HRP980227A2 - Particulate products - Google Patents

Description

This invention relates to particulate products obtainable using supercritical fluids. More precisely, the invention relates to new crystalline forms of fluikasone propionate, which is S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl oxyandrosta-1,4-diene-17β-carbotiate.

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Fluticasone propionate is described and protected in British patent no. 2088877 (see his example 14). This compound has proven anti-inflammatory activity, and is particularly useful for the treatment of respiratory diseases, especially asthma. Fluticasone propionate was obtained in crystalline form, designated Form 1, by dissolving the crude product (obtained, e.g., as described in British Patent No. 2088877) in ethyl acetate and then recrystallization. It has also been shown that standard water spray-drying techniques yield fluticasone propionate exclusively in the known form 1. According to the present invention, fluticasone propionate can be obtained in a new polymorphic form, designated as form 2. Form 2 can be characterized for example with its X-ray diffraction pattern air (see infra).

The particulate products of this invention are obtained with the supercritical fluid technique that we developed.

The applications of supercritical fluids (SCFs) and their properties are widely documented, see for example, J. W. Tom and P. G. Debendetti: "Particle Formation with Supercritical Fluids - A Review", J. Aerosol. SCi., 22 (5), p. 555-584, (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its upper critical pressure (Pc) and critical temperature (Tc), simultaneously. Supercritical fluids have been of considerable interest due to their unique properties. These characteristics include:

- High diffusivity, low viscosity and surface pressure compared to liquids.

- The large compressibility of supercritical fluids compared to an ideal gas causes large changes in fluid density for small changes in pressure, which in turn result in highly controlled solvation power. Densities of supercritical fluids are typically in the range of 0.1-0.9 g/ml under normal operating conditions. Thus, selective extraction with one supercritical fluid is possible.

- Many supercritical fluids are normal gases under atmospheric conditions, which eliminates the evaporation/concentration phase required in conventional liquid extraction.

- Most of the commonly used supercritical fluids create non-oxidizing or non-degrading atmospheres for sensitive and thermolabile compounds, due to their inertness and the use of moderate temperatures in operating conditions. Carbon dioxide has been extensively used as SCF due to its low cost, non-toxicity, non-flammability and low critical temperature.

These characteristics led to the development of some extraction and particle formation techniques using supercritical fluids. Two processes of particle formation have been identified in particular:

Rapid expansion of supercritical fluid (RESS) (see, for example, J. W. and P. G. Debendetti: "supra") involves dissolving a substance of interest in a supercritical fluid followed by rapid expansion of the resulting supercritical solution at atmospheric pressure, resulting in the precipitation of particles of the dissolved substance.

Gas anti-solvent (GAS) recrystallization (P. M. Gallagher, et al.: "Supercritical Fluid Science and Technology", ACS Symp. Ser., 406, p. 134, (1989)) is particularly useful in situations where the substance of of interest is not soluble, or has very low solubility in supercritical fluid or modified supercritical fluid. In this technique, the solute is dissolved in a conventional solvent. A supercritical fluid, such as carbon dioxide, is introduced into the solution, which leads to a rapid expansion of its volume. As a result, the strength of the solvent is drastically reduced over a short period of time, causing the particles to settle.

There is a need for techniques where the product can be obtained with consistent and controlled physical criteria, including control of particle size and shape, quality of the crystalline phase, chemical purity, and improved handling and fluid translation properties.

Furthermore, it would be very convenient to obtain micron-sized particles directly, without the need to grind products in this size range. Such grinding leads to multiple problems, such as increased static charge and increased particle cohesiveness, as well as reduced product yield. This also leads to high friction between the particles, which can affect the dissolution of the particles after introduction.

WO95/01324 describes a device for forming a particulate product in a controlled manner, using a supercritical fluid particle formation system. The disclosure of WO95/01324 is incorporated herein by reference. The device comprises a container for forming particles, with means for controlling the temperature of said container and means for controlling the pressure of said container, together with means for co-introducing a supercritical fluid into said carrier and a carrier containing at least one substance in the suspension solution, so that the dispersion and carrier extraction occurs essentially simultaneously with the action of the supercritical fluid.

As used herein, the term "supercritical fluid" refers to a fluid at or above its critical pressure (Pc) and critical temperature (Tc), simultaneously. In practice, the pressure of the fluid is likely to be in the range 1.01 Pc - 7.0 Pc, and its temperature in the range 1.01 Tc - 4.0 Tc.

The term "carrier" means a fluid which dissolves a solid material or solid materials to form a solution, or which forms a suspension of a solid or solid materials which do not dissolve or have low solubility in the fluid. The carrier may contain one or more fluids.

As used herein, the term "supercritical solution" refers to a supercritical fluid having a derived and dissolved carrier.

The term "dispersion" means the formation of carrier droplets containing at least one substance in solution or suspension.

The term "particulate product" includes products in the form of a single component or multiple components (eg, intimate mixtures of one component in a matrix of another).

If necessary, the device may also contain additional means for collecting the particulate product, for example means for retaining the product in the vessel for forming the particles, such as a filter, thereby reducing the loss of the product together with the resulting supercritical solution. An alternative means can use a cyclone separation device.

The above-mentioned device and its application are suitable for the production of dry particulate products, with controlled particle size and shape, and the ability to control over operating conditions, especially pressure, using, for example, an automated back-pressure regulator, such as Model no. 880-81 manufactured by Jasco Inc, . Thus, improved control eliminates pressure fluctuation across the particle formation vessel providing more uniform dispersion of the carrier (containing at least one substance in solution or suspension) with the supercritical fluid, for small droplet size distribution during the particle formation process. In the formation of particles, there is very little or no possibility for the dispersed droplets to re-unite to form larger droplets because the dispersion occurs with the action of a supercritical fluid, which is also ensured through mixing with the carrier and rapid removal of the carrier from the substance(s) of interest.

The simultaneous co-introduction of a carrier containing at least one substance in solution or suspension and a supercritical fluid, according to the procedure described here, enables a high degree of control of parameters such as temperature, pressure and flow rate, or mutual control of the carrier fluid and the supercritical fluid at an exact point when they come in contact with each other.

Further advantages for forming particles according to this invention include quality control of the crystalline and polymorphic phases, as all particles will have the same stable temperature and pressure conditions during formation, as well as the potential for improved purity. This last characteristic can contribute to the high selectivity of supercritical fluids under different operating conditions, enabling the extraction of one or more impurities from the carrier containing the substance of interest.

