DESC:FIELD OF INVENTION:
The present invention relates to a novel and improved purification process of fluticasone propionate. The present invention also relates to pharmaceutical compositions comprising said fluticasone propionate 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 propionate, first described by U.S. Pat. No. 4,335,121, is a corticosteroid acting as a potent anti-inflammatory and which is used as crystalline Form 1 in the treatment of rhinitis, eczema, psoriasis, asthma and chronic obstructive pulmonary disease (COPD).

It has the chemical name S-(fluoromethyl)-6a,9-difluoro-11ß-17-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carbothioate, 17-propionate and the following chemical structure:

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 fluticasone propionate would be a significant contribution to the art.

Though fluticasone propionate 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 product that can be easily formulated to give pharmaceutical compositions.

OBJECTIVES OF THE INVENTION:
Therefore, it is an object of the present invention to provide a novel and improved process to purify fluticasone propionate with a view to providing fluticasone propionate with increased bioavailability.

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

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

Yet another object of the present invention is to provide fluticasone propionate containing 90% of the particles smaller than 10 micrometers.

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

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

SUMMARY OF THE INVENTION:
In line with the above objectives, the present invention provides a novel and improved process for the purification of fluticasone propionate.

In one embodiment, the present invention provides a novel and improved process for the purification of fluticasone propionate comprising the steps of:
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) dissolving a surfactant in a second solvent to form a second solution;
c) adding the first solution to a second solution;
d) removing the solvent; and
e) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

As used herein, the term "surfactant” refers to any agent which preferentially absorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/air interface. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, such that, upon absorbing to microparticles, they tend to present moieties to the external environment that do not attract similarly-coated particles, thus reducing particle agglomeration. Surfactants may also promote absorption of a drug and increase bioavailability of the drug.

Providing a surfactant on the surfaces of the particles can reduce the tendency of the particles to agglomerate due to interactions such as electrostatic interactions, Van der Waals forces, and capillary action. The presence of the surfactant on the particle surface can provide increased surface rugosity (roughness), thereby improving aerosolization by reducing the surface area available for intimate particle-particle interaction. The use of a surfactant which is a natural material of the lung can potentially reduce opsonization (and thereby reducing phagocytosis by alveolar macrophages), thus providing a longer-lived controlled release particle in the lung.

The surfactant may be incorporated throughout the particle and on the surface during particle formation, or may be coated on the particle after particle formation. The surfactant can be coated on the particle surface by adsorption, ionic or covalent attachment, or physically “coordinated with” the surrounding matrix. The surfactant can be, for example, incorporated into controlled release particles, such as polymeric microspheres.

In the process of the present invention, the inventor has developed a new method wherein surfactant is physically coordinated with the surrounding matrix. The particles incorporating a surfactant have improved aerosolization properties. The particle can be fabricated with features which enhance aerosolization via dry powder inhaler devices, and lead to lower deposition in the mouth, throat and inhaler device.

The present invention further provides fluticasone propionate which is stable and crystalline in nature.

The crystalline nature of fluticasone propionate according to the present invention is characterized by X-ray powder diffraction.

The advantages of the process include simplicity of manufacturing, eco-friendliness and suitability for commercial use.

The fluticasone propionate 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.

The present invention provides fluticasone propionate containing low residual solvent content.

The present invention provides fluticasone propionate containing 90% of the particles smaller than 10 micrometers.

The present invention provides a pharmaceutical composition comprising fluticasone propionate 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 propionate prepared by the processes of the present invention in combination therapy with one or more other medicaments in addition to fluticasone propionate 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 propionate, for the preparation of a pharmaceutical composition and to a pharmaceutical composition comprising an effective amount of fluticasone propionate 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 asthma, chronic obstructive pulmonary disease (COPD) or other respiratory disorder.

The present invention provides a method of treating respiratory disorders such as, for example, asthma or chronic obstructive pulmonary disease (COPD), which comprises administration by inhalation of an effective amount of fluticasone propionate.

