WO2020121006A2

WO2020121006A2 - Method and apparatus to produce nanoparticles in an ostwald ripening flow device with tubes of variable path length

Info

Publication number: WO2020121006A2
Application number: PCT/HU2019/050046
Authority: WO
Inventors: Ferenc Darvas; Enikő MANEK; Hunor MAKKAI
Original assignee: Innostudio Inc.
Priority date: 2018-10-19
Filing date: 2019-10-21
Publication date: 2020-06-18
Also published as: WO2020121006A3

Abstract

The present invention relates to a method and apparatus for producing nanoparticles in an Ostwald ripening flow device comprising tubes of variable path length. The method comprising subjecting the nanoparticles to Ostwald ripening, the Ostwald ripening being performed in a channel system comprising tubes of continuously variable path length, wherein for optimal Ostwald ripening the path length of the tubes being varied by slid- ing a lower tube member and an upper tube member relative to each other to a desired extent, said lower tube member comprising channels extending parallel with one another, said upper tube member comprising a sealing toothing that blocks each channel at one end thereof and arranged displaceably on the lower tube member to form the device with the channel system comprising said tubes. The apparatus comprises a channel system defining a flow path with an inlet and an outlet for Ostwald ripening of nanoparticles, wherein the flow path of the channel system is formed by a combination of a lower tube member (100) comprising channels extending parallel with one another and an upper tube member (200) comprising a sealing toothing (230) that blocks each channel at one end thereof and displaceably connected to the lower tube member. Furthermore, said lower tube member and said upper tube member are slidable relative to each other to a desired extent to enable continuous variability of the length of each tube formed by the channels of said channel system.

Description

METHOD AND APPARATUS TO PRODUCE NANOPARTICLES IN AN OSTWALD RIPENING FLOW

DEVICE WITH TUBES OF VARIABLE PATH LENGTH

The present invention relates to the flow synthesis of nanoparticles. More particularly, the present invention relates to a method and apparatus for producing nanoparticles in an Ostwald ripening flow device comprising tubes of variable path length.

Background Art

1.1. Nanoparticles containing active ingredients.

Active ingredients (AIs) generally have low water-solubility, which leads to a limited biological availability and formulation difficulties in the pharmaceutical, agricultural, food, cosmetics and other industries. Conventional technologies increase the solubility of active ingredients by various micronization methods, which usually result in a particle sizes ranging from 2 pm to 355 pm. In most cases, however, micronization of AIs does not have a signifi cant solubility enhancing effect. This problem may be overcome by further reducing the parti cle size into the nanosize range (< 1pm). Nanoparticles are considered to be a transition be tween bulk materials and molecular structures. As the surface area to volume ratio significant ly increases by reducing the particle size - contrary to bulk materials - nanoparticles show size-dependent properties. The extra specific surface may contribute to increased solubility, enhanced bioavailability and higher reactivity of nanoformulae (Figure 1).

The above-referred reasons raise the need for rapid, controllable and reproducible methods for synthetizing nanoparticles with special structures and narrow particle size distri bution. The special structure may imply nanoparticles comprising a single component (mo- nostructured nanoparticles), or two or more components (composite nanoparticles).

1.2.. Basic types of nanoparticle production

Nanoparticles can be produced by bottom-up or top-down technologies (see Figure 2). Bottom-up techniques arrange atomic or molecular components into covalently or physically bounded assemblies (for example with precipitation from a solution), while the top-down methods render large components towards the nanometer magnitude by mechanical comminu tion (e.g. milling, grinding) techniques (F. Darvas, Gy. Dormdn, V. Hessel: Flow Chemistry Vol. 2., Walter de Gruyter GmbH, Lepzig (2014), ISBN 978-3-11-028915-2).

In the pharmaceutical industry, two main top-down methods are used to produce AI nanoformulae: high-pressure homogenization (see e.g. Dissocubes^®: US Pat. No. 5,858,410; Nanopure: PCT/EPOO/06535, or Nanoedge™: US Pat. No. 6,884,436) and milling (see Nano- crystal™: US Pat. No. 5,145,684). However, due to the time consuming nature of raw materi al pre-treatment and parameter optimization, as well as high material requirements, the appli cation of these batch techniques is not profitable in the drug development stage. In addition, in the case of nanomilling, the possible change in the crystal structure, the high energy de mand for the cooling of the process and the special safety regulations arising from the han dling of toxic nanopowders must be also taken into account.

