CONDITIONING PROCESS OF MICRONIZED FLUTICASONE FUROATE

Abstract

The application relates to a process for conditioning micronized fluticasone furoate in polymorphic Form 1 which comprises exposure at a temperature of 65-150°C for at least 1 day in the absence of humidity. The conditioning allows the bioavailability properties of the compound to be maintained constant over time in the pharmaceutical composition containing it. Formula (I) Fluticasone furoate.

Description

“PROCESS FOR CONDITIONING MICRONIZED FLUTICASONE FUROATE”***** ***** *****FIELD OF THE INVENTIONThe present invention relates to the sector of the synthesis of active ingredients (API) for pharmaceutical use, and in particular to a post-micronization conditioning process of [(6S,8S,9R, IOS, 11 S , 13 S, 14S , 16R, 17R)-6,9-difluoro- 17-(fhioromethylsulfanylcarbonyl)- 11- hydroxy- 10, 13, 16-trimethyl-3-oxo-6,7,8, 11,12,14,15,16-octahydrocyclopenta[a]phenanthren- 17-yl]-furan-2-carboxylate, a compound also known by the name of Fluticasone Furoate and whose formula is reported below:STATE OF THE ARTFluticasone Furoate is a steroidal active pharmaceutical ingredient used for the treatment of allergic or inflammatory diseases of the respiratory tract, such as allergic rhinitis, asthma and chronic obstructive pulmonary disease (COPD).In pharmaceutical formulations, Fluticasone Furoate is present in the form of a micronized powder, as a suspension or as an inhalation powder.In these formulations, which have a predominantly local action at the level of nasal, bronchial and pulmonary tissues, the particle size of the active ingredient (API) and the specific solid form (polymorph) are essential to ensure the efficacy of the medicament as the particle granulometry determines the localization of the active ingredient in the respiratory tree, while the polymorph affects the dissolution rate of the active ingredient and therefore its absorption kinetics at a local level, in addition to influencing the aerodynamic properties of the powder and the interaction with the excipients.US 8337816 B2, for example, reports in paragraphs 6 and 7 (column 1, page 5) that the active ingredients used as powders for inhalation use should have sizes lower than 10 micrometers, and preferably between 3 and 6 micrometers.US 6759398 B2 reiterates this concept in column 5 on page 11, and suggests in theexamples that in formulations for the treatment of inflammatory diseases of the lower respiratory tract, Fluticasone Furoate should be micronized and have an average diameter equal to 3 pm (Examples 12-13), while in formulations for intranasal use the active ingredient should still be micronized, although the size thereof is not specified (Example 14).The most common method for obtaining such powders, as suggested again in US 6759398 B2 in column 5 on page 11, is micronization, i.e. a high-energy process that through the use of fluids (usually gas) at high pressure is able to grind solid particles until they reach sizes of the order of a few micrometers. However, a typical and almost never avoidable drawback of this method is the formation of a percentage of amorphous product originating from the starting crystalline form and caused by the high physical stress to which the powders are subjected during the process.The presence of amorphous product, being this a thermodynamically unstable form compared to crystalline forms, is particularly undesirable in the context of pharmaceutical products for inhalation use since its transformation into more stable forms, namely crystalline forms (recrystallization), can give rise to both particle aggregation phenomena that modify the granulometry of the active ingredient over time, and the formation of crystalline forms different from the initial desired one.Both these phenomena modify the efficacy of the API, the first by altering the way in which the active ingredient is distributed along the respiratory tree following inhalation of the medicament, the second by altering the dissolution profile of the active ingredient in biological fluids.In the article “An in vivo and in vitro comparison of two powder inhalers following storage at hot / humid conditions”, L. Borgstrom et al., J. Aerosol Med. 2005 18:3, 304-310, for example, the authors report an in vivo efficacy reduction during accelerated stability tests of the drug Seretide Diskus (Fluticasone Propionate), due to the increase in particle size of the API over time.The patent EP 1305329 B2, on pages 8, 25, 26, reports the existence of Fluticasone Furoate in three different non-solvated polymorphic forms called Form 1, Form 2 and Form 3, each characterized by a different physical stability, as well as different solvated forms, indicating on page 9 the non-solvated Form 1 as the preferable one for formulation purposes.In the experimentation carried out, the present inventors have observed that, following micronization of the Fluticasone Furoate polymorph Form 1 prepared as described in Example 1 - “first alternative method” on page 25 of EP 1305329 B2, micronized Fluticasone Furoate isobtained, consisting of the starting polymorphic form 1 and a high amount of amorphous product, in some cases quantifiable as 45% of the total mass of the API.The