EP3924126A1 - Method and device for treating particles and nanoparticles of an active pharmaceutical ingredient - Google Patents

Abstract

The invention relates to a method and device for treating particles and nanoparticles.

Description

Title: Method and device for processing particles as well as nanoparticles of a

active pharmaceutical ingredient

description

The invention relates to a method for processing particles, in particular micro- and nanoparticles, in a suspension. The invention also relates to a device for processing such particles. Of

The invention also relates to nanoparticles of a pharmaceutical active ingredient.

Particles with sizes in the micro or nanometer range have a wide range of applications in a wide variety of areas of technology. The important thing here is the Manufacture of particles of certain sizes and

Be size distributions. The size, shape and / or

Texture, e.g. a surface or a

Crystalline structure, the particles can also be important properties of the particles.

Traditionally, colloid mills have been used to crush particles with sizes in the micro or nanometer range. Such mechanical

Comminution devices are sometimes subject to high wear and tear, and their use also means that particles from the material of the mill get into the suspension. From EP 2 735 390 A1 the time shift is

Irradiation of a suspension with several lasers

known . By irradiating a substrate with a first laser, particles are converted into an aqueous

Medium generated. A beam of the aqueous medium with the particles is then irradiated by a second laser in order to fragment or comminute the particles.

The invention is based on the object of providing a method and a device for efficient, in particular reproducible and in particular post-controllable processing, in particular comminuting, of particles in a liquid jet. Furthermore, the invention is based on the object of creating nanoparticles of a pharmaceutical active substance which are pollution-free and understandable

Have manufacturing history.

According to the invention, this object is achieved by a method according to claim 1, a device according to claim 12 and nanoparticles according to claim 19.

The method according to the invention relates in particular to the processing of particles in the

Initial state a size in the micrometer,

Have submicrometer and nanometer range.

In particular, the size of the particles can be less than 0.1 mm, in particular less than 0.01 mm, and more than 1 nm, in particular 500 nm. For the purposes of the invention is in particular when to carry out the

inventive method an inventive

Device is used.

The inventive method for processing

Particles comprises the steps: a) generating a jet of liquid. By doing

The particles are carried along with the liquid jet. The particles are in suspension in the liquid jet.

The liquid jet can be in a

Management structure, such as a channel, pipe or

Hose. The guide structure is transparent to the laser beam used, at least in sections. The liquid jet can but also be a freely falling jet of liquid. A freely falling liquid jet is to be understood as a liquid jet that is not guided. In particular, this releases a gravity (in particular

straight) downward falling liquid jet understood. The liquid jet can emerge from a jet generating device, for example a nozzle, which is used to generate the jet, without pressure or under pressure. With a liquid jet there is in particular a continuous one

Meant liquid column and not a consequence of

single drop. b) irradiating the liquid jet with at least two laser beams from different directions.

The irradiation by means of several laser beams from different directions serves as all areas in the cross section of the

To irradiate liquid jet. In particular, it is provided that the laser is arranged on the

Direct the liquid jet so that no sections remain in the cross-section that are not covered by laser radiation. In other words, the laser beams are directed onto the liquid jet in such a way that all sections of the cross section of the liquid jet are captured by the laser beams. This is further explained below in Described in detail. This means that all particles carried along can be processed with the laser beams in one pass. Within the meaning of the invention

in particular that pulsed laser beams (in particular pulse duration of the laser beams in the picosecond range,

Femtosecond range or nanosecond range) can be used. In particular, the irradiation with the lasers serves to break up the particles. The irradiation runs without wear and, in contrast to mechanical processing or comminution, without contamination of the particles or the suspension.

Wavelengths that interact sufficiently with the particles in order to efficiently shred them are particularly suitable. Also are high

Repetition rates of the laser pulses advantageous. The

Wavelength of the laser beams can in particular, for example. 532 nm or 1030 nm or 515 nm or 343 nm, with several laser beams with

different wavelengths can be used. In particular, Yb: YAG lasers can be used. c) Analysis of the suspension before and / or after

Irradiate by means of the laser beams.

The method according to the invention therefore provides that the suspension in which the particles are contained is analyzed. This analysis can be done before or after the irradiation. In particular, the Suspension before and after irradiation

analyze. The analysis can be used to control the irradiation process. In particular, the storage of the

Analysis results. In an analysis that the

Irradiation is carried out beforehand, it can be checked whether the supplied particles have the appropriate initial size. It is also possible to determine the parameters of the irradiation in step b) based on the analysis results of the analysis before

Adjust irradiation. In an analysis that follows the irradiation, the result of the

Irradiation, especially the size reduction of the particles, can be checked. Implementation of the

Analysis before and after the irradiation process can, for example, (also) be used to check whether there are any disturbances in the irradiation process

exist. The parameters of the irradiation in step b) based on the

Adapt the analysis results of the analysis after the irradiation, for example until a target value is reached. d) collecting the liquid in the liquid jet

a collecting vessel. This enables an actual catching of an unguided freely falling

Be meant liquid jet. However, collecting in a collecting vessel can also mean introducing a guided jet of liquid. Steps c) and d) can be provided alternatively or jointly.

The particles can comprise inorganic material or consist of inorganic material. In particular, the material can be metal, for example gold or

Be platinum. Such particles can be used, for example, as catalysts. In the context of the invention, the use of the method according to the invention or the use of the device according to the invention for processing

Particles from active pharmaceutical ingredients (or

Particles that comprise pharmaceutical active ingredients), in particular poorly water-soluble pharmaceutical active ingredients. Active ingredients that are suitable to be processed with the inventive method or. to be crushed are, for example. :

Ampicillin, benzylpenicillin-benzathine,

Benzylpenicillin procaine, cefazolin, ceftazidime,

Imipenem, Chloramphenicol, Ciprofloxacin, Phenobarbital, Phenytoin, Metronidazole, Trimethoprim, Sulfamethoxazole, Linezolid, Paraaminosalicylic Acid, Amphotericin B,

Fluconazole, 5-fluorocytosine, acyclovir, quinine,

Melarsoprol, azathioprine, ciclosporin, folinic acid,

Carboplatin, Dacarbazine, Actinomycin D, Daunorubicin, Docetaxel, Etoposid, I fos famid, Paclitaxel, Cortisol, Methylprednisolone, Biperiden, Digoxin, Adrenaline,

Lidocaine, verapamil, amiodarone, digoxin, furosemide, Selenium sulfide, fluorescein, tropicamide, dexamethasone, ondansetron, testosterone, medroxyprogesterone, estradiol-17beta-cipionate, glucagon, azithromycin, ofloxacin, tetracycline, prednisolone, timolol, atalkropine, ergometrine and, in general: mother LSkornine and

Methylergometrine, fluphenazine, risperidone, clozapine, fluoxetine, carbamazepine, diazepam,

Beclometasone dipropionate, budesonide, ipratropium bromide, salbutamol, budesonide, chloroquine, penicillamine,

Ketoconazole, fenofibrate, naproxen.

