ES2761663T3 - Particle production method - Google Patents

Abstract

A method for producing a batch of particles of a substance in a production arrangement, said particles having predetermined sizes, comprising the steps of: mixing within a spray nozzle (101, 201, 301) and under flow conditions a stream of solution of a solution (102, 202) in which said substance is dissolved or dispersed with a fluid stream of a fluid (103, 203) that is in a subcritical state or more preferably in a supercritical state, the proportion being of said fluid stream and said selected solution stream to promote nucleation and particle formation of said substance in said mixture; providing one or more compensating agents (107, 207), influencing the size characteristics of said particles, to said fluid stream (103, 203); passing said mixture in the form of a spray (204) through a spray outlet (109, 209, 309) of said spray nozzle (101, 201, 301) to a particle collection chamber (105, 205), and separating and collecting within said particle collection chamber (105, 205) said particles of said mixture.

Description

DESCRIPTION

Particle production method

Technical field

The invention relates to a method for the controlled production of a batch of particles of predetermined sizes and / or morphology from a solution comprising a particle-forming substance dissolved or dispersed in a solvent. The method comprises i) mixing the solution with a fluid, which is typically in a subcritical state or, more preferably, in a supercritical state, within a spray nozzle, ii) forcing the mixture out of the nozzle as a jet (spraying) through a nozzle spray outlet, and iii) separating and collecting the formed particles from the mixture. Nucleation and particle formation take place after mixing at the nozzle.

The particles formed are typically intended to be used in compositions for in vivo use, although other uses are also possible.

The terms "controlled" and "control" refer primarily to the repeatable production of batches where the particles are within preset limits with respect to size characteristics, such as mean particle size, distribution of particle size, etc., and interparticle homogeneity with respect to morphology (i.e., the crystalline characteristics of the individual particles, eg, degree of amorphism and / or crystalline properties).

All patent applications and issued patents cited in the specification are incorporated in their entirety as bibliography.

Background of the Art

The generic particle formation technique mentioned above comprises supercritical fluid enhanced dispersion in solution (SEDS technique) which is a technique for which the invention is particularly well suited. Various arrangements, including usable nozzles, are described in US 5,851,453 (WO 9501221), US 6,063,188 and US 2006073087 (WO 9600610), US 6,440,337 (WO 9836825), WO 9944733, US 6,576. .262 (WO 9959710), US 7,150,766 and US 6,860,907 (WO 0103821), WO 0115664, US 2007116650 (WO 05061090), etc.

The SEDS techniques used so far have worked primarily for laboratory scale production. When scaling to the pilot plant scale, there have been increasing problems with obtaining sufficiently small particles (medium size) and / or particles that have a sufficiently narrow size distribution.

The solvents for the particle-forming substance have been aqueous or non-aqueous, depending on the solubility characteristics and the type of substance to be transformed into a particulate state. For aqueous solvents, the problem with size and size distribution has been more pronounced than for non-aqueous solvents due to a stronger tendency for mainly formed particles to aggregate. For biologically active substances, such as most proteins, which require a specific three-dimensional structure for activity, and other biopolymers, aqueous solvents are normally preferred, since nonaqueous solvents and / or organic solvents are often denaturing.

A typical spray tip has contained separate internal lines for solution and fluid. These lines have been fused in an up-mix arrangement or at the spray outlet of the nozzle. In a typical variant, one of the pipes is placed inside the other pipe at least when approaching the spray outlet and / or the mixing arrangement, for example with the cylindrical external pipe and coaxial with the internal pipe and an angle of fusion between the two conduits and between the two currents of essentially 0 °. The nozzle has typically been placed in a chamber (particle collection chamber) in which the formed particles have been separated and have been collected from the solvent and the used fluid. Particle productivity has been low. Scaling up has been difficult mainly due to the fact that the characteristics and / or morphology of the particle size will change with increasing productivity with increasing nozzle parameters such as flow rates, internal duct dimensions, concentration of the particle-forming substance in the solution, etc. The ranges available for average sizes and particle size distributions have been unsatisfactory for many substances, particularly for particles intended for pharmaceutical uses. These problems have been further exacerbated in batches where the desired average particle size is in the part lower of the interval of | jm, for example <10 | jm, such as <5 | jm or <3 jim.

A promising solution to these problems is provided through the spray nozzle presented in WO 2005061090. In this nozzle, the supercritical or subcritical fluid stream is fused with the substance containing solution stream at an angle p that is in the range of 30 ° -150 °. In the most important variants, the flow of one of the streams, for example, the solution stream, at the melting point, is cylindrical with a direction that coincides with the direction of the axis of this cylindrical flow, while the flow of the other current is annular and is directed radially outward with a center positioned on the axis of the cylindrical flow. See Figures 1-3 of WO 2005061090. The nozzle design presented in WO 2005061090 has been shown to facilitate higher productivity and better control of morphology, mean particle size and size distribution. Therefore, it has been possible to reduce the average sizes and prepare batches with narrower size distributions. Despite the promising results obtained with this nozzle, there is still a need for improvements that facilitate even higher productivity and / or control of wider ranges of size and morphology to cover a greater diversity of substances and their different uses.

Organic water-miscible solvents, such as ethanol, have been included as a modifier in the solution containing the particle-forming substance to facilitate the removal of water from the fluid, thereby promoting nucleation and particle formation. See, for example, US 6,063,188 and US 2006073087 (WO 9600610). In other variants, the supercritical fluid has contained the modifier:

• US 7,108,867 and US 2007009604 (WO 2002058674) describe a process in which the particle-forming substance dissolves in water together with an agent exhibiting a solubility with a negative dependence on temperature, and the supercritical fluid contains a liquid that is miscible with both water and supercritical fluid. The procedure is carried out at a temperature above the cloud point of the agent.

• US 6,461,642 (WO 0030613) describes a process in which water is included in the supercritical fluid before mixing it with the solution containing the particle-forming substance.