The present invention further provides the use of fluticasone propionate in the manufacture of a medicament for the treatment of 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 preparation of fluticasone propionate with a view to improving the flowability and bioavailability of fluticasone propionate.

The fluticasone propionate of the present invention may provide multiple benefits in preparing formulations of fluticasone propionate, 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 propionate, as a hydrophobic drug, commonly has low bioavailability. The fluticasone propionate 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 propionate comprising the steps of:
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) dissolving a surfactant in a second solvent to form a second solution;
c) adding the first solution to a second solution;
d) removing the solvent; and
e) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

Fluticasone propionate 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 propionate 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 US4,335,121 B2. The initial particle size of fluticasone propionate employed for this disclosure is in the range of 20-50 microns.

Preferably, fluticasone propionate used is Form I.

In one aspect, as depicted in step (a), the first solvent is one or more organic solvents, preferably selected from the group consisting of polar solvents such as C1-C4 alcohols; esters such as ethyl acetate, methyl acetate; polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; ketones such as acetone, butanone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; nitriles such as acetonitrile, propionitrile; chlorinated organic solvents such as chloroform, dichloromethane, ethylene dichloride, hydrocarbons such as toluene, xylene, heptane, cyclohexane and the like or any combination thereof. More preferably, the first solvent is a polar aprotic solvent, such as ethyl acetate, methyl acetate, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, trioxane, N-methyl pyrrolidone, dimethyl acetamide; acetone, butanone, ethyl methyl ketone, methyl isobutyl ketone, methyl vinyl ketone; acetonitrile, propionitrile or mixtures thereof. Most preferably, the first solvent is a ketone. In a preferred embodiment the solvent is acetone.

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 10°C to about 120°C or from about 20°C to about 100°C, or from about 30°C to about 80°C. In a preferred aspect, the dissolution temperature is from about 50°C to about 70°C.

In one aspect, as depicted in step (b), surfactants include, but are not limited to, aTween-type surfactants, diphosphatidylglycerol (DPPG); hexadecanol; fatty alcohols such as polyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid, sorbitan trioleate (Span 85); glycocholate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate; tyloxapol and a phospholipid and the like or mixture thereof.

Tween-type surfactants (Polysorbates, Sorbitan esters, poly(oxy-1.2 ethanediyl) derives, Tweens) are water soluble nonionic surface active agent comprised of complex esters and ester-ethers derived from hexahydric alcohols, alkylene oxides and fatty acids by adding polyoxyethylene chains to hydroxyl of sorbitol and hexitrol anhydrides (hexitans and hexides) derived from sorbitol and then partially esterifying with the common fatty acids such as lauric, palmitic, stearic and oleic acids or mixture thereof.

In one embodiment the Tween-type surfactant is selected from one or more of Tween 20, Tween 40, Tween 60 or Tween 80, also known in the pharmaceutical industry as polysorbate20, polysorbate 40, polysorbate 60 and polysorbate 80. Polysorbate 20 (Polyoxyethylated Sorbitan Monolaurate) is a laurate ester, Polysorbate 60 (Polyoxyethylated Sorbitan Mono Stearate) is a mixture of stearate and palmitate esters; and Polysorbate 80 (Polyoxyethylated Sorbitan Monooleate) is an oleate ester.

Such Tween type surfactants are commercially available and /or can be prepared by techniques known in the art.

In a preferred embodiment the Tween-type surfactant is polyoxyethylene sorbitan monoleate (polysorbate 80. Tween 80) having the chemical name polyoxyethylene (20) Sorbitan Monooleate.

Specifically, it has been found that presence of surfactant provides improved stability and resistance to aggregation, desired particle formation and precipitation of fluticasone propionate from the solution. The combination of one or more of these two types of surfactants provide improved stability and resistance to surface denaturation aggregation, particle formation and precipitation compared with either surfactant alone.