The means for co-introducing the supercritical fluid and the carrier into the particle forming vessel preferably allows them to be introduced in accordance with the flow directions, and more preferably takes the form of a coaxial opening, as described below. This ensures that there is no contact between the formed particles and the fluid carrier around the nozzle tip area. Such contact could reduce control over the size and shape of the final product. Extra control over droplet size, in addition to that provided by the orifice design, is achieved by controlling the flow rate of the supercritical fluid and the fluid carrier. At the same time, keeping the particles in the particle formation vessel eliminates the potential for contact with the carrier fluid, which could otherwise occur in the depressurization of the supercritical solution. Such contact could affect the shape and size, and potentially the yield, of the product.

Thus, in the device described herein in WO95/01324, the means for co-introducing the supercritical fluid and the carrier (comprising at least one substance in solution or suspension) into the particle forming vessel preferably comprises an end outlet nozzle which is connected to the interior of the vessel. The nozzle has coaxial passages terminating adjacent to each other at the outlet end, where at least one of the passages serves to carry a stream of supercritical fluid, and at least one of the passages serves to carry a stream of carrier in which the substance is dissolved or suspended.

Preferably, the outlet opening (tip) of the nozzle will have a diameter in the range of 0.05 to 2 mm, more preferably between 0.1 and 0.3 mm, and typically about 0.2 mm. The sharp angle of the final outlet will depend on the desired speed of the fluid introduced through the nozzle. Increasing the angle can be used, for example, to increase the velocity of the supercritical fluid introduced through the nozzle, thereby increasing the amount of physical contact between the supercritical fluid and the carrier. Typically (but not necessarily) the acute angle will be in the range of about 10° to about 50°, preferably between about 20° to about 40°, and most preferably about 30°. The nozzle can be made of any suitable material, for example stainless steel.

In one embodiment, the nozzle has two coaxial passages, an inner and an outer. In another, preferred embodiment, the nozzle has three coaxial passages, inner, middle and outer. This last design allows greater versatility in the application of the device, because if necessary, two carriers with supercritical fluid can be introduced into the vessel for particle formation. Improved dispersion and finer particles can also be obtained if such a nozzle is used to introduce the carrier stream sandwiched between the inner and outer supercritical fluid streams, as this ensures that both sides of the carrier are exposed to the supercritical fluid. However, it should be noted that the nozzle may have any suitable number of coaxial passages.

The inside diameters of the coaxial passages can be suitably chosen for any particular device application. Typically, the ratio of inner diameters to outer diameters can be in the range of 2 to 5, preferably between 3 and 5. Where an intermediate passage is included, the ratio of outer to inner diameters can be in the range of 1 to 3, preferably between about 1, 4 and 1.8.

Certain examples of such coaxial nozzles and their typical dimensions are illustrated in Figures 2A, 2B and 4.

The temperature of the particle forming vessel can be maintained (preferably ± 0.1 C°) by means of a thermal liner, or more preferably by means of an oven. The pressure of the particle forming vessel is conventionally maintained (preferably ± 2 bar) by means of a lower pressure regulator. It should be noted that such a device will be available from, for example, a manufacturer of supercritical fluid extraction equipment, eg, Jasco Inc., .

The invention provides a process for the formation of a particulate product of fluticasone propionate, which comprises the co-introduction of a supercritical fluid and a carrier containing at least fluticasone propionate in solution or suspension, into a vessel for the formation of particles, where temperature and pressure are controlled, so that dispersion and extraction of the carrier occurs essentially simultaneously with the action of the supercritical fluid.

Dispersion and extraction will typically occur immediately upon introduction of the fluid into the particle forming vessel. Co-introduction of the supercritical fluid and the carrier containing at least fluticasone propionate in solution or suspension is preferably performed using a nozzle of coaxial design.

A suitable vessel for forming the particles used herein is described in WO95/01324.

Suitable chemicals for use as supercritical fluids include carbon dioxide, nitrogen suboxide, sulfur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane, and trifluoromethane. Carbon dioxide is particularly preferred.

The supercritical fluid may optionally contain (but is not limited to) one or more modifiers, for example methanol, ethanol, ethyl acetate, acetone, acetonitrile, or any mixture thereof. When a modifier is used, it must not form more than 20%, more precisely 1% - 10%, of the supercritical fluid.

The term "modifier" is well known to those skilled in the art. A modifier (or co-solvent) can be described as a chemical that, when added to a supercritical fluid, changes the essential properties of the supercritical fluid at or around the critical point.

Looking at the choice of carrier for fluticasone propionate, where fluticasone propionate is to be treated as a solution, it should be soluble in the carrier chosen, and the carrier chosen should be soluble in the supercritical fluid chosen. The selection of a suitable combination of supercritical fluid, modifier (where desired) and carrier for any desired product can be made by the average person skilled in the art.

Suitable solvents may be, for example, methanol, ethanol, ethyl acetate, acetone, acetonitrile, or any mixture thereof.

When the process of the invention is carried out, control parameters, such as size, shape and crystal structure, will depend on the working conditions used. Variables include the flow rates of the supercritical fluid and/or carrier containing the substance(s), the carrier used to dissolve the substance(s), the concentration of the substance(s) in the carrier, and the temperature and pressure within the particle forming vessel.

It should be noted that the precise operating conditions of this device will depend on the choice of supercritical fluid, and on the presence or absence of modifiers.

Table 1 shows critical pressures and temperatures for some selected fluids:

Table 1

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In practice, it may be desirable to maintain a pressure substantially greater than Pc (eg 100-300 bar for carbon dioxide) while the temperature is above Tc (eg 35-75 °C for carbon dioxide) within the particle formation vessel.

The supercritical fluid and/or carrier flow rates can be controlled to achieve the desired particle size, shape and/or form. Although the flow ratio will depend on the desired characteristics of fluticasone propionate, typically the ratio of carrier flow rate to supercritical fluid flow rate will be between 0.001 and 0.1, preferably between 0.01 and 0.07, and most preferably about 0.03.

The process described herein preferably additionally includes collecting the particulate product by monitoring its formation. It may also include obtaining the supercritical solution formed, separating the components of the solution, and recycling one or more of these components for future use.

According to a desirable aspect of this invention, obtaining a fluticasone propionate compound that is easy to handle, in an easily fluidized crystalline form, with controlled particle size and shape, and optionally with controlled morphology and level of agglomeration is ensured.

The invention also provides a novel crystalline form of fluticasone propionate, designated Fluticasone Propionate Form 2, as described herein. The precise conditions under which form 2 of fluticasone propionate is formed can be determined empirically. Below are several examples of procedures (see example 5) that have been found to be suitable in practice.

As mentioned above, the control of parameters such as size, shape and crystal structure in the particulate product will depend on the operating conditions used when performing the process of the invention. By suitable adjustment of the process variables, the relative amounts of forms 1 and 2 of fluticasone propionate obtained with the apparatus described herein can be varied by those skilled in the art. The experimental ranges for each polymer form can be determined empirically for the particular device used.