See also US 5,851,453 (WO 9501221), US 6,063,188 and US 2006073087 (WO 9600610). Supercritical fluids containing a solvent have also been used to modify preformed particles. See US 6,475,524 (WO 0030614).

In WO 9501221 and WO 9600610 it has been suggested to recycle the supercritical fluid and / or to carry out an SEDS procedure in an arrangement comprising several particle collection chambers. It is suggested that the cameras be run in sequence with the collection of one camera while another camera is started, i.e. a type of continuous procedure.

WO 00/30613 discloses a process for preparing particles containing a substance in solvated form, dissolving the substance in a first solvent, introducing the solution and a supercritical or subcritical fluid into an apparatus. The fluid contains an antisolvent and a second solvent, which is water.

WO 03/008082 discloses a method of preparing a target substance in particulate form by introducing into a particulate formation container, via a separate first and second fluid inlet means, a target solution of the substance in a fluid vehicle and a compressed fluid antisolvent. The anti-solvent is allowed to remove the vehicle to form particles of the substance. The anti-solvent and the target solution enter the container in different places.

WO 02/068107 discloses an apparatus for particle formation of a substance using the GAS process. The apparatus comprises a particle formation container and means for introducing a solution of the substance and a supercritical fluid into the particle formation container. The means comprises a nozzle having a central hole serving to transport a flow of solution and a plurality of separate external holes serving to transport a flow of supercritical fluid optionally mixed with a modifier. OBJECTS OF THE INVENTION

The main objectives are to provide improvements with respect to at least one of the problems mentioned above, in particular to solve problems related to productivity and / or control of size and / or morphology.

A subobjective is to produce batches of particles in a controlled manner, each of which features particles with a) an average particle diameter in the range <20 | jm, such as <10 | jm, <5 | jm, <3 | jm or <2 | jm, with a lower limit of 0.1 jim or 0.5 jim , me

b) a particle size distribution with> 80% of the particles within a range of <30 jim, such as <20 jim, <15 jim, <10 jim, <5 jim, <3 jim or <2 Jim. Batches can be conceived in which the width is even smaller, such as <1 jim or <0.5 jim, preferably for batches with average particle sizes of <3 jim, and / or c) a particle size distribution in which at least 80% of the particles are within a size range that has a width of <75%, such as <± 50% or <± 25% of the average particle diameter.

The terms "particle size", "particle size diameter" and "particle size distribution" in this specification refer to values obtained as indicated in the Experimental Part (laser diffraction using the Malvern Mastersizer 2000 Instruments Ltd, Worcestershire, UK). For the meaning of "mean particle size" or "mean particle diameter", see also Experimental Part.

Another subobjective is to allow controlled production of batches of particles, each of which features particles with improved interparticle homogeneity with respect to morphological characteristics, such as crystal type or degree of amorphism and / or crystalline characteristics. In other words, this subobject generally means batch production where> 50%, such as> 60%,> 70%,> 80%,> 90%, or> 95% of the individual particles in a batch have the same balance between crystalline and amorphous characteristics and / or between different crystalline forms.

Another subobjective is to enable controlled production of batches of particles with a productivity of> 0.5 g / h, such as> 1.0 g / h,> 2.0 g / h,> 5.0 g / h or> 10 g / h per chamber used to separate and collect the particles produced or per production arrangement in which there is one or more particle collection chambers. This subobject includes providing a production arrangement in which these intervals are feasible.

Another sub-object is to achieve a combination of two or more of the objects and / or sub-objects indicated above. Preferred combinations involve productivity levels as indicated above.

FIGURES

Figure 1 illustrates a typical variant of a nozzle of the inventive arrangement.

Figure 2 illustrates a preferred nozzle and corresponds to Figures 1-3 of WO 2005061090.

Fig. 3 illustrates another preferred nozzle and corresponds to Fig. 5 of WO 2005061090.

Figures 4a-b illustrate a collection chamber containing two or more spray nozzles. Figure 4a shows the collection chamber from above, while Figure 4b provides a side view.

Figures 5a-b illustrate the presence of two or more particle collection chambers in the same production arrangement. Figure 5a shows the collection chambers from above, while Figure 5b provides a side view of them.

The reference numbers in the figures comprise three digits. The first digit refers to the figure number and the second and third digits to the specific item. The corresponding elements in the different figures generally have the same second and third digits.

THE INVENTION

The present inventors have recognized that, for the method defined above, these objects can be achieved by allowing the subcritical or supercritical fluid entering the mixture (step (i)) to contain an agent that influences the sizes of the particles obtained, that is, a so-called "compensating agent", preferably without causing the separation of the fluid or of the fluid / solution mixture into different phases (a liquid phase and a fluid phase, for example). The compensating agent can be introduced into the fluid stream, that is, upwards with respect to the position of the mixture of the fluid stream with the liquid stream. The typical positions for the introduction are: a) a storage tank for the fluid located upwards with respect to the spray nozzle, or b) a transport duct between said storage tank and the nozzle, which includes several functions that can be part or be connected to (= located along) the conduit, or c) to a transport conduit for the fluid inside the nozzle, that is, between the entrance of this conduit and the mixing position of stage (i ). The effects of adding a compensating agent that does not cause liquid / fluid phase separations, at these positions, on particle sizes and / or morphology are tremendous and unexpected.

The present inventors have also recognized that it is not possible to achieve a sufficient increase in productivity for a profitable large-scale production of particles by a) increasing nozzle dimensions or parameters such as flow rate, concentrations, etc., or b) execution multiple nozzles / chambers in sequence. Instead, it is more feasible to equalize the spray step in the arrangement by running several spray nozzles at least partially in parallel. In other words, by using a production arrangement in which there are (i) two or more spray nozzles placed in the same collection chamber and / or (ii) two or more collection chambers containing one, two or more spray nozzles.