A separate standalone invention are also

Nanoparticles, an active pharmaceutical ingredient,

in particular one or more of the above-mentioned active ingredients, which by means of steps a) and b)

were comminuted and analyzed by means of step c). That the particles were created by steps a) and b) can be seen from the particles

For example, they can recognize that they have no

Impurities and have a narrow range of sizes, which is due to the irradiation of the entire

Liquid jet cross section is achieved by means of the laser from different directions, show. The

The analysis result (analysis step c)) is assigned to nanoparticles. This means that the

Analysis result is reproducible and a connection to the characterized by this analysis result

There is nanoparticle, so that it is clearly identifiable which particles are or are described by the corresponding analysis. were "measured". On the independent invention of the nanoparticles will be discussed in more detail below.

In particular, it is provided that the material of

Particles have a solubility in the liquid (the

Suspension) of less than 10 g / L, in particular less than 1 g / L, in particular a physiological solution can be provided as the liquid. In the

physiological solution, the particles can be present in dispersed form.

According to the invention it can be provided in the method and in the case of the particles that the particles in the

Starting state, ie are or are dispersed in the liquid by means of an auxiliary before irradiation. were. For this purpose, an additive such as cellulose, hydroxyethyl cellulose, polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), polyvinylpyrrolidone (PVP),

Polysorbart 80, sodium citrate, phosphate buffer for

Particle stabilization may be contained in the suspension. The presence of such an additive can also be found on the particles or. the suspension in which the particles are present.

For laser irradiation in step b) or. to form the laser arrangement in the corresponding device:

It can be provided that the liquid jet in step b) is irradiated with at least three laser beams from different directions in each case. Through this the liquid jet is reliably the

Exposed to laser radiation. Or . a particularly uniform intensity of the laser radiation within the liquid jet is guaranteed. The (two, three or more) laser beams can run rotationally symmetrically with respect to the liquid jet.

The laser beams are preferably pulsed

Laser beams. This can increase the effectiveness of the machining. A pulse repetition rate of the laser pulses is typically matched to the flow velocity of the liquid jet in such a way that all partial volumes of the liquid jet are hit by at least one laser pulse of all laser beams.

The laser beams can flow in the direction of flow

Liquid jet offset to each other on the

Hit liquid jet. In particular, however, it can be provided that at least two laser beams, in particular all laser beams, in the flow direction of the liquid jet at the same height on the

Hit liquid jet. In other words, the laser beams hit the same point in flow direction, i.e. in a common area of impact, on the liquid jet. This increases the energy acting on the particles captured by the laser beams and ensures that no liquid volumes are caused by the fluid-mechanical influences of irradiation

escape. In the case of pulsed laser beams, the individual pulses of the multiple laser beams preferably hit at the same time or at least substantially at the same time on the liquid jet.

Essentially simultaneous impingement means that a time offset of the impingement of the pulses of the multiple laser beams is so small that the particles do not cover any significant distances in the flow direction of the liquid jet during this time interval. Distances that are smaller can be regarded as insignificant distances,

in particular are one or more orders of magnitude smaller than a length (measured in

Flow direction of the liquid jet) of the laser-liquid interaction zone. In other words, the timing of the pulses can be based on the

The flow velocity must be coordinated so that no liquid volume passes the area of impact without being irradiated by a laser pulse. The laser beams preferably run in a common plane which, in particular, is oriented perpendicular to the liquid jet. This can further increase the effectiveness of the processing. In particular, diffraction effects when the laser beams strike the liquid jet can be avoided or at least reduced. In general, it is provided that the laser beams are each inclined or, in particular, at right angles to the direction of flow

Hit liquid jet. Especially with At right angles, diffraction and / or reflection effects can be reduced or avoided.

The lasers of the laser arrangement or. When carrying out the method, the liquid jet can in particular be directed at an angle to the flow direction that is smaller than or equal to the Brewster angle. It can be provided that depending on the type of radiation used and the optical

Properties of the phase boundaries between

Jet of liquid and surrounding air

The angle of incidence is selected at which the reflection when the laser beam hits the

Liquid jet is minimized and when the laser beam passes through, the transmission at the phase boundary between the liquid jet and the surrounding air is minimized when exiting. By using the internal reflections of the phase boundary, as much laser energy as possible can be held or in the liquid jet. can be used, while at the same time the reflection is minimized when entering.

As already described, the particles can be comminuted (fragmented) in step b). The

inventive method or. its step b) can be carried out several times in order to obtain or even smaller particles. to their size distribution

improve . In the method according to the invention and the device according to the invention, the pulse duration of the laser beams (in particular to bring about a comminution of the particles) can be in the picosecond range, ie at least one picosecond, in particular less than 100 picoseconds, in particular a few hundred

Picoseconds, but the pulse duration can also be more than a nanosecond (short-pulsed and ultra-short-pulsed laser radiation). A wavelength of

Laser beams, especially with a pulse duration im

Picosecond range can be at least 500 nm, preferably at least 520 nm, particularly preferably at least 530 nm, and / or the wavelength of the laser beams can be at most 560 nm, preferably at most 540 nm, particularly preferably at most 535 nm. The wavelength of the laser beams can in particular, for example. 532 nm or 1030 nm or 515 nm or 343 nm, with multiple laser beams with different wavelengths

can be used. In particular, Yb: YAG lasers can be used.

In an alternative to this, however, likewise

advantageous variant of the invention, the particles in step b) or. be remelted and / or fused in the device. When remelting the

Particles is at least a portion of the surface of the particles melted and it is after

Solidification of the particles gives the particles a different shape and / or a different surface structure. In other words, the particles can be reshaped, especially to obtain particularly round (spherical) particles. Furthermore, targeted defects,

especially in the surface of the particles. When merging, multiple particles

connected with each other . In this way, particles with special properties can be obtained. Particles can also be produced from hybrid materials. A chemical conversion of the particles can take place. The pulse duration of the laser beams can

(especially for remelting) are in the nanosecond range, i.e. be at least one nanosecond and less than one microsecond (short pulsed

Laser radiation). A wavelength of the laser beams (in particular for remelting or in particular with a pulse duration in the nanosecond range) can be at most 380 nm, preferably at most 360 nm, particularly preferably at most 350 nm, and / or the wavelength of the laser beams can be at least 310 nm, preferably

at least 330 nm, particularly preferably at least 340 nm. In particular, the wavelength is

Laser beams 343 nm.

