Continuous production of particles

Abstract

The invention relates to a method and a device for producing particles and to a particle dispersion.

Description

Continuous production of particles Reference to related applications This application claims priority over German patent application 102022 107247.9 filed on 28 March 2022. The entire content of this German priority application is incorporated herein by reference. Technical background The invention relates to a method and a device for producing particles and a particle dispersion. State of the art

[0001] Over the past three decades, significant research efforts have focused on polymeric biomaterials, particularly poly(lactide-co-glycolide) (PLGA). PLGA is a biocompatible, biodegradable polymer that has been FDA-approved for medical applications for decades. A selection of approximately 20 depot formulations, such as the microparticulate Lupron Depot®, the solid implant Propel, and the in situ gel Perseris, are available. tm are available 1 PLGA is also the most widely used polymer for nanoparticulate drug delivery vehicles and a variety of small molecules. 2 and macromolecules such as peptides 3 , proteins 4 and DNA / RNA 5have been successfully formulated. Nanoparticulate formulations can enable both increased solubility and bioavailability of poorly soluble substances by increasing the surface area, as well as the modified release of substances through polymer degradation and particle surface modification.

[0002] However, there are currently no therapeutics on the market that use PLGA in nanoparticulate formulations. This could be because no cost- and time-efficient mass production methods exist, thus limiting their potential clinical application. Currently, there are a few approaches for the large-scale mass production of PLGA nanoparticles, for example, the semi-automated nanoprecipitation system developed by Rietscher et al. 6 , the nanoprecipitation system based on MicroJetReactor technology 7 or the emulsion solvent evaporation technique modified by Schiller8 , which uses focused ultrasound or, in general, microfluidic approaches 9,10 Since particles must subsequently be cleaned before using solvents or stabilizers, this represents another costly and time-consuming factor in commercial production.

[0003] A rotating disc is a multifunctional device that promises automated mass production at reasonable costs for the manufacturer. These systems enable a continuous flow process in which high centrifugal forces are used to disperse the liquid on the rotating disc into a thin film, thereby creating a large surface area to volume ratio of the liquid. This technology has been in use for decades, for example, to carry out various rapid chemical reactions in so-called spinning disc reactors (SDRs), including polymerization. 11 , neutralization12 , recrystallization 13 to achieve this. Furthermore, a large number of nanoscale chemical compounds have been produced through reactive precipitation, e.g., hydroxyapatite. 14 , TiO2 15 , ZnO 16 and magnetic Fe3O4 17, 18 As described in the literature, spinning disc technology has been successfully used for the ionic gelation of chitosan nanoparticles. 19 and for the solvent-antisolvent precipitation of nanoparticles consisting of beta-carotene 20 , Strength 21 , or curcumin. 22 What these methods have in common is a two-phase supply of the reaction liquids. Therefore, the rapid and homogeneous micromixing capability of the rotating disk is utilized. 23 ' 14 In addition, this technology enables increased and controllable heat and mass transfer, which supports many syntheses and processes that are otherwise limited in this respect.24 This also applies to concentrated liquids, as described by Akhtar et al. 25 described as a mild method due to the short contact time with the heating plate.

[0004] Besides methods such as emulsion solvent evaporation, salting out and electrospray drying, solvent-antisolvent precipitation is a commonly used technique for the production of PLGA nanoparticles. 26, 27, 28 The precipitation mechanism is described in the literature as a four-stage process: supersaturation, nucleation, and growth through condensation and coagulation. The addition of dissolved polymer to the antisolvent, with which the solvent is completely miscible, results in reduced solubility and leads to supersaturation when the equilibrium saturation concentration is exceeded. Above the critical supersaturation concentration, nucleation is induced. 29However, the reproducibility of particle properties is limited to small volumes in many processes. Therefore, there is a need for further processes for the production of particles. Summary of the invention

[0005] The invention relates to a method for producing particles comprising applying a solution to a rotating surface; wherein the solution comprises: a) at least one polar aprotic organic solvent; b) one protic solvent; c) at least one polymer; and d) at least one compound to be encapsulated.

[0006] The invention further relates to a particle dispersion comprising a) particles comprising i) at least one polymer; ii) at least one encapsulated compound and b) water, wherein the dispersion contains no organic solvent or the amount of organic solvent present is less than 1 wt% based on the total amount of the dispersion.

[0007] Furthermore, the invention relates to a device for producing particles, preferably nanoparticles, comprising a) a rotating surface; b) a means for dispensing liquids onto the rotating surface, mounted above the rotating surface; c) a physical shield that retains substances applied to the rotating surface by means of b).

[0008] In one embodiment, the inventive method enables the production of particles, particularly nanoparticles, in a continuous process. Due to the simple process steps employed, the inventive method also allows for the production of particles in commercially relevant sizes, exceeding laboratory scale, at low cost. By applying the solution to a relatively large surface area and the resulting thin film, the organic solvent is easily removed without further separate purification steps. Brief description of the characters

[0009] Fig. 1: Nanoprecipitation by solvent evaporation in an SDS. A: Schematic representation of an SDS. Blue arrows show the movements of the plates and the sample liquid. B: Petri dish after nanoprecipitation with central droplet position. From a certain distance from the center of the plate, dried polymer residues appear in a radial pattern (red arrow). The nanoparticle dispersion collects at the edge of the dish.