The present inventors have also recognized that the incorporation of a compensating agent in the subcritical or supercritical fluid and / or the parallel execution of the spray nozzles in the same arrangement in combination with the recycling of the fluid used will achieve additional advantages over profitability and controllability of the production process.

A primary aspect of the invention is a method of producing a batch of particles of a substance having predetermined sizes (primarily measured as mean particle diameter and / or particle size distribution) and / or morphology, as described in claim one.

The main characteristic feature of the method includes:

A) the additional stages of:

(iv) carry out a sequence comprising the steps of: a) collecting the solution-fluid mixture after decreasing in said substance during step (iii), b) separating the fluid from the solvent, c) and recirculating (106, 206) the fluid separated in sub-stage (b) to said fluid stream (103, 203), and / or

(v) providing one or more compensating agents (107, 207) to the fluid stream (103, 203), i.e., in an upward position from the mixing position (108), and / or

B) carry out at least steps (i) and (ii) simultaneously on two or more separate spray nozzles (401a, b ..., 501a, b ...) belonging to the same production arrangement in the that there are one, two or more particle collection chambers in spray communication with the spray nozzles with

(a) at least two of the nozzles placed in spray communication with the same particle collection chamber (405), and / or

(b) each of the two or more particle collection chambers (505a, b ...) containing at least one nozzle (501a, b ...) (containing = placed in spray communication with).

The method is typically carried out in the production setup described below. If there are several spray nozzles and particle collection chambers, they are part of the same production arrangement. The meaning of the term "simultaneous" is provided below.

The average size, size distribution and particle morphology in the batches produced are typically within the limits provided under the title "Objects of the Invention".

Steps (i) - (iii) and sub-steps (a) - (c) are carried out in the order given, possibly with one or more additional steps inserted between steps (i) and (ii), between steps (ii) and (iii), between sub-stages (a) and (b), and / or between sub-stages (b) and c).

The pressure drop across the nozzle (101, 201, 301), the type of solvent in the solution, the type of fluid, the relationship between the volumetric flow rates of the solution and the fluid currents in the mixture, the concentration (s) and type of compensating agent (s) in the fluid in the mixture, etc., are selected to be effective in promoting nucleation and particle formation by providing particles of the predetermined sizes and / or morphology at the spray outlet (109, 209, 309). Preferably, neither mixing of the compensating agent with the fluid stream or fluid stream with the solution stream will cause phase separation into liquid / fluid phases, i.e. a single-phase system is preferred (except for the desired particles formed in the process).

Another unclaimed embodiment is a production arrangement (100) to be used in the method. It is illustrated in the drawings and includes at least:

a) a spray nozzle (101, 201, 301) having an internal transport line (210 or 212, 310 or 312) with an inlet (111, 113, 211, 213) for the fluid, an internal transport line (210 or 212, 310, or 312) with an inlet (111, 113, 211, 213) for the solution, and a supply arrangement mixing (114, 214, 314) to mix the fluid and the solution with each other downstream from the internal transport lines (210, 212, 310, 312), and a spray outlet (109, 209, 309),

b) a chamber (105) containing the spray outlet (109) and a separation function (115) to separate and collect the particles produced from the fluid / solution mixture (= particle collection chamber), and c) a transport line (116, 216) external to the nozzle to transfer fluid (103, 203) to the fluid inlet (111, 113, 211, 213) of the nozzle (101, 201).

The term "containing" in part (b) means that the spray is directed to the particle collection chamber (105), that is, it is in spray communication with the chamber.

The main characteristic feature of the arrangement is that it comprises

a) one or more inlet conduits for introducing a compensating agent (107, 207) and / or previously used fluid (106, 206) into the method (method) at a position in the fluid stream (103, 203) of upstream of the mixing arrangement (114, 214), for example, through the inlet / conduits (117/139, 217/239 and 118/119, 218/219, respectively) in the fluid stream (103 , 203) of the process, that is, and / or b) two or more spray nozzles (401a, b ..., 501a, b ...) with at least two of them in spray communication with

i) the same collection chamber (405) and / or

ii) different collection chambers (505a, b ...) each of which contains at least one, two or more spray nozzles, and / or

c) a recycle function (118 119 120, 218 219) for recycling fluid (106, 206) used in the process into the fluid stream (103, 203) through at least one inlet (118, 218) , that is, in an upward position with respect to the mixing arrangement (114, 214).

As illustrated in the drawings, arrangement (100) also comprises a transport line (121, 221) for transferring the solution to the nozzle (101, 201) in addition to the fluid transport line (116, 216) already mentioned. One or both of the nozzle's external transport lines can be connected at its rising end to a storage tank for the fluid or solution (122 and 123, respectively). They are also normally equipped with appropriate functions for temperature control (including, for example, heating elements (141) and / or pressure and flow control (124a, b, c)) (including, for example, valves, pumps, etc.) to withstand the temperature, flow rates and / or pressures required in the collection chamber (105) and in the upward fluid stream (103, 203) of this chamber (105), for example, supporting a subcritical or supercritical state of the fluid and / or the fluid / solution mixture and / or the predetermined average size, size distribution and / or morphology of the particles to be produced A storage tank, for example for the fluid (122), can be in the form of a pressurized tube or can be connected to said tube.