The device can be designed in such a way that the laser beams in the area of incidence have a width which exceeds the diameter of the liquid jet. This also applies to the procedure. The device can, for example. one focusing device for each laser beam

have, via which the laser beam can be focused or. its width is adjustable. For the analysis in step c) or the analysis device and the analysis result:

The analysis of the suspension includes in particular a

Particle size measurement. The maximum

Particle size can be determined. That is also conceivable

Determination of the minimum particle size. In particular, however, it is provided that a size distribution of the particles is measured.

In the context of the present invention, it can be provided in particular that the device has a

Analysis device comprises which is used to carry out a (in particular on-line or off-line) measurement by means of dynamic light scattering (DLS) or laser diffraction

is trained. The method can comprise a corresponding analysis step c). By spreading to the

It is possible for particles of the suspension

To determine size distribution. Using dynamic

Light scattering allows measurements to be carried out in a short period of time, this method being particularly suitable for narrow size distributions, such as the one at hand

Device or the method are achievable, especially when the size distribution has only one mode.

In the context of the present invention, it can be provided in particular that the device has a

Analysis device comprises which is used to carry out an offline measurement by means of an analytical disc centrifuge is trained. The method can comprise a corresponding analysis step c). This analysis can be used for the analysis of one or more modes

Particle size distributions. Particles with a tendency to agglomeration can also be measured with this method.

In the context of the present invention, it can be provided in particular that the device has a

Includes analysis device which is designed to carry out a measurement by means of ultrasonic extinction.

The measurement can be carried out in-line, on-line or also off-line. The procedure can be a

corresponding analysis step c). In this way, in particular a particle size distribution can be recorded in-line, which, for example, can be used to quickly correct process parameters, if

Deviations from a target value are recorded.

According to the invention it can also be provided that an X-ray diffraction measurement is carried out as part of the method

Determination of the crystal structure of the particles is carried out or a corresponding analysis device can be provided in the device. It can in particular be provided that the crystal structure of the particles is determined or stored and / or compared with (for example with reference values, for example from previous measurements) on the basis of characteristic values obtained from the analysis. The corresponding measurement is typically carried out as an off-line measurement or the The analysis device is set up for an off-line measurement. In particular, it is provided that the

appropriate analysis is carried out on particles in the dried state. For this purpose, the method can include a drying step preceding the analysis (e.g.

Spray-drying or freeze-drying step) or the device a corresponding one

Include drying device.

According to the invention it can also be provided that a spectroscopic measurement in the

Analysis step c) is carried out. In the sense of the

In the present invention, it is provided in particular that the device comprises an analysis device which is used to carry out an on-line or in-line

Spectroscopy measurement (for example, spectroscopy in the UV, VIS, NIR or MIR range is conceivable), or it is provided that the method has a corresponding

Analysis step c) comprises. This provides a fast analysis method by means of which the suspension can be analyzed directly. In particular, this variant does not require a sample to be taken, which then has to be disposed of, which makes the method more efficient.

In the context of the present invention, it can be provided in particular that the device has a

Includes analysis device which is provided for performing an offline measurement by means of X-ray photoelectron spectroscopy (XPS). The procedure can be a

corresponding analysis step c). This is a chemical analysis of the surface of the particles is possible. In particular, it is provided that the corresponding analysis is carried out on particles in the dried state. For this purpose, the method can include a drying step preceding the analysis (e.g. spray drying or

Freeze-drying step (lyophilization) or the device include a corresponding drying device.

In the context of the present invention, it can be provided in particular that the device has a

Analysis device comprises, which for performing an offline measurement by means of nuclear magnetic resonance spectroscopy (NMR spectroscopy), for example. For the identification of chemical

Bonds of the particles is formed. The method can comprise a corresponding analysis step c).

According to the invention, it can also be provided that a chromatographic (in particular HPLC that is high-performance liquid chromatography) measurement is carried out within the framework of the method or the device comprises a correspondingly configured analysis device. The corresponding analysis device is typically designed to carry out an off-line measurement by means of high performance liquid chromatography (HPLC). It is also conceivable to use this analysis method as an in-line measurement, for example via a fluidic bypass, for example via the flow divider described in this application. A

Chromatographic separation can also be provided for purification or particle size selection. An in-line or on-line pH value and / or temperature measurement can also be provided.

It is also possible to use several of the just mentioned types of analysis or analysis devices in combination or to provide them in the device according to the invention.

According to the invention it can be provided that an analysis is carried out before and after the irradiation, by means of which the same measured variable (as already described above, e.g.

maximum or minimum particle size,

Particle size distribution or crystal structure) is recorded, in particular using the same measurement method.

According to the invention it can be provided that the

Liquid jet is separated in batches or

is collected in batches. This also means when the liquid jet between individual batches

is interrupted. According to the invention, an analysis result can be assigned to each batch as part of the method.

According to the invention, the result of the analysis can be stored in a database. In particular, within the framework of the method, a

assigned analysis result can be stored.

In the context of the method according to the invention, it can be provided that the analysis is on-line and / or in-line Measurement includes. So that at least part of the liquid of the liquid jet is continuously analyzed or the liquid jet itself is analyzed in real time. For this purpose, for example, the freely falling beam can be subjected to an analysis or measurement before or after the irradiation. It is also conceivable that the beam is captured and fed to an on-line measurement via a line. The liquid of the liquid jet can also before it reaches the jet generating device

will be subjected to an analysis or measurement before the irradiation is carried out.

In the context of the method according to the invention it can be provided that the analysis includes a batch measurement, in particular a batch measurement being carried out for each batch. This means that one measurement is carried out for each batch. This can be carried out "on-line" during the handling of the batch or "off-line" in such a way that in contrast to the on-line

measurements or analyzes carried out, first the batch is collected and then a sample is taken, which is subjected to an analysis or the whole

Batch is analyzed. For an analysis of the whole

Batch, a "contactless" analysis method (for example an optical measuring method) is preferably used, which can reduce the risk of contamination.

In the context of the method according to the invention it can be provided that the liquid of the liquid jet is divided into a main flow and a secondary flow. For many Analysis methods is only a small amount of

Liquid required. Correspondingly, the secondary flow can be fed to the analysis device and the main flow can already be processed further. It is also conceivable that the secondary flow is mixed again with the main flow after the analysis. The division into a main stream and a secondary stream is particularly useful for

Conducting on-line analyzes. The analysis results can be saved continuously in digital form. In particular, the method can compare newly determined analysis results with those that have already been determined, in particular in quasi real time

saved analysis results or others

Include reference values. It can be provided that, based on this comparison, an adjustment of

Process parameters is made. For example, parameters of the laser radiation, such as the

Pulse duration or intensity can be adjusted based on the calibration. It is conceivable, for example, that a certain maximum particle size is specified and

Analysis results are continuously compared with this target variable and the parameters of the laser radiation are adjusted until the analysis results match the target variable.