[0010] Fig. 2: Effect of polymer concentration on nanoparticle size. A: Results of DLS measurements on the size formation of PLGA nanoparticles as a function of the polymer concentration used in the SDS. The trend line shown (R²=0.99216) indicates an almost linear relationship between polymer concentrations up to 18 mg / ml and particle size. B: Results of DLS measurements on the size formation of PLGA nanoparticles as a function of the polymer concentration used in the BT method.

[0011] Fig. 3: Influence of polymer type on nanoparticle size in SDS and BT processes. A: PLGA types with different MS content. B: PLGA types with different molecular weights.

[0012] Fig. 4: SEM images of PLGA nanoparticles. AE: Different PLGA types precipitated in ACE and H2O in SDS. A: Resomer RG 502H (50% MS content, 17,000 g / mol), 241 ± 34 nm. B: Resomer RG 503H (50% MS content, 38,000 g / mol), 127 ± 2 nm. C: Resomer RG 504H (50% MS content, 54,000 g / mol), 84 ± 20 nm. D: Resomer RG 653H (65% MS content, 38,000 g / mol), 198 ± 38 nm. E: Resomer RG 753H (75% MS content, 38,000 g / mol), 227 ± 45 nm. FH: Resomer RG 503H precipitated in various solvent / non-solvent mixtures by direct drying onto silicon dioxide platelets. F: ACE and H2O, 183±65 nm. G: ACN and H2O, 386±115 nm. H: ACE and ethanol, 348±86 nm. In each image, the diameters of 30 particles were measured.

[0013] Fig. 5: Influence of solvent and non-solvent on the size of the nanoparticles. Resomer RG 503H dissolved in different compositions of solvents and non-solvents in SDS.

[0014] Fig. 6: CUR loading in the SDS and BT processes. A: Results of DLS measurements of 1% (w / w) CUR-loaded nanoparticles of different polymer concentrations. B: EE, DL, and yields of 1% (w / w) CUR-loaded nanoparticles of different polymer concentrations. C: Results of DLS measurements of different CUR loadings in the SDS and BT processes. D: EE and DL of different CUR loads in the SD and BT processes.

[0015] Fig. 7: Freshly produced nanoparticle dispersions. Left: Dispersion produced by SDS (total sample volume). Right: Dispersion produced by BT (aliquot: 0.5 ml; total volume: 11.5 ml).

[0016] Fig. 8: Acetone content as a function of time. Detailed description of the invention *■*■*■*

[0017] The invention relates to a method for producing particles and / or a particle dispersion comprising applying a solution to a rotating surface.

[0018] The particles are preferably nanoparticles, more preferably the particles have an intensity-weighted average particle size (Z average size) of 20 to 1000 nm, even more preferably 100 to 600 nm, and particularly preferably 120 to 200 nm.

[0019] The particles preferably have an overall polydispersity index (PDI) of 0.016 to 0.2, preferably 0.016 to 0.1. Where sd = standard deviation from the hypothetical Gaussian distribution z ave = intensity-weighted average particle size

[0020] The particles preferably have a ^-potential of -20 to -50 mV, more preferably -25 to -40 mV.

[0021] The application is preferably carried out by dripping or spraying, dripping is more preferred.

[0022] The solution comprises: a) at least one polar aprotic organic solvent; b) one protic solvent; c) at least one polymer; and d) at least one compound to be encapsulated.

[0023] The at least one polar aprotic solvent preferably i) has a volatility greater than 3 and / or ii) is selected from the group consisting of: acetone, acetonitriles and THF, preferably acetone. t90 (β-utyl acetate)

[0024] Volatility is defined as follows: Volatility = t90 (sample) t 90 = Time until 90% of the sample has evaporated.

[0025] Preferably, the amount of one polar-aprotic organic solvent in the solution or dispersion, based on the total weight of the solvents in the solution or dispersion, is 95 to 70 wt.%, more preferably 92 to 75 wt.%, even more preferably 91 to 80 wt.%, most preferably 90 wt.%.

[0026] The at least one protic solvent is preferably selected from the group consisting of: water, ethanol, methanol and isopropanol, preferably water.

[0027] Preferably, the amount of the at least one protic solvent in the solution or dispersion, based on the total weight of the solvents in the dispersion, is 5 to 30 wt.%, more preferably 8 to 25 wt.%, even more preferably 9 to 20 wt.%, most preferably 10 wt.%.

[0028] The at least one polymer is preferably poly(lactide-co-glycolide) (PLGA). Preferably, in the poly(lactide-co-glycolide) (PLGA) i) the ratio of lactic acid to glycolic acid is 20:80 to 80:20, preferably 50:50, 65:35, or 70:25 and / or ii) the molecular weight is 6000 to 60000 g / mol, preferably 6500 to 55000 g / mol.

