WO2003090668A2

WO2003090668A2 - Method of obtaining amorphous solid particles

Info

Publication number: WO2003090668A2
Application number: PCT/FR2003/001255
Authority: WO
Inventors: Michel Perrut; Jennifer Jung; Fabrice Leboeuf
Original assignee: Separex
Priority date: 2002-04-23
Filing date: 2003-04-18
Publication date: 2003-11-06
Also published as: FR2838654B1; AU2003262803A8; AU2003262803A1; WO2003090668A3; FR2838654A1

Abstract

The invention relates to a method of obtaining amorphous solid particles from at least one product, with controlled particle size. The inventive method is characterised in that it comprises the following steps consisting in: solution treating the product in a compressed fluid; reducing the pressure of said solution by means of a spray nozzle (12) inside a spray chamber (14) which is swept by an inert gas current; maintaining the spray chamber (14) at a temperature that is significantly lower than the vitreous transition temperature of the product, preferably at least 30 °C below said temperature; and collecting the particles thus formed.

Description

PROCESS FOR OBTAINING AMORPHOUS SOLID PARTICLES

The present invention relates to a process for obtaining amorphous solid particles from products, in particular pharmaceuticals, pure or as a mixture, having a controlled particle size.

The morphology of the solid state of a body is an essential parameter acting on its properties and therefore its potential uses, especially when several forms can co-exist like crystalline or amorphous forms, or in different polymorphic forms also called allotropes. This is. particularly important for pharmaceutical products whose morphology can have a great impact on pharmacological properties such as bioavailability, therapeutic efficacy, side effects and dosage.

We know that it is advantageous, in certain fields of industry, and in particular in the pharmaceutical field, to be able to have a reliable process allowing the generation of amorphous particles of products. Indeed, it is preferred to administer the active ingredients orally consisting of small A molecules (as opposed to biomolecules such as proteins) orally and their absorption requires their prior dissolution in the gastrointestinal liquid which is essentially aqueous. This is why many techniques have been developed to improve the dissolution of the numerous active principles which are of great therapeutic interest but which are poorly absorbed because of their very low solubility in aqueous media. The most common method is to reduce the size of the particles, so as to increase their contact surface with the dissolution medium. A large number of methods and apparatuses have been proposed for this purpose, and first of all the grinding which has been described in numerous documents among which we will cite "The Theory and Practice of the Pharmaceutical Industry", Chapter 2, "Milling" p.45, (1986), micronization, homogenization and controlled precipitation from organic solutions.

More recently, a great deal of work has been devoted to obtaining very small particles using supercritical fluid technology, as described in detailed bibliographic reviews citing hundreds of patents and publications, published by U.D. Kompella and K. Koushik, "Critical reviews in Therapeutic Carrier Systems" (18 (2), 2001, p.173-199), HS Tan and S. Borsadia in "Expert Opinions on Therapeutic Patents" (11 (5), 2001 p.861-872), and J. Jung and M. Perrut, in the “Journal of Supercriticals Fluids” (20, 2001, p.179-219).

During the implementation of these various methods, particular attention is paid to the morphology of the solid thus micronized, since the formation of a partially amorphous material, or consisting of a mixture of polymorphs, could cause significant pharmacological problems. Indeed, transitions of subsequent phases, particularly the re-crystallization of an amorphous phase, during storage of the product, could profoundly modify its kinetics of dissolution and its bio-availability. It is now well established that the amorphous forms have better dissolution kinetics, and ultimately better bioavailability, than the crystalline forms of the active ingredients which are very slightly soluble in aqueous media, as described by MJ Joziakowski in "Water -Insoluble Drug Formulation ", ISBN 1-57491-105- 8, 2000, chapter 15, p.555-561. On the other hand, the use of stable amorphous forms makes it possible to avoid the formation of crystalline polymorphs, the presence of which at variable and poorly controlled concentrations also constitutes a major problem.