It is also conceivable that the analysis results can be sent to a

Database, for example from an official authority such as the European Chemicals Agency (ECHA) be transmitted. In particular, the transmission can take place in batches.

The analysis results can be stored in at least one blockchain within the scope of the invention. This enables forgery-proof continuous storage of the analysis results. In particular, the blockchain can be written on for a further batch. In this context, a blockchain is understood to mean a database whose integrity, i.e. Protection against subsequent manipulation by storing a hash value of a previous data record in the subsequent data record, i.e. by cryptographic

Concatenation, is secured. Exactly one blockchain can be provided. Several blockchains can also be provided. In particular, provision can be made for new data records to be created in the blockchain for each batch. The blockchain can be stored and processed in a distributed computing system. A central computing system can also be provided. Access rights to information from the blockchain can be configurable. Access to the blockchain can be restricted.

For example, a cryptographic key is used to provide a subscriber with the encrypted

Transmission of the status changes enables and thus prevents the readability of the status by unauthorized persons. This encryption can be chosen so that it does not affect the headers in this case

be transmitted unencrypted to enable the verification of a data record. Through cryptographic Key pairs can give one or more participants in the blockchain targeted access to encrypted

Data records are made possible without these becoming generally accessible to all other participants in the blockchain. It can also be provided that the

The method according to the invention is carried out on several corresponding devices and these devices each share their analysis results in a common

Write blockchain. Correspondingly, several

Devices according to the invention can be designed to be networked with one another in such a way that they can write their analysis results in a common blockchain.

To the device:

The device according to the invention comprises:

On the one hand, a beam generating device for generating one loaded with particles

Liquid jet. The

The jet generating device can for example be designed as a nozzle. The

Emitter generating device can be designed to be able to adjust the diameter of the liquid jet. In particular, can

be provided that the

Radiation generating device generates an unguided liquid jet. The device is preferably designed in such a way that the unguided liquid jet, in particular in a straight line, is generated in a freely falling manner. - further a laser arrangement. The laser arrangement is designed such that it is used for

Generating at least two laser beams is used. In particular, the laser beams can be pulsed. For this purpose, reference is made to the above statements on pulsed laser beams. The

Laser arrangement can be designed in accordance with the statements made there. The laser arrangement is designed such that there are two

Directs laser beams onto the liquid jet, the laser beams striking the liquid jet in different directions.

The corresponding advantages in connection with the avoidance of unirradiated sections of the liquid jet were already in

Connection with the procedure explained.

- Further a collecting vessel that is formed and

is arranged to the liquid of the

to collect irradiated liquid jet.

- and in addition or as an alternative to that

Collecting vessel an analysis device. The

Analysis device is designed and arranged in the device that the suspension of the liquid jet by means of the

Analysis device can be analyzed. This analysis can be done before or after irradiation

respectively . The analysis facility is for this purpose accordingly integrated into the device, e.g. Can be used via appropriate fluidic connections. It is also conceivable that an analysis can be carried out by means of the analysis device both before and after the irradiation.

For this purpose, the analysis device can in each case comprise separate measuring devices for the analysis upstream and downstream of the irradiation or use the same measuring device for both analyzes.

The device can further comprise an enclosure which is impermeable to the laser radiation of the laser beams.

The housing surrounds an impact area of the

Laser beams on the liquid jet to get a

Avoid leakage of laser radiation and the

To increase the operational safety of the device.

The device can comprise a reflection housing. The reflection housing is particularly around the

Area of impact, in particular all around, arranged around. The reflection housing has a

reflective inner, so the liquid jet facing surface. The (inner, dem

The surface facing the liquid jet is in particular designed and arranged in such a way that it emits laser radiation through the liquid jet

through it returns into the liquid jet

reflected. E.g. can be the inner surface of the

Reflection housing circular and concentric to Be formed arranged liquid jet. It can be provided that the reflection housing has several lenses (for example cylinder lenses) for coupling in the

individual laser beams into the reflection housing

having . The lenses are typically arranged and designed in such a way that they further direct the laser beam onto the liquid jet in the same direction in which it strikes the lens.

On the one hand, the reflective housing prevents

Laser radiation after by rays of the

Liquid jet emerges from the impingement area, which increases operational safety. On the other hand, better use is made of the laser radiation used, since radiation that has passed through the liquid jet is reflected back through the reflective housing and directed back onto the liquid jet.

The device preferably also has at least one power measuring device for measuring a residual power of at least one of the laser beams on the other side of the liquid jet. From the remaining power (if the output power is known) the

Degree of absorption when the laser beam hits or determine the laser beams on the liquid jet. The degree of absorption can be used to control the device for effective processing of the particles, for example for power regulation of the

Laser array The laser arrangement is preferably designed in such a way that the laser beams run in a common plane. The plane can in particular be aligned perpendicular to the liquid jet. The

Laser arrangement can comprise at least two, preferably three, lasers (in the sense of laser beam sources). However, the laser arrangement can also have precisely one laser and one beam splitter device for generating the at least two laser beams and at least two

Have light guide devices for guiding the at least two laser beams. See for example the above explanations on irradiation.

Typically, the device is set up in such a way that all laser beams are designed in the same way. In particular, all laser beams preferably have the same wavelength. In the case of pulsed laser beams, the pulse durations and are typically the same

Set pulse repetition rates. The light pulses of the laser beams hit the liquid jet preferably synchronously with one another. The pulse energy of the

individual laser beams can be identical. Alternatively, at least one of the laser beams can have a different pulse energy. The device can be used for

Implementation of the different types or

Further training of step b) must be set up.

The analysis device can be a

Include particle size measuring device. Of particular interest can be the maximum or minimal particle size or the size distribution of the particles before or after the irradiation.

The analysis device can be a

X-ray diffraction measuring device include. It can be of interest to characterize the crystal structure of the particles. In particular, it can be of interest to detect a change in the crystal structure. For this purpose, a corresponding measurement can be carried out before and after the irradiation and then the measurement results can be compared.

The analysis device can further a

comprise chromatographic measuring device.

For example, the molecular structure of the particles can be of interest. In particular, it may be of interest to check whether the irradiation changes the

chemical composition of the particles. In further developments, the analysis device can be a measuring device for performing spectroscopic

Measurements (e.g. photoelectron spectroscopy, Fourier transform infrared spectroscopy and / or UV / VIS spectroscopy). The analysis device can be a measuring device for performing a

Particle size analysis (e.g. using dynamic

Light scattering, analytical centrifugation or

Laser diffraction). The analysis device can be a measuring device for carrying out crystal analysis (for example by means of X-ray diffraction) or a chromatographic measurement (for example HPLC).