[0029] The concentration of the polymer in the solution is preferably 0.1 to 25 mg / ml, more preferably 5 to 13 mg / ml.

[0030] In one embodiment, the concentration of the polymer in the solution is 1.5 to 3 mg / ml, preferably 2 mg / ml.

[0031] In one embodiment, the concentration of the polymer in the solution is 5 to 7 mg / ml, preferably 6 mg / ml.

[0032] In one embodiment, the concentration of the polymer in the solution is 10 to 14 mg / ml, preferably 12 mg / ml.

[0033] Preferably, the at least one compound to be encapsulated or the at least one encapsulated compound is i) a pharmaceutically active compound from the class of “small molecule” and / or ii) a low molecular weight compound with a molecular weight of <900 g / mol and / or iii) a low molecular weight compound with a logP value >0.

[0034] The amount of the at least one compound to be encapsulated in the solution is preferably 0.5 to 10 wt%, more preferably 1 to 8 wt%, and even more preferably 1 to 5 wt% in relation to the amount of polymer (w / w).

[0035] In one embodiment, the amount of the at least one compound to be encapsulated in the solution is 0.5 to 1.5 wt%, preferably 1 wt% in relation to the amount of polymer (w / w).

[0036] In one embodiment, the amount of the at least one compound to be encapsulated in the solution is 1.8 to 2.5 wt%, preferably 2 wt%, in relation to the amount of polymer (w / w).

[0037] In one embodiment, the amount of the at least one compound to be encapsulated in the solution is 3.5 to 6.5 wt%, preferably 5 wt%, in relation to the amount of polymer (w / w).

[0038] The definition of the logP value is known to those skilled in the art. P is the n-octanol-water cO₂. Distribution coefficient. LogP can be defined as follows: logP = log—. c0 is the concentration of the substance under consideration in the n-octanol phase. Cw is the concentration of the substance under consideration in the aqueous phase.

[0039] Preferably, the rotating surface is i) a disk, preferably a glass disk or a wafer, and / or ii) coated with polyvinyl alcohol, and / or iii) a disk and the disk rotates about an imaginary axis that is 90° to the surface of the disk and is located exactly in the center of the disk, and / or iv) the rotating surface rotates at 700 rpm to 3000 rpm, and / or v) the rotating surface is smooth or may have a texture, preferably the rotating surface is smooth and / or vi) the rotating surface is circular.

[0040] rpm = rounds per minute = revolutions per minute.

[0041] Preferably, after the solution is applied to the rotating surface, the particles are in the form of a dispersion.

[0042] The process can include a further drying step in which the particle dispersion obtained after applying the solution to the rotating surface is dried. Preferably, the drying is carried out by freeze-drying. The freeze-drying is preferably carried out according to methods generally known to those skilled in the art for freeze-drying processes.

[0043] In one embodiment, the solution comprises: a) at least one polar-aprotic organic solvent; wherein the amount of the one polar-aprotic organic solvent in the solution or dispersion, based on the total weight of the solvents in the solution or dispersion, is 95 to 70 wt.%, preferably 92 to 75 wt.%, more preferably 91 to 80 wt.%, and even more preferably 90 wt.%; b) a protic solvent; wherein the amount of the at least one protic solvent in the solution or dispersion, based on the total weight of the solvents in the dispersion, is 5 to 30 wt.%, preferably 8 to 25 wt.%, more preferably 9 to 20 wt.%, and even more preferably 0 wt.%.-%; c) at least one polymer; wherein the concentration of the polymer in the solution is preferably 0.1 to 25 mg / ml, more preferably 5 to 13 mg / ml; and d) at least one compound to be encapsulated; wherein the amount of the at least one compound to be encapsulated in the solution is 0.5 to 10 wt%, preferably 1 to 8 wt%, more preferably 1 to 5 wt% in relation to the amount of polymer (w / w).

[0044] The invention further relates to a particle dispersion, producible according to the method as described above, wherein the at least one protic solvent is water.

[0045] In one embodiment, the invention, optionally producible by the method as described above, relates to a particle dispersion comprising a) particles comprising i) at least one polymer; ii) at least one encapsulated compound and b) water,

[0046] wherein the dispersion contains no organic solvent or the amount of organic solvent present is less than 1% by weight based on the total amount of the dispersion. The definitions for the particles, the polymer, and the encapsulated compound, as defined above for the process, are preferably also applicable to this embodiment. Furthermore, the invention relates to a device for producing particles, comprising: a) a rotating surface; b) a means for delivering liquids onto the rotating surface, mounted above the rotating surface; c) a physical shield that retains substances applied to the rotating surface by means of b).

[0047] The physical shield can be attached directly to the rotating surface and rotate with the surface.

[0048] The physical shield can be designed such that the rotating surface rotates independently of the physical shield. The physical shield can be designed to retain the substances on the rotating surface or to retain them outside the rotating surface. Examples of these embodiments are shown in Figure 1.