Downstream from the particle collection chamber (105) there is preferably a function (120) to separate the fluid from the solution / fluid mixture, i.e. to give solvent exhausted fluids. If present, this function (120) is generally in the form of a cyclone. The downstream (outlet) end of the collection chamber (105) and the upstream end of the fluid separation function (120) are connected to each other through a transport line (125) that normally contains a back pressure regulator ( 126) to allow changes in flow rate through the spray outlet (109). The fluid separation function (120) typically contains an outlet conduit (127) with a valve (128) to allow the outlet of the solvent released from (= decreased in) fluid and an outlet (129) for the fluid released from ( = decreased in) solvent. In this position, the solvent is in the liquid state and the fluid in the gaseous state. In variants adapted for return-to-process fluid recirculation, the fluid outlet line (119, 219) of the fluid separation function (120) is typically connected through an inlet line (118, 218) to the fluid stream (103, 203), that is, in an up position of the mixing arrangement (114, 214) as discussed elsewhere in this specification. Spray nozzle

As already mentioned, the spray nozzle comprises an outlet (109, 209, 309) into which a spray (jet), an arrangement for mixing (214, 314) the solution with the fluid, and internal transport lines can be formed. (210, 212, 310, 312) for the fluid and the solution. In preferred variants, the nozzle also comprises a mixing microcavity (214 ') as part of the mixing arrangement (214) and / or an outlet transport line (230) guiding the mixture from the mixing arrangement (214) to the spray outlet (109). If both an outlet conduit 230 and a mixing cavity 214 'are present, they may partially or fully coincide. In preferred variants, one of the aforementioned transport lines (210, 212, 310, 312) is inside the other, preferably because it is coaxial with each other, as described above for the spray nozzles previously known and used in the field. .

Mixing in the mixing arrangement (214, 314) is promoted by creating turbulence when the fluid stream and solution stream merge. For this purpose, the mixing arrangement may contain some kind of obstacle to direct flow in or upwards from the position where the solution stream and the fluid stream merge, for example by designing the conduits in question (for example, such as a mixing cavity) with mechanical means of altering the flow, such as with an abrupt twist or bend (typically> 30 °) and / or an abrupt change in cross-sectional dimension (widening or narrowing). Suitable mixing arrangements comprise that the solution stream (202, 302) and the fluid stream (203, 303) fuse at an angle p selected from the range of 0 ° -180 °, typically with a mixing cavity descending from the melting point. Preferred melting angles p are selected from the range of 30 ° -150 °, such as 85 ° -105 °, with 90 ° being the most preferred value. In most cases, this also means that the internal nozzle transport lines (210, 212, 310, 312) for the solution and the fluid, respectively, fuse at an angle p 'which is also selected from these intervals with the same preferences.

The internal transport conduits of the preferred nozzles are coaxial and are illustrated in Figures 2 and 3 with absolute preference for the type described in Figure 2. These nozzles have a descending part (231, 331) and an ascending part (232, 332). The descending part hinders the direct flow through the descending end of at least one of the nozzle's internal transport ducts (210, 212, 310, 312), thus transforming the direction of flow of the current passing through it. end in a disk-shaped annular flow comprising an outwardly directed radial component passing through a slot (233, 333) defined between the descending portion (231, 331) and the ascending portion (232, 332). Thereafter, this disk-shaped flow is fused with the flow of the other internal transport line at a melting angle p which is in the range indicated above with the same preferences. The combined flow leaves the nozzle as an annular spray that is preferably directed radially outward, possibly comprising an axial component. If no axial component is available, the spray direction will define an angle of 90 ° with the axial direction of the coaxial internal transport lines (= of the nozzle). If an axial component is present, the angle will deviate from 90 °. Each internal transport pipe (210, 212) ends when fused with the other (in the mixing arrangement), i.e., a nozzle internal transport pipe for which flow has been impeded by the downstream part (231, 331) also comprises a part (234 235, 334 335) of the slot (233, 333).

Therefore, the variant of figure 2 comprises a descending part (231) and an ascending part (232) (= the lower part and the upper part in the drawing). In the ascending part (232) there is an internal transport pipe (212) and an external cylindrical transport pipe (210) coaxial with the internal transport pipe (212). The slot (233) defined between the descending and ascending parts (231, 232) encompasses in the descending direction a disk-shaped annular conduit (234 235) plus an annular mixing / mixing cavity arrangement (214/214 ') plus an annular outlet duct (230) for the mixture obtained plus an annular spray outlet (209). The direct flow in the outer cylindrical conveying conduit (210) is hindered by the downstream part (231) and is transformed into a radially outwardly disk-shaped annular flow in the disk-shaped conduit (234, 235). The downstream part (231) is also designed to hinder the direct flow of the current in an internal transport conduit (212), but the hindering is carried out within the downstream part (231) by transforming the internal current into a cylindrical current of opposite flow direction with a diameter that is greater than the diameter of the cylindrical flow of the original external current. This last flow transformation is achieved by designing the downstream part (231) with a forward extension (236) of the internal transport duct (212) followed by a disk-shaped duct (237) and a cylindrical duct connected (238) to the same as entering a direction that is opposite to the direction of the front extension (236) so that it can merge with part (234) of the disc-shaped duct (234 235) upwardly of the external transport duct (210) in the rising end of the mixing arrangement (214). The melting angle p 'is 90 ° in this figure 2. Other melting angles can be achieved by

a) design the surface of the descending part (231) at the point of fusion with an angle <or> 90 ° in relation to the axis of the cylindrical duct (238), or

b) making the cylindrical duct (238) conical.

If different 90 ° melting angles are created in this way, then it is appropriate to also design the mating surface of the rising part with a coincident curvature.

Figure 3 provides a variant with a downward hindering portion 331 that does not contain parts of the internal fluid and solution transport passages. The ascending part (332) comprises the coaxial cylindrical transport lines (310, 312), one for the solution and the other for the fluid. The descending part (331) hinders the direct flow in both conduits in the same position. The groove (333) between the two parts provides for the transformation of a cylindrical stream into a disk-shaped stream with a radially outward directed flow in the disk-shaped conduit (334 335), mixing with the outer cylindrical stream in the annular mixing arrangement (314), and conveying the mixture in the annular outlet transport line (330) to an annular spray outlet (309). The melting angles p and p 'are 90 °. Other melting angles can be achieved by making the surface of the descending part at the melting point conical and by designing the mating surface of the ascending part with a coincident curvature.

For nozzle variants in which the internal transport lines (210, 212, 310, 312) are coaxial, it is preferred to use an internal transport line (212, 312) for the solution stream (202, 302) and a external transport line (210, 310) for the fluid stream (203, 303) as indicated in the drawings.