The device can be a flow divider device

include. The flow divider device is designed to the liquid of the liquid jet in a

Main stream and a secondary stream to share. The

The device can be set up in such a way that the secondary flow is fed to the analysis device. In particular, it can be provided that the secondary flow is merged or combined again with the main flow following the analysis. is mixed and the device has a corresponding line management. Such a flow divider device can be provided before and / or after the beam generating device.

The device can further comprise a portioning device. By means of the portioning device, it is possible, or the liquid jet. to portion its liquid in batches so that the individual batches are fluidically separated from one another. The

Portioning device can be coupled to the analysis and detection methods mentioned in such a way that automated portioning takes place as soon as the suspension and / or particle properties move outside of predetermined target values.

It can further be provided that the device comprises a filling device, by means of which one

certain amount of fluid that is already the Has undergone irradiation, can be transferred into a vessel. The device can also have a

Identifying device comprise which one

Relationship between a certain amount of

Liquid (for example a batch or part of a batch), which can be filled into a vessel, for example, and a data record that contains analysis results for this amount of liquids.

It can further be provided that the device comprises a removal device which is designed to remove sample volumes of the liquid from the liquid jet. The removal device can be in

Direction of flow in front of and (e.g. two

Extraction devices) / or after the

Beam generating device be arranged. The

Removal device can, for example, for a

manual sampling must be set up. Automated sampling is also conceivable, which

for example at certain time intervals or in response to a user-based control pulse

automated sampling and feeding to

Analysis device performs.

It can also be provided that the device comprises a sterile filtration device. The

Still filtration device enables aseptic filling of the liquid from the liquid jet into a vessel. It can be advantageous if the vessel

is sealable. This can be used directly after the Treatment of the particles, a filtration and filling of the particle suspension take place and, if the vessel is sealable, this is then sealed and the particles can be stored or removed in an unpolluted state. be delivered.

The device can also comprise a spray drying or freeze drying device. This enables the particles present in suspension to be easily converted into powder form. The integration of such a drying device into the device offers the advantage of a closed process chain in a single device. This can in particular reduce the risk of contamination during processing of the

Particles are reduced.

Correspondingly, the method according to the invention can also comprise a sterile filtration step or a spray drying or freeze drying step.

About the nanoparticles:

As already mentioned at the beginning, nanoparticles of a pharmaceutical active ingredient represent an independent part of the present invention. The nanoparticles were comminuted using steps a) and b) and analyzed using step c). The analysis result is available in a form that can be assigned to the nanoparticles. This can be used to provide evidence of quality, for example.

The analysis result can be available locally alternatively, in particular additionally, also have been transmitted to an external database and stored there, e.g. to the database of an authority.

The nanoparticles can be in the form of a batch that was fragmented under uniform process conditions in step b). The nanoparticles can be assigned a data record that includes the analysis result. In addition, the data record can be a characteristic of the irradiation in step b)

Include operating parameters.

The batch of nanoparticles can be in a mechanically manageable vessel. The vessel can

especially a machine-readable one

Include identification features (e.g. a QR code). This can simplify the assignment of the batch to the data record or the analysis result.

The nanoparticles can be present in a suspension in an aqueous medium. The suspension can further comprise an additive for particle stabilization. In the context of the invention is in particular cellulose,

Polyvinyl alcohol, polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), polysorbate 80 or another surface and / or interface-active substance is provided as an additive, as already mentioned at the beginning. The type and / or concentration of the additive can be contained in the data set. This means that a manageable amount of nanoparticles is available, with the Properties of the suspension liquid as well as the

Parameters for the production of the nanoparticles are available in a directly available and comprehensible form.

The particles can also using a

Spray drying or freeze drying step in

Have been transferred in powder form. The powdery particles can then have been transferred to a vessel as described above.

Further aspects and details of the present

Invention are illustrated in the accompanying drawing and described in more detail using exemplary embodiments:

Show it :

Fig. 1 shows a cross section through a

Liquid jet when processing with a method according to the prior art;

2 shows a device according to the invention with two

Lasers in a schematic side view;

Fig. 3 shows a laser arrangement with three lasers in the

Processing of particles in one

Liquid jet, in a schematic plan view; Fig. 4 shows a schematic representation of the impingement of the laser beams on the liquid jet when the particles are processed with the laser arrangement of FIG. 3;

Fig. 5 is a flow chart of an inventive

Method for processing particles;

Fig. 6 shows a device according to the invention with two

Lasers in a schematic side view;

Fig. 7 shows a further laser arrangement with three lasers when processing particles in a liquid jet, in a schematic plan view;

8 shows a further laser arrangement with three lasers during the processing of particles in a liquid jet, in a schematic plan view;

Fig. 9 a further flow diagram of a

inventive method for processing particles; ;

Fig. 10 is a schematic representation around a

Impact area when looking along a liquid jet; Fig. 11 a schematic representation around one

Area of impact when looking orthogonal to the liquid jet;

Fig. 12 a schematic representation around one

Area of impact when looking along a jet of liquid;

Fig. 13 shows a further laser arrangement with two lasers during the processing of particles in a liquid jet, in a schematic plan view; and

Fig. 14 shows a further laser arrangement with a laser processing particles in a liquid jet, in a schematic plan view.

Figure 1 shows a cross section through one

Liquid jet 1 with particles (not shown) during processing with a single laser beam 2 according to the prior art according to EP 2 735 390 A1.

The laser beam 2 detects the liquid jet 1 in its entire width coming from the beam direction. The laser radiation is, however, diffracted when it strikes the interface 3 between the liquid jet 1 and the environment 4 (air). As a result of the diffraction, in addition to an irradiated section 5, sections 6 also arise within the cross section of the liquid jet 1, which cannot be reached by the laser beam 2. In these sections 6 not recorded

Particles are therefore not hit by the laser radiation and cannot be processed.

FIG. 2 shows a device 10 according to the invention for processing particles. The device 10 comprises a beam generating device 12 for generating a liquid jet 14 loaded with particles. The device 10 further comprises a laser arrangement 16 with two lasers 18a, 18b. The lasers 18a, 18b send pulsed

Laser beams 20a, 2 Ob. The laser beams 20a, 2 Ob are from opposite directions on the

Liquid jet 14 directed. The laser arrangement 16 and the beam generating device 12 are arranged overall within a housing 22. The housing 22 is impermeable to the laser radiation of the laser beams 20a, 2 Ob. The device 10 further comprises a first analysis device 23a and a second

Analysis device 23b.

The beam generating device 12 comprises a

Storage vessel 24 in which a liquid 26, here an aqueous liquid 26, is suspended therein

Particles (not shown) is held. A jet generating device 27 with a nozzle 28 is arranged on the storage vessel 24.

