk density, flow properties, morphic form (e.g., amorphous, crystalline, hydrate), morphology of drug particles (e.g., shape, crystal habit, texture, surface area, rugosity), residual solvent content, and impurities should be within an appropriate limit, range, or distribution to ensure the desired product quality.

The compound stability is one of the most important criteria by most of the regulatory agencies. Therefore, one need to demonstrate that even after the formulation the stability of the compound or its respective form is intact over a period of shelf life. The compound transformations can occur also in the different solid state, because of changes in humidity or temperature or oxidative degradation conditions.

The prior art discloses the importance of the production conditions of the medicinal products reported to undergo unwanted and undesirable transformations, if the process conditions are not opportunistically controlled. Consequently, a stable and pure fluticasone furoate would be a significant contribution to the art.

US 7,592,329 B2 discloses processes for the preparation of unsolvated Form 1 of fluticasone furoate (I). The process for preparing crystalline unsolvated Form 1 of fluticasone furoate, comprises dissolving fluticasone furoate in methylisobutylketone or ethyl acetate and producing fluticasone furoate (I) as unsolvated Form 1 by addition of an anti-solvent such as iso-octane or toluene, wherein the overall yield is about 82%.

Alternatively, the process for preparing crystalline unsolvated Form 1 of fluticasone furoate, comprises evaporative crystallization in a mixture of acetone : water system followed by addition of toluene and crystallization at 98-105 ?C followed by cooling to 10?C.

Alternatively, the process for preparing crystalline unsolvated Form 1 of fluticasone furoate, comprises formation of solvated API complex These complexes of the invention are converted to unsolvated Form 1 by removal of the guest molecule (eg high temperature vacuum drying on heating at typically to around 105-115°C.)

However, the high temperature drying/crystallization is challenging task at commercial scale.

WO 2012/029077 discloses an improved process for the purification of fluticasone furoate using an aprotic solvent or a mixture of solvents optionally using water as mixture. More specifically, the process disclosed is purification using MEK as solvent. However, the API has tendency to form MEK solvate. In an alternate process pure fluticasone furoate is obtained by crystallization in ethyl acetate followed by evaporation and addition of water for yield improvement (yield:95%).

However, it was observed that evaporation and cooling crystallization suffers from uncontrolled crystal growth and can lead to particle size growth in absence of controlled utility and seeding.

Though fluticasone furoate and its process of manufacture has been described in the prior art, there is continuous need in the art to provide a significantly more stable and pure product that can be easily formulated to give pharmaceutical compositions. Thus, there exists a continuous need for an efficient process of preparing fluticasone furoate with high chemical purity and good overall yield, which is suitable for industrial scale up.

The present invention provides an improved purification process for synthesis of fluticasone furoate which avoids all the disadvantages associated with the prior art processes.

Objectives of the invention
Therefore, it is an object of the present invention to provide a novel and improved process to purify fluticasone furoate with a view to providing fluticasone furoate with increased bioavailability.

Another object of the present invention is to provide crystalline unsolvated Form 1 of fluticasone furoate.

Another object of the present invention is to provide industrially advantageous, cost effective and environmentally friendly processes for the preparation of fluticasone furoate.

Yet another object of the present invention is to provide fluticasone furoate having desired particle size and low residual solvent content.

Yet another object of the present invention is to provide fluticasone furoate having improved flowability.

Yet another object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of fluticasone furoate.

Summary of the invention
In line with the above objectives, the present invention provides a novel and improved process for the purification of fluticasone furoate.

In one embodiment, the present invention provides a novel and improved process for the purification of fluticasone furoate comprising the steps of:
a) dissolving fluticasone furoate in a first solvent mixture comprising polar protic and polar aprotic solvent to form a first solution;
b) mixing two or more polar solvents to form a second solution
c) adding the first solution to a second solution;
d) stirring for sufficient time; and
e) isolating pure unsolvated fluticasone furoate Form 1.

The process of the present invention has several advantages
a. Use of binary/ternary solvents system reduces reaction temperature making it suitable for industrial scale up
b. The purification process removes traces of the unknown impurity referred to in the European Pharmacopeia.
c. Fluticasone furoate obtained by the process contains low residual solvent content.
d. In situ formation of stable and crystalline unsolvated Form 1 of fluticasone furoate. The crystalline nature of fluticasone furoate according to the present invention is characterized by X-ray powder diffraction.
e. The advantages of the process include simplicity of manufacturing, eco-friendliness and suitability for commercial use.
f. The fluticasone furoate obtained by the process of the present invention is relatively stable towards the moisture and humidity, thereby representing a crystalline form of pharmaceutical compound, thus enhancing the efficacy of the parent molecule in lower doses.
g. The fluticasone furoate obtained by the process of the present invention contains 90% of the particles smaller than 20 micrometers.