Conventionally crystallized fluticasone propionate, even after micronization (fluid milling), exists in a form with very poor flow characteristics. For example, it is cohesively and statically batched, which results in difficulties in handling the drug substance in pharmaceutical formulation processes.

In another aspect of the present invention, fluticasone propionate is provided in a form with a dynamic density of less than 0.2 g/cm 3 . In a preferred aspect of the present invention, fluticasone propionate is provided in a form with a dynamic mass density in the range between 0.05 and 0.17 g/cm3, and particularly in the range between 0.05 and 0.08 g/cm3.

The dynamic mass density (W) indicates the fluid characteristics of the substance, and is defined as:

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where P is the packed mass density (g/cm3), A is the air-saturated mass density (g/cm3), and C is the compressibility (%); where C is calculated using the equation:

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Clearly, the number for W corresponds to a high degree of fluidity.

When compared to conventionally crystallized fluticasone propionate, before and after micronization, the fluticasone propionate of this invention exhibits a significantly lower dynamic mass density than conventionally crystallized fluticasone propionate, as illustrated in Table 7 (see Example 6 below).

It should be noted that in the case of an inhaled pharmaceutical material, such as fluticasone propionate, it is particularly desirable to obtain a drug substance that is easily translated into a fluid, thereby potentially improving its inhalation properties.

The fluticasone propionate of this invention has been observed to have improved handling and fluidization characteristics compared to conventionally crystallized fluticasone propionate.

Furthermore, the possibility of crystallizing the size and shape of the fluticasone propionate particles of the present invention is provided, as illustrated herein with electron micrographs.

Preferably, the fluticasone propionate of the present invention is within a particle size range suitable for pharmaceutical dosage forms delivered by inhalation or insufflation. A suitable particle size range for this application is 1 to 10 microns, preferably 1 to 5 microns. The particles generally have a uniform particle size distribution, as measured by a coefficient of 1 to 100, typically 1 to 20, eg 5 to 20.

The particle size distribution of fluticasone propionate according to the invention can be measured with conventional techniques, for example with laser diffraction, with the "Twin Impinger" analytical process, or with the "Cascade Impaction" analytical process. As used herein, reference to the "Twin Impinger" test means "Preparations for Inhalation: Aerodynamics assessment of fine particles using apparatus A" as defined in British Pharmacopoeia 1993, Supplement 1996, p. A522-527, applied to a dry powder inhalation formulation. As used herein, reference to the "Cascade Impaction" test means "Preparations for Inhalation: Aerodynamics assessment of fine particles using apparatus D" as defined in British Pharmacopoeia 1993, Supplement 1996, p. 527, applied to a metered dose inhaler formulation. The preferred fluticasone propionate of the invention is of medium particle size between 1 and 10 microns, and has been found to have a respirable fraction of 14% by weight or greater.

Fluticasone propionate of the present invention typically has a low cohesiveness, for example from 0 to 20%, and preferably from 0 to 10%, using measurement procedures based on those described in R.L. Carr: "Chemical Engineering", pp. 163-168, (1965).

Fluticasone propionate according to the invention can be used to obtain a pharmaceutical preparation that can be prepared for use in a conventional way, using a pharmaceutically acceptable carrier or excipient, optionally with additional medical means. Preferred carriers include, for example, polymers (eg, starch) and hydroxypropylcellulose, silica, sorbitol, mannitol, and lactose (eg, lactose monohydrate). The preparations may be in a form suitable for administration by inhalation or insufflation, or for oral, oral, parenteral, topical (including nasal) or rectal administration. Inhalation or insufflation is preferred.

In a preferred pharmaceutical preparation according to the invention, fluticasone propionate and carrier are co-crystallized together, using the process and apparatus described herein, to form multicomponent particles containing fluikasone propionate and carrier. Such multicomponent particles represent a further aspect of the invention.

In a preferred aspect, the invention provides a pharmaceutical preparation in the form of a dry powder suitable for inhalation or insufflation, containing the fluticasone propionate according to the invention and a suitable powder base, such as lactose or starch (suitably lactose), as a carrier. Preparations containing fluticasone propionate and lactose in the form of multicomponent particles are especially preferred. The dry powder preparation can be presented in the form of a dosage unit, for example in capsules or cartridges (from, for example, gelatin), or ointment packages from which the powder can be taken in using an inhaler or insufflator.

For administration by inhalation, the fluticasone propionate made according to the invention may conveniently be delivered in an aerosol spray presentation from a pressurized pack, such as a metered dose inhaler, using a suitable propellant such as dichlorofluoromethane, or preferably fluorocarbon, or a fluorocarbon which contains hydrogen such as HFA134a (1,1,1,2-tetrafluoroethane), HFA227 (1,1,1,2,3,3,3-heptafluoro-n-propane), or mixtures thereof. Such aerosol spray presentations may include surfactants (eg, oleic acid or lecithin), co-solvents (eg, ethanol), or other excipients suitable for use in such formulations.

Inhalation or insufflation formulations are intended for prophylactic administration in humans suffering from allergic and/or inflammatory conditions of the nose, throat or lungs, such as asthma and rhinitis, including hay fever. Aerosol formulations are made so that each metered dose or "puff" of aerosol contains from 20 to 1000 micrograms, preferably 25 to 150 micrograms of fluticasone propionate of the invention. Administration may be several times a day, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. The total daily dose with the aerosol will be within the range of 100 micrograms to 10 mg, preferably 100 micrograms to 1.5 mg.

The following is a brief description of the drawing:

- Figure 1 shows the schematic design of the device described here.

- Figure 2A shows a cross-section of a coaxial nozzle for use in the device described herein.

- Figure 2B shows a longitudinal section of the end of a coaxial nozzle for use in the device described herein.

- Figures 3A and 3B show schematic designs of alternative devices.

- Figure 4 shows a longitudinal section of the end of an alternative coaxial nozzle.

- Figures 5 to 7 are scanning electron microscopy (SEM) photographs of fluticasone propionate as obtained in Example 2.

- Figure 8 is a photograph (SEM) of fluticasone propionate, as obtained in Example 3.

- Figure 9 is an X-ray powder diffraction (XRPD) pattern of fluikasone propionate, as obtained in Example 2.

- Figure 10 is an X-ray powder diffraction (XRPD) pattern of fluikasone propionate, as obtained in Example 3.

- Figure 11 is a differential scanning calorimetry (DSC) profile of fluticasone propionate, as obtained in Example 2.

- Figure 12 is a differential scanning calorimetry (DSC) profile of fluticasone propionate, as obtained in Example 3.

- Figure 13 is the fourier transform infrared (FTIR) spectrum of fluticasone propionate, as obtained in example 2.

- Figure 14 is the fourier transform infrared (FTIR) spectrum of fluticasone propionate, as obtained in example 3.