The radiator generation device 27 or. Nozzle 28 lets the liquid 26 with the particles out of the Exit storage vessel 24 so that the

Liquid jet 14 is created. The nozzle 28 works here without pressure (from the back pressure of the liquid in the

Storage vessel 24 apart). In an alternative not shown, the nozzle 28 with a pump could

Jet generating device 27 may be connected, which would allow the liquid 26 to emerge from the nozzle 28 under pressure. After exiting the nozzle 28, the falls

Liquid jet 14 freely (unguided) below

Influence of gravity straight down. Different geometries of the nozzle are conceivable here, resulting in advantageous shape changes

Liquid surface geometries can lead to unwanted refractions of the laser radiation

reduce and if necessary let minimize. For example, nozzle geometries can be provided in a slot shape.

After the particles carried along in the liquid jet 14 have been processed by the laser beams 20a, 2 Ob, the liquid jet 14 with the processed particles reaches a collecting vessel 30. In the collecting vessel 30, a liquid 32 with the processed particles suspended therein collects. The storage vessel 24

and the collecting vessel 30 can be vertical, for example. be spaced between 10 cm and 1 m.

In the present example, the storage vessel is 24

fluidly connected to the analysis device 23a.

This allows liquid from the storage vessel 24 to the analysis device 23a. The fluidic connection 34 shown in Figure 2 is only

shown symbolically and also includes a possibility of returning the removed liquid. On

appropriately trained way is that

Analysis device 23a or with the collecting vessel 30 via a further fluidic connection. Line 36 connected. This enables the analysis of the liquid 32 with the processed particles.

The analysis device 23a also includes a

Measuring device for performing measurements on

Liquid jet 14 per se, which is symbolically represented by the arrow with the reference symbol 33. The fluidic connection or. Line 34 connects the analysis device 23a in the present example with the storage vessel 24. The line 34 can, however, for example. also be connected directly to the beam generating device 28. The further line 36 for the analysis device 23a, in the present case the collecting vessel 30 with the

Connecting analysis device 23a, can alternatively, for example, also with a derivation 38 from the

Collecting vessel 30 be connected. A discharge line 38 serves to discharge the liquid 32 from the collecting vessel 30.

The discharge line 38 in the present example comprises a flow divider device 40, via which a secondary flow 42 can be separated from a main flow 44 of the liquid 32, which is discharged from the collecting vessel 30. In the present example, this secondary stream 42 is fed to an analysis device 23b, which can be provided in the device 10 in addition or as an alternative to the analysis device 23a. After the liquid has been analyzed in the analysis device 23b, the

Secondary stream 42 is fed back to main stream 44 and mixed with it.

The main stream is then optionally one

Drying device 46 or one

Sterile filtration device 48, the one

Filling device 48 for filling the suspension comprises a corresponding vessel 50.

The vessel 50 has an identification feature 52, which in the present case is designed as a QR code.

In addition to the discharge line 38 and the line 36, the collecting vessel 30 is also fluidically connected to a removal device 54. In the present case, it is possible to take samples manually using the removal device 54.

The two lasers 18a, 18b of the laser arrangement 16 are shown in FIG

Figure 2 at the same level with respect to a

Flow direction of the liquid jet 14 is arranged. The laser beams 20a, 2 Ob meet in a common

Area of incidence 55 on the liquid jet 14. The area of incidence 55 and a path of the laser beams 20a,

2 Whether between lasers 18a, 18b and the area of impact

34 lie within the housing 22. FIG. 3 shows an alternative laser arrangement 16 with three lasers 18a, 18b, 18c during the processing of

Particles 56, which in a liquid jet 14

be carried.

The lasers 18a, 18b, 18c are here arranged rotationally symmetrically with respect to the liquid jet 14

(here at an angle of 120 ° to each other). The

Laser beams 20a-20c run in a common horizontal plane 60 (the plane of the drawing) perpendicular to the liquid jet 14.

In the present case, focusing devices 62, which in the present example are designed as lens optics 62a, 62b, 62c, are provided for focusing the laser beams 20a-20c on the liquid jet 14.

Figure 4 shows an enlarged representation of the

Impact area 55 of the laser beams 20a-20c on the liquid jet 14 during the processing of the particles 56 with the laser arrangement 16 according to FIG

The diameter 64 of the liquid jet 14 is less than a width 66 of the laser beams 20a-20c. FIG. 5 shows a flow chart of a method according to the invention for processing particles. The method can be carried out with the device 10 already described. In a first step 100, a liquid jet 14 is generated, in which particles 38 are entrained.

In a step 102, the liquid jet 14 is irradiated with several, preferably pulsed, laser beams 20a-20c from different directions. The particles 38 in the liquid jet 14 are processed by the laser beams 20a-20c. One of the laser arrangements 16 described above can be used for this purpose.

In a step 104, the suspension is analyzed after the irradiation by means of the laser beams 20a-20c. The result of the analysis is transmitted to a database 106, in which it is in a correspondingly treated or. crushed particles 56 assignable manner is stored.

FIG. 6 shows a device 10 according to the invention for processing particles. The device 10 comprises a device 12 for generating a jet 14 of liquid loaded with particles. The device 10 further comprises a laser arrangement 16 with two lasers 18a, 18b. The lasers 18a, 18b send pulsed

Laser beams 20a, 2 Ob. The laser beams 20a, 2 Ob are from opposite directions on the

Liquid jet 14 directed. The laser arrangement 16 and the device 12 are, as in FIG. 2, arranged as a whole within an enclosure 22. The device 12 comprises a storage vessel 24 in which a liquid 26, here an aqueous liquid 26, with particles (not shown) suspended therein is stored. On the storage vessel 24 is one

Jet generating device 27 with a nozzle 28

arranged. The nozzle 28 works here without pressure but can also be operated under pressure. After exiting the nozzle 28, the liquid jet 14 falls freely (unguided) under the influence of gravity.

After the particles carried along in the liquid jet 14 have been processed by the laser beams 20a, 2 Ob, the liquid jet 14 with the processed particles reaches a collecting vessel 30. In the collecting vessel 30, a liquid 32 with the processed particles suspended therein collects. See also figure 2.

FIG. 3 shows a laser arrangement 16 with three lasers 18a, 18b, 18c, similar to FIG. 3. This laser arrangement 16 could be used in the device 10 according to FIG. 2 or 6 instead of the laser arrangement 16 shown there.

The laser beams 20a-20c run here in a common horizontal plane 40 (the plane of the drawing) perpendicular to the liquid jet 14 and are

arranged rotationally symmetrically with respect to the liquid jet 14. Two of the laser beams 20a-20c each enclose an angle of 120 ° between them. In addition to a respective lens system 62a, 62b, 62c, a power measuring device 68a, 68b, 68c is arranged for each of the lasers 18a-18c. The power measuring devices 68a-68c determine the remaining powers of the respective ones

Laser beams 2 Oa-20c after this with the

Liquid jet 14 and the particles 38 interacted, in particular the particles 38 processed.