The present invention further provides a pharmaceutical composition comprising fluticasone furoate prepared by the processes of the present invention and processes for the preparation of the novel composition.

The present invention further provides pharmaceutical composition comprising fluticasone furoate prepared by the processes of the present invention either alone or in combination therapy with one or more other medicaments in addition to fluticasone furoate such as beta adrenergic agonists and anti-cholinergic compounds in a single pharmaceutical composition or separate pharmaceutical composition.

The present invention provides use of fluticasone furoate, for the preparation of a pharmaceutical composition and the pharmaceutical composition comprising an effective amount of fluticasone furoate of the present invention and at least one pharmaceutically acceptable excipient. Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g. inhalation aerosols (also known as metered dose inhalers (or MDIs)) and inhalation powders (also known as dry powder inhalers (or DPIs)), suspension, liquid solution, etc.

Administration of pharmaceutical composition may be indicated for the treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment. Treatment may be of non-allergic and allergic rhinitis, asthma, chronic obstructive pulmonary disease (COPD) or other respiratory disorder.

The present invention provides a method of treating non-allergic and allergic rhinitis and / or respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease (COPD), which method comprises administration by inhalation of an effective amount of fluticasone furoate prepared according to the process of the present invention.

The present invention further provides the use of fluticasone furoate in the manufacture of a medicament for the treatment of non-allergic and allergic rhinitis and/or respiratory disorders, eg. asthma or chronic obstructive pulmonary disease (COPD).

As mentioned above the advantages of the invention include the fact that pharmaceutical composition according to the invention may be more environmentally friendly, more stable, less susceptible to Oswald ripening or drug deposition onto internal surfaces of a metered dose inhaler, have better dosing uniformity, deliver a higher FPM, give lower throat deposition, be more easily or economically manufactured, or may be otherwise beneficial relative to known formulations.

Detailed description of the invention:
This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with applicant’s invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this specification, and may be variously modified.

The present invention provides a novel and improved process for the purification of fluticasone furoate with a view to improving the flowability and bioavailability of fluticasone furoate.

The fluticasone furoate of the present invention may provide multiple benefits in preparing formulations of fluticasone furoate, for example, improved processability increased stability of the pharmaceutical formulation or API, or improved pharmacokinetic properties of the pharmaceutical formulation. It is further recognized that fluticasone furoate, as a hydrophobic drug, commonly has low bioavailability. The fluticasone furoate of the present invention may help improve the bioavailability of the API.

In one embodiment, the present invention provides a novel and improved process for the purification of fluticasone furoate comprising the steps of:
a) dissolving fluticasone furoate in a first solvent mixture comprising polar protic and polar aprotic solvent to form a first solution;
b) mixing two or more polar solvents to form a second solution;
c) adding the first solution to a second solution;
d) stirring for sufficient time; and
e) isolating pure pure unsolvated fluticasone furoate Form 1.

Fluticasone furoate used for the above process, as well as for the following processes, may be in any polymorphic form or in a mixture of any polymorphic forms such as an amorphous, crystalline, semi-crystalline, hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.

Fluticasone furoate used in the processes of the present invention can be obtained by any method known in the art, such as the one described in the US 7,101,866 B2. The initial particle size of fluticasone furoate employed for this disclosure is in the range of 20-50 microns.

Preferably, fluticasone furoate used is either in the form of a MEK solvate or Form 1.

In one aspect, as depicted in step (a), the first polar aprotic solvent is one or more organic solvents, preferably selected from the group comprising of C2-C10 esters such as ethyl acetate, ethyl lactate, methyl acetate, methyl pentanoate, amyl acetate, isopropyl acetate, isobutyl acetate, and butyl acetate; the first polar protic solvent is one or more organic solvents, preferably selected from the group comprising of water, C1-C5 alcohols such as methanol, isobutanol, t-butanol, and isoamyl alcohol or mixture thereof.

In one embodiment fluticasone furoate is dissolved in a binary solvent system comprising polar aprotic solvent and polar protic solvent.

In a preferred embodiment the binary solvent system comprises ethyl acetate and methanol.

In one aspect, the volume ratio of polar aprotic solvent to the polar protic solvent is ranging from about 10:1 to 1:1 , preferably, 10:1 to 5:1, more preferably 3:1.

In an alternative embodiment fluticasone furoate is dissolved in a ternary solvent system comprising polar aprotic solvent, polar protic solvent and water.