Numerous methods have been proposed in order to prepare amorphous forms of solids, and in particular pharmaceutical active principles. It is possible to obtain an amorphous solid phase by melting the solid followed by abrupt cooling, for example in liquid nitrogen, provided however that the compound is not degraded by such an operation. This limitation is particularly marked for pharmaceutical active ingredients consisting of molecules which are often complex and not very stable to heat, and which crack before reaching the melting temperature.

Other methods are known for obtaining amorphous phases: precipitation from a solution in a volatile organic solvent by evaporation of the solvent, spray drying, roller drying and lyophilization. Thus, the production of cefuroxime axetil by these four methods will be cited as an example, as described in American patents US-A-4, 562, 181 and US-A-5, 013, 833. In certain cases, we can also obtain an amorphous phase by grinding, as described by example for this same compound in US patent US-A-6,060,599.

In fact, for reasons of stability of the amorphous phase, this is generated in most pharmaceutical applications in the form of a solid solution or dispersion of the active ingredient in an excipient, as described for example by AR Nanda, CE. Rowlins, N.P. Barker and P.-C. Sheen in "Water-Insoluble Drug Formulation", ISBN 1-57491-105-8, 2000, chapter 14, p.493-523.

Solid solutions or dispersions are generally made by one of the following methods: a) fusion or extrusion of the active-excipient mixture followed by solidification at ordinary temperature; b) Co-precipitation of the active-excipient mixture previously dissolved in a volatile organic solvent which is then evaporated; c) Dissolving the active ingredient in a solvent and bringing this solution into contact with the molten excipient, then cooling to ordinary temperature and removing the solvent. However, the result obtained is hardly predictable and the methods completely empirical. In addition, the complete removal of the organic solvent in the latter two methods constitutes a significant additional difficulty. With regard to the technology of supercritical fluids, most of the patents and publications describe the production of fine particles having the same crystalline morphology as the starting product. Thus, the particles generated by rapid decompression of a supercritical solution, a process generally designated by the acronym RESS (In English: "Rapid Expansion from Supercritical Solutions "), have the same crystalline morphology as the starting material, as has been shown for example for mevilonin and a steroid by KA Larson and ML King, Biotechnology Progress, 2, n ° 2, 1986, p.73 -82, for griseofulvin by H.-J. Martin, PC Sch idt and MA Wahl, "Proceedings of the 7 ^th Meeting on Supercriticals Fluids", Antibes-France, December 2000, p.53-57, or for ibuprofen by D. Kayrak, U. Akman and 0. Hotacsu, "Proceedings of the 6 ^th Meeting on Supercriticals Fluids", Maiori-Italy, September 2001, p.337-342.

Likewise, the particles generated by the anti-solvent process, known by different acronyms such as SAS, PCA, ASES, or SEDS, are generally crystalline, most often with the same morphology as the starting material, and more rarely in another form. allotropic, as described for salmaterol xinafoate in PCT patent application No. WO 95/01221, for lactose and sucrose by S. Palakodaty, P. York, M. Hanna and J. Pritchard, “Proceedings of the 5 ^th Meeting on Supercriticals Fluids ”, Nice-France, March 1998, p.275-280, for sulfathiazole by A. Kordikowski, T. Shekunov and P. York,“ Proceedings of the 7 ^th Meeting on Supercriticals Fluids ”, Antibes- France, December 2000, p.117-122, for ibuprofen, ketoprofen, salicylic acid and nicotinic acid in PCT patent application No. WO 99/59710, for acetomiphene and p-actoxyacetanilide by BY Shekunov, Bristow, P. York and AHL Chow, “Proceedings of the 7 ^th Meeting on Supercriticals Fluids ”, Antibes-France, December 2000, p. 111-116, for phenytoin in PCT patent application No. WO 97/31691, for nitrotrazolone by S. -Y; Lee, G.-B Lim, K.-K Koo, B.-S. Park and H. -S. Ki, "Proceedings of the 7 ^th Meeting on Supercriticals Fluids", Antibes (France), December 2000, p.123-127.