- Figures 15 to 19 are HPLC chromatograms for fluikasone propionate products, as described in example 4.

- Figures 20 to 24 are XRPD patterns for fluticasone propionate products, as described in Example 5.

The following is a detailed description of a preferred embodiment of the apparatus and method described herein, with reference to Figures 1, 2, 3 and 4. Figures 1 and 3 are simplified flow diagrams of the apparatus, and Figures 2A, 2B and 4 show nozzles that may be used therein.

Referring to Figure 1, the device comprises a container 6 for forming particles. This is a typical standard reaction vessel, for example of the type available from Keystone Scientific Inc., of suitable capacity for the particular application, into which the material is placed. The temperature and pressure of the vessel are maintained at a constant desired level, using the furnace 7 and the lower pressure regulator 8, respectively.

In application, the system is initially subjected to pressure, to achieve stable conditions. A suitable gas, for example carbon dioxide, is led from the source 1 through the conductor 11 to the cooler 2, in order to ensure the transition to the liquid state, and is led with the conductor 12 to the pump 4. From there, it is led with the conductor 13 into the container 6 through the nozzle 20. A solution or dispersion of the solid material of interest, in this case fluticasone propionate in a suitable carrier, for example methanol, is led from source 5 with guide 14 to pump 3, and led with guide 15 to container 6 via nozzle 20.

The nozzle 20 may be as shown in Figure 2 (A and B), or Figure 4. The one shown in Figure 2 comprises coaxial inner and outer tubes 30 and 40, respectively. These define an inner passage 31 and an outer passage 41. The tubes 30 and 40 have tapered tapered end portions 32 and 42, respectively. The ends of the end portions 32 and 42 define openings 33 and 43, respectively, with the opening 43 being a short distance downstream of the opening 33. As indicated in Figure 2B, the angle of the sharpened end portion 42 is about 30° in this example (not a limitation).

The alternate nozzle in Figure 4 comprises three coaxial tubes 50, 60, and 70 defining an inner passage 51, an intermediate passage 61, and an outer passage 71, respectively. The tubes 60 and 70 have tapered tapered end portions 62 and 72, and the angle of the tapered end portion 72 is about 30° in this example.

The nozzle from Figure 4 enables three fluids to be introduced into the container 6 at the same time, which leads to an increase in the possibilities of using the device. For example, it is possible to add via one of the three passes a desired carrier or other additive intended to form a part, or to be mixed with the final particulate product. The additive is then dispersed simultaneously with the substance of primary interest. Also, immediately before dispersion with supercritical fluid, reactions can be performed in situ, with the introduction of two or more reactants in two special carriers through two nozzle passages, where the reaction takes place at the exit of the passage or immediately before, or in the dispersion.

Alternatively, the nozzle of Figure 4 may be used to introduce a carrier stream (passage 61) interposed between the inner and outer supercritical fluid streams (passes 51 and 71).

This leads to improved dispersion of the carrier, and thus greater control and uniformity of the particle size of the final product. This indeed makes it possible to form finer products than can be achieved using a two-pass nozzle.

In the nozzle shown, the inner tube 50 has an inner diameter of 0.25 mm; the middle tube 60 has an inner diameter of 0.53 mm; and the outer tube 70 has an inner diameter of 0.8 mm and an outer diameter of 1.5 mm. The tip opening (73) has an inner diameter of 0.2 mm. All pipes are made of stainless steel.

However, the nozzle can be made of any suitable material and have any suitable dimensions. For example, internal diameters may range from 0.05-0.35 mm (internal); 0.25-0.65 (medium); and 0.65-0.95 (external), and preferably 0.1-0.3 mm (internal); 0.3-0.6 mm (medium); and 0.07-0.9 mm (external). It is likely that the tip opening has an internal diameter in the range of 0.1-0.3 mm, preferably 0.18-0.25 mm.

In the apparatus of Figure 1, a supercritical fluid is fed under pressure (at a high flow rate when compared to the flow rate of the carrier) through, for example, a nozzle passage 31, from the nozzle shown in Figure 2, and a solution or suspension of the solid material of interest in the carrier ( hereinafter referred to as "fluid") is simultaneously guided under pressure through the outer passage 41. It is believed that the high velocity of the supercritical fluid arising from the orifice 33 causes the liquid from the end of the outer passage 41 to break up into a drop, from which the carrier is essentially extracted simultaneously with supercritical fluid, which results in the formation of particles of solid material previously held in the carrier. However, it should be understood that although this is believed to occur, we do not want to limit ourselves to this theoretical explanation, and the occurrence of actual physical processes need not be precisely as indicated.

Also, although the configuration described is in which the supercritical fluid passes through the inner passage 31, and the carrier passes through the outer passage 41, the configuration can also be reversed, i.e. with the supercritical fluid in the outer passage 41 and the carrier in the inner passage 31. Similarly in the nozzle from the picture 4, any of the three passages may be used to carry any of the more desired fluids, as appropriate.

The nozzle 20 provides the dispersion of the carrier containing the solid material of interest, the drag action under the pressure of the high velocity supercritical fluid, and also the complete mixing of the dispersed carrier with the supercritical fluid which simultaneously extracts the carrier from the dispersed liquid, resulting in the immediate formation of particles of the solid material of interest. Because the supercritical fluid and the carrier are introduced coaxially, and the dispersion occurs essentially simultaneously with the extraction of the carrier, a very high degree of control of the conditions (e.g., pressure, temperature, and flow rate) is possible, which affects the formation of particles, at the precise time when it happens.

The formed particles are retained in the particle forming vessel by means of collection means 21. The resulting supercritical solution is led with the guide 16 to the lower pressure regulator 8, and then led with the guide 17 to the separation vessel 9, where it expands, which causes the separation of the supercritical fluid gas from the liquid carrier. The gas can be led with the guide 18 to the container 10, and returned with the guide 19 to the cooler 3. The carrier can also be collected with the following application. A means, not shown, can ensure the smoothing of the pulsed flow of fluid and carrier obtained with pumps 3 and 4, so that all irregularities in the flow are eliminated, or at least reduced.

When sufficient particle formation has occurred in vessel 6, it is flushed with clean and dry supercritical fluid to ensure removal of any remaining carrier. The vessel can then be depressurized, thereby removing the particulate product.

Alternative devices are shown schematically in Figures 3A and 3B and are used in continuous particle formation. The one shown in Figure 3A comprises two particle forming vessels 6a and 6b, each of the type shown in Figure 1, and each containing an inlet nozzle 20 and a particle collection means 21 (such as a filter). Furnace 7 serves both vessels.

In the device of Figure 3A, valve A controls the supply of supercritical fluid and carrier (containing the substance of interest) to vessels 6a and 6b, and one-way valves E and F control the openings from the two vessels to the lower pressure regulator 8. Valve D controls the carrier supply to valve A. Valves B and C are needle valves and elements 80 and 81 are drains.