Figure 5 shows a laser arrangement 16 for a

Device 10 with exactly one laser 18 in the

Processing of particles 56 in a

Liquid jet 14 are carried along.

The laser assembly 16 includes a

Beam splitter device 72. The beam splitter device 72 divides the laser radiation emitted by the laser 18 into three separate laser beams 20a, 20b, 20c. The laser assembly 16 further includes three

Light guide devices 70a, 7 Ob, 70c. The

Light guide devices 70a-70c guide the laser beams 20a-20c to the liquid jet 14. Die

Light guide devices 70a-70c are here as

Fiber optic cable trained. For focusing or. Shapes of the laser beams 2 Oa-20c cannot be closer

exit optics shown on the

Light guide devices 70a-70c may be provided. In the embodiment according to FIG. 5 will be the

Particles 56 by the laser beams 2 Oa-20c are remelted (melted) and fused. A wavelength of the laser beams 2 Oa-20c is 343 nm here. A

The pulse repetition rate of the laser beams 2 Oa-20c may be 100 Hz or more. A pulse duration of the light emission can be 10 nanoseconds. The laser beams 20a-20c can each have a fluence of at least 0.5 J / cm2. The aqueous liquid 26 can be a

contain inorganic oxidizing agent. The particles 38 can consist of gold or platinum.

FIG. 9 shows a flow chart of a method according to the invention for processing particles. The method can be carried out with the devices 10 described above

be performed .

In a first step 100, a liquid jet 14 is generated, in which particles 38 are entrained. A device 12 according to FIG. 2 can be used for this purpose.

Then, in a step 102, the liquid jet 14 is irradiated with several, preferably pulsed, laser beams 20a-20c from different directions.

The particles 38 in the liquid jet 14 are processed by the laser beams 20a-20c. One of the above-described laser arrangements 16

can be used. In a first step 100, a liquid jet 14 is generated, in which particles 38 are entrained.

In a step 102, the liquid jet 14 is irradiated with several, preferably pulsed, laser beams 20a-20c from different directions. The particles 38 in the liquid jet 14 are processed by the laser beams 20a-20c. One of the laser arrangements 16 described above can be used for this purpose.

In a step 103, the liquid 32 (with processed particles) of the liquid jet 14 is collected in a collecting vessel 30.

Figures 10, 11 and 12 illustrate the use of a

Reflection housing 74. The device 10 can,

in particular in the area of the impact area 55, comprise a reflection housing 74. In Figure 10, the arrangement of a reflective housing 74 is around the

Area of impact 55 of a single laser beam 20 is shown. Further laser beams 20 are provided in planes arranged offset thereto along the flow direction 76 of the beam.

The reflection housing 74 is in particular around the

Impact area 55, in particular over the entire circumference, arranged around. The reflection housing 74 has a reflective inner one, that is to say it faces the liquid jet

Surface 78 on. The (inner, the liquid jet facing) surface 78 is in particular designed and arranged such that it reflects laser radiation that passes through the liquid jet 14 back into the liquid jet 14. E.g. the inner surface 78 of the reflective housing 74 can be

be arranged circular and concentric to the liquid jet 14. It can be provided that the reflective housing 74 has a plurality of lenses 80 (e.g.

Cylindrical lenses) for coupling the individual

Has laser beams 20 in the reflection housing 74. The lenses 80 are typically of this type

arranged and designed so that they further direct the laser beam 20 onto the liquid jet 14 in the same direction in which it strikes the lens 80.

The reflection on the inner surface 78 is in each case by corresponding in FIGS. 10 to 12

Arrow courses 82 shown.

A variant is shown in FIG. 12 in which three laser beams 20a, 2 Ob and 20c in one plane through corresponding lenses 80a, 8 Ob and 80c

Reflection housing 74 are coupled in and strike the liquid jet 14 there and are correspondingly reflected on the inner surface 78 of the reflection housing 74. The coupling does not necessarily have to take place via lenses 80. It can also be provided that the

Laser beams 20 are guided onto the beam 14 at an angle that runs obliquely to the direction of flow 76, so that, as shown in FIG. 13, they can be guided into the reflection housing 74 from below or from above, for example.

The lasers 20 of the laser arrangement or when carrying out the method can in particular be directed at an angle to the flow direction 76 of the liquid jet 14 which is smaller than or equal to the Brewster angle. Brewster's angle is represented by line 84 in FIG. It can be provided that depending on the type of radiation used and the optical properties of the phase boundaries between

Liquid jet 14 and surrounding air

Angle of incidence 86 is selected at which the

Reflection when the laser beam 20 strikes the liquid jet 14 is minimized and when

When the laser beam 20 passes through the transmission at the phase boundary between the liquid jet 14 and

surrounding air is minimized when exiting. In FIG. 14, a further laser is provided which radiates onto the liquid jet 14 from a different direction, but this is not shown.

In addition to the following

Claims also define inventions, each in combination with those mentioned in the description Further training is to be understood as possible. The individual features mentioned in the aspects are also to be understood as possible developments of the inventions described in the description and the claims.

Aspects:

Method for processing particles with the

Steps,

a) generation of a liquid jet in which the particles are entrained,

b) irradiating the liquid jet with at least two, in particular pulsed, laser beams from different directions.

2. The method according to aspect 1, characterized in that the liquid jet in step b) is irradiated with at least three, in particular pulsed, laser beams from respectively different directions.

3. The method according to aspect 1 or 2, thereby

characterized in that the laser beams are rotationally symmetrical with respect to the liquid jet.

4. The method according to any one of the preceding aspects, characterized in that the laser beams in

The direction of flow of the liquid jet hit the liquid jet at the same height. 5. The method according to any one of the preceding aspects, characterized in that the laser beams run in a common plane.

6. The method according to any one of the preceding aspects, characterized in that the particles are comminuted in step b).

7. The method according to aspect 6, characterized in that a pulse duration of the laser beams is in the picosecond range.

8. The method according to aspect 6 or 7, thereby

characterized in that a wavelength of the laser beams is at least 500 nm, preferably at least 520 nm,

particularly preferably at least 530 nm, and / or that the wavelength of the laser beams is at most 560 nm, preferably at most 540 nm, particularly preferably

at most 535 nm, very particularly preferably that the wavelength of the laser beams is 532 nm.

9. The method according to any one of aspects 1 to 5, characterized in that the particles in step b)

be remelted and / or merged.

10. The method according to aspect 9, characterized in that a pulse duration of the laser beams in

Nano-second range. 11. The method according to one of aspects 9 or 10, characterized in that a wavelength of the laser beams is at most 380 nm, preferably at most 360 nm, particularly preferably at most 350 nm, and / or that the wavelength of the laser beams is at least 310 nm,

preferably at least 330 nm, particularly preferred

is at least 340 nm, very particularly preferably that the wavelength of the laser beams is 343 nm.