present inventors have also observed the tendency of the amorphous fraction of the micronized product to recrystallize, partially restoring the overall crystallinity of the powder, thus confirming the thermodynamic instability of the amorphous Fluticasone Furoate. This reduction in the amorphous product content of the micronized powder is extremely slow and is accompanied by an increase in the granulometry, which, as previously stated, is an undesirable phenomenon as it alters the pharmacological performance of the medicinal product.In order to eliminate, or at least limit, the negative effects of uncontrolled recrystallization of the amorphous product present inside the micronized powders, it is known in literature the use of conditioning processes, i.e. physical treatments performed on the newly micronized powder capable of promoting the conversion of the amorphous product into a crystalline form in a short time, and therefore obtaining a material with greater physical stability. In the case of micronized APIs for inhalation use, since the efficacy of the drug also depends on the size of the API particles and the crystalline form, it is also essential that there is no significant increase in the granulometry due to aggregation phenomena during the conditioning. Furthermore, in the case where different polymorphic forms are possible, the presence of amorphous product constitutes a further problem as it is possible that the amorphous product may recrystallize in a different polymorphic form than the starting one, thus potentially compromising the bioavailability of the API.The situations to be avoided in the conditioning processes may therefore be summarized as follows:• Non-micronized crystalline API polymorph X (100%) — Micronized crystalline API polymorph X + amorphous product — > Micronized crystalline API polymorph X with increased particle size;• Non-micronized crystalline API polymorph X (100 %) — > Micronized crystalline API polymorph X + amorphous product — > Micronized crystalline API polymorph X + polymorph Y.• Non-micronized crystalline API polymorph X (100 %) ~^ Micronized crystalline API polymorph X + amorphous product — > Micronized crystalline API polymorph X with increased particle size + polymorph Y.The literature reports several conditioning modalities that have demonstrated their efficacy against different micronized APIs, such as exposure to atmospheres with particularhumidity levels, exposure to solvent atmospheres, exposure to high temperatures, and combinations of these factors.By way of example, US 6656453 B2 reports in Examples 1-4 the use of particular conditions of relative humidity (60-85% RH) at room temperature or at moderately high temperatures (40 °C) in order to condition Salbutamol Sulfate.EP 2968152 B2 reports in Examples 2 and 3 the conditioning of Budesonide and Fluticasone Propionate using an atmosphere consisting of ethanol vapors.The article “The influence of secondary processing on the structural relaxation dynamics of Fluticasone propionate”, R. Depasquale et al., AAPS PharmSciTech 2015, 16:3, 589-600, reports that Fluticasone Propionate, a product structurally related to Fluticasone Furoate and sharing with it the tendency to form amorphous product during micronization, can be effectively conditioned using different combinations of temperature and humidity at different times of exposure of the powder to these conditions.The application to micronized Fluticasone Furoate of the conditioning methods described in these prior art documents on active ingredients also of steroidal nature, however, has not proven to be effective. In fact, the objective of substantially reducing the content of amorphous product in a short time, without increasing the granulometry of the powder and / or without changing the crystalline form, is not achieved using these methods.Laboratory tests carried out by the present inventors during their research into effective conditioning methods have shown that exposure of micronized Fluticasone Furoate to an atmosphere saturated with solvent vapors, while allowing a rapid increase in the crystallinity of the powder as evidenced by DRX analysis, causes a significant increase in the size of the powder particles. In fact, following exposure of micronized Fluticasone Furoate powders to different solvent atmospheres, including ethyl acetate, mixtures of ethyl acetate and toluene or heptane, isopropyl alcohol, methyl isobutyl ketone, a substantial reduction in the content of amorphous product was observed, even after just 2 hours of exposure, which starting from a value greater than 20% by weight was constantly found below 10% at the end of the conditioning. However, the size of the particles resulted to be considerably increased, indicating that this type of treatment would cause a substantial aggregation of the particles that make up the powder.Exposure of the powder to acetone vapors caused the transformation of the crystalline form of the product into a solvated form.A further conditioning method is reported in EP 2234595 Bl and consists of exposing thepowders to high temperatures in the absence of humidity. However, this procedure has been applied only to Glycopyrronium Bromide (page 3 column 4 paragraph