1.3. Batch and continuous production of nanoparticles

Currently both batch and continuous type reactors are used for the synthesis of AI na noparticles. Batch-type reactors are usually more economic for larger batch sizes. However, continuous flow methods offer several advantages over the batch technologies, such as e.g. the precise control of nanoformulation parameters, better control in material properties (e.g. particle size), easy scalability, lower production costs and less toxic exposure. In the case of using flow technology for nanoparticle production, the size of the synthetized nanoparticles can easily be influenced by the flow rate, as is shown in Fig. 3 for platinum nanoparticles.

The bottom-up techniques for the production of low water-soluble AI nanoparticles are usually based on controlled precipitation and are carried out in batch conditions (see e.g. US Patent Nos. 8,974,827 B2, and 8,541,511 B2, as well as US Published Patent Appl. Nos. 20140328763 AI, 20110053927 AI, and 20130243874 AI). The controlled precipitation of hydrophobic compounds in continuous flow is based on the flash nanoprecipitation method (A.I. Ch. E. Journal 49 (9) 2264 2282 (2003) and Chemical Engineering Science 63 (11) 2829-2842 (2008)). In the flash nanoprecipitation technique, the organic solution of the hy drophobic compounds is precipitated by the excess amount of an antisolvent, which usually results in the formation of solid nanoparticles or emulsion droplets with the size of 50-300 nm. Advantages of the flash nanoprecipitation method are the relatively narrow particle size distribution and the easy control of formation parameters. Although a few patents describe the flash nanoprecipitation of hydrophobic compounds in microfluidic circumstances (see e.g. US Published Patent Appl. Nos. 20070122440 AI, 20100330368 AI, 20110022129 AI, 20100022680 AI, and 20150174549 AI), these techniques do not examine and/or control the supramolecular structure, shape or stability of the synthetized nanoparticles.

Contrary to static methods, in microfluidic reactors the wall effect provides the re markable possibility of developing interactions between the AI and the formulating agents by adjusting the setup of the system. Conventional microfluidic systems for the production of nanoparticles comprise one or more material resource feeding unit connected to the flow path, and usually a reactor unit for the synthesis of nanoparticles connected to the outlet unit in the same cascade. The microfluidic based approach can provide numerous additional advantages, such as good mixing, improved heat and mass transfer, increased safety, reduced cost, as well as fast and precise adjustment and modification of process parameters over conventional technologies.

An instrument and method is described for the synthesis of nanoparticles in continuous flow mode in International Appl. No. PCT/HU2009/000040, regarded as the closest prior art document, where the properties and structure of the produced nanoparticles can be modified during the process by optimizing the working parameters of the device together with the pro cess parameters. In the described system, nanoparticle formation takes place in a first reactor unit, which is connected to a first feeding unit in the flow path. The instrument also contains at least a second reactor unit, wherein the product of the first reactor unit can be modified by the addition of a second starting solution. Said second feeding unit is connected to the flow path through a mixing element inserted between the first and second reactor units.

1.4. Unresolved issues in relation to the most perfect continuous bottom-up process

Although, in comparison with static systems, flow systems are generally much more suitable for the production of nanoparticles with desired properties, conventional microfluidic methods still have significant drawbacks as only 70-80% of the active molecules are suitable for nanoparticle synthesis with these methods and in most cases the stability of the obtained nanoparticles is not sufficient. Currently, no methods or devices are known for ensuring the stability of the nanoparticle formulae or, where appropriate, the prevention of re-dissolution of the synthetized nanoparticles. Neither it is solved how to synthetize nanoparticles of mate rials with high water solubility and/or low logP value (low octanol/water partition coeffi cient).

Furthermore, in some cases conventional microfluidic methods require a very large number of experiments to find the optimal parameter range required to synthetize nanoparti cles with the desired physicochemical properties (e.g., particle size, AI content, or solubility) and stability.