In even other variants of spray nozzles that contain both internal and external type internal transport lines, there is no downward part to hinder the direct flow of the streams. These types of nozzles are believed to be less preferred and are illustrated in Figures 3 and 4 of US 5,851,453 (WO 9501221). The mixing arrangement of the nozzles illustrated in these figures begins at the outlet of the inner duct (31) and extends to the outlet of the outer duct (41) which is also the outlet of the spray nozzle. The mixing cavity is defined between the exits of the internal and external ducts. The melting angle between the transport conduits for the solution and the fluid, respectively, will be approximately 0 °. Reference numbers are the same as those indicated in WO 9501221 (US 5,851,453). See also WO 9600610 (US 6,063,188 and US 2006073087).

In other nozzle variants, the fluid / solution mixture is mixed with other streams, for example, containing a subcritical or supercritical fluid or a liquid / solvent, before exiting through the spray outlet / into the collection chamber of particles. See, for example, US 6,440,337 (WO 9836825).

The spray direction of the aforementioned spray nozzles in which one of the transport lines is placed inside the other can be purely axial and / or purely radial relative to these transport lines.

Adjusting the flow rate through the nozzle is accomplished by adjusting the pressure difference across the nozzle (201, 301), for example, by adjusting the back pressure regulator (126) downward from the chamber. for collecting particles (105) and / or changing the outlet of the pressure regulation means (pumps, valves, etc.) (124a, b) upwards with respect to the nozzle. In variants that feature adjustable flow obstacles, these can be used to fine-tune the flow rate through the spray outlet (209, 309). For example, in the type of nozzles illustrated in Figures 2 and 3 and also in US 2007116650 ^{(W or} 05061090), the width of the groove (233, 333) formed between the descending part (231, 331) and the rising part (232, 332) is typically adjustable by arranging such that one or both of the two parts are axially movable relative to one another. As the width of the slot changes, the speed of the volumetric flow through the slot (233, 333) will change. Fine adjustment of the flow rate across the width is obtained if the two parts (231, 232, 331, 332) are pressed together by a chain, gas damper or other elastic and / or compressible means attached to a adjustable compression force. See also US 2007116650 (WO 05061090).

The suitable dimensions of the ducts and the nozzle openings indicated above can be found in the aforementioned patents and patent applications.

During the method of the invention, and when the fluid is in the supercritical state, the pressure within the immediately rising and falling nozzle arrangement is typically above the critical pressure (Pc) and critical temperature (Tc) of the fluid. used. For pressure, this generally means a pressure in the range (1.0-7.0) x Pc or in the range> 10 bar, suitably> 20 bar, preferably by> 30 bar, greater than the Pc with upper limits illustrative of 100 bar, 200 bar and 300 bar higher than the PC. The expression "above Tc" (in ° C) generally means within (1.0-4.0) x Tc or within the range of> 5 ° C, suitably> 10 ° C, with preference for> 15 ° C above Tc with illustrative upper limits of 10 ° C, 40 ° C and 50 ° C above Tc.

For fluids in the subcritical state, the pressure is typically within the ranges indicated above and the temperature is below the critical temperature, such as in the range (0.9-1.0) x Tc. This it applies in particular to fluids that are gases at atmospheric pressures and ambient temperature (20-30 ° C). For other fluids, the pressure and temperature used in the invention may be lower and cover temperatures up to room temperature and even lower and pressures p to atmospheric pressure, for example, the range 1 bar <p <20 bar or 1.25 bar <p <10 bar.

Adequate pressure drops across the nozzle (201, 301) are typically in the range of 10 60 bar, such as> 10 bar but <50 bar, such as <40 bar or <30 bar. The flow rate through the spray outlet (209, 309) should be selected from the range of 50 to 200 ml / min, with in many cases preferred values of at least 75 ml / min. At the rising end of the mixing arrangement (114, 214, 314), the volumetric flow rate of the solution stream (102, 202, 302) containing the particle-forming substance is typically selected to be less, as <90%, <80% or <70%, that the flow rate provided by the saturation of the solvent in the solution in the supercritical fluid at the prevailing pressure and temperature, i.e. solvent phase separations should be avoided / fluid. In typical variants, suitable volumetric flow rates of the solution stream (102, 202, 302) can be found at the rising end of the mixing arrangement (114, 214, 314) in the range of 0.01-20% , such as> 0.1%,> 0.5%,> 1% and / or <15%, <or <10% or <5%, of the flow rate of the fluid stream (103, 203, 303 ). The volumetric flow rate of the compensation agent stream (107, 207) in its mixture with the fluid stream in the inlet duct (117, 217) is typically selected from the same relative percentage range as the rate of flow. flow of the solution containing the particle-forming substance, typically without causing phase separations when the streams are mixed. If the compensating agent is present in the recycled fluid (106, 206), suitable compensating agent flow rates can be found as such relative to the velocity of the fluid stream in the inlet conduit (118, 218) in the lower part of the 0.01-20% range, for example <5%, <3% or <1, depending on how effective the fluid separation function is (120) or if more compensation, vehicles, etc. descending from the separation function (120).

The particle collection chamber

In the inventive arrangement there is at least one particle collection chamber (105, 405, 505). A particle collection chamber can contain at least one spray nozzle (101, 401a, b ..., 501a, b ...).

In Figure 1, a variant of the particle collection chamber with which a nozzle is associated is illustrated. This variant was previously discussed. See also below.

Figures 4a-b shows a collection chamber (405) carrying two or more nozzles (401a, b ...) with spray outlets (409a, b ...). The transport conduits for the fluid (416a, b ...), for the solution (421a, b ...) and for the compensation agent (439a, b ...) are connected, in an upward direction, to a storage tank for fluid, solution, and buffer, respectively. On the downstream side of the chamber there is an outlet duct (425) with a back pressure regulator (426). Outlet line (425) can transport, downstream from the back pressure regulator, the solvent / fluid mixture to the waste or to a separation function in which the fluid is separated from the solvent and possibly recycled to return to the fluid stream.