[0022] ), an API (page 3 column 4 paragraph

[0024] ) which is structurally completely different from Fluticasone Furoate and exists as a single solid form, i.e. it does not show the characteristic of polymorphism. This “thermal” conditioning method, suitable for reducing the aggregation of the particles after micronization, cannot be correlated with the reduction of amorphous product content, since Glycopyrronium Bromide does not generate any amorphous product during micronization (page 5 column 7 paragraph

[0038] ). EP 2234595 Bl also provides that the conditioning treatment should be carried out immediately after micronization (page 4, paragraph 33, and page 5 paragraph 49), while it would be more useful for industrial production purposes not to have this constraint, and to have greater freedom in choosing the time of conditioning.The need to identify a new conditioning method for micronized Fluticasone Furoate that can effectively reduce the content of amorphous product and accompanied by a minimal or no effect on the powder granulometry, which regenerates the crystalline form (polymorph) of the pre-micronization API and does not have any negative effects on the chemical quality of the API, is therefore still felt in the sector.FIELD OF THE INVENTIONThis and other objects are achieved by the present invention, which relates to a conditioning process of micronized Fluticasone Furoate which comprises exposing the micronized Fluticasone Furoate to a temperature from 65 °C to 150 °C for at least 1 day in the absence of humidity.In a second aspect thereof, the present invention relates to micronized Fluticasone Furoate conditioned by the process described above.BRIEF DESCRIPTION OF THE FIGURESFigure 1: Superposition of X-ray diffractograms of micronized Fluticasone Furoate powders, the lower line corresponds to the product after the conditioning process as described in Example 1, while the upper line corresponds to the unconditioned product.Figure 2: SEM images of the powders before and after conditioning as described in Example 1.DETAILED DESCRIPTION OF THE INVENTIONThe invention consists of a conditioning process of micronized Fluticasone Furoate Form 1 useful for significantly reducing its amorphous product content while avoiding, or in any case minimizing, the growth of the particle size, avoiding the formation of a different crystallineform (polymorph) and the chemical degradation of the treated sample.In the remainder of the description, the following definitions and abbreviations are adopted:- the term “micronized” is intended to mean a product made up of micrometric particles obtained by physical methods of particle size reduction; typically, but not exclusively, this process is performed using fluidized bed mills called “jet-mills”;- the term “amorphous product” is intended to mean a particular solid form of a substance characterized by structural disorder; an amorphous product, in its pure form, is characterized by the absence of defined diffraction peaks in the DRX analysis;- the term “aggregation” is intended to mean a process whereby micronized particles tend spontaneously, or by means of an external agent, to irreversibly weld together (sinterize) forming larger particles, called “aggregates”;- the term “Fluticasone Furoate” is intended to mean the polymorph Fluticasone Furoate defined as “Form 1” in EP 1305329 B2, having diffraction peaks in DRX analysis on powders at 7.4, 9.7, 14.8, 15.2, 16.1, 18.9, 23.1 and 30.4 ± 0.2° 29 using the X-ray radiation Cu Ka as the analytical wavelength;- the term “micronized Fluticasone Furoate” is intended to mean Fluticasone Furoate already subjected to micronization with any technique known in the art, and having an average diameter of less than 10 pm;- the term “API” (Active Pharmaceutical Ingredients) is intended to mean pharmacologically active raw materials;- the term “average diameter” or “D[4,3]” is intended to mean the average diameter of the particle volumetric distribution as measured using the laser diffraction technique; the indications “dlO”, “d50”, “d90” are intended to mean the diameter value such that 10%, 50%, and 90%, respectively, of the particles that make up the powder have a diameter equal to or less than this value.Micronized Fluticasone Furoate is the starting point of the present invention and may be purchased from commercial sources or prepared using any suitable equipment and technique adapted to produce a powder with an average diameter of less than 10 pm, preferably less than 5 pm; for example, it may be produced using the procedure described in EP 1305329 B2. The most widely used methods in the industry to obtain a micronized product, and which may lead to the formation of an amorphous product, are for example jet-milling and ball-milling.Preferably, the starting polymorphic form of Fluticasone Furoate is Form 1, described inEP 1305329 B2.The temperature and time of the conditioning process of micronized Fluticasone Furoate are essential in order to obtain the recrystallization of the amorphous component without growth of the particle size and without formation of a different crystalline form (polymorph) than the starting pre-micronization one.The starting micronized Fluticasone Furoate is conditioned at a temperature equal to or greater than 65 °C for at least 1 day.According to a preferred embodiment of the invention, the starting micronized Fluticasone Furoate is conditioned at a temperature comprised between 65 and 150 °C, preferably between 65 and 120 °C, even more preferably between 75 and 85 °C.The conditioning time of the powder, in the above temperature ranges, is comprised between 1 and 12 days, preferably between 2 and 8 days, even more preferably 5 days.The conditioning may be carried out in any atmosphere, for example in air or in an inert atmosphere; in the case of using an inert atmosphere, this is preferably formed by nitrogen