The aim of the present invention is to eliminate, or at least to alleviate the shortcom ings of the processes and devices of the present state of technology; especially, to provide a continuous microfluidic apparatus and process for producing core-shell or other type of nano particles of AIs with low water solubility and/or being unstable, as well as for enabling the production of nanoparticles from hydrophilic AIs. Description of the Invention

2.1. Nucleation and stabilization

In classical nucleation theory, the formation of particles is conceptually separated into two mechanisms, the nucleation and the following ripening phase. In the nucleation process, a rapid increase in the free monomer concentration in the solution results in a burst-formation of nuclei (seeds) which later act as templates for crystal growth. During the ripening phase, the final particle size, structure and stability are determined by various reorganization pro cesses. In the Ostwald ripening mechanism ( Ostwald , W. Z. Phys. Chem. 1900, 34, 495.), smaller particles re-dissolve in the solution due to their higher solubility, while the diffusion of the resulted free monomers contribute to a further growth of the larger particles. Here, the process following the burst-formation of nuclei (seeds) leading to obtain an already stable solution of the nanoparticles is called the ripening process. During intraparticle ripening, a diffusion of monomers occurs from the inside of particles to their surface which leads to changes in particle shape and/or crystalline state. In the aggregation process, the coalescence of single particles result in particle size growth. During the Ostwald ripening process, the av erage particle size changes in accordance with the equation of

that is, the particle size (r) changes with time as

wherein K is the rate constant, s is the surface energy, D is the diffusion coefficient of the dissolved molecule, v is the volume of the dissolved molecule, t is the time, C_eq is the solubili ty of the solute, C is the concentration of the solute, and S stands for the supersaturation (= C/Ceq).

A key issue for colloidal precipitation-based nanoization is the proper design and im plementation of the Ostwald ripening, as well as the design, control, and operation of suitable pieces of equipment; however, according to our best knowledge, there are currently no Ost- wald-optimized devices on the market. The Ostwald ripening process is influenced by the flow rate, the tube design, as well as the characteristic hydrodynamic parameters (e.g. length, diameter, surface roughness) of said tube, besides the usual parameters derived from the basic equation (e.g. temperature, pressure, solvent-specific physicochemical characteristics). Be- cause these parameters are interrelated, in practice, it is very difficult to find a solution that provides an industrially applicable, high-quality method within the tolerance limits of the flow rate, and also provides a high-quality process for organic matters with logP, logD (distri bution coefficient determined in the octanol/water system which also takes into account ion ized forms of molecules) values and other parameters in wide ranges.

Studying AI nanoparticle productions it has been established that in the nanoparticle synthesis of poorly water soluble AIs, surprisingly, two phases are to be distinguished. In the first stage the rapid formation of nanoparticle nuclei occurs, which is followed by a ripening process - i.e. the growth and stabilization of nuclei - in a second stage. Although the Ostwald theory describes a ripening process of nanoparticles, it does not describe the correlations be tween the ripening mechanisms and the molecular properties of the AI. In the experiments performed, we made a surprising discovery that the required duration of ripening is inversely proportional to the hydrophobicity of the molecule. We also found that the physicochemical (i.e. LogP, LogD values) (M. Kuchar: QSAR in design of bioactive compounds, J.R. Prous Publishers, Barcelona, 1984, ISBN 84-499-6941-7)), absorption and stability properties of the nanoparticles can be unexpectedly controlled between broad limits by choosing the ripening properties and the construction of the nanoizing device. However, the conventional one-tube reactors do not allow at all to control and regulate the ripening process of nanoparticles after nucleation. Therefore, known instruments like the one disclosed in International Patent Appl. No. PCT/HU2009/000040, can rarely be used for the formulation of unstable AIs, and are not suitable for fine tuning the properties of the nanoparticles either.

Summary of the Invention

The present invention relates to a continuous flow mode apparatus for synthetizing core-shell or other type of nanoparticles which allows to separate the nucleation and the ripen ing process. The apparatus is formed with tubes of variable path length which is unusual in the world of flow type devices. Thus, to ensure that the nanoparticles produced in the appa ratus get stabilized within optimal Ostwald ripening time, besides changing the flow rate, the tube length can also be varied. The tube designed to accommodate the ripening consists of a lower tube member and an upper tube member. Connection for the inlet and the outlet fluid flows is provided by a respective hole in the lower tube member. A channel system milled into the lower tube member is closed by the upper tube member, so that the two tube members form together a single complete tube. The channels are fully open at the edge of the lower tube member. Said channels are closed up by teeth properly formed on the upper tube member in such a way that recesses in front of said teeth pass the liquid between each parallel channel; by changing the position of the upper and lower tube members relative to one another along the longitudinal direction of the channels, the total length of the complete tube thus formed will proportionally change.