12. The method according to any one of the preceding aspects, characterized in that the liquid jet falls freely down under the influence of gravity.

13. Having apparatus for processing particles

- a device for generating a jet of liquid loaded with particles,

- a laser arrangement for generating at least two, in particular pulsed, laser beams,

wherein the laser arrangement is set up to generate the at least two laser beams from in each case

different directions to direct the liquid jet.

14. The device according to aspect 13 further comprising a housing which is impermeable to the laser radiation of the laser beams and which has an impact area of the

Laser beams surrounding the liquid jet. 15. Device according to aspect 13 or 14, thereby

characterized in that the laser arrangement comprises at least two, preferably three, lasers. 16. Device according to aspect 13 or 14, thereby

characterized in that the laser arrangement has exactly one laser, one beam splitter device for generating the at least two laser beams and at least two

Having light guide devices for guiding the at least two laser beams.

17. Device according to one of aspects 13 to 16

further comprising at least one

Power measuring device for measuring a residual power of at least one of the laser beams beyond the

Liquid jet.

Claims

Claims A method for processing particles (56) in a suspension, the method comprising the steps of: a) generating (100) a liquid jet (14) in which the particles (56) are entrained; b) irradiating (102) the liquid jet (14) with at least two, in particular pulsed, laser beams (20a, 20b, 20c) each from different ones Directions, particularly to comminute the particles (56); c) analysis (104) of the suspension before and / or after the irradiation by means of the laser beams (20a, 20b, 20c); and or d) collecting the liquid (32) of the liquid jet (14) in a collecting vessel (30). 2. The method according to claim 1, characterized in that the analysis (104) of the suspension a Particle size measurement, an X-ray diffraction measurement and / or a chromatographic measurement. 3. The method according to claim 1 or 2, characterized characterized in that an analysis is carried out before and after the irradiation, by means of which the same measured variable is recorded, in particular using the same measurement method. 4. The method according to any one of the preceding claims, characterized in that the liquid jet (14) is collected in batches and each batch one Analysis result is assigned. 5. The method according to any one of the preceding claims, characterized in that the result of the analysis (104) is stored in a database (106), in particular an analysis result assigned to each batch is stored in the database (106), in particular with the analysis results in at least one blockchain can be stored. 6. The method according to any one of the preceding claims, characterized in that the analysis (104) comprises an on-line and / or an in-line measurement. 7. The method according to any one of the preceding claims, characterized in that the analysis (104) comprises a batch measurement, in particular a batch measurement being carried out for each batch. 8. The method according to any one of the preceding claims, characterized in that the liquid of the The liquid jet (14) is divided into a main stream (44) and a secondary stream (42) and the analysis (104) is carried out on the liquid of the secondary stream (42) is carried out, in particular with the secondary stream (42) following the analysis again with the Main stream (44) is mixed. 9. The method according to any one of the preceding claims, characterized in that it comprises a sterile filtration step in which the liquid des The liquid jet (14) is aseptically filled into a, in particular sealable, vessel (50). 10. The method according to any one of the preceding claims, characterized in that it comprises a spray-drying or freeze-drying step in which the particles (56) present as a suspension in the liquid are converted into powder form. 11. The method according to any one of the preceding claims, characterized in that the analysis results are compared with a target variable or a preceding analysis result and the irradiation (102), in particular the pulse duration and / or laser power, in step b) based on this comparison, if necessary is adjusted. 12. Apparatus (10) for processing particles (38) comprising: a beam generating device (12) for generating one loaded with particles (56) Liquid jet (14), a laser arrangement (16) for generating at least two, in particular pulsed, laser beams (20a, 20b, 20c), the Laser arrangement (16) is set up to the at least two laser beams (20a, 20b, 20c) from different directions on the To direct the liquid jet (14), a collecting vessel which is designed and arranged to collect the liquid (32) of the irradiated liquid jet (14), and optionally at least one Analysis device (23a, 23b) which is set up to analyze the suspension before and / or after the irradiation (102) by means of the laser beams (20a, 20b, 20c). 13. Device according to the preceding claim, characterized characterized in that the analysis device has a Particle size measuring device, a X-ray diffraction measuring device and / or a chromatographic measuring device comprises. 14. Device according to one of the preceding claims 12 or 13, characterized in that the device (10) comprises a flow divider device (40) which is designed to absorb the liquid of the To divide the liquid jet (14) into a main stream (44) and a secondary stream (42), the device (10) being designed such that the secondary stream (42) is fed to the analysis device (23a, 23b), in particular wherein the secondary stream ( 42) is recombined with the main flow (44) following the analysis (102). 15. Device according to one of the preceding claims 12 to 14, characterized in that the device (10) comprises a portioning device which is designed to portion the liquid of the liquid jet (14) into batches and to fluidically separate the batches from one another. 16. Device according to one of the preceding claims 12 to 15, characterized in that the device (10) comprises a sampling device (54) which is designed to take sample volumes of the liquid from the To be taken from the liquid jet (14). 17. Device according to one of the preceding claims 12 to 16, characterized in that it is a Sterile filtration device (48) for the aseptic filling of the liquid of the liquid jet (14) into an, in particular sealable, vessel (50). 18. Device according to one of the preceding claims 12 to 17, characterized in that it is a Drying device (46), in particular one Spray-drying or freeze-drying device, which is designed for the purpose of the To convert liquid present as a suspension particles (56) in powder form. 19. Nanoparticles which comprise a pharmaceutical active substance, in particular consist of a pharmaceutical active substance, characterized in that they are made using a method according to one of the Claims 1 to 11 were fragmented, the nanoparticles being assigned an analysis result which was obtained by analysis step c). 20. Nanoparticles according to the previous claim, characterized characterized in that the nanoparticles are in the form of a Batch are present that were fragmented under uniform process conditions in step b), the nanoparticles being assigned a data record which includes the analysis result and in particular at least one operating parameter characteristic of the irradiation (102) in step b). 21. Nanoparticles according to the previous claim, characterized characterized in that the batch of nanoparticles is present in a mechanically manageable vessel (50) and the vessel (50) is a machine-readable one Identification feature (52) which uniquely assigns the data record to the vessel (50), in particular wherein the nanoparticles using a Sterile filtration were transferred into the vessel (50). 22. Nanoparticle according to one of the preceding claims 19 to 21, characterized in that the nanoparticles are present in a suspension in an aqueous medium, in particular wherein the suspension comprises an additive for particle stabilization, in particular Cellulose, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), sodium dodecyl sulfate (SDS) or another surface-active substance, in particular where the type and / or concentration of the additive is contained in the data set. 23. Nanoparticle according to one of the preceding claims 19 to 21, characterized in that the particles (56) using a spray drying or Freeze-drying step were converted into powder form.