or argon.The pressure at which the process is carried out may be from ambient pressure (typically, values of 980-1030 mbar) to sub-atmospheric pressures, lower than 100 mbar, preferably lower than 10 mbar.The conditioning process of the micronized powder of Fluticasone Furoate Form 1 of the present invention may be performed, and is effective, over a long period of time; it may be performed immediately after micronization, but also within a period of up to 6 months after micronization.The micronized Fluticasone Furoate, after the conditioning treatment of the invention, maintains unchanged also the chemical purity value it had before micronization and before conditioning, thus maintaining its suitability for pharmaceutical use in humans. The purity analyses carried out by the inventors indicate that the thermal treatment does not cause any degradation of the product, despite the high temperatures reached during the process and the prolonged times of exposure to heat.Micronized Fluticasone Furoate subjected to the conditioning object of the invention shows a substantial reduction in the amorphous product content, which drops below 10% by weight regardless of the starting percentage post micronization; this allows the API powders not to undergo significant changes in their characteristics over time, and therefore the maintenance of the efficacy of the pharmaceutical formulation over its entire lifespan.The granulometry of the conditioned powder shows no or slight growth in the average size of the particles in the order of a few tenths of a micron, and in any case of less than 15%.EXPERIMENTAL PARTThe invention is now illustrated by means of some examples intended for illustrative and non-limiting purposes.Abbreviations - MeaningMeOH: methyl alcohol;ACN: acetonitrile;TFA: trifluoroacetic acid.The water used in the experiments is to be understood as purified water unless otherwise specified.The organic solvents used in the descriptions are to be understood as of technical grade, unless otherwise specified.The reagents and catalysts used are to be understood as of commercially available quality, unless otherwise specified.HPLCThe analyses were performed using the instrument Agilent Model 1200 Infinity chromatography system; UV Detector MODEL G1315D.HPLC MethodChromatographic conditions:- Column: Zorbax SB-C8, 150 mm x 4.6 mm, 3.5 pm- Flow rate: 1.5 ml / min- Detector: UV 245 nm- Injection volume: 10 pl- Temperature: 50 °C- Mobile Phase A: MeOH:ACN: 0.1% TFA aqueous solution (10:30:60 v / v)- Mobile Phase B: MeOH:ACN (25:75 v / v)Water Titration according to Karl-Fisher MethodKarl-Fisher water content was determined following the methodology reported in the European Pharmacopoeia (2.5.32) for Fluticasone Furoate, using 100 mg of sample and the evaporation method at 110 °C, using for this purpose the Stromboli gas phase extraction system (Mettler Toledo) coupled to the C30 coulometric titrator model (Mettler Toledo).DRXDRX analysis on powders was performed using a Bruker D2 Phaser diffractometer (2nd ed.) operating in Bragg-Brentano geometry and equipped with a 6-position rotating multisampler. The X-ray source used is an X-ray tube with a Copper anode, operated at 30 kV and 10 mA. The analytical wavelength used is the Copper Ka (Kai, 2 1= 1.54184 A). K is filtered off through a Nickel filter. The X-ray detector is a linear solid-state detector model LYNXEYE.The samples were deposited as a thin layer on “zero background” silicon sample holders. The diffractogram was recorded in the 4.0-40° 20 angular range with increments of 0.016° and a scanning speed of 1.0 s / increment. The sample was rotated at 60 rpm during the analysis.Data were processed and analyzed using the DIFFRAC.EVA software (Bruker).The % content of amorphous product was automatically determined by the software based on the ratio between the integrated areas of the diffraction peaks and the total integrated area of the diffractogram.SEM MicroscopySEM microscopy was performed using a Jeol JSM-IT200 scanning electron microscope (SEM) equipped with a tungsten thermionic source. Images were acquired in high vacuum using a beam voltage of 20 kV and an Evengart-Thomley secondary electron detector (SED). The analyte powder was deposited onto the sample holder by means of a double-sided adhesive carbon film and then subjected to metallization before analysis.Granulometry AnalysisGranulometry analysis was performed using a Malvern Mastersizer 2000 laser granulometer using the following operating conditions:- Dispersion system: Hydro 2000S- Dispersing medium: water- Data interpretation theory: Fraunhofer- Particle shape: irregular- Sensitivity: normal- Dispersion system: Hydro 2000S- Dispersing medium: water- Background scans: 10000 (10 s)- Sample scans: 10000 (10 s)- Stirring: 2000 rpm- Optical concentration: 5%-l 0%- Pre-measurement pause: 30 s- Refractive index of the dispersing medium: 1.33Procedure: About 60 mg of powder are weighed in a 50 mL glass container, to which 3 drops of Tween® 80 (polyethylene glycol sorbitan monooleate, a surfactant) are added, then the mixture was amalgamated with a spatula. 40 mL of water are added, the suspension is mixed and then, under magnetic stirring, it is sonicated using a probe ultrasonicator (Sonics Vibracell 750) operated under the following conditions:- Amplitude: 21%- Total time: 120 s- Pulse On: 1 s- Pause: 2 sThe suspension thus obtained is added to the above-mentioned dispersing medium contained in the Hydro 2000S unit until the indicated optical concentration is reached. 