The device can be "continuously" operational as follows. Valve A is first positioned to supply fluids to vessel 6a, in which particle formation takes place, as described in connection with Figure 1. Valve E is positioned so that the resulting supercritical solution can be diverted from vessel 6a to the lower pressure regulator 8 for next recycling.

When sufficient particle formation has occurred, valve D closes to stop carrier flow while supercritical fluid continues to flow through vessel 6a to dry (rinse) the product. Valve A is then set to supply fluids to empty vessel 6b, and valve D is opened again, while valve B is slowly opened to depressurize vessel 6a. The one-way valve E eliminates any possibility of flow back from vessel 6b, or interruption of the particle formation process now occurring in vessel 6b. The vessel 6a is removed to collect the product and then readjusted and repressurized to be ready for reuse. The supercritical solution is drained from vessel 6b via valve F, which is suitably adjusted.

When the formation of particles in vessel 6b is complete, the valves are repositioned again to allow formation of particles in vessel 6a, while vessel 6b is rinsed and emptied. In this way, the formation of particles in the device can continue without interruption.

The apparatus shown in Figure 3B comprises only one particle forming vessel 6, which does not contain any means for collecting particles, and two particle collecting vessels 25a and 25b downstream of vessel 6. The supercritical fluid carries the formed particles to the collecting vessels 25a and 25b.

The device also contains an inlet nozzle 20, two drains 26, a lower pressure regulator 27, a furnace 7 and valves A-H. The supercritical fluid and solution (carrier) are fed into nozzle 20 as shown.

The device can be used as follows. Initially, (valves C, D, E, and F closed) the system is pressurized and stable operating conditions are achieved. Valves B and H are then closed, which induces the flow of supercritical fluid only through valve A. The carrier and substance of interest are introduced into vessel 6, and the particles formed are transferred with the supercritical fluid through valve A to collection vessel 25a, which contains a device for retained particles. The device for retained particles is placed at the outlet of the vessel, so as to ensure maximum collection of the contents. The supercritical solution without solid material (supercritical fluid and carrier) flows through the valve G into the lower pressure regulator 27. Emerging from the lower pressure regulator, the supercritical pressure is expanded in a high-pressure resistive vessel (not shown), where the carrier is separated from the gas and both are recycled.

When the collection vessel 25a is full, the interruption is performed, the valves A and G are closed, and the valves B and H are opened at the same time. This allows the flow of the supercritical solution, which appeared in the vessel 6, into the second collection vessel 25b. Valves C and G are opened after interrupting the flow, so as to ensure a high flow of supercritical fluid in order to flush out the full container 25a for collection, i.e. the content of the supercritical solution is replaced with the content of the supercritical fluid. It is estimated that 1 - 2 cycles of replacing the contents of the supercritical fluid collection vessel provide dry powder. The flushing time is generally very short, thanks to the fact that the particles occupy only part of the contents of the collection vessel. After flushing, valves C and G are closed, and valve F (needle valve) is slowly opened on the full container 25a for collection. As the particulate product occupies only a small amount of the contents of the vessel, the supercritical fluid is easily discharged, by suitable extraction of the internal contents.

The full collection container 25a is removed, and the dry powder is collected. After re-installation and re-pressurization via valve C, the vessel is ready for reuse at the same time as the second collecting vessel 25b, which in the meantime became full by collecting the product from vessel 6.

Advantages of using the device in Figure 3B include:

1. Eliminating depressurization and pressurization phases from the reaction vessel each time product is collected. This can mean a significant reduction in the amount of fluid being discharged, especially when using a large volume vessel for particle formation (increasing content), or expensive cleaning gases.

2. Significant time saving during the rinsing (drying) procedure. In the process of mass formation of particles, only the very volume of the reaction vessel is occupied with the product, and the remaining volume (where dispersion takes place) is occupied by the supercritical solution. This mixture will eventually be replaced with at least the same volume of supercritical fluid in the flushing process, which can otherwise take a lot of time when increasing the content.

3. The environment and workers are less exposed to the products during the obtaining phase. In some cases, it is difficult to collect products directly from a large reaction vessel due to handling inadequacies, or because the products of interest are sensitive to light, oxygen, or humidity, which can affect their characteristics and purity.

The invention is further illustrated by the following non-limiting examples. Examples 1 to 9, which illustrate the preparation of fluticasone propionate and its physical properties, were carried out using an apparatus of the type illustrated in Figures 1 and 2, using a 32 ml particle forming vessel and a two-propellant coaxial nozzle having the following dimensions:

outer diameter inner diameter

outer tube: 1.58 mm 0.75 mm

inner tube: 0.63 mm 0.20 mm

The tip opening (43 in Figure 2B) was 0.32 mm in diameter, and both the inner and outer tubes were made of stainless steel.

Example 1 Particle size distribution

Data for four samples of fluticasone propionate of the present invention, obtained using the methods and apparatus described herein, are presented in Table 2 below. Particle size was determined with laser diffraction (Malvern Mastersizer).

Sample 1 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 300 bar, 35 °C, and a flow rate ratio of 0.014 via a coaxial nozzle in a particle forming vessel.

Sample 2 was obtained using a solution of fluticasone propionate in acetone (0.5% w/v) co-introduced with CO2 at 100 bar, 35° and a flow rate ratio of 0.014 via a coaxial nozzle in a particle forming vessel.

Sample 3 was obtained using a solution of fluticasone propionate in acetone (0.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Sample 4 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.014 via a 3-component coaxial nozzle in a forming vessel particle.

The data presented in Table 2 show that the particle size can be manipulated depending on the conditions. The particle size data for sample 4 show that a particle size similar to that of conventionally crystallized fluticasone propionate (micronized) can be achieved. The uniformity index is not significantly different from that of conventionally crystallized fluticasone propionate (micronized).

Table 2

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Example 2 Particle shape data

The shape of the particles was obtained with scanning electron microscopy. Data for three samples of fluticasone propionate of the present invention, obtained using the process and apparatus described herein, are presented in Figures 5 through 7.

Sample 5 was obtained using a solution of fluticasone propionate in methanol (0.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel. The shape of the particles is described as needle-like with a high aspect ratio of 200:1 (Figure 5).

Sample 6 was obtained using a solution of fluticasone propionate in acetone (1.5% w/v) co-introduced with CO2 at 200 bar, 55 °C, and a flow rate ratio of 0.029 via a coaxial nozzle in a particle forming vessel. The shape of the particles is described as similar to snowflakes (Figure 6).

Sample 7 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.014 via a coaxial nozzle in a particle forming vessel. The shape of the particles is described as quant (Figure 7).