Likewise, the particles generated by a process which is a variant of these two processes, recently described as the depressurization of an expanded organic liquid solution according to the acronym DELOS (In English: "Depressurization of an Expanded Liquid Organic Solution"), consist of a crystalline solid having the same morphology as the starting material, as shown for aspirin and acetomiphene by N. Ventosa, S. Sala, J. Veciana, J. Libre and J. Torres, "Proceedings of the 6 ^th Meeting on Supercriticals Fluids ”, Maiori-Italy, September 2001, p. 325-328 and p.349-354. In fact, very few publications or patents relate to the development of amorphous particles by micronization processes using a liquefied gas, a subcritical liquid or a supercritical fluid. Furthermore, none of these documents describes the preparation of a completely amorphous phase. Thus, several authors report a drop in the degree of crystallinity, most often without quantifying it, as for example for mevilonin and a steroid by KA Larson and ML King, in the article already cited in Biotechnology Progress, 2_, n ° 2 , 1986, p. 73-82, for ibuprofen by D. Kayrak, U. Akman and 0. Hotacsu, in the article already cited in “Proceedings of the 6 ^th Meeting on Supercriticals Fluids”, Maiori September 2001, p. 337-342.

Similarly, the generation of sugar particles from aqueous solutions by the anti-solvent method, described in the article already cited by S. Palakodaty, P. York, M. Hanna and J. Pritchard, "Proceedings of the 5 ^th Meeting on Supercriticals Fluids", Nice-France, March 1998, p. 275-280, leads either to a crystallized solid for lactose and sucrose, or to an apparently amorphous solid for trehalose and maltose. On the other hand, also using an anti-solvent process, S. Jaarno, M. Rantakyla and 0. Aaltonen, "Proceedings of the 4 ^th Meeting on Supercriticals Fluids", Sendai-Japon, May 1997, p. 263-266, obtained, from a solution in methanol of sodium cro oglycate, particles whose morphology ranged from a fully amorphous state to a fully crystalline state, this morphology possibly depending, according to these authors, on the content of ^'particles residual solvent. In the light of this list of results, it appears that the generation of amorphous particles is possible according to several methods which risk leading to degradation or pollution by an organic solvent of the active principle or of the excipients, or which do not allow control the particle size of the particles, or which do not allow an amorphous state to be obtained in a reliable and reproducible manner.

The object of the present invention is to provide a process for obtaining amorphous particles, in particular from an active pharmaceutical ingredient, using a liquefied gas, a subcritical liquid or a supercritical fluid while operating under conditions allowing control the particle size distribution of the particles.

We will first recall the different states of a fluid and its properties in each of these states. We know that bodies are generally known in three states, know solid, liquid or gas and that we pass from one to the other by varying the temperature and / or pressure. In addition to the solid state, there is the liquid state and the gaseous state separated by the vaporization / condensation curve. However, there is a point beyond which one can pass from the liquid state to the gas or vapor state without going through a boiling point or, conversely, through a condensation, but continuously: this point is called the critical point PC. The supercritical state is characterized either by a pressure and a temperature respectively higher than the pressure and the critical temperature in the case of a pure body, or by a representative point (pressure, temperature) located beyond the envelope critical points represented on a diagram (pressure, temperature) in the case of a mixture. It therefore has, for a very large number of substances, a high solvent power which is incommensurate with that observed in this same fluid when it is in the state of compressed gas. The same is true of so-called "subcritical" liquids, that is to say liquids which are in a state characterized either by a pressure higher than the critical pressure and by a temperature below the critical temperature in the case of a pure body, either by a pressure higher than the critical pressures and a temperature lower than the critical temperatures of the components in the case of a mixture (see on this subject the article of Michel PERRUT - The Techniques of the Engineer “ Extraction by supercritical fluid, J 2 770 - 1 to 12, 1999 ”). The large and modular variations in the solvent power of supercritical fluids are also used in many extraction processes. (solid / fluid), fractionation (liquid / fluid), analytical or preparative chromatography, treatment of materials (ceramics, polymers, ...) and generation of particles. Chemical or biochemical reactions are also carried out in such solvents.