3 measurements are performed, and the result reported is the average of these measurements. The data are expressed as volume distribution.EXAMPLE 1300 g of micronized Fluticasone Furoate, obtained from Fluticasone Furoate Form 1 , were spread on a steel tray. The container was then introduced into a vacuum oven and subjected to heating at a pressure lower than 100 mbar, and a temperature of 80 ± 5 °C, for 96 hours. At the end of the treatment, the tray was removed from the oven and the solid was quantitatively recovered. The solid was then analyzed for chemical purity, water content, particle size (measures of granulometric distribution), amorphous product content, obtaining the following results:The diffractograms that provided the crystallinity data, and confirmed both the maintenance of the crystalline form pre- and post-conditioning and the reduction of the amorphous product content following conditioning, as apparent from the lowering of the baseline in the diffractogram of the conditioned product compared to the diffractogram of the pre-conditioning product, are reported in Figure 1.Finally, SEM micrographs on the initial sample (pre-conditioning) and final product (post-conditioning) of this example were obtained, as reported in Figure 2, which confirm the maintenance of the particle size after the process of the invention.EXAMPLE ! 250 g of micronized Fluticasone Furoate Form 1 (at a different amorphous product content than the starting sample of Example 1) obtained from Fluticasone Furoate Form 1, were spread on a steel tray. The container was then introduced into a vacuum oven and heated at a pressure lower than 100 mbar, and a temperature of 80 ± 5 °C, for 96 hours. At the end, the tray was removed from the oven and the solid was quantitatively recovered. The solid was then analyzed for chemical purity, water content, particle size and amorphous product content, obtaining the following results:The results obtained in this example essentially mirror those obtained in Example 1.EXAMPLE 32 g of micronized Fluticasone Furoate, obtained from Fluticasone Furoate Form 1, were weighed in a glass container. The open container was placed inside a vacuum oven and subjected to heating at 80±5 °C, and a pressure lower than 100 mbar, for 48 hours. At the end, the vacuum was broken using nitrogen and the sample was removed from the oven and closed with a polyethylene cap. The solid was then analyzed for amorphous product content by DRX, and particle size by laser granulometry, providing the following data:The post-conditioning crystalline form is the polymorph Form 1. EXAMPLE 4 - COMPARATIVEThe procedure applied to Fluticasone Propionate described in Depasquale et al. AAPS PharmSciTech 2015, 16:3, 589-600, was applied to Fluticasone Furoate, as follows.2 g of micronized Fluticasone Furoate obtained from Fluticasone Furoate Form 1, were weighed in a glass container. The open container was placed inside a climate chamber previously set to subject the sample to an environment at 60 °C and 44% RH. After 48 hours, the sample was removed from the climate chamber and closed with a polyethylene cap. The solid was then analyzed for amorphous product content by DRX, and particle size by laser granulometry.The post-conditioning crystalline form is the polymorph Form 1.Conditioning operated at 60 °C, again using a humid atmosphere, while obtaining the desired reduction of the amorphous product content, was accompanied by an excessive growth of the particle size. EXAMPLE 5 - COMPARATIVEThe procedure applied to Fluticasone Propionate described in Depasquale et al. AAPS PharmSciTech 2015, 16:3, 589-600, was applied to Fluticasone Furoate, as follows.2 g of micronized Fluticasone Furoate, obtained from Fluticasone Furoate Form 1, were weighed in a glass container. The open container was placed inside a climate chamber previously set to subject the sample to an environment at 40 °C and 75% RH. After 48 hours, the sample was removed from the climate chamber and closed with a polyethylene cap. The solid was then analyzed for amorphous product content by DRX, and particle size by laser granulometry.The exposure of the micronized powder to a humid atmosphere has proven to be ineffective; in fact, it was not possible to find a substantial reduction in the amorphous product content below the desired levels (<10%) over the course of a few days of treatment.EXAMPLE 6 - COMPARATIVE0.5 g of micronized Fluticasone Furoate, obtained from Fluticasone Furoate Form 1, were placed inside a glass vial which, in turn, was placed inside a glass container containing a layer of water on the bottom such as to allow 100% humidity to be generated inside. Once the vial containing the powder sample was placed inside the container, this was sealed and left at a temperature of 20-25 °C for 48 hours. At the end, the vial containing the powder was removed from the conditioning chamber and the amorphous product content was evaluated by DRX, obtaining the following results:As can be seen from the data in the tables of Comparative Examples 5 and 6, exposure of the micronized Fluticasone Furoate powder to high levels of relative humidity, both at room temperature and at higher temperatures, proved to be ineffective in reducing the amorphous product content. In fact, this procedure only produced marginal changes in the amorphous product content, with a reduction of one, maximum two absolute percentage points compared to pre-conditioning, even after several hours of treatment.Exposure of the micronized Fluticasone Furoate powder to humidity at temperatures of 60 °C, on the contrary, proved to be capable of reducing the amorphous product content, as can be seen from the table of Comparative Example 4; however, the particle size of the obtained product increased by more than 15%.The conditioning process of the present invention, on the other hand, allowed a significant reduction in the amorphous product content in the micronized Fluticasone Furoate; as shown in Examples 1-3, the relative difference in amorphous product content between pre- and postconditioning is up to -50%. Furthermore, the particle size before and after conditioning remains almost unchanged, as well as the polymorph remains unchanged after conditioning.