2.2 Nanoparticle synthesis in an Ostw aid-ripening flow device with tubes of variable path length placed into a microgravity space

According to Fick's first and second laws, the above-referred Ostwald ripening process is influenced by the concentration gradient formed in the medium, which in turn is gravity- dependent. When placing the apparatus according to the invention into reduced gravitational field, further advantages can be achieved. There is also a difference in the temperature de pendence of the diffusion process in gravity and microgravity: in terrestrial gravity, the diffu sion depends on the reciprocal of the temperature, while in microgravity it is directly propor tional to the square of the temperature. All this affects the Ostwald ripening process, which makes it possible to formulate nanoparticles according to the invention from materials which cannot be nanoized under other conditions.

The subject of this invention is a continuous flow microfluidic apparatus and process for producing core-shell or other type nanosized systems consisting of one, two or more con stituents, preferably nanoparticles, nanoemulsions, nanosuspensions and colloidal solutions containing biologically active organic molecules. The size and stability of said nanosized sys tems can be controlled over a wide range by adjusting the flow parameters, the pressure, the temperature, as well as the ripening time.

In what follows, the invention is explained in more details with reference to the draw ing, wherein

- Figure 1 shows the exponential increase in the number of atoms and molecules on the outer surface of the particles as a function of the decrease in particle size;

- Figure 2 illustrates nanoparticle production techniques;

- Figure 3 shows the change in size of the platinum nanoparticles as a function of the applied flow rate;

- Figure 4 is a plan view of the lower tube member of an Ostwald ripening unit used in a pos sible exemplary embodiment of a continuous flow microfluidic apparatus according to the invention; - Figure 5 is a plan view of the upper tube member of an Ostwald ripening unit used in the exemplary embodiment of the continuous flow microfluidic apparatus according to the inven tion as illustrated in Figure 4;

- Figure 6 is a cross-sectional view of the lower tube member and the upper tube member shown in Figures 4 and 5, respectively;

- Figure 7 is an enlarged view of a portion of the upper tube member illustrated in Figure 5;

- Figures 8 and 9 are perspective views of the lower and upper tube members of an Ostwald ripening unit comprising tubes with variable path length used in the apparatus according to the invention from different directions; and

- Figure 10 is a block diagram of a preferred embodiment of the apparatus according to the present invention with the connections of the individual components.

Figure 4 shows a lower tube member 100 of an Ostwald ripening unit used in a possi ble exemplary embodiment of the continuous flow microfluidic apparatus according to the invention, edge grooves 110 facilitating a stable running of the lower tube member and an upper tube member on one another, holes 120 forming a flow outlet and a flow inlet of said unit, a system of channels 130 milled into the lower tube member, portions 131 connecting every other channel with one another, as well as free ends of said channels at the edge 132 of the lower tube member.

Figure 5 shows the upper tube member 200 of the Ostwald ripening unit used in the exemplary embodiment of the continuous flow microfluidic apparatus according to the inven tion as illustrated in Figure 4, edge protrusions 210 facilitating the stable running of the lower tube member and the upper tube member on one another, a comb-structured toothing 230 blocking the channels of the lower tube member, as well as recesses 231 connecting the chan nels and formed in front of each individual tooth of said toothing.

In Figure 6, both the lower tube member 100 and the upper tube member 200 can be seen in cross-section.

Figure 7 is an enlarged, more detailed view of the upper tube member 200, which shows the protrusions 210 at the edges of the upper tube member, the toothing 230, as well as the recesses 231 formed in front of the toothing which connect the channels.

Figures 8 and 9 illustrate the lower and upper tube members of the Ostwald ripening unit constructed with tubes of variable path length used in the apparatus according to the in vention from different directions in perspective view. The main components of the apparatus schematically shown in Figure 10 are: a feed ing/inlet unit 1, preferably with four inlet reservoirs 7, 8, 9, 10 and preferably with two out lets, a reactor unit 2 with two inlets and one outlet, a nanoformulation ripening unit 3 with one inlet and one outlet, an outlet reservoir 4 with one inlet for storing the ripened mixture, as well as an analytical unit 5 and a control unit 6 with a user interface. As will be apparent to a skilled person in the art, the units at issue are connected to each other by means of suitable pipes, in a manner illustrated in Figure 10.