In a preferred embodiment the ternary solvent system comprises ethyl acetate, methanol and water.

In one aspect, the volume ratio of polar aprotic solvent to the polar protic solvent to water is ranging from about 8:1:1 to 5:4:1, preferably, 7:2:1 to 6:3:1, more preferably 6:3:1.

In one aspect, as depicted in step (a), the dissolution temperature may range from about 10°C to about the reflux temperature of the solvent(s), depending on the solvent(s) used for dissolution. The dissolution temperature may range from about 20°C to about 70°C or from about 25°C to about 65°C, or from about 30°C to about 60°C. In a preferred aspect, the dissolution temperature is from about 45°C to about 55°C.

In one aspect, the first solution is first cooled and filtered through Cartridge Filter to remove insoluble.

In one aspect, as depicted in step (b), the second solvent is an anti-solvent. The fluticasone furoate may be insoluble or poorly soluble in the second solvent and addition of the solvent may cause fluticasone furoate to precipitate out of solution. One of skill in the art will be familiar with a variety of suitable solvents that have characteristics to facilitate this process.

The suitable second polar protic solvent is one or more organic solvents, preferably selected from the group comprising of water and C1-C5 alcohols such as methanol, , isobutanol, t-butanol, and isoamyl alcohol. For example, in some embodiments, water and methanol are used to form a second solution.

In one aspect, the volume ratio of water to methanol is ranging from about 10:1 to 1:1, preferably, 10:1 to 7:1, more preferably 7:3.

In one aspect, as depicted in step (c), the first solution is added to second solution at a control rate.

Optimally, the second solution is added to first solution at a control rate.

In a preferred aspect, the mixing is done at a temperature ranging from about 20°C to about 30°C.

In one aspect, as depicted in step (d), after mixing, the solution is further stirred at a temperature ranging from about 20°C to about 30°C, for about 30 minutes to about 3 hours, preferably, for about 1 hour to about 2 hours.

In one aspect, solution is further chilled to a temperature ranging from about -10°C to about 10°C preferably, from about -5°C to about 5°C, for about 30 minutes to about 5 hours, preferably, for about 2 hour to about 4 hours.

In one aspect, as depicted in step (e) isolation comprises removing the solvent by filtration, centrifugation, decantation, evaporation, solution concentration, spray drying, lyophilization or by any technique known in the art.

In one aspect isolated solid is dried to yield the fluticasone furoate into a solid form. Any suitable techniques known in the art may be used, for example, filtering and then drying under vacuum.

The initial drying may be done in a vacuum oven at a temperature ranging from about 25°C to about 40°C or from about 30°C to about 35°C. In a preferred aspect, the drying temperature is from about 25°C to about 30°C, for about 1 hour to about 10 hours, preferably for about 1.5 hours to about 5 hours, more preferably for about 2 hours to about 3 hours.

In one aspect, the final drying may be done in a vacuum oven at a temperature ranging from about 40°C to about 100°C or from about 50°C to about 90°C. In a preferred aspect, the drying temperature is from about 25°C to about 30°C, for about 1 hour to about 10 hours, preferably for about 1.5 hours to about 5 hours, more preferably for about 2 hours to about 3 hours

The drying may be done in a vacuum oven at a temperature ranging from about 40°C to about 100°C or from about 50°C to about 95°C, or from about 60°C to about 80°C. In a preferred aspect, the drying temperature is from about 75°C to about 85°C, for about 2 hours to about 30 hours, preferably for about 5 hours to about 25 hours, more preferably for about 10 hours to about 20 hours.

In one aspect, fluticasone furoate obtained by the processes of the present invention, is optionally further recrystallise in a suitable solvent or solvent mixture.

The resultant crystalline fluticasone furoate obtained by the above process can then be analysed to determine "crystalline purity," by known analytical techniques as substantially described herein.

As used herein the term "crystalline purity," refers to a particular crystalline form of a compound in a sample which may contain amorphous form of the compound, one or more other crystalline forms of the compound other than the crystalline form of the compound of this invention, or a mixture thereof wherein the particular form of the compound is present in an amount of at least about 80%, preferably at least about 95%, most preferably at least about 99% crystalline.

In one aspect, XRD and IR data indicates that the obtained fluticasone furoate is a stable unsolvated Form 1.

Particle size

Particle size is one of the most important properties of an inhaled aerosol because it strongly affects the probability and location of deposition of the aerosol particles in the respiratory tract. The mass of aerosol particles with diameters less than a certain size is also important because health effects of inhaled aerosols are correlated with such quantities.