The spray outlets (409a, b ...) of the nozzles (401 a, b ...) in the same chamber (405) are typically positioned at the same level, symmetrically around a central axis of the chamber, and in an upper part of the chamber with the axis of the cylindrical ducts and / or the coaxial ducts typically vertically directed, preferably in a downward flow direction. The number of nozzles in a chamber is typically one, two, three, four, five or more, with an upper limit typically of 10 or 20. The maximum number of nozzles optimally placed in a chamber is determined by the diameter of the camera perpendicular to the central axis of the camera. For a chamber having a transverse diameter of 20 cm, the optimum maximum number of nozzles in US 2007116650 (WO 05061090) is seven. These seven nozzles should be placed with one nozzle on the central axis of the camera and the other six nozzles symmetrically around this axis. This is analogous to the preferred positioning for a camera featuring three nozzles. See figure 4.

The arrangements illustrated in Figures 5a-b contain two or more collection chambers (505a, b ...) with at least one, two or more nozzles per collection chamber. The external transport lines of the nozzle for the fluid (516a, b ...), for the solution (521a, b ...) and for the compensation agent (539a, b ...) are connected in an upward direction to a storage tank for the fluid, solution, and / or clearing agent, respectively (not shown). The storage tank for the same type of liquid, fluid and agent can be common for the collection nozzles / chambers. On the downstream side of the chamber there is an outlet duct (525a, b ...) with a back pressure regulator (526a, b ...). The outlet ducts (525a, b ...) can be fused before or after the back pressure regulator into a common duct (542) that transports the solvent / fluid mixture to waste or to a separation function in which the fluid is separated of the solvent and recycles to return to the disposal fluid stream.

The transport of fluid or solution to several spray nozzles from a common storage tank can be done through a separate conduit for each nozzle, without branching, or through a common starting conduit that is divided, in one or more positions, into one, two or more branch lines (primary branch lines) each of which connects to one or more spray nozzles. If a primary branch duct connects to two or more spray nozzles, the primary branch duct additionally branches into secondary branch ducts, etc. It may be appropriate to include an adequate flow and / or pressure control function for the equitable transport of solution and fluid to each branch line destined for a spray nozzle, in order to facilitate an acceptable low variability between nozzles, with respect to particle sizes and morphology, in order to achieve preset (= default) values for mean size, size distribution, and morphology. This type of function must regulate and control the downstream back pressure regulator (s) with respect to the collection chambers and / or the pumps, and / or the valves upwards with respect to the nozzle and / or the force that presses the ascending parts and descending (231, 331, 232, 332) together.

As seen in Figures 4-5, a particle collection chamber preferably has a circular cross section, at least at the level of the spray nozzles.

The number of particle collection chambers in an arrangement is typically one, but can also be two, three, four, five, or more, with typical upper limits of 10 or 20.

At the rising end of a chamber (105), there is typically an outlet for the selective output of the decreased fluid / solution mixture relative to the particulate-forming substance, i.e. devoid of the particles produced in the chamber. To accomplish this, a function (115) for separating the mixture from the formed particles, such as a filter, is typically included at the downstream end of the particle collection chamber (105). This outlet is typically placed at a level below the spray outlet (s) of the nozzles.

In the event that the production arrangement comprises two or more chambers and / or two or more nozzles as discussed above, these chambers and / or nozzles can operate in sequence to produce a large batch of particles having a size and morphological characteristics Default. In other words, the particles produced in one chamber can be collected while starting another chamber. See, for example, US 5,851,453 (WO 9501221), US 6,063,188 and US 2006073087 (WO 9600610). Alternatively or in order to further increase productivity relative to a particular batch, multiple nozzles and / or chambers that are present in the same production arrangement can operate simultaneously. The term "simultaneously" in the context of a production arrangement comprising two or more chambers / nozzles includes that the periods of time during which a chamber / nozzle is used overlap, at least partially, with the periods of time in which it is used by one, two or more of the other chambers / nozzles in the arrangement. The overlap can be anything from 100% to above 0%, such as> 1%,> 5%,> 10%,> 25%, or> 50%, etc. Exact overlap depends on practical considerations, but the highest productivity for a production layout should be possible for 100% overlap. The cameras and nozzles used in both sequential and simultaneous modes must be essentially the same.

The clearing agent

A compensating agent is an agent that when present in the fluid, which is in a subcritical or supercritical state in the mixture, influences the mean size, size distribution and / or morphology of the particles. A typical type of compensating agent promotes nucleation and / or particle formation of the particle-forming substance in the solution and / or in the fluid / solution mixture, for example, it is an antisolvent for the particle-forming substance. This type of agent typically also acts as a precipitating agent.

Another type of typical compensating agents promotes the solubilization of the particle-forming substance, for example, it is a solvent for the particle-forming substance.

Typical compensating agents can be selected from liquids that are capable of affecting the particle-forming substance as indicated in the preceding paragraphs. They should preferably be partially miscible with or soluble in the supercritical or subcritical fluid and / or the solvent in the solution. In other words, the preferred compensating agents do not cause phase separations other than the formation of the desired particles. Candidates are provided under the heading "The Solution and the Fluid". In particular, it is worth mentioning liquids that form azeotropes with one or more components of the solvent in the solution, liquids that can dehydrate or hydrate the particles formed, etc.

The clearing agent can, in principle, enter the arrangement at any position in the stream of fluid, that is, in any upward position with respect to the mixing arrangement (114). Therefore, the introduction can be through a separate inlet duct (217) connected to

A) the internal transport pipe (210) for the fluid (inside the nozzle (201)), and / or

B) the external transport line (116,216) that guides the fluid to the nozzle (101,201), for example, in a heating function (141), and / or

C) the provision in an upward position of the external transport duct (116), for example, to a storage tank (122) for the fluid attached directly or indirectly to the upstream end of the external transport duct (116) for the fluid, to a heating position (141) placed along the external transport duct (116).