Example 3 Reproducibility

Three different solutions of fluticasone propionate in acetone (1.5% w/v) were co-introduced with CO2 at 200 bar, 55 °C, and a flow rate ratio of 0.029, via a coaxial nozzle in a particle-forming vessel on three different days ( samples 6, 8, 9). Particle size, particle shape, polymorphic form, and impurity profile were tested. Particle size, particle shape, polymorphic form and impurity profile show that the technique is reproducible when some crystallization parameters are used.

a) Particle size

Particle size was determined with laser diffraction (Malvern Mastersizer).

The data are shown below in Table 3.

Table 3

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b) Shape of particles

The shape of the particles was determined with scanning electron microscopy. Data for samples 6 and 8 are shown in Figures 6 and 8, respectively.

c) Polymorphic form

The polymorphic form was determined with X-ray powder diffraction, differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy for samples 6 and 8. The data are shown in Figures 9 through 14.

Figures 9, 11 and 13 refer to sample 6, while figures 10, 12 and 14 refer to sample 8.

d) Impurity profile

The impurity profile was determined by HPLC for samples 6 and 8. The data are shown in Table 4 and Figures 16 and 17 (referring to samples 6 and 8, respectively).

Example 4 Impurity profile

The impurity profile was determined by HPLC for samples 5, 6, 8, 10, and compared with conventionally crystallized fluticasone propionate. The data are shown in Table 4 and Figures 15 to 19 (referring to samples 5, 6, 8, 10, and conventionally crystallized fluticasone propionate, respectively).

Sample 10 was obtained using a solution of fluticasone propionate in acetone (0.5% w/v) co-introduced with CO2 at 100 bar, 35 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

The data show that fluticasone propionate obtained with this invention does not change the impurity profile when compared to conventionally crystallized fluticasone propionate. However, there is a very small reduction in total impurities (5 t/t) for fluticasone propionate obtained with this invention.

Table 4

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(Remark: Limit quantification = 0.045 % t/t)

Example 5 Crystallinity and polymorphism

X-ray powder diffraction (XRPD) patterns were generated using a Siemens D 5000, or a Philips X'pert MPD. The powders were scanned over a 2θ angle range of 1.5° to 60°, or 0° to 35°, with a step of 0.02-0.05° for 3-5 seconds, using CuKα radiation. The Siemens D5000 measures the intensity as the number of cycles per second, and the Philips X'pert MPD measures the intensity as the number of cycles.

Data for samples 2, 6 and 11 were compared with that of conventionally crystallized fluticasone propionate. (see Figures 20, 9, 21 and 22, respectively).

The preparation of samples 2 and 6 is described above. Sample 11 was obtained using a solution of fluticasone proionate in acetone (0.5% w/v) co-introduced with CO2 at 300 bar, 75 °C, and a flow rate ratio of 0.014 via a coaxial nozzle in a particle forming vessel.

The data show that the crystallinity can be controlled with the crystallization parameters. Using the technique of this patent, the crystallinity of fluticasone propionate can be significantly improved over conventionally crystallized fluticasone propionate.

As mentioned above, the relative amounts of forms 1 and 2 of fluticasone propionate obtained with the apparatus described herein can be varied with suitable adjustment of the process variables of the invention. The experimental ranges for each polymorphic form can be determined empirically for the particular device used. Using the preparative process and apparatus described herein, samples 1, 2, 5-12 and 14-16 were found to be form 2 of fluticasone propionate; samples 3 and 17 were a mixture of forms 1 and 2 of fluticasone propionate; and sample 13 is form 1 of fluticasone propionate.

The two polymorphic forms of fluticasone propionate are well characterized with their XRPD traces. Table 5 shows the key 2θ peaks for the identification of two polymorphic forms of fluticasone propionate by XRPD. Figure 23 shows the XRPD traces of folded forms 1 and 2 of fluticasone propionate.

Table 5

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Fluticasone propionate traces obtained according to the present invention are qualitatively different from conventionally crystallized fluticasone propionate traces. Conventionally crystallized fluticasone propionate ("form 1") was found to have a monoclinic crystal structure with

a = 7.722 Å, b = 14.176 Å, c = 11.290 Å, β = 98.458 °.

Conversely, the XRPD traces of fluticasone propionate obtained according to the present invention ("form 2") were analyzed and proved to be a pure polymorph with an orthorhombic structure having

a = 23.404 Å, b = 14.048 Å, c = 7.695 Å, all angles are 90 °.

Form 2 was found to be stable towards conversion to form 1, i.e. after 62 weeks at room temperature and atmospheric humidity, no conversion was seen. Figure 24 shows the stability of form 2 of fluticasone propionate by XRPD.

The water content of the two crystalline forms of fluticasone propionate obtained with the apparatus described herein was also determined, and compared with that of conventionally crystallized and micronized fluticasone propionate. The results are shown in table 6.

Table 6

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Example 6 Mass density

Dynamic mass densities for conventionally crystallized fluticasone propionate (micronized and non-micronized) and fluticasone propionate of the present invention are shown in Table 7.

Sample 12 was obtained using a solution of fluticasone propionate in ethyl acetate (0.5% w/v) co-introduced with CO2 at 300 bar, 35 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Sample 13 was obtained using a solution of fluticasone propionate in acetonitrile (0.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Table 7

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The dynamic mass density of the fluticasone propionate of this invention is significantly lower than that of conventionally crystallized fluticasone propionate (mictonized and non-micronized).

The data presented in Table 7 show that the dynamic mass density of the fluticasone propionate of this invention can be controlled using the crystallization parameters from the process described within the invention.

Example 7 Static batch test

The relative static batch of fluticasone propionate of this invention can be controlled with crystallization parameters. The data show that there is no significant reduction in the relative statics of the fluticasone propionate of this invention when compared to conventionally crystallized fluticasone propionate. Fluticasone propionate collected from the particle forming vessel using the described apparatus is dry and easy to handle. Conventionally micronized fluticasone propionate is cohesive, difficult to handle, and statically batched.

A simple test was performed to determine the relative static charge based on the amount of drug remaining on the walls of the vial after swirling a predetermined amount of drug in the vial for 2 minutes. A greater amount of drug remains in the vial, and a greater relative static charge is combined with the drug substance. The results are shown in Table 8.

Table 8

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Sample 14 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 300 bar, 75 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Sample 15 was obtained using a solution of fluticasone propionate in acetone (3.5% w/v) co-introduced with CO2 at 90 bar, 85 °C, and a flow rate ratio of 0.028 via a coaxial nozzle in a particle forming vessel.