As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as laser scattering, sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. The particle size measurement can be performed with a Malvern Mastersizer 2000 with the Hydro 2000G measuring cell, or with a Horiba LA-910 laser scattering particle size distribution analyzer.

According to the present invention, the fluticasone furoate obtained by the process of the present invention has an initial particle size below 20 microns.

In one aspect, fluticasone furoate of the present invention is milled or micronized /sieved further as needed to obtain the desired particle size characteristics.

In one aspect, Fluticasone furoate has 97% (D 97) of the particles smaller than 10 micrometers.

In another aspect, Fluticasone furoate has 90% (D 90) of the particles smaller than 5 micrometers.

In yet another aspect, Fluticasone furoate has median particle size (D 50) of the particles smaller than 3 micrometers.

In yet another aspect, Fluticasone furoate has 10% (D 10) of the particles smaller than 1 micrometers.

Residual solvent content
In one aspect, fluticasone furoate obtained by the process of the present invention has low residual solvent content. Preferably, fluticasone furoate meets the requirement of other Class 1, 2 and 3 residual solvents per USP chapter < 467 > and no other organic solvents are present.

The process of the present invention has certain advantages over prior art process
1. Use of Binary solvent system (ester: alcohol) or a Ternary solvent system (ester: alcohol: water) for dissolution of fluticasone furoate <60 ?C.
2. Use of ternary solvent system preferably (ester: alcohol: water) for crystallization of fluticasone furoate
3. Use of a binary solvent system (alcohol : water) as an antisolvent solution
4. Reverse mode anti-solvent crystallization wherein the API solution is added into antisolvent solution to reduce the solubility of the API in the solution and to produce pure crystals.
5. Use of phase diagram for optimization of design space (homogeneous phase) in terms of composition of ternary system (ester: alcohol : water) without impacting process yield (~90%).
6. The input material used for crystallization is either Form 1 or MEK solvate of fluticasone furoate which upon ternary solvent crystallization results into desired unsolvated Form 1 of fluticasone furoate .
7. US 7,592,329 B2discloses preparation of various complex/solvate formation which is desolvated at a very high temperature to yield desired unsolvated Form 1 of fluticasone furoate. However, the process of the present invention results in-situ formation of unsolvated Form 1 which upon drying remains as stable unsolvated Form 1.
8. controlled and robust antisolvent crystallization process using ternary solvent system which results in the consistent PSD preferably less than 20 micron and which can be easily further micronized to respiratory PSD requirements.

The resultant micronized crystalline fluticasone furoate obtained by any of the above process can then be formulated in a suitable pharmaceutical form employing known formulatory techniques.

EXAMPLES

The following examples are merely illustrative, and not limiting to the remainder of this disclosure in any way.

Example 1
Process for the purification of fluticasone furoate

Fluticasone furoate MEK solvate (100 g) was charged into reactor containing mixture of Ethyl Acetate (1200 mL) and Methanol (400 mL). The reaction mass was heated to 50°C to 55°C and dissolution was checked. It should be complete. The solution was cooled to 25°C to 30°C and filtered through Cartridge Filter.
The clear solution was then slowly added to a mixture of purified water (2800 mL) and Methanol (1200 mL) at 25°C to 30°C slowly in 30-60 minutes. The suspension was stirred for 1 hour at 25°C to 30°C, chilled further to 0°C to 5°C and stirred for 2 hours at 0°C to 5°C.
The fluticasone furoate was isolated by filtration, washed with purified water and dried at
First at 25°C to 30°C under vacuum for 2 hours and then at 80°C to 85°C under vacuum for 16 hours.
Water content - NMT 0.30%.
Yield:80-90% w/w, unsolvated basis 90-95%
Particle size: <20 microns
The dried material was sifted, micronized, the particle size of material was checked and packed in virgin food grade double clear HMHDPE bag, enclosed in TLHB bag and kept in Aluminium container.
The sample was analysed by XRPD and found to be unsolvated Form 1 of fluticasone furoate.

Example 2
Process for the purification of fluticasone furoate

Fluticasone furoate Form 1 (10 g) was charged into reactor containing mixture of Ethyl Acetate (120 mL) and Methanol (40 mL). The reaction mass was heated to 50°C to 55°C and dissolution was checked. It should be complete. The solution was cooled to 25°C to 30°C and filtered through Cartridge Filter.
The clear solution was then slowly added to a mixture of purified water (280 mL) and Methanol (120 mL) at 25°C to 30°C slowly in 30-60 minutes. The suspension was stirred for 1 hour at 25°C to 30°C, chilled further to 0°C to 5°C and stirred for 2 hours at 0°C to 5°C. The fluticasone furoate was isolated by filtration, washed with purified water and dried initially at 25°C to 30°C under vacuum for 2 hours and then at 80°C to 85°C under vacuum for 16 hours.
Water content - NMT 0.30%.
Yield:90-95% w/w
Particle size: <20 microns

The dried material was sifted, micronized, the particle size of material was checked and packed in virgin food grade double clear HMHDPE bag, enclosed in TLHB bag and kept in Aluminium container.
The sample was analysed by XRPD and found to be unsolvated Form 1 of fluticasone furoate.