A clearing agent can be added to the system alone or in combination with one or more components. These other components may encompass other compensating agents, a vehicle that is preferably fluid miscible and / or is a solvent for the compensating agent in question, etc. This includes that the fluid can also be used as a vehicle for the clearing agent. The composition used for the introduction of a compensating agent may or may not be in a subcritical or supercritical state. The conduit (139, 239) through which a compensating agent is added to the fluid stream (103) is equipped with the appropriate valve function, pumps, and other functions (140, 240) to control the flow rate in relation to fluid flow (103).

The preferred position in which the compensating agent is added is within the external transport line (116, 216) that transfers fluid to the nozzle.

The addition of a compensating agent can be in one, two or more positions in the fluid stream. The same or different agents can be introduced in different positions.

A way to add a compensating agent can be achieved if the fluid after step (iii) is separated from the solvent / solution and recycled to one of the positions where the compensating agent is introduced into the system / arrangement. In many cases, the fluid recycled in this way will contain residual amounts of the solvent in which the substance was initially dissolved or dispersed. These residual amounts will typically influence the particle size and / or morphology of the particles formed, thus acting as a compensating agent. It is also possible to add a separate clearing agent to the recycled fluid during its transport back to the main fluid stream, i.e. add this type of agent to the recycle line (119).

The proportion of compensating agent incorporated into the fluid stream is discussed elsewhere in this specification.

Fluid Stream and Solution Stream

Illustrative supercritical fluids are gaseous at room temperature and atmospheric pressure. They are generally selected as being capable of acting as atomizing and anti-solvent agents against the particulate-forming substance dissolved in the solution. The particular compounds / elements that can be selected are: carbon dioxide (Pc = 74 bar and Tc = 31 ° C), nitrous oxide (Pc = 72 bar and Tc = 36 ° C), sulfur hexafluoride (Pc = 37 bar and Tc = 45 ° C), ethane (Pc = 48 bar and Tc = 32 ° C), ethylene (Pc = 51 bar and Tc = 10 ° C), xenon (Pc = 58 bar and Tc = 16 ° C), trifluoromethane (Pc = 47 bar and Tc = 26 ° C) and chlorotrifluoromethane (Pc = 39 bar and Tc = 29 ° C) and the mixtures. Pc means critical pressure and Tc critical temperature.

Illustrative subcritical fluids are liquids at room temperature and atmospheric pressure. In the same way as for supercritical fluids, they are typically selected for their ability to act as atomizing and anti-solvent agents against the particulate-forming substance dissolved in the solution. Suitable fluids of this type can be found in the same group of liquids as provided in the following paragraph, provided that they are selected according to the ability to act as atomizing and anti-solvent agents relative to the particle-forming substance.

Illustrative solvents are typically in the liquid state but are volatile at room temperature and atmospheric pressure. They are also generally capable of maintaining the particulate-forming substance in dissolved form at the process temperature of the solution stream, i.e. the concentration of the dissolved substance must be below the saturation concentration of the substance , typically <80% of the saturation concentration at the applied pressures and temperatures upward from the mix arrangement. Suitable concentrations of the particle-forming substance in the solutions are typically in the range <20%, such as <10%, <5% or <3% with limits below <005% or 0.1% (all in w / v -%). The term "Volatile" for solvents in the context of the invention typically means boiling points of <150 ° C, such as <110 ° C or <100 ° C, at atmospheric pressure. Examples are inorganic solvents, including water, as well as non-aqueous inorganic solvents, and organic solvents including symmetric and asymmetric C ^1-5 dialkyl ketones, such as acetone, butanone, pentanones, etc., symmetric and asymmetric C ^1-5 dialkyl ethers. , such as diethyl ether, methylpropylether, methylbutyl ether, methylpentyl ether, ethylpropyl ether, etc., C ^1-5 alkanols including fluorinated forms and various primary, secondary and tertiary forms thereof, such as methanol, ethanol, isopropanol, n-propanol, butanols and pentanols different, etc., alkyl esters of C ^1-5 carboxylic acids ^C1-5, such as ethyl acetate, dimethylsulfoxide, dimethylformamide, acrylonitrile, etc. A potential useful fluorinated alkanol is trifluoroethanol. The term solvent includes liquid mixtures.

Particle-forming substance

The term "substance" will be interpreted in the context of the invention in general terms, including individual compounds, as well as mixtures of compounds, even if the typical substance to be transformed represents a single compound or a mixture of compounds that have chemical and physical characteristics Similar. Many of the substances that will be transformed into particles in the method are biologically active or function as a vehicle, an additive, an excipient, etc. in compositions in which the particles must be incorporated after production according to the invention. The most important substances must be used pharmacologically, which means that the term "biologically active" also means "therapeutically active". In the solution to be used in the invention, the substances can be soluble in water or insoluble in water, in the desired concentration. These can exhibit a polypeptide structure and / or a non-polypeptide structure, such as a nucleotide structure, a carbohydrate structure, a lipid structure, a steroid structure, being a hormone, a sedative, an anti-inflammatory substance, etc.

A pharmaceutical formulation of the disclosure comprises a therapeutically active component (drug) that has been incorporated into the formulation together with vehicles / vehicles, additives, etc. pharmaceutically acceptable and optional. At least one of the components of the formulation, typically a therapeutically active ingredient, such as the drug, or a vehicle or an additive, has been used in the form of particles manufactured according to the method presented herein. Typical formulations are tablets, capsules, pills, granules, dispersions, aerosols, ointments, solutions, etc.