[0049] The means (b) positioned above the rotating surface can be designed to dispense the liquid dropwise onto the rotating surface or as a spray, preferably dropwise. For example, the liquid can be applied using a syringe or cannula. Examples 1. Materials

[0050] PLGA [50:50 Lactic acid:Glycolic acid (MS:GS) with M w 7000-17000 g / mol (Resomer RG592H), M w24000-38000 g / mol (resomer RG503H) and M w 38000-54000 g / mol (Resomer RG504H); 65:35 MS:GS with M w 24,000–38,000 g / mol (resomer RG653H); 75:25 MS:GS with 22,000–36,000 g / mol (resomer RG753H) were obtained from Evonik Industries AG (Essen, Germany). CUR (curcumin) was obtained from Sigma Aldrich (Steinheim, Germany). Polyvinyl alcohol [PVA, Mw ~ 31,000 (Mowiol® 4-88)] was provided by Kuraray Europe (Hattersheim, Germany). Acetone (ACE, analytical grade), acetonitrile (ACN, HPLC gradient grade), tetrahydrofuran (THF, analytical grade), and ethanol (HPLC grade) were obtained from Fisher Scientific UK Ltd (Loughborough, UK). Methanol and isopropanol, both HPLC grade, were obtained from VWR International (Darmstadt, Germany). The water used was Millipore Q-Gard 2, purified by the water purification system from Merck Millipore (Billerica, USA). 2. Implementation - Spinning Disk Systems 2.7 Prototype I

[0051] The simple prototype I is composed of several modules (Figure 1A, left diagram). A modified, propeller-free computer fan (12x12 cm, AVC, Taipei, Taiwan) forms the core of the system. The lid of a glass Petri dish (Steriplan 15x100 mm, Brand GmbH & Co. KG, Weinheim, Germany) is permanently attached inverted to the fan's motor to hold the Petri dish, which is inserted into the lid and secured with rubber. The Petri dish serves as an interchangeable precipitation and collection vessel. A laboratory power supply (EA-PS 2323A, EA Elektro-Automatik GmbH & Co. KG, Viersen GmbH, Germany) provides power to the fan with variable voltage to adjust the rotational speed of the fan and the Petri dish. The rotational speed of the inserted Petri dish was measured with a tachometer (Voltcraft®, DT-10L, Conrad Electronic AG, Wollerau, Switzerland). A syringe pump (PHD 2000 programmable, Harvard Apparatus Inc.)A device from Holliston, USA) was used to control the flow rate of the polymer-solvent-antisolvent mixture into the inserted, rotating Petri dish. The tip of the needle (0.55 x 25 mm), attached to a syringe (5 ml - 20 ml), all purchased from Braun Melsungen AG (Melsungen, Germany), was positioned approximately 3 mm above the inserted Petri dish. 2.2 Prototype II

[0052] For continuous sample collection, a second prototype was constructed using a special glass vessel. This vessel includes a round recess for the fan motor, indentations to prevent leaks, and a sample outlet at the bottom (Figure 1A, right-hand diagram). The polymer-solvent-antisolvent mixture was applied to A glass petri dish lid was dripped onto the fan motor and attached in a suitable manner. With the new prototype, larger quantities of liquid could be added, thus enabling increased nanoparticle production and sample collection during operation. 3. Particle production 3.1 Nanoprecipitation by evaporation-triggered SDS

[0053] To prepare polymeric nanoparticles, 10 mg of Resomer RG503H was dissolved in ACE and stirred vigorously for 10 minutes before water was added at an ACE:water ratio of 9:1 to obtain a polymeric solvent-antisolvent mixture of 2 mg / ml. The fan motor was started at 5 V, corresponding to a rotation speed of approximately 841 rpm. The solution was applied to the center of the rotating petri dish at a syringe pump flow rate of 0.5 ml / min. A 2% PVA solution was used to coat the petri dish and allowed to dry at ambient conditions to stabilize the deposited nanoparticles in the dispersion, which was used as the standard preparation method. The resulting nanoparticle dispersion was removed from the edge of the inserted petri dish (Prototype I). The parameters given were used in the following investigations (standard procedures) unless otherwise stated. 3.2 Influence of different parameters on the NP size

[0054] To investigate the influence of system-specific settings on particle size, rotational speeds of 841 rpm (5 V), 2051 rpm (5.5 V), and 2727 rpm (7 V) and needle positions for applying the solution at distances of 0, 1.5, and 3 cm from the center of the inserted Petri dish were tested. rpm = revolutions per minute.