Example 3
Process for the purification of fluticasone furoate
Fluticasone furoate Form 1 (10 g) was charged into reactor containing mixture of Ethyl Acetate (150 mL), Methanol (75 mL) and Water (25 mL). The reaction mass was heated to 50°C to 55°C and dissolution was checked. The solution was cooled to 25°C to 30°C and filtered through Cartridge Filter.

The clear solution was then slowly added to a mixture of purified water (375 mL) and Methanol (125 mL) at 25°C to 30°C slowly in 30-60 minutes. The suspension was stirred for 2 hours at 25°C to 30°C. The fluticasone furoate was isolated by filtration, washed with purified water and dried initially at 25°C to 30°C under vacuum for 2 hours and then at 80°C to 85°C under vacuum for 16 hours.
Water content - NMT 0.30%.
Yield:90-95% w/w
Particle size: <20 microns.

Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
,CLAIMS:1. An improved process for the purification of fluticasone furoate comprising the steps of:
a) dissolving fluticasone furoate in a first solvent mixture comprising polar protic and polar aprotic solvent to form a first solution;
b) mixing two or more polar solvents to form a second solution;
c) adding the first solution to a second solution followed by stirring for sufficient time at a temperature ranging from about 20°C to about 30°C; and
d) isolating pure unsolvated fluticasone furoate Form 1.

2. The process as claimed in claim 1, wherein, the fluticasone furoate employed in step a) is selected from an amorphous, crystalline, semi-crystalline, hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof.

3. The process as claimed in claim 2, wherein, the fluticasone furoate is either in the form of a MEK solvate or Polymorphic Form 1.

4. The process as claimed in claim 1, wherein, the initial particle size of fluticasone furoate employed in step a) is in the range of 20-50 microns.

5. The process as claimed in claim 1, wherein, the first polar aprotic solvent is selected from the group comprising of C2-C10 esters such as ethyl acetate, ethyl lactate, methyl acetate, methyl pentanoate, amyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate and the first polar protic solvent is selected from water; C1-C5 alcohols such as methanol, isobutanol, t-butanol, and isoamyl alcohol or mixture thereof.

6. The process as claimed in claim 5, wherein, the ratio of polar aprotic solvent to the polar protic solvent is ranging from about 10:1 to 1:1
7. The process as claimed in claim 5, wherein, the fluticasone furoate is dissolved in a binary solvent system comprises polar aprotic solvent and polar protic solvent.

8. The process as claimed in claim 7, wherein, the binary solvent system comprises ethyl acetate and methanol.

9. The process as claimed in claim 1, wherein, the fluticasone furoate is dissolved in a ternary solvent system comprises polar aprotic solvent, polar protic solvent and water.

10. The process as claimed in claim 9, wherein, the volume ratio of polar aprotic solvent to the polar protic solvent to water is ranging from about 8:1:1 to 5:4:1.

11. The process as claimed in claim 9, wherein, the ternary solvent system comprises ethyl acetate, methanol and water.

12. The process as claimed in claim 1, wherein, the dissolution temperature may range from about 10°C to about the reflux temperature of the solvent(s).

13. The process as claimed in claim 12, wherein, the dissolution temperature may range from about 20°C to about 70°C or from about 25°C to about 65°C, or from about 30°C to about 60°C.

14. The process as claimed in claim 1, wherein, the first solution is first cooled and filtered through Cartridge Filter to remove insoluble.

15. The process as claimed in claim 1, wherein, the polar protic solvent used in second solution is selected from the group comprising of water and C1-C5 alcohols such as methanol, isobutanol, t-butanol, and isoamyl alcohol.

16. The process as claimed in claim 15, wherein, the water and methanol are used to form a second solution.

17. The process as claimed in claim 16, wherein, the volume ratio of water to methanol is ranging from about 10:1 to 1:1.

18. The process as claimed in claim 1, wherein, the isolation of fluticasone furoate comprises removing the solvent by filtration, centrifugation, decantation, evaporation, solution concentration, spray drying and lyophilisation.

19. The process as claimed in claim 1, wherein, the pure fluticasone furoate is a stable unsolvated Form 1, having a particle size below 20 microns.