EXPERIMENTAL PART

Example 1: A 2% w / v budesonide solution in acetone was introduced into the nozzle of figure 2 placed in the arrangement of figure 1 (except for recyclability) using a separate high performance liquid chromatography pump 1.4 ml / min, along with the 125 g / min of scCO ² (approximately 150 ml / min) that was modified with the 4.2 ml / min acetone of the compensating agent. The pressure in the system was 100 atm and the temperature was 60 ° C. All streams come into contact within the nozzle and budesonide powder forms and collects in the particle collection chamber. The scCO ² and acetone were drained through the outlet of the back pressure regulator. Then, an additional washing procedure was carried out to remove the mixed solvent in the scCO ² . After the washing procedure, CO ² was slowly drained from the chamber. Once the CO ² was completely removed, the particles were collected on the filter and on the wall for analysis. The particles were characterized by laser diffraction on a Mastersizer 2000 (Malvern Instruments Ltd, Worcestershire, UK) Example 2: Another experiment was carried out with the apparatus used in Example 1. The procedure parameters were set to the same values as in Example 1, except for the flow rate of the compensating agent which was now 2.1 ml / min.

Example 3: Another experiment was carried out with the apparatus used in Example 1, to control reproducibility. The procedure parameters were set to the same values as in Example 1. Example 4: Another experiment was carried out with the apparatus used in Example 1. The procedure parameters were set to the same values as in Example 1, except for the flow rate of the compensating agent which was now 1.4 ml / h.

Example 5: Another experiment was carried out with the apparatus used in Example 1. The used nozzle was exchanged for a newly manufactured nozzle of the same type. The procedure parameters were set to the same values as in Example 1.

Results of Examples 1-5

Claims (13)

1. A method of producing a batch of particles of a substance in a production arrangement, said particles having predetermined sizes, comprising the steps of: mixing inside a spray nozzle (101, 201, 301) and under flow conditions a solution stream of a solution (102, 202) in which said substance dissolves or disperses with a fluid stream of a fluid ( 103, 203) which is in a subcritical state or more preferably in a supercritical state, the ratio of said fluid stream and said solution stream being selected to promote nucleation and particle formation of said substance in said mixture; providing one or more compensating agents (107, 207), which influence the size characteristics of said particles, to said fluid stream (103, 203); passing said mixture in the form of a spray (204) through a spray outlet (109, 209, 309) of said spray nozzle (101, 201, 301) to a particle collection chamber (105, 205), and separating and collecting within said particle collection chamber (105, 205) said particles from said mixture. The method according to claim 1, characterized in that the ratio of said fluid stream and said solution stream in the mixture and the ratio and type of said compensating agents are selected to maintain a single fluid phase after said mixing. 3. The method of any of claims 1-2, characterized by: carry out a sequence that includes the sub-stages of: a) collecting said mixture after it has been exhausted in said substance during said separation and collection step, b) separating said fluid from the solvent of said solution in a separation function (120), and c) recirculating (106, 206) said separated fluid in step (b) to said fluid stream (103). The method according to claim 3, characterized in that said recirculated fluid contains at least one of said compensating agents. 5. The method of any of claims 1-4, characterized in that said mixing and passage steps are carried out in two or more separate and essentially identical spray nozzles (401a, b ...) belonging to said production arrangement with a) at least two of said spray nozzles being placed in spray communication with the same particle collection chamber (405), and / or b) two or more particle collection chambers (505a, b ...), each of said particle collection chambers (505a, b ...) containing at least one spray nozzle (501a, b ... ) and optionally executing particle formation in said two or more spray nozzles simultaneously. 6. The method of any of claims 1-5, characterized in that the predetermined mean diameter of said particles from said batch is selected to be <20 pm or <10 pm and / or the size distribution of said particles in said batch it is that> 80% of said particles present sizes with an interval with the width of <20 pm. The method of any of claims 1-6, characterized in that a volumetric flow rate of at least one of said one or more compensating agents in its mixture with said fluid stream gives a concentration in said fluid stream that is not it is saturated and is selected within the range of 0.01-20% of a volumetric flow rate of said fluid stream. The method of any of claims 1-7, characterized in that at least one of said one or more compensating agents is a liquid at atmospheric pressure and ambient temperature (25 ° C). 9. The method of any of claims 1-8, characterized in that at least one of said one or more compensating agents promotes nucleation and particle formation of said substance in said mixture, for example, is an antisolvent for said substance . The method of any of claims 1-9, characterized in that at least one of said one or more compensating agents promotes the solubilization of said substance, for example, is a solvent for said substance. 11. The method of any of claims 1-10, characterized in that said mixture is started by fusing said fluid stream and said solution stream at an angle selected from the range of 30 ° -150 ° with preference for 90 °. 12. The method of any of claims 1-11, characterized in that A) said spray nozzle (201, 301) comprises a) two internal transport conduits for said solution and said fluid, respectively (202, 203, 203, 303), whose internal conduits are coaxial at least in their ascending parts and, at their descending ends (238, 234), fuse each other in b) a mixing arrangement (214, 314) followed by and / or matching c) said spray outlet (209, 309), and a1) the descending part (238, 342) of one of said two internal transport lines (210, 212, 310, 312) is cylindrical and provides a cylindrical flow in the fusion position with the other internal transport line, and the descending part (234, 334) of the other of said two internal transport ducts has a disk shape and provides an annular flow that is directed radially outwards from a center that coincides with the axis of said cylindrical flow, selecting the melting angle between the two internal transport lines between the range of 30 ° -150 °, b1) said mixing arrangement (214, 314) is annular and comprises an ascending annular end in the fusion of said two internal transport conduits (210, 212, 310, 312) and a descending annular end, and c1) said spray outlet (209) is annular and communicates in the upward direction with said descending annular end of said mixing arrangement, and B) performing said mixing step in said mixing arrangement and said passing step in said spraying outlet, said solution stream entering said mixing arrangement through the interior (212, 312) of said two internal transport lines and said fluid stream through the exterior (210, 310) of said two internal transport lines. 13. The method according to any of claims 1-12, characterized in that said particles obtained in said separation and harvesting steps are incorporated as an ingredient in a pharmaceutical formulation containing a therapeutically active substance possibly combined with a vehicle or an additive.