Feeding/inlet unit 1 : The inlet reservoirs 7, 8, 9, 10 store the starting materials. These reservoirs can also preheat and hold the starting materials at given temperatures. The supply is performed through two inlet switch valves 11, 12 by means of two inlet pumps 13, 14 operat ing independently. The pumps ensure that the materials are mixed in proper proportions in the system. Moreover, the pumps allow the liquid to flow through the system, and also provide an appropriate flow rate of the materials. The pumps heat the liquid materials through two heat ing units 15, 16 and then transfer them to the reactor unit.

Reactor unit 2: Fluids coming from the supply side are received by two inlet check valves 17, 18 which prevent the backflow of said fluids. The valves are followed by a mixing reactor 19 wherein the mixture of desired ratio is formed. The mixing reactor can also be heated to ensure the right temperature throughout the system. The design of said mixing reac tor follows a unique geometry tested by chemists.

Ripening unit 3: The ripening unit is responsible for maintaining proper flow and tem perature conditions within it for a predetermined period of time. The optimal Ostwald ripen ing according to the present invention is achieved in a chemically inert telescopic tube 20 with variable path length within the ripening unit, wherein both the temperature and the ripen ing time are controlled. A required value of the ripening time is set by changing the path length of said ripening tube 20 and the material flow rate. An operator of the apparatus does not need to have knowledge about the internal structure of the system, he only inputs the de sired time, from which the apparatus automatically calculates and then adjusts and sets the desired path length of said ripening tube.

Outlet reservoir 4: A unit for storing the ripened mixture which requires no heating.

Analytical unit 5: The analytical unit takes a sample from the output reservoir 4 and performs an analysis, then transmits the thus obtained results to the control unit 6, wherein a user can evaluate the results. The evaluation of results can also take place in an automated manner. As is shown in Figures 4 to 9, the ripening unit 3 comprises a tube with variable path length consisting of the lower tube member, the system of channels in the form of a milling that is milled into said lower tube member, and the upper tube member formed with teeth ar ranged in a comb-like structure. The inlet and outlet flow connections are each formed by a through hole at the middle along the length of the lower tube member. The milling starting at the upward facing portion of the hole will form the tube that allows fluid to flow through the ripening unit. Said tube is completed when the upper tube member is placed onto the lower tube member in the desired position and covers the milling. Fluid inlet and outlet are provided by the downward facing portion of the respective hole formed in the lower tube member.

The total length of the longitudinal channels milled into the lower tube member will determine the maximum path length of the ripening unit. This can easily be scaled by increas ing the dimensions, length and the density of the adjacent channels. Near to the middle of the lower tube member every other channel is in fluid connection, but at the end of the lower tube member, said channels are completely open.

Appropriate connections are provided by the upper tube member, the complete flow path forms in the structure created by placing the two members on one another, i.e. assem bling the ripening tube. The relative position of the lower and upper tube members can be varied, this position affects the total path length of the ripening unit linearly. The edge protru sion at each of the edges of the upper tube member and the edge groove at each of the edges of the lower tube member fit together, which fit guides their movement and prevents any un desired displacement, rotation, and/or twisting of said members. The function of the upper tube member is to cover the channels and thus to form several parallel flow pipes, as well as to seal the ends of said channels and to ensure a proper connection between said flow pipes in front of the sealings, and thus to establish a long, continuous flow channel system.

Thus, novelty of the present invention over the conventional process and instrument for forming nanoparticles in flow described in International Appl. No. PCT/HU2009/000040 is at least the provision of separate, optionally also optimized units for nuclei formation and nuclei ripening. According to International Appl. No. PCT/HU2009/000040, an intermediate product is obtained in a first reactor unit, while the desired properties of the nanoparticles can be obtained by the addition of supplementary components in a second reactor unit. This ap proach does not provide the possibility for stabilizing unstable nanoparticles and fine-tuning process and instrument parameters with regard to the physicochemical characteristics of the active ingredient to be nanoized. As a result, the prior art system is not specifically suitable for the nanoization of materials that have a logP and/or a solubility value each exceeding a respective given value. Uniqueness of the present invention lies in the application of a ripen ing unit comprising tubes of varying path length which, if necessary, can be operated in a par allel mode.