Sample 16 was obtained using a solution of fluticasone propionate in ethyl acetate (0.5% w/v) co-introduced with CO2 at 300 bar, 35 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Sample 17 was obtained using a solution of fluticasone propionate in acetone (0.5% w/v) co-introduced with CO2 at 100 bar, 75 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Example 8 Twin Impinger test

A small amount of medication is loaded into each bladder of the four-bladder Rotadisk™. The contents of each Rotadisk™ were emptied via the DiskhalerTM, into a Twin Impinger device set at an airflow rate of 60 liters per minute. Each stage of the Twin Impinger device contained an amount of solvent for dissolving methanol (stage 1: 7 ml, and stage 2: 30 ml). RotadiskTM and DiskhalerTM were washed with methanol and the resulting solution was made up to 50 ml. Stage 1 of the Twin Impinger was washed with methanol and the resulting solution made up to 50 ml. Stage 2 of the Twin Impinger was washed with methanol and the resulting solution made up to 50 ml. The solutions were examined with UV spectroscopy and the amount of drug delivered to each stage of the Twin Impinger device was calculated. The results are shown in table 9. Table 10 shows the size data of the samples used.

Table 9

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Table 10

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A grade 2 deposit represents a mass of fine particles (respiratory dose) that reaches deep into the lungs. The delivered dose (sum of stage 1 and stage 2) represents the total dose available for inhalation and efficient discharge of the drug from the device.

The fluticasone propionate of this invention does not show significant improvement in stage 2 deposition. An interesting feature of this invention is that supercritical fluid crystallized fluticasone propionate with a particle size larger than conventionally crystallized fluticasone propionate (micronized), gives an equivalent deposition (respiratory dose) in stage 2 Twin Impinger.

The fluticasone propionate of the present invention shows an improved delivered dose which shows that the drug discharges well from the device and represents the amount of drug to be inhaled. It is again an interesting characteristic from this invention that the supercritical fluid of crystallized fluticasone propionate with a particle size larger than conventionally crystallized fluticasone propionate (micronized), gives a higher delivered dose.

These data demonstrate that the fluticasone propionate of the present invention has improved fluidity and flow properties.

Example 9 Solvent content test

The solvent content of the fluticasone propionate of this invention was investigated with nuclear magnetic resonance (NMR) and compared with that of conventionally crystallized fluticasone propionate. Each sample was tested for acetone content. (conventionally crystallized fluticasone propionate is crystallized from acetone). Furthermore, sample 5 was crystallized from methanol, and was therefore tested for methanol. Table 11 shows the solvent content data for each sample.

Table 11

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The data indicate that there are undetectable levels of residual solvent within the fluticasone propionate of this invention. The lack of residual solvent in the samples is consistent with GAS (gas anti-solvent) recrystallization and RESS (rapid expansion of supercritical solution).

Advantages of the lack of residual solvent within the sample include: improved stability due to lack of solvent-drug interactions at storage temperature and humidity; reduced crystal imperfections and improved crystal structure due to lack of solvent absorption.

Examples 10-12 Metered Dose Inhaler Performance

In the following tests, two types of metered dose inhalers (MDIs) were produced, both of which contained fluticasone propionate and HFA134a. The Type A inhaler was a 125 microgram, 120 actuation model. The Type B inhaler was a 50 microgram, 120 actuation model.

Type A inhalers were obtained by measuring 20 mg of the drug in an 8 ml Presspart aluminum can. The can was crimped to a 63 microliter Valois DF60 valve before pressure filling the cannister with 12 g of Propellent HFA134a. Type B inhalers were obtained in the same way, but using only 8 mg of the drug. MDI performance was measured based on the drug deposit on the can, valve and actuator, on the dose delivered via application, and on the respiratory dose.

The following crystallization conditions were used to obtain the samples for loading into the above-mentioned MDIs:

Sample 19 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 100 bar, 35 °C, and a flow rate ratio of 0.043 via a coaxial nozzle in a particle forming vessel.

Sample 20 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 100 bar, 35 °C, and a flow rate ratio of 0.014 via a coaxial nozzle in a particle forming vessel.

Sample 21 was obtained using a solution of fluticasone propionate in acetone (2.5% w/v) co-introduced with CO2 at 100 bar, 35 °C, and a flow rate ratio of 0.033 via a coaxial nozzle in a particle forming vessel.

Sample 22 was obtained using a solution of fluticasone propionate in acetonitrile (2.0% w/v) co-introduced with CO2 at 100 bar, 35 °C, and a flow rate ratio of 0.022 via a coaxial nozzle in a particle vessel.

Example 10 Drug deposit

The drug deposited in the can, on the valve and on the actuator was measured at the beginning of inhaler administration (after actuation 1 & 2) and at the end of inhaler administration (after actuation 119 & 120). After an appropriate number of actuations, the interior of the inhaler was rinsed in acetonitrile to remove any drug deposited on the surface. The drug found on the initiator was washed in a suitable container with 50 ml of acetonitrile/water (50:50 v/v). The inhaler was then frozen in liquid nitrogen, the valve quickly removed, and the contents of the drug suspension emptied into a container. The propellant material from the suspension was allowed to evaporate and the remaining drug was dissolved in 50 ml of acetonitrile/water (50:50 v/v). The drug on the valve components was washed in a suitable container with 50 ml of acetonitrile/water (50:50 v/v). The medication on the can was also washed in a suitable container with 50 ml of acetonitrile/water (50:50 v/v). The resulting solutions were analyzed with HPLC.

Tables 12 and 13 present the drug deposition profile for Type A and Type B inhalers, respectively.

The fluticasone propionate of this invention exhibits significantly lower drug deposition on the can, valve, and actuator than conventionally obtained fluticasone propionate. As a result of less drug deposition, the concentration of drug in the suspension is higher, leading to higher amounts of drug delivered from the inhaler. This is confirmed in Examples 11 (dose through application) and 12 (cascade shock testing) which show a higher dose to be delivered over the lifetime of the inhaler.

Table 12

Drug deposition profile for type A inhaler

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Table 13

Drug deposition profile for type B inhaler

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Fluticasone propionate of the present invention also shows no significant increase in drug deposition on the can and valve during the lifetime of the inhaler. As a result, the delivery dose is consistent over the lifetime of the inhaler as demonstrated in the following example.

Example 11 Dose delivered through administration

The dose delivered via inhaler administration was measured with a Type B inhaler. Doses were collected as run pairs at the start of administration (runs 1 & 2), mid-administration (runs 60 & 61), and end of administration (runs 119 & 120). The doses were collected as follows: two runs were fired into a 500 ml separatory funnel (closed at one end with a cotton cloth), having an air flow drawn through it of 20 liters per minute. The separatory funnel was washed with acetonitrile in a 100 ml volumetric flask containing 50 ml of water. The resulting solution was made up to volume and analyzed by HPLC.

Table 14 shows the dose-delivered-through-application data for the Type B inhaler, for which the target dose delivered per actuation is 44 micrograms.