Claims

CLAIMS1. Process for conditioning micronized Fluticasone Furoate containing a portion of amorphous product, obtained from the Fluticasone Furoate polymorph Form 1, having diffraction peaks from DRX analysis on powders at 7.4, 9.7, 14.8, 15.2, 16.1, 18.9, 23.1 and 30.4 ± 0.2° 20 using X-ray radiation Cu Ka as the analytical wavelength, wherein said process comprises exposing the micronized Fluticasone Furoate to a temperature from 65 °C to 150 °C for at least 1 day, in the absence of humidity.

2. Process according to claim 1, wherein said portion of amorphous product of micronized Fluticasone Furoate is equal to or greater than 10% by weight of the product.

3. Process according to any one of claims 1 or 2, wherein said micronized Fluticasone Furoate was obtained from said polymorph Form 1 by a jet-milling or ball-milling treatment.

4. Process according to any one of the preceding claims, wherein the temperature is comprised between 65 °C and 120 °C.

5. Process according to claim 4, wherein the temperature is comprised between 75 °C and 85 °C.

6. Process according to any one of the preceding claims, wherein such conditioning occurs over a period of time comprised between 1 and 12 days.

7. Process according to claim 6, wherein such conditioning occurs over a period of time comprised between 2 and 8 days.

8. Process according to any one of the preceding claims, wherein such conditioning occurs at a pressure equal to or lower than 1030 mbar.

9. Process according to claim 8, wherein such conditioning occurs at a pressure lower than 100 mbar.

10. Process according to any one of the preceding claims, wherein such conditioning occurs in an inert atmosphere obtained using nitrogen or argon.

11. Process according to any one of the preceding claims, wherein the conditioning is carried out immediately after micronization or within a period of up to 6 months.