[0055] The dependence of polymer type, polymer concentration, and solvent composition on nanoparticle size was also investigated. Precipitation was performed for various polymer types, different molecular weights of 50:50 MS:GS (resomers RG 502H, 503H, 504H), different MS:GA ratios (resomers RG 503H, 653H, 753H), and PLGA concentrations of 0.5–22 mg / ml of resomer RG 503H. The influence of solvent and antisolvent on particle size was examined, comparing ACE, ACN, and THF as solvents and water, ethanol, methanol, and isopropanol as antisolvents. To demonstrate the evaporation effect on particle formation, solvent-antisolvent mixtures were prepared as described above and dried on silica wafers for SEM imaging. For size evaluation, 30 randomly selected particles were measured using Fiji software. 3.3 Nanoprecipitation by the standard BT process

[0056] Different concentrations of Resomer RG 503H and various types of PLGA were compared with respect to the size of the resulting nanoparticles produced by commonly used nanoprecipitation. Resomer RG 503H in masses of 10–40 mg and various PLGA types (Resomer 502H, 503H, 504H, 653H, and 753H) at a mass of 25 mg were dissolved in 1.5 ml of ACE for 10 min with vigorous stirring. Polymer solutions were added with stirring to 10 ml of an aqueous solution containing 2% PVA using a syringe pump set to an injection rate of 0.5 ml / min. The resulting nanoparticle dispersion was purified by centrifugation at 10,000 g for 20 min and washed twice to remove excess stabilizer.It is worth noting that the SDS product consisted of a small antisolvent phase with a high concentration, in contrast to the bench top (BT) product, which consisted of a large antisolvent phase and a small solvent phase. 3.4 CUR loading of NP

[0057] To prepare CUR-loaded nanoparticles, CUR was dissolved in ACE to obtain a 1% solution. In SDS (Prototype I), Resomer RG 503H was dissolved in ACE, and the CUR solution was added to achieve polymer concentrations of 2, 6, and 12 mg / ml and an initial drug content of 1% (w / w) relative to the polymer. In an experiment, a polymer concentration of 6 mg / ml and initial drug contents of 1, 2, and 5% (w / w) relative to the polymer were adjusted. The resulting nanoparticle dispersions were collected and centrifuged at 10,000 g for 20 min (Rotina 420 R, Andreas Hettich GmbH & Co. KG, Tuttlingen, Germany) to eliminate free drug. In BT, CUR-loaded nanoparticles were produced with an initial polymer concentration of 12 mg / ml and purified in the same manner as described in section 3.3.In the nanoprecipitation using the standard BT method, ACE was partially replaced by CUR stock solution (1% in ACE) to obtain initial concentrations of 1%, 2%, and 5% (w / w) of the polymer. Quantifications (DL and EE) were performed as described in Section 5. 3.5 Transferability to Prototype II

[0058] To test the transferability to Prototype II, a polymer-solvent-antisolvene mixture was prepared in a quantity of 20 ml and precipitated under the same parameters as for Prototype I. The rotating dish was not coated with PVA because the amount of coated material used in Prototype I is insufficient for the larger quantities of polymer used in Polymer II (3.1 Nanoprecipitation by Evaporation-triggered SDS). The collection vessel was pre-moistened to increase the liquid volume and allows the produced nanoparticle dispersion to be collected. 4. Determination of yield and evaluation of NP stability

[0059] The yield was determined by freeze-drying collected nanoparticle dispersions, prepared at concentrations of 2, 6, and 12 mg / ml (alpha 3-4 LSCbasic, Martin Christ Gefriertrocknungsanlagen GmbH, Osterode am Harz, Germany), for 24 hours. The stability of nanoparticles (resomer RG 503H in Prototype I) prepared with and without a PVA coating on the tray was investigated in Prototype I. Therefore, the resulting dispersion was stored at 4 °C, and its quality with respect to colloidal properties (size, PDI, and μ-potential) was evaluated based on the freshly prepared dispersion after 7, 14, 21, and 28 days using Zetasizer measurements. For Prototype II, stability was investigated only under PVA-free conditions. 5. Particle Characterization 5.1 Particle size, polydispersity index and ^-potential

[0060] Nanoparticle size and polydispersity index (PDI) were determined using dynamic light scattering; the potential was determined using electrophoretic analysis. Light Scattering (Nano ZS, Malvern Panalytical GmbH, Malvern, UK and Almelo, the Netherlands). The analysis was performed at a backscattering angle of 173° and at 25°C using appropriately diluted samples. 5.2 Particle Morphology

[0061] The surface morphology of dried samples was determined by scanning with an electron microscope (Zeiss EVO 15, Carl Zeiss AG, Oberkochen, Germany) after sputtering with a 10 nm gold layer under vacuum conditions (Q150R Rotary-Pumped Sputter Coater, Quorum Technologies Ltd., Laughton, UK) at a working distance of 16.5 mm and an accelerating voltage of 5 kV. 5.3 CUR Quantification

[0062] Samples for CUR quantification were freeze-dried for 24 h and quantified with respect to DL and EE. The particles were then dissolved in ACN (1 mg / ml), filtered (0.45 pm, RC membrane filter Titan 3, Thermo Fisher Scientific Inc., Waltham, USA), and analyzed by fluorescence spectroscopy (plate reader Infinite M200, Tecan Trading AG, Männedorf, Switzerland). The excitation and emission wavelengths were set to 415 nm and 515 nm, respectively. The calibration curve used for calculating the CUR concentration was... The effect was linear in the range of 0.1-1 pg / ml. The drug loading (DL%) and encapsulation efficiency (EE%) were calculated according to equations (1) and (2). 6. Results and Discussion 6.1 Nanoprecipitation by evaporation-triggered SDS