Table 14

Dose delivered through inhaler type B application

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The fluticasone propionate of this invention exhibits a dosing profile over the duration of the inhaler that is consistently close to the target dose of 44 micrograms. This profile is significantly better than that of conventionally crystallized fluticasone propionate (micronized), and which shows a significant increase in dose per initiation through inhaler administration.

The dose variability at each point through administration of the fluticasone propionate inhaler of the present invention is compared with that of conventionally crystallized fluticasone propionate (micronized), and it shows an improvement towards the end of administration of the inhaler.

The delivered dose for fluticasone propionate of the present invention is consistently higher than that of conventionally crystallized fluticasone propionate (micronized), due to less drug deposition on the can and valve, as demonstrated in Example 10.

Example 12 Cascade impact test

Cascade impact testing was performed on a type A inhaler. The procedure used is in accordance with "Preparation for Inhalation; Aerodynamic assessment of fine particles using apparatus D" as defined in British Pharmacopoeia 1992, Supplement 1996, p. A527, applied to the formulation of metered dose inhalers.

Cascade impact data are presented below in Table 15, for bulk inhalers made using the material of sample 19, and compared to inhalers made using conventionally crystallized and micronized material.

Deposits in degrees 3, 4 and 5 represent fine particles of the mass that reach deep into the lungs. The delivered dose (ex trigger) represents the total dose available for inhalation and efficient discharge from the device.

Table 15

Cascade impact data for type A inhaler

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Fluticasone propionate of the present invention does not show significant improvement in fine particle mass. An interesting feature of this invention is that the supercritical fluid of crystallized fluticasone propionate with particles larger than those of conventionally crystallized fluticasone propionate (micronized), gives the equivalent of fine particle mass in the cascade impactor.

The fluticasone propionate of the present invention shows an improved delivered dose which shows that the drug discharges well from the device and represents a larger amount of drug for inhalation. This is achieved with less drug deposition on the can/valve, which increases the drug concentration in the suspension. Again, an interesting feature of this invention is that the subcritical fluid of crystallized fluticasone propionate with particles larger than those of conventionally crystallized fluticasone propionate (micronized), provides a higher delivered dose. The data show that the fluticasone propionate of the present invention has improved fluidity and flow properties.

Claims (29)

1. S-Fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyl oxyandrosta-1,4-dien-17β-carbotiate (fluticasone propioant), characterized by the fact that it is in a suitable crystalline form handling and suitable for translation into a fluid, with controlled particle size and shape. 2. S-Fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-1,4-dien-17β-carbotiate (fluticasone propioant), indicated by the fact that it has an orthorhombic crystal structure. 3. Fluticasone propionate as claimed in claim 1 or claim 2, characterized in that it has a dynamic mass density of less than 0.2 g/cm3. 4. Fluticasone propionate as claimed in claim 3, characterized in that it has a dynamic mass density in the range between 0.05 and 0.17 g/cm 3 . 5. Fluticasone propionate as claimed in claim 4, characterized in that it has a dynamic mass density in the range between 0.05 and 0.08 g/cm 3 . 6. Fluticasone propionate as claimed in any of claims 1 to 5, characterized in that it has a particle size in the range of 1 to 10 microns. 7. Fluticasone propionate as claimed in any of claims 1 to 6, characterized in that it has a uniformity coefficient of 1 to 20. 8. Fluticasone propionate as claimed in any of claims 1 to 7, characterized in that it has a respiratory fraction of 14% or more by weight. 9. Fluticasone propionate as claimed in any of claims 1 to 8, characterized in that it has a cohesiveness of 0 to 20%. 10. Fluticasone propionate as claimed in claim 9, characterized in that it has a cohesiveness of 0 to 10%. 11. Fluticasone propionate as claimed in any of claims 1 to 9, characterized in that it has a pure polymorphic form 2 characterized by X-ray powder diffraction of a tracer, essentially as shown in Figure 23. 12. A process for obtaining fluticasone propionate as claimed in any one of claims 1 to 11, characterized in that it comprises co-introducing a supercritical fluid and a carrier containing at least fluticasone propionate in solution or suspension in a vessel for forming particles, where the temperature is controlled and pressure, so that the dispersion and extraction of the carrier occurs essentially simultaneously with the action of the supercritical fluid. 13. The method as claimed in claim 12, characterized in that the co-introduction of the supercritical fluid and the carrier containing at least fluticasone propionate in solution or suspension is performed using a nozzle of coaxial design. 14. The method as claimed in claim 12 or claim 13, characterized in that the supercritical fluid is carbon dioxide. 15. A pharmaceutical preparation, characterized in that it contains fluticasone propionate as claimed in any one of claims 1 to 11 together with at least one pharmaceutically acceptable carrier or excipient. 16. A pharmaceutical preparation as claimed in claim 15, characterized in that the carrier is silicon dioxide or hydroxypropyl cellulose. 17. Pharmaceutical preparation as claimed in claim 15, characterized in that the carrier is lactose. 18. A pharmaceutical preparation as claimed in claim 17, characterized in that it is in the form of a dry powder suitable for inhalation. 19. A pharmaceutical preparation as claimed in any one of claims 15 to 17, characterized in that it is in the form of an aerosol spray presentation. 20. A pharmaceutical preparation as claimed in claim 19, characterized in that the aerosol spray representation is a metered dose inhaler. 21. Pharmaceutical preparation as claimed in claim 19 or claim 20, characterized in that the aerosol spray form contains HFA124a as propellant. 22. A pharmaceutical preparation as claimed in any one of claims 15 to 21, characterized in that it contains multicomponent particles containing fluticasone propionate as a carrier. 23. The process for obtaining fluticasone propionate as claimed in claim 22, characterized in that it comprises the co-introduction of a supercritical fluid, a carrier and a carrier containing at least fluticasone propionate in solution or suspension in a vessel for particle formation, where temperature and pressure are controlled, so that the dispersion and extraction of the carrier occurs essentially simultaneously with the action of the supercritical fluid, and the fluticasone and the carrier co-crystallize together. 24. The method as claimed in claim 23, characterized in that the co-introduction of the supercritical fluid, the carrier and the carrier containing at least fluticasone propionate in solution or suspension is performed using a nozzle of coaxial design. 25. Fluticasone propionate as claimed in any of claims 1 to 11, characterized in that it is used in therapy. 26. Fluticasone propionate as claimed in any one of claims 1 to 11, characterized in that it is used for the production of a medicine for combating respiratory diseases. 27. Use as claimed in claim 26, characterized in that the respiratory disease is asthma. 28. A method of treating a human or animal body suffering from a respiratory disease, characterized in that it comprises introducing into said human or animal body an effective amount of fluticasone propionate, as required in any of claims 1 to 11. 29. The method of treatment as claimed in claim 28, characterized in that the respiratory disease is asthma.