EXAMPLES

1. Synthesis of nanoparticles of hydrophobic model compounds in a conventional reactor and in a reactor according to the invention

A preferred embodiment of the invention allows to control the size of core-shell or other type of nanoparticles of non- or very low water soluble compounds in a planned manner based on the physicochemical properties of the AIs. During the experiments nanoparticles of hydrophobic model molecules were prepared in the conventional microfluidic instrument and in a microfluidic apparatus according to the present invention.

In the conventional instrument, 300 mg model compound and 700 mg non-ionic triblock copolymer dissolved in 100 mL tetrahydrofuran was used as a starting solution. The prepared solution was passed into the precipitating reactor unit 2 at a flow rate of 7 ml/min by the first inlet pump 13. Meanwhile, using the second inlet pump 14, from the inlet reservoirs 9, 10, 100 ml distilled water was passed into the T-shape mixing unit 19 of said precipitating reactor unit at a flow rate of 21 ml/min, wherein the aqueous phase was mixed with the solu tion containing the model compound and the non-ionic triblock copolymer. Nanoparticle nu clei were continuously produced at atmospheric pressure and temperature due to the con trolled nanoprecipitation in the T-shaped mixing unit 19. After production, the mean value (D50) of the particle size distribution of the nanoparticles was analyzed by a dynamic light scattering (DLS) method. Three parallel DLS measurements were carried out on each sample. Particle sizes given in Table 1 below (second column) are averages of the three DLS meas urements.

In the microfluidic apparatus according to the present invention, 300 mg model com pound and 700 mg non-ionic triblock copolymer dissolved in 100 mL tetrahydrofuran was used as the starting solution. Using the first inlet pump 13, the prepared solution was passed into the precipitating reactor unit 2 at a flow rate of 7 ml/min. Meanwhile, using the second inlet pump, from the inlet reservoirs 9, 10, 100 ml distilled water was passed into the T-shape mixing unit 19 of the reactor unit 2 at a flow rate of 21 ml/min, wherein the aqueous phase was mixed with the solution containing the model compound and the non-ionic triblock co polymer. The nanoparticle nuclei were continuously formed at atmospheric pressure and tern- perature due to the controlled nanoprecipitation in the T-shaped mixing unit 19. The thus pro duced nuclei were stabilized in the ripening tube 20 of the ripening unit 3 for 1.3 minutes, 2.0 minutes and 2.6 minutes. After ripening, the particle size distribution of the nanoparticles was analyzed by the dynamic light scattering (DLS) method. Three parallel DLS measurements were carried out on each sample. Particle sizes given in Table 1 below (third to fifth columns) are averages of the three DLS measurements.

Compared to the conventional method, in the apparatus according to present invention the size of nanoparticles of hydrophobic compounds can be controlled in a wide range by ad justing the parameters of the ripening process and the settings of the ripening unit.

Table 1. DLS particle sizes of model compound nanoparticles produced at different ripening durations in the conventional microfluidic instrument and in a microfluidic apparatus accord ing to the present invention.

2. Synthesis of nanoparticles from the active ingredient of 4-[(5R/S)-5-(3,5-Dichlorophenyl)~ 4, 5-dihydro-5-trifluoromethyl-l, 2-oxazol-3-yl ]-N-[ 2-oxo-2-(2, 2, 2-trifluoroethylamino)ethyl /- o-toluamide A preferred embodiment of the invention allows to stabilize highly unstable active compounds by choosing/modifying the properties of the ripening process and the ripening reactor unit. A particular example of this accomplishment is the production of stable nanopar ticles of the AI fluralaner (4-[(5/iAV)-5-(3, 5-di chi orophenyl)-4, 5-dihydro-5-tri fluorom ethyl - l,2-oxazol-3-yl]-/V-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-0-toluamide) with the general structural formula of