It should be noted that the physico-chemical properties of carbon dioxide as well as its critical parameters

(critical pressure: 7.4 MPa and critical temperature:

31 ° C) make it the preferred solvent in many applications, especially since it has no toxicity and is available at very low prices in very large quantities. Other fluids can also be used under similar conditions, such as nitrous oxide, light hydrocarbons having two to four carbon atoms, ethers and certain halogenated hydrocarbons.

In the following, and for convenience of language, we will call compressed fluid any fluid brought to a pressure substantially higher than atmospheric pressure. A fluid brought to a pressure higher than its critical pressure will be called a fluid at supercritical pressure, that is to say either a supercritical fluid proper, or a liquid called sub-critical as defined above. Likewise, liquid gas will be called a liquid, consisting of a compound which is in the gaseous state at atmospheric pressure and at ambient temperature, brought to a pressure and to a temperature respectively below its critical pressure and temperature.

According to numerous patents and scientific publications, as can be found in a recent publication, already cited, of J. JUNG and M. PERRUT in the "Journal of Supercriticals Fluids", 20, 2001, p. 179 to 219, we know that we can obtain microparticles, with a particle size generally between 1 and 10 μm, and nanoparticles with a particle size generally between 0.1 and 1 μm, by using a method implementing the supercritical fluids known by the acronym RESS, described for example in patent US-A-4,582,731, which consists in very quickly relaxing at low pressure a solution of the product to be atomized in a compressed fluid. Those skilled in the art know that the RESS process is only applicable to molecules soluble in the compressed fluid, which considerably limits its field of application when carbon dioxide is used. However, recent patents and publications teach that the RESS process finds a more interesting field of application if a fluid having a significantly greater solvent power with respect to the polar molecules is used. This is particularly the case for dimethyl ether as it has been described in several patents, including American patent application No. 20010000143, or PCT patent application No. WO 99/52504 and American patent US-A-6 , 299, 906. Diethyl ether has also been described as a solvent for inorganic products in an application similar to the RESS process intended for the projection of thin films. These two compounds, as well as other ethers or derived products also having properties similar to these two compounds, can be used in the process according to the invention, although their very flammable nature requires reinforced safety measures. However, spraying a solution in a liquefied gas, such as for example in one of these ethers, can lead to the formation of droplets of liquid if the enthalpy of the compressed fluid before spraying is not greater than or equal to the enthalpy of the gas at its dew point at the pressure prevailing in the atomization chamber. In this case, the process of formation of solid particles is seriously altered and we often observe the formation of particles of very variable size and the agglomeration of these particles in the presence of fluid in liquid phase. In order to avoid this problem, the procedure is carried out conventionally by bringing the solution in the compressed fluid to a high temperature before spraying, greater than 120 ° C. in the case of the ethers mentioned for example, with the proven risk of degradation of the molecules of the product. to atomize if the latter is thermolabile, which is often the case for pharmaceutical active ingredients. The present invention thus relates to a process for obtaining amorphous solid particles of at least one product, with controlled particle size distribution, characterized in that it comprises the steps consisting in dissolving the product in a compressed fluid , expand this solution through an atomization nozzle within an atomization chamber swept by a stream of inert gas, maintain the atomization chamber at a temperature much lower than the glass transition temperature of the product, preferably at minus 30 ° C below this, collect the particles thus formed.

According to the invention, the product to be sprayed is dissolved in a compressed fluid according to the techniques usually used by those skilled in the art, the compressed fluid being defined as it was said previously, that is to say under the form of a liquefied gas, a subcritical liquid or a supercritical fluid, chosen for its solvent power vis-à-vis the product or mixture used. This solution is then expanded through a device with a high pressure drop, for example a spray nozzle, to an atomization chamber maintained at a pressure much lower than that at which the dissolution took place and swept by a inert gas stream, possibly preheated. The fluid is then found entirely in gaseous form, which causes a very strong reduction in its solvent power, and, consequently, the supersaturation of this fluid in solute and the precipitation of this solute in the form of very fine particles. However, surprisingly, it has been found that the particles thus produced in a tiny fraction of a second, are actually amorphous when they are generated because the crystal lattice has not had time to form, and can be collected in this state, however, on condition that they are kept at a temperature below a certain value situated far below the melting temperature of the solid and even below its glass transition temperature, favorably at least 30 ° C. below it. This condition is not respected in the operations described in the literature, so that the solid can rearrange itself in the form of a crystalline structure and the collected particles are no longer in an amorphous state, but in a state either entirely crystallized or partially crystallized and partially amorphous, depending on the properties of the solid and the operating conditions used.