The Tween-type surfactant is present in the composition from about 0.01 to about 50% by weight. In some embodiments, the concentration of the Tween-type surfactant is from about 0.05% to about 30% by weight, from about 0.75% to about 15% by weight, or about 1.0% to about 10%.

Fluticasone propionate is generally present in the composition in an amount of about 50% to about 99.99 % by weight. In some embodiments, Fluticasone propionate is present at a concentration of from about 70% to about 99.95% by weight, from about 85% to about 99.25%, or from about 90% to about 99.0 % by weight.

In a preferred embodiment, the weight ratio of Fluticasone propionate to the polysorbate is ranging from about 1 :0.001 to 1: 0.1, preferably 1:0.0025 to 1:0.01.

In one aspect, as depicted in step (b), the second solvent is an anti-solvent. The fluticasone propionate may be insoluble or poorly soluble in the second solvent and addition of the solvent may cause fluticasone propionate 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 solvent is one or more organic solvents. For example, in some embodiments, water is used as the second solvent.

In one aspect, as depicted in step (b), the dissolution temperature may range from about 10°C to about the reflux temperature of the anti-solvent(s), depending on the solvent(s) used for dissolution. The dissolution temperature may range from about 0°C to about 60°C or from about 10°C to about 50°C, or from about 20°C to about 40°C. In a preferred aspect, the dissolution temperature is from about 30°C to about 60°C.

In one aspect, as depicted in step (b), after dissolution, the second solution is further chilled to a temperature ranging from about -10°C to about 20°C or from about -5°C to about 15°C, or from about -5°C to about 10°C. In a preferred aspect, the temperature is from about -5°C to about 5°C.

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 one aspect, as depicted in step (d), removing of the solvent is done by filtration, centrifugation, decantation, evaporation, solution concentration spray drying, lyophilization or by any technique known in the art.

In one aspect, as depicted in step (e) isolation comprises isolation and drying the fluticasone propionate into a solid form. Any suitable techniques known in the art may be used, for example, filtering and then drying under vacuum.

The drying may be done in a vacuum oven at a temperature ranging from about 30°C to about 100°C or from about 40°C to about 95°C, or from about 50°C to about 90°C. In a preferred aspect, the drying temperature is from about 60°C to about 90°C, for about 1 hour to about 40 hours, preferably for about 5 hours to about 35 hours, more preferably for about 10 hours to about 30 hours.

In another embodiment, fluticasone propionate may be purified by the following steps:
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) adding a surfactant; and
c) removing the solvent to isolate pure fluticasone propionate.
wherein fluticasone propionate has low solvent content.

In yet an alternative embodiment, fluticasone propionate may be purified by the following steps:
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) adding the first solution to a second solvent to form a second solution;
c) adding a surfactant to the second solution; and
d) isolating pure fluticasone propionate.
wherein fluticasone propionate has low solvent content.

In yet an alternative embodiment, fluticasone propionate may be purified by the following steps:
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) dissolving a surfactant in a second solvent to form a second solution
c) adding the second solution to a first solution;
d) removing the solvent; and
c) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

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

The resultant crystalline fluticasone propionate obtained by any of 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 propionate is a stable 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 propionate obtained by the process of the present invention has an initial particle size below 20 microns.

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

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

In another aspect, Fluticasone propionate has 90% (D 90) of the particles smaller than 6.5 micrometers.

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

In yet another aspect, Fluticasone propionate has 10% (D 10) of the particles smaller than 1.5 micrometers.

Drugs intended for inhalation as dry powders should be used in the form of micronized particles which are generally obtained by milling or through other techniques such as spray-drying. Dry powder formulations intended for inhalation are typically prepared by mixing the micronized drug with coarse carrier particles, giving rise to ordered mixture where the micronized active particles adhere to the surface of the carrier particles whilst in the inhaler device. The carrier makes the micronized powder less cohesive and improves its flowability, making the handling of the powder during the manufacturing process (pouring, filling, etc.) easier. However, it is known that dry powders tend to become electrostatically charged. During the various manufacturing operations (milling, mixing, transport and filling), powders accumulate electrostatic charges from inter-particulate collisions and contact with solid surfaces (e.g. vessel walls). This leads to drug loss via segregation, adhesion and agglomeration formation. Furthermore, the more energy involved during a process, the greater the propensity for the materials to build-up significant levels of electrostatic charges.