In the experiments 4-[(5//AV)-5-(3, 5-di chi orophenyl)-4, 5-dihydro-5-tri fluorom ethyl - l,2-oxazol-3-yl]-/V-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-0-toluamide nanoparticles were prepared with the device according to the present invention. As a starting solution, 600 mg 4-[(5AAS)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-trifluoromethyl-l,2-oxazol-3-yl]-/V-[2- oxo-2-(2,2,2-trifluoroethylamino)ethyl]-o-toluamide and 3.0 g poly(ethylene glycol)- poly(propylene glycol) block copolymer dissolved in 100 ml toluene was used. From the inlet reservoirs 7, 8 by using the first inlet pump 13, the prepared solution was passed into the pre cipitating reactor unit 2 at the flow rate of 8 ml/min. Meanwhile, from the inlet reservoirs 9, 10 by means of the second inlet pump 14, a solution of 250 mg poly-sorbate type surfactant dissolved in 100 ml distilled water was passed into the T-shape mixing unit 19 in the precipi tating reactor unit at the flow rate of 30 ml/min, wherein this solution was mixed with the solution containing 4-[(5/iAV)-5-(3,5-dichlorophenyl)-4,5-dihydro-5-trifluorom ethyl -1 ,2- oxazol-3-yl]-/V-[2-oxo-2-(2,2,2-trifluoro-ethylamino)ethyl]-o-toluamide and poly(ethylene glycol)-poly(propylene glycol) block copolymer coming from the first feeding unit. Nanopar ticle nuclei were continuously formed at atmospheric pressure due to the controlled nanopre cipitation in the T-shaped mixing unit 19. The thus produced nuclei were then stabilized in a 40 meter long ripening tube in the ripening unit 3, after which they were passed to the dynam ic light scattering device coupled to the apparatus, which detected the particle size of the ripen nanoparticles continuously. The size and stability of the nanoparticles were controlled by changing the parameters of the ripening process and the ripening unit. Particular examples of this accomplishment are specified in Table 2 below.

Table 2. Particle sizes and stability of 4-[(5f?AS)-5-(3,5-Dichlorophenyl)-4,5-dihydro-5- trifluoromethyl-l,2-oxazol-3-yl]-/V-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-0-toluamide nanoparticles in case of different ripening times; by increasing the ripening time, temporal stability of the colloid of the synthetized nanoparticles can be increased.

Claims

1. A method to produce nanoparticles in a device of a flow apparatus, comprising sub jecting the nanoparticles to Ostwald ripening, the Ostwald ripening being performed in a channel system comprising tubes of continuously variable path length, wherein for optimal Ostwald ripening the path length of the tubes being varied by sliding a lower tube member and an upper tube member relative to each other to a desired extent, said lower tube member comprising channels extending parallel with one another, said up per tube member comprising a sealing toothing that blocks each channel at one end thereof and arranged displaceably on the lower tube member to form the device with the channel system comprising said tubes.

2. The method according to claim 1, further comprising applying a Dynamic Light Scat tering, DLS, analytical unit built into the channel system to characterize said nanopar ticles.

3. The method according to claim 1 or claim 2, comprising performing the Ostwald rip ening of nanoparticles in a space of reduced gravity to influence the properties of the nanoparticles.

4. The method according to claim 3, comprising using a microgravity space as the space of reduced gravity.

5. A device to produce nanoparticles in a flow apparatus, the device comprising a chan nel system defining a flow path with an inlet and an outlet for Ostwald ripening of na noparticles, said flow path of the channel system being formed by a combination of a lower tube member (100) comprising channels extending parallel with one another and an upper tube member (200) comprising a sealing toothing (230) that blocks each channel at one end thereof and displaceably connected to the lower tube member, said lower tube member and said upper tube member being slidable relative to each other to a desired extent to enable continuous variability of the length of each tube formed by the channels of said channel system.

6. The device according to claim 5, wherein said device further comprising an analytical unit built into the channel system for determining nanoparticle size distribution to characterize the nanoparticles.

7. The device according to claim 6, wherein the analytical unit comprises a Dynamic Light Scattering, DLS, measuring unit.

8. The device according to any of claims 5 to 7, said device further comprising more than one lower tube members and more than one upper tube members arranged alternately on top of each other as layers to form a multi-path channel system, wherein a single layer consists of one lower tube member and one upper tube member, and wherein any channel system is formed by the upper tube member of a first layer and the lower tube member of a second layer combined together, said first and second layers being con secutive layers of the device.