One of the means used to maintain the temperature of particles as soon as they are formed below the temperature where their morphology is transformed by re- crystallization, consists in using the cooling linked to the sudden expansion of the compressed fluid during atomization. As has been said before, one must nevertheless take care not to place oneself in conditions where the fluid partially transforms into liquid because, then, the droplets would redissolve the particles and the process would be seriously altered. The present invention makes it possible to avoid such a drawback by carrying out a sweeping of the atomization chamber by a current of inert gas which has the effect of greatly reducing the partial pressure of the fluid after its decompression and of providing the required enthalpy for ensure its passage to the gaseous state without formation of liquid phase. The inert gas used can advantageously be nitrogen (usually brought to a temperature between 10 ° C and 150 ° C and preferably between 20 ° C and 80 ° C) or a mixture of nitrogen and argon, and can be preheated before being introduced into the spray chamber.

In addition, the particles can be easily obtained in a sterile manner as soon as their recovery is done according to the usual rules of sterility, the process itself being intrinsically sterile and in no way increasing the biological charge of the products used. It will even be noted that, as widely described in the prior art, pressurized carbon dioxide and ethers are biocides, which can only, when used according to the present invention, facilitate sterility. the operation, or even destroy the microorganisms possibly present in products accidentally.

According to the invention, it is possible to use, as compressed fluid, an ether such as diethyl ether or dimethoxymethane, or a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms. It is also possible to use a mixture comprising at least two compounds chosen from carbon dioxide, nitrous oxide, dimethyl ether, diethyl ether, dimethoxymethane and a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms.

Furthermore, the product may consist of at least one active principle or of a formulation comprising at least one active principle, of food, pharmaceutical, cosmetic, agrochemical or veterinary interest. The product may also consist of a mixture of active principles and at least one excipient, consisting of at least one lipid, or at least one polymer, conventionally used in the pharmaceutical or cosmetic industries, so that the particles composites thus obtained are stable and directly usable in presentations for therapeutic, cosmetic, veterinary or phytosanitary use. The present invention also relates to the solid particles obtained by the process according to the invention.

Embodiments of the present invention will be described below, by way of non-limiting example, with reference to the appended drawing in which: Figure 1 is a schematic view of an installation for implementing the method 1 according to the invention.

FIG. 2 is a graph representing the X-ray diffraction profiles respectively obtained with a raw celecoxib powder, of particles obtained according to the invention under two different conditions after 24 h of storage, carbon dioxide having been used as solvent. FIG. 3 is a graph representing the X-ray diffraction profiles respectively obtained with a crude celecoxib powder, of particles obtained according to the invention after 21 days and after 24 h of storage, dimethyl ether having been used as solvent. There is shown in Figure 1 an installation for implementing the method according to the invention. In this installation, a stream of compressed fluid from a reserve 1 is sent by a pump 2 through a heat exchanger 3 which will bring it to the desired pressure and temperature and bring it through a pipe 4 to an extraction autoclave 6 in which is placed a basket 8 containing a product to be atomized. A solution is thus produced in the autoclave 6 which is supplied via a line 10 to. a nozzle 12, through which it undergoes decompression within an atomization chamber 14 which is maintained at a pressure much lower than that prevailing in the extraction autoclave 6, which has the effect of causing the precipitation of the product in the form of particles. The atomization chamber 14 has an electrical resistance heating system and is provided with a basket 16 closed at its base by a porous sintered metal disc on which there is a filter 18 consisting of a filter paper disc. The atomization chamber 14 is provided with a spray nozzle 20 which is supplied with nitrogen gas by a distribution line 22, which is optionally preheated in an exchanger 24, via a rolling valve 26.