On the other hand, the reduction of electrostatic chargeability may improve the flow properties during the operations of the manufacture process (sieving, pouring) and during the filling of the inhaler. This in turn would lead to an improved homogeneity of the active ingredient in the formulation, and hence to an improved reproducibility and accuracy of the delivered dose and the fine particle dose.

It has observed that when surfactant is physically “co-ordinated with” the surrounding matrix, the stability and resistance to surface denaturation aggregation, particle formation and precipitation.

In the process of the present invention when surfactant is physically “co-ordinated with” the surrounding matrix, fluticasone propionate remains stable even after micronization, and shows resistance to surface denaturation aggregation, particle formation and precipitation. Further, no agglomeration or change in particle size occurs if it has been stored for a period of time.

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

In the present invention, acetone LR manufactured by a process which involves alkylation of benzene with propylene to give cumene followed by cumene hydroperxoide through Hock reaction is used as a solvent.

In the present invention when acetone manufactured by the above process is used as a solvent, unreacted benzene could contaminate acetone and present as potential impurity in the final product. Benzene is a highly toxic compound, and long-term exposure to benzene can cause anaemia, leukemia, and other medical conditions. The ICH has classified benzene as a Class 1 solvent with a limit of NMT 2 ppm, and pharma and pharma-related industries are very concerned about controlling and minimizing the levels of benzene in their products. Benzene and 50 other solvents of the four ICH classes have been screened by headspace GC to detect residual solvents as impurities in APIs.

However, the inventors have developed a strategy to control benzene an ICH Q3C Class 1 impurity that may be present in acetone solvent at ppm concentration. It was observed that by repetitive crystallization of fluticasone propionate, the benzene content was found to be below limit of quantitation.

The resultant micronized crystalline fluticasone propionate 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 Propionate using 1% polysorbate 80
Fluticasone propionate (6.00 kg) was charged into reactor containing acetone LR grade (130.00 Lits). The reaction mass heated to 55°C to 60°C and dissolution was checked. It should be complete. The clear solution was then slowly added to a mixture of purified water (440 Lit) and polysorbate 80 (60 ml) at 0°C to 5°C slowly in 30-60 minutes. The suspension was stirred for 15-20 minutes and filtered. The fluticasone propionate was isolated by filtration, washed with purified water and dried at 80°C to 85°C under vacuum for 20 hours.
LOD less than 0.50%.
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.
Benzene content Limit : NMT 2.0 ppm
Before purification : 2.8 ppm
After purification : 0.6ppm ( Below LOQ)

Particle size
(by Laser Diffraction) Standards in µm Observed in µm
D10 NMT 1.5 0.8
D50 NMT 3 1.5
D90 NMT 6.5 2.8
D97 NMT 10 3.5

Example 2
Process for the purification of Fluticasone Propionate using 1% polysorbate 80
Fluticasone propionate (6.00 kg) was charged into reactor containing acetone LR grade (130.00 Lits). The reaction mass heated to 55°C to 60°C and dissolution was checked. It should be complete. The clear solution was then slowly added to a mixture of purified water (440 Lit) and polysorbate 80 (60 ml) at 0°C to 5°C slowly in 30-60 minutes. The suspension was stirred for 15-20 minutes and filtered. The fluticasone propionate was isolated by filtration, washed with purified water and dried at 80°C to 85°C under vacuum for 20 hours.
LOD less than 0.50%.
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.