[0063] Particles were produced using SDS based on a modified nanoprecipitation technique. The large surface area of ​​the rotating plate triggered extensive evaporation of the applied solvent (ACE). Consequently, the precipitated nanoparticles produced a milky, highly concentrated nanoparticle dispersion in the small amount of antisolvency (Figure 7). However, some loss of polymer on the rotating tray was evident, which is described in detail in Section 6.3. A production volume of 5 ml resulted in a dispersion volume of 0.3–0.4 ml. Assuming that the solvent component (4.5 ml) was completely removed by evaporation, as determined by olfaction, this means that 60–80% of the aqueous phase was recovered. The amount of acetone in the obtained suspension fell below 0.5% after a period of >30 minutes (Figure 8). 6.2 Influence of different parameters on the NP size 6.2.1 Effect of PLGA concentration

[0064] Higher PLGA concentrations resulted in larger particles, as expected for the SDS and BT methods (Figure 2). In the latter case, however, the effect was much smaller. Within the tested concentration range, sizes of approximately 120–380 nm were achieved using SDS (Figure 2A). Up to a concentration of 16 mg / ml, an almost linear relationship between polymer concentrations and particle size was observed. Above a concentration of 16 mg / ml, fluctuating sizes of 335–380 nm indicate limited reproducibility and that a plateau had been reached or a maximum controllable particle size had been exceeded. The particle size distribution became more pronounced with increasing polymer concentration, as indicated by an increasing PDI from 0.016 to 0.2, correlating with particle size. In the linear range, however, the PDI did not exceed 0.2, indicating a still narrow distribution (Müller and Schuhmann, 1996). Using the BT method, particle sizes of approximately 150–220 nm with very narrow size distributions (PDI < 0.1) were achieved (Figure 2B). When higher concentrations of 50 mg and more were dissolved in 1.5 ml of ACE to produce larger nanoparticles, a homogeneous nanodispersion could not be achieved, and visible precipitates formed directly at the tip of the cannula. 6.2.2 Effect of PLGA Types

[0065] As shown in Figures 3A and B, the type of PLGA did not affect the particle size during nanoparticle production using the BT method. Particle sizes were constant around 180–195 nm and uniform, and low PDIs of <0.1 were achieved. In contrast, the evaporation-triggered method using SDS resulted in significantly larger particles with increasing MS content in the polymer (Figure 3A), approximately 140 nm for MS:GS 50:50 compared to 230 nm for MS:GS 75:25.

[0066] With increasing viscosity or molecular weight, smaller particles were found in the SDS (Figure 3B). The lowest molecular weight (7000–17000 g / mol) produced particles almost twice the size of those at the highest molecular weight (38000–54000 g / mol) (243.3 ± 5.7 nm vs. 127.7 ± 2.2 nm), with the size difference between the mean molecular weight PLGA (24000–38000 g / mol) and the highest PLGA (10–15 nm) being quite small. Investigating different molecular weights in the BT setup had only a minor effect (193.3 ± 2.1 nm at 7000–17000 g / mol vs. 181.7 ± 0.5 nm at 38000–54000 g / mol). The influence of diffusion was not pronounced. Figure 4A-E SEM shows images that clearly demonstrate the differences in particle sizes obtained when different PLGAs are used. 6.2.3 Effect of rotational speed and drip position

[0067] Since the rotational speed of the rotating dish could only be indirectly adjusted via the voltage of the power source, the rotational speeds were reproducible but could not be freely set. Three speeds with the greatest possible differences were tested. The produced particles had similar sizes (841 rpm: 140.9 ± 1.3 nm, 2051 rpm: 146.5 ± 11.2 nm, and 2727 rpm: 139.2 ± 9.4 nm) with small distributions (PDI < 0.05). Furthermore, different droplet positions relative to the center of the disc did not result in any relevant changes or correlating trends in particle size (0 cm: 140.9 ± 1.3 nm, 1.5 cm: 126.4 ± 2.0 nm, and 3 cm: 134.0 ± 2.4 nm). All PDIs showed small distributions (PDI < 0.05). 6.2.4 Effect of solvent and antisolvene type

[0068] When using different solvents, a change in particle size was observed in SEM and DLS (Figure 4F-H, Figure 5). Larger particles were formed with ACN and THF (approximately 230 nm) than with ACE (approximately 140 nm; Figure 5).