EXAMPLES OF IMPLEMENTATION

Examples of implementation are presented in order to illustrate the process according to the invention.

To do this, a pilot-size installation was used in accordance with the principle diagram represented in FIG. 1 in which the compressed fluid was carbon dioxide (it would of course also have been possible to use dimethyl ether) with an operating pressure of 30 MPa and a temperature range from 0 to 120 ° C. The extraction autoclave 6 had a total volume of 1 liter and the atomization chamber 14 had a total volume of 4 liters. The unit was equipped with numerous sensors making it possible to measure the pressures, temperatures and mass flow rates of the fluids. The product used was a commercial pharmaceutical active ingredient, commonly called celecoxib, the crystalline or amorphous morphology of which has been described in PCT applications No. WO 01/42221 and WO 01/42222. I) First series of examples - Use of carbon dioxide as solvent:

Example the

In the previously described installation, 10 g of celecoxib were introduced via line 4 into the extraction autoclave 6. A flow rate of 5 kg / h of carbon dioxide at 50 ° C. and 29 MPa percolated this autoclave and then expanded through the nozzle 12 in the atomization chamber 14, which simultaneously was swept by a flow of nitrogen from the distribution line 22 after being preheated to 80 ° C in the exchanger 24 and which has expanded in nozzle 20, the rolling valve 26 having been adjusted so that the nitrogen flow rate is of the order of 10 kg / h, and placed in direct communication with a vent line opening into the atmosphere. It was observed that the equilibrium temperature in the gas flow was 0 ° C. After two hours of stabilized operation under these conditions, the flow of carbon dioxide was stopped and the atomization chamber 14 was opened, from which the basket 16 containing a very fine powder deposited on the filter was removed. 18, and for a small part on the walls of the basket. 0.9 g of particles were thus recovered which were stored at -18 ° C under nitrogen.

Example lb

The procedure was identical to that implemented in the previous example. Thus, the atomization chamber 14 was swept by a flow of nitrogen preheated to 40 ° C. in the exchanger 24 which expanded in the nozzle 20, the rolling valve 26 having been adjusted so that the flow of nitrogen is around 10 kg / h, and has been put into communication direct with a vent line opening into the atmosphere.

It was observed that the equilibrium temperature in the gas flow was -30 ° C. After two hours of stabilized operation under these conditions, the flow of carbon dioxide was stopped and the atomization chamber 14 was opened, from which the basket 16 containing a very fine powder deposited on the filter was removed. 18, and for a small part on the walls of the basket. There was thus recovered 0.95 g of particles which were stored at -18 ° C under nitrogen.

The particles collected in Examples 1a and 1b were observed under a scanning electron microscope. These particles were presented in almost identical fashion, like very porous agglomerates with a diameter of the order of 10 to 20 μm, and consisted of elementary sub-micron particles (average size evaluated approximately at 0.2 μm).

The morphology of the particles obtained in the two previous examples was compared with that of the starting material by X-ray diffraction. FIG. 2 shows the X-ray diffraction profiles obtained with the raw celecoxib powder (upper curve 1), with the sample la (intermediate curve la) and with the sample lb (lower curve lb). To facilitate the comparative reading of these curves, the upper curve and the intermediate curve have been shifted by a value of 3000 strokes and 2000 strokes respectively. It clearly appears that the starting material is crystallized and that the powder obtained by the process according to the invention is completely amorphous when the temperature in the spraying chamber is very low (sample lb) or very partially crystalline when this temperature is close to 0 ° C (sample la)

II) Second series of examples: Use of Dimethyl ether as solvent:

Example 2a

In the same installation, 20 g of celecoxib were introduced into the extraction autoclave 6. A flow rate of 4 kg / h of dimethyl ether at 80 ° C. and 8 MPa percolated this autoclave and expanded through the nozzle 12. The atomization chamber 14 was put into direct communication with a line of vent opening into the atmosphere and its walls were heated to around 60 ° C. After 15 minutes of operation under these conditions, the flow of dimethyl ether was stopped, the autoclave was purged of dimethyl ether by a weak stream of nitrogen via the rolling valve 26 and the nozzle 20, and one opened the autoclave then the basket 16 was recovered. On the filter 18, an agglomerated white solid was collected.