Example 3
Process for the purification of Fluticasone Propionate using 0.25% polysorbate 80
Fluticasone propionate (6.00 kg) was charged into reactor containing acetone LR grade (130.00 Lits). The reaction mass heated to 55°C to 60°C and dissolution was checked. It should be complete. The clear solution was then slowly added to a mixture of purified water (440 Lit) and polysorbate 80 (15 ml) at 0°C to 5°C slowly in 30-60 minutes. The suspension was stirred for 15-20 minutes and filtered. The fluticasone propionate was isolated by filtration, washed with purified water and dried at 80°C to 85°C under vacuum for 20 hours.
LOD less than 0.50%.
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 stability of Fluticasone Propionate API prepared as per the present disclosure was studied by storing the samples at 15-30°C, upto 1 month. The samples were analysed for PSD content at pre-determined time intervals.

The data indicates that there is no significant change with respect to particle size of Fluticasone Propionate API prepared by using 0.25% polysorbate, in the storage conditions up to 1 month. Fluticasone Propionate API was free of any segregation, adhesion and agglomeration formation when polysorbate content reduced from 1% to 0.25%. The stability data collected after 1 month of storage are tabulated below in Table 1.

Results of examples 2 and 3 are tabulated in Table 1 below.
Table 1
Polysorbate 80 content Polysorbate 80 content in ppm Particle size by Malvern 2000 wet method

Time interval D50 in µm D90 in µm
1% w/w
Example 2 1502 Initial 1.6 2.7
After 1 month 2.3 4.1
0.25% w/w
Example 3 440 Initial 1.6 2.8
After 1 month 1.6 2.8

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 purification of fluticasone propionate comprising;
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) dissolving a surfactant in a second solvent to form a second solution;
c) adding the first solution to a second solution;
d) removing the solvent; and
e) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

2. The improved process as claimed in claim 1, wherein crude fluticasone propionate is selected from polymorphic form or in a mixture of polymorphic forms which include but is not limited to amorphous, crystalline, semi-crystalline, hydrated, solvated, non-solvated or mixture of hydrated, solvated or non-solvated forms thereof in an amount ranging between 50% to 99.99 % by weight.

3. The improved process as claimed in claim 1, wherein in the process step (a);
i. the first solvent is acetone;
ii. the dissolution temperature ranging between 50°C to 70oC.

4. The improved process as claimed in claim1, wherein in step (b),
i. the surfactant is polysorbate 80;
ii. the anti-solvent is water;
iii. the dissolution temperature ranging between30°C to 60°C.

5. The improved process as claimed in claim 4, wherein in step (b) the second solution after dissolution is chilled to a temperature ranging from -10°C to 20°C.

6. The improved process as claimed in claim 1, wherein the weight ratio of Fluticasone propionate to the polysorbate 80 ranges between 1 :0.001 to 1: 0.1, preferably 1:0.0025 to 1:0.01.

7. The improved process as claimed in claim 1, wherein the step (c) may comprise adding the second solution to the first solution.

8. The improved process as claimed in claim 7, comprising;
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) dissolving a surfactant in a second solvent to form a second solution;
c) adding the second solution to a first solution;
d) removing the solvent; and
e) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

9. An improved process for purification of fluticasone propionate with low residual solvent content comprising;
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) adding a surfactant; and
c) removing the solvent to isolate pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

10. An improved process for purification of fluticasone propionate with low residual solvent content comprising;
a) dissolving fluticasone propionate in a first solvent to form a first solution;
b) adding the first solution to a second solvent to form a second solution;
c) adding a surfactant to the second solution; and
d) isolating pure fluticasone propionate;
wherein fluticasone propionate has low solvent content.

11. The improved process as claimed in any one of the claims 1 to 10, wherein fluticasone propionate may be recrystallized from the solvent (s).

12. The improved process as claimed in any one of the claims 1 to 11, wherein the fluticasone propionate is Form I with particle size ranging between 1.5micrometers to 10micrometers and with residual solvent content NMT 0.8ppm.

13. A pharmaceutical composition comprising fluticasone propionate prepared by the process as claimed in any one of the preceding claims optionally in combination with one or more other actives selected from beta adrenergic agonists and anti-cholinergic compounds.