[0069] Figure 4F-H shows SEM images of PLGA nanoparticles produced solely by drying the solvent-antisolvene mixtures on silica wafers. Replacing the solvent from ACE with ACN or the antisolvene from H₂O with ethanol resulted in a visible increase in size as a result of the drying process alone. Changing the antisolvene from water to alcohols also caused a change in size. Precipitation in methanol, ethanol, and isopropanol led to particle sizes of approximately 210–220 nm (Figure 5). 6.3 Yield of nanoparticles produced with SDS

[0070] Yield determination showed lower particle yields with higher polymer concentrations. Therefore, yields of 88.8 ± 2.1% at 2 mg / ml, 72.8 ± 4.8% at 6 mg / ml, and 40.6 ± 2.7% at 12 mg / ml of PLGA were obtained. The polymer loss can be attributed to the drying of the PLGA particles on the rotating dish (Figure 1B). The higher the concentrations, the more particles dried on the dish before reaching the edge and being collected. Up to a distance of 3 cm from the center of the dish, little or no PLGA appeared to remain on the dish. Beyond this distance, the particle suspension flowed radially to the edge. Most of the polymer loss appears to occur in these streams. 6.4 Stability of SDS-produced nanoparticles

[0071] None of the investigated particles showed any visible or measurable changes in stability, such as nanoparticle clumping, a decrease in the potential, and a subsequent increase in particle size and PDI due to agglomeration. For example, the maximum size deviation after 28 days of storage at 4 °C was 2–6 nm for all investigated particles. Accordingly, the particle size remained constant over the measured time. The size distributions showed slight fluctuations, but all PDIs remained below 0.1. The average maximum decrease in the potential was 5.6 mV (PVA-coated trays) and 7.6 mV (uncoated trays). Overall, all measured potentials were below -30 mV (-39 ± 2 mV) and therefore showed good stability, even after 28 days.Therefore, when comparing the data obtained using an uncoated rotating disk and the data obtained using a PVA-coated shell, it can be concluded that coating the shell with a stabilizer (e.g., PVA) is not necessary to achieve the desired results. The quality of the particles was maintained, at least during storage for 28 days. The particles produced in Prototype II also proved to be stable. 6.5 Loading characteristics of CUR-loaded NPs

[0072] The particle sizes of the CUR-loaded nanoparticles (Figure 6A and C) produced by both the SDS and BT processes were similar to those of unloaded particles (Figure 2A and B). Therefore, the loading had no effect on the particle size in these concentration ranges.

[0073] In the SDS, increasing the polymer concentration with a constant initial loading of 1% (w / w) CUR led to an increased DL (Figure 6B). This also resulted in a higher EE at a concentration of 6 mg / ml compared to 2 mg / ml. In contrast, at even higher concentrations of 12 mg / ml, the EE was lower than at 2 mg / ml. Since the encapsulation efficiency was calculated by multiplying the amount of recovered drug in 1 mg of formulation by the yield of the formulation to retain the total amount of recovered drug in the prepared sample, the EE correlates with the yield. The increased DL could not compensate for the much higher particle loss (79.6% vs. 43.5% yield, Figure 6B).

[0074] To compare the loading properties of the two processes, polymer concentrations were selected that would yield similar particle sizes. Figure 6D shows that higher DL and EE values ​​were achieved with SDS. The DL of SDS particles is twice that of BT particles (approximately 80–90% of the initial CUR used per mass of polymer, compared to approximately 40–45%). The EE of SDS particles (approximately 60–70%) was also significantly higher than that of BT particles, which was repeatedly found to be between 10% and 25%. 6.6 Particle production with setup for continuous production (Prototype II)

[0075] The particles produced with Prototype II had a size of 135.5 ± 5.5 nm, a PDI of 0.017 ± 0.002, and a zeta potential of -29.2 ± 3.2 mV. Thus, the obtained particles have comparable properties to those produced with Prototype I (140.9 ± 1.3 nm, 0.016 ± 0.008, -28.3 ± 2.7 mV). The stability of the particles was also successfully tested. With an initial test volume of 20 ml, it was difficult to collect the produced particles due to the low initial volume of the dispersion. Therefore, it was necessary to additionally moisten the collection vessel with water. This increased the final volume and diluted the final dispersion. Collecting the particles on the rotating tray without interrupting production allows for the use of larger (unlimited) volumes. Therefore, the particles can be harvested continuously to obtain larger quantities of the particle dispersion. Consequently, no additional water would be necessary for moistening. Yield determination showed an average reduction of 9.4 ± 5% compared to Prototype I. Referenzen e 2019, 304, 125-134. harmaceutics and Biopharmaceutics 2017, 117, 363- lease 2012, 194, 138-147. Pharmaceutics and Biopharmaceutics 2017, 118, 48- ology, Biology, and Medicine 2007, 3, 173-183. 859-1863. 019, 42, 2018-2027. 95-3006. very 2016, 13, 1447-1460. 2, 7, 623-629. eering 2000, 20, 1127-1146. hemistry Research 2013, 52, 16832-16841. emistry Research 2000, 39, 2175-2182. ing Science 2012, 76, 73-80. ing Journal 2014, 258, 171-184. 007, 19, 5453-5459. ls 2008, 18, 922-927. noparticles Using Spinning Disc Processing 2006. ciences 2010, 99, 4326-4336. rican Chemical Society 2006, 128, 13847-13853. thesis 2019, p. 507. Processing: Process Identification 2014, 80, 1-10. and Technology 35, 1229-1237. eat and Mass Transfer 1999, 42, 2543-2556. ng and Technology 2011 , 02. armaceutics 1989, 55, R1-R4. terface Science 2014, 417, 121-130. e 2011 , 36, 887-913. Technology 2013, 34, 109-123.