Example 2b In the same installation, operating in a similar manner to that described in Example 2a, 20 g of celecoxib were introduced into the extraction autoclave. A flow rate of 4 kg / h of dimethyl ether at 80 ° C. and 8 MPa percolated this autoclave and expanded through the nozzle 12. The atomization chamber 14 was swept by a flow of nitrogen preheated to 80 ° C in the exchanger 24 and expanded in the nozzle 20, the rolling valve 26 having been adjusted so that the nitrogen flow rate is of the order of 10 kg / h, and was put into direct communication with a vent line opening into the atmosphere. It was observed that the equilibrium temperature in the gas flow was -10 ° C. After 15 minutes of operation stabilized under these conditions, the flow of dimethyl ether was stopped, the autoclave was purged of dimethyl ether while maintaining the stream of nitrogen for about one minute, the autoclave was opened and recovered the basket 16. On the filter 18, 5.2 g of very fine particles were collected which were observed under a scanning electron microscope. These particles appeared as very porous agglomerates with a diameter of the order of 5 to 15 μm, made up of elementary sub-micron particles.

The collected particles were stored under nitrogen at -18 ° C. Their morphology was compared with that of the starting material after storage for 24 h (sample 2a) and after storage for 21 days (sample 2b) by X-ray diffraction.

FIG. 3 shows the X-ray diffraction profiles obtained with the raw celecoxib powder (upper curve 2), with sample 2a (lower curve 2a) and with sample 2b (intermediate curve 2b). To facilitate the comparative reading of these curves, the two upper curves have been shifted by a value of 2000 strokes and 1000 strokes respectively. It is clear that the starting material is crystallized and that the powder obtained by the process according to the invention is completely amorphous, even after 3 weeks of storage. On the contrary, as shown in Example 2a, the spraying does not lead to a usable powder if the method according to the invention is not used.

Claims

1.- Process for obtaining amorphous solid particles of at least one product, with controlled particle size distribution, characterized in that it comprises the steps consisting in: - dissolving the product in a compressed fluid, relaxing this solution through an atomization nozzle (12) within an atomization chamber (14) swept by a stream of inert gas, maintain the atomization chamber (14) at a temperature much lower than the transition temperature glassy product, preferably at least 30 ° C below it, - collect the particles thus formed.

2.- Method according to claim 1, characterized in that one uses, as compressed fluid, carbon dioxide.

3.- Method according to claim 1, characterized in that one uses, as compressed fluid, nitrous oxide.

4.- Method according to claim 1, characterized in that one uses, as compressed fluid, an ether chosen from dimethyl ether, diethyl ether or dimethoxymethane.

5.- Method according to claim 1, characterized in that one uses, as compressed fluid, a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms.

6.- Method according to claim 1, characterized in that a mixture is used as compressed fluid comprising at least two compounds chosen from carbon dioxide, nitrous oxide, dimethyl ether, diethyl ether, dimethoxymethane and a hydrocarbon having between 2 and 10 carbon atoms, preferably between 2 and 5 carbon atoms.

7.- Method according to any one of the preceding claims, characterized in that one uses, as inert gas, nitrogen brought to a temperature between 10 and 150 ° C, and preferably between 20 and 80 ° C.

8.- Method according to any one of the preceding claims, characterized in that a product consisting of at least one active principle or of a formulation comprising at least one active principle, of food or pharmaceutical interest, is used, cosmetic, agrochemical or veterinary.

9.- Method according to any one of the preceding claims, characterized in that one uses a product consisting of a mixture of active principles and at least one excipient, consisting of at least one lipid, or at least one polymer, conventionally used in the pharmaceutical or cosmetic industries, so that the composite particles thus obtained are stable and directly usable in presentations for therapeutic, cosmetic, veterinary or phytosanitary use.

10. - Amorphous solid particles obtained by a process according to any one of claims 1 to 9.