Claims

Claims 1. A method for producing particles comprising applying a solution to a rotating surface; wherein the solution comprises: a) at least one polar aprotic organic solvent; b) a protic solvent; c) at least one polymer; and d) at least one compound to be encapsulated, wherein optionally the particles obtained after application to the rotating surface are in the form of a dispersion.

2. A particle dispersion comprising a) particles comprising i) at least one polymer; ii) at least one encapsulated compound and b) water, wherein the dispersion contains no organic solvent or the amount of organic solvent present is less than 1% by weight based on the total amount of the dispersion.

3. A particle dispersion, producible according to the method of claim 1, wherein the at least one protic solvent is water.

4. The method according to claim 1 or the particle dispersion according to claim 3, wherein the at least one polar aprotic solvent i) has a volatility greater than 3 and / or ii) is selected from the group consisting of: acetone, acetonitriles and THF, preferably acetone.

5. The method according to claims 1 and 4 or the particle dispersion according to claims 3 and 4, wherein the at least one protic solvent is selected from the group consisting of: water, ethanol, methanol and isopropanol, preferably water.

6. The method according to any one of claims 1, 4 and 5 or the particle dispersion according to claims 2 to 5, wherein the at least one polymer is poly(lactide-co-glycolide) (PLGA) and optionally i) the ratio of lactic acid:glycolic acid is 20:80 to 80:20, preferably 50:50, 65:35, or 70:25 and / or ii) the molecular weight is 6000 to 60000 g / mol, preferably 6500 to 55000 g / mol.

7. The method according to claims 1 and 4 to 6 or the particle dispersion according to claims 2 to 6, wherein the at least one compound to be encapsulated or the at least one encapsulated compound is i) a pharmaceutically active compound of the class “small molecule” and / or ii) a low molecular weight compound with a molecular weight of <900 g / mol and / or iii) a low molecular weight compound with a logP value >0.

8. The method according to claims 1 and 4 to 7 or the particle dispersion according to claim 3, wherein the amount of the at least one protic solvent in the solution or dispersion, based on the total weight of the solvents in the dispersion, is 5 to 30 wt.%, preferably 8 to 25 wt.%, more preferably 9 to 20 wt.%, most preferably 10 wt.%.

9. The method according to claims 1 and 4 to 8 or the particle dispersion according to claim 3, wherein the amount of one aprotic organic solvent in the solution or dispersion, based on the total weight of the solvents in the solution or dispersion, is 95 to 70 wt.%, preferably 92 to 75 wt.%, more preferably 91 to 80 wt.%, most preferably 90 wt.%.

10. The method according to claims 1 and 4 to 9 or the particle dispersion according to claim 3, wherein i) the rotating surface is a disk, preferably a glass disk or a wafer and / or ii) the surface is coated with polyvinyl alcohol and / or iii) a disk and the disk rotates about an imaginary axis that is 90° to the surface of the disk and is located exactly in the center of the disk and / or iii) the rotating surface rotates at 300 rpm to 10000 rpm, preferably 700 rpm to 3000 rpm and / or iv) the method is a continuous process.

11. The method according to claims 1 and 4 to 10 or the particle dispersion according to claim 3, wherein the intensity-weighted mean particle size (Z-average) is from 20 to 1000 nm, more preferably from 100 to 600 nm, and even more preferably from 120 to 200 nm.

12. The method according to claims 1 and 4 to 11 or the particle dispersion according to claim 3, wherein i) the polydispersity index (PDI) of the particles is 0.016 to 0.2, preferably 0.016 to 0.1; ii) the ^-potential is -20 to -50 mV, preferably -25 to -40 mV.

13. The method according to claims 1 and 4 to 11, wherein i) the application is carried out by dripping or spraying, more preferably by dripping and / or ii) the method comprises a further drying step in which the particle dispersion obtained initially after applying the solution to the rotating surface is dried, preferably by freeze-drying.

14. A device for producing particles, preferably nanoparticles, comprising a) a rotating surface; b) a means for delivering liquids onto the rotating surface, mounted above the rotating surface; c) a physical shield that retains substances applied to the rotating surface by means of b).

15. The apparatus for producing particles according to claim 14 wherein i) the shielding c) includes an outlet d) which allows the removal of substances during the production of the particles; and / or ii) the physical shielding is attached directly to the rotating surface and rotates with the surface or the rotating surface rotates independently of the shielding; iii) the means attached above the rotating surface b) is suitable for dispensing the liquid drop by drop or as a spray onto it, preferably drop by drop.

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