Method for initiating crystallization by means of plasma and crystallization generator

Abstract

The invention relates to a method for initiating the crystallization of a solute present in a solution (S) at a concentration that makes it metastable, comprising the application of one or more plasma pulses to the solution (S).

Description

[0001] Description

[0002] Title: Plasma crystallization initiation process and crystallization generator

[0003] The present invention relates to a method for crystallizing a solute present in a solution, in particular to initiating crystallization from a metastable state of the solute dissolved in the solution, and to a crystallization generator enabling such crystallization to be initiated.

[0004] Previous technique

[0005] Crystallization is a crucial operation in many industrial processes, particularly in the pharmaceutical industry, where crystal characteristics, such as polymorphism, morphology, and size distribution, must be precisely controlled. These characteristics directly influence subsequent crystal processing, especially filtration, and / or the therapeutic efficacy of drugs, particularly their bioavailability.

[0006] Thus, industrial crystallization relies on the conditions for initiating crystallization to guarantee the quality of the crystals, in particular obtaining a distribution of crystals calibrated in size and exhibiting a precise crystallographic shape.

[0007] Currently, seeding is the primary method used to initiate crystallization on an industrial scale. This method involves introducing a primer, consisting of a precise mass of powder with a calibrated size distribution and a precise crystalline shape, into the solution. However, this method has several drawbacks. From a regulatory standpoint, seeding is intrusive and introduces a risk of solution contamination, requiring specific and costly management of both the primer batch and the solution. Logistically, a batch of primers must be maintained for each type of primer and regularly characterized to ensure its stability in order to be able to quickly initiate product production. From a safety perspective, seeding can be hazardous to the operator due to the potential explosive atmosphere generated by organic solvent vapors and the potential toxicity of the primer.Finally, increasing the production capacity required for an industrial-type process necessitates the production of a primer consisting of a larger mass of powder, with seeding protocols to be defined at each change of scale, which complicates the launch of industrial production.

[0008] Other external field initiation techniques, such as laser, electric field, and ultrasound, have been investigated. However, most of these techniques are limited to small, stagnant volumes of solution containing the solute to be crystallized and do not allow for satisfactory stability and reproducibility of the crystals produced. Only sonocrystallization, using ultrasound, has reached the pharmaceutical pilot scale, but its high power consumption is prohibitive due to its impact on production costs and its propensity to cause secondary nucleation by breaking the produced crystals, making it less efficient than seeding as described above.

[0009] Several publications report the ability of a continuous plasma flow to trigger crystallization in solution, notably the articles by Dubinov AE and Lyubimtsevaa VA, "Rapid Crystallization of Natural Sugars in Bee's Honey under the Influence of Nanosecond Microdischarges," Cryst Growth Des. 15(10) 4975-8 (2015), 10.1021 / acs.cgd.5b00889, and Ito et al. 2011, "Plasma-Assisted Biological Macromolecular Crystallization," Appl. Phys. Express 4 026201, doi: 10.1143 / APEX.4.026201. However, none of these publications provide methods for controlling initiation and integrating plasma crystallization under conditions representative of industrial situations.

[0010] Description of the invention

[0011] There is therefore a need for a crystallization process, particularly for initiating crystallization, involving a solute in a solution in which it is dissolved, enabling controlled and precise crystallization at low cost. Furthermore, there is a need for a simple, safe crystallization process, capable of meeting stringent safety standards, requiring minimal upstream logistics, and easily scalable for industrial production.

[0012] There is also a need for a crystallization generator to implement such a process.

[0013] The invention addresses this need by means of a method for initiating the crystallization of a solute present in a solution at a concentration that gives it a metastable state, comprising the application of one or more plasma pulses to the solution.

[0014] By "metastable state", it is understood that the solution is in a state between the solubility limit of the compound in the solution and the limit of the metastable zone defined by the spontaneous and instantaneous crystallization of the solution, that is to say without external intervention and in less than a few seconds.

[0015] The term "application of one or more plasma pulses" refers to bringing the solution into contact with a small amount of gas plasma for a brief period, once or several times. Preferably, apart from the plasma pulses, the solution is not in contact with a gas plasma. The process may involve applying a plasma for the plasma pulse only for a predetermined duration.

[0016] Each plasma pulse can have a total application time to the liquid of between 10 ns and 1 s.

[0017] The process according to the invention can be implemented in a crystallization reactor without requiring human intervention within the reactor. Initiation is achieved by seeding created in situ. Indeed, the localized application of the plasma generates localized nucleation that forms a primer with a repeatable crystallographic structure. The invention notably allows the primer structure to be adapted according to the plasma parameters and the conditions of the plasma application.

[0018] This process allows for non-intrusive and controllable crystallization initiation, offering numerous implementation advantages over conventional seeding initiation, commonly used in the pharmaceutical industry. In particular, it reduces the risk of contamination, eliminates the need to store batches of primers, and minimizes handling. Because the process is controllable, it allows for easy variation of the crystallization initiation protocol during research and development trials, enabling the identification of optimal conditions for obtaining a predefined crystal powder with minimal operator intervention.Furthermore, unlike conventional priming methods, which are limited by the number and type of primer batches available, the process according to the invention allows for greater versatility in primer types and the performance of a large number of industrial tests or primings without the issue of primer availability and quality. This can free up operator time and allow for testing a wider range of conditions.

[0019] Furthermore, the precision of the plasma characteristics and the precision of the localization in the solution of the initiation generated by this process allows for a quality of crystals, as well as a reproducibility of the initiation, compatible with industrial and pharmaceutical requirements.

[0020] Furthermore, since the energy is delivered in a timely and precise manner, this reduces overall electricity consumption, making it eligible for industrialization.

[0021] Using one or more plasma pulses allows for a short-duration and precise application of the plasma to the solution, thus improving crystallization accuracy and reproducibility. As we will see later, the plasma pulse(s) can be generated from a gas emitted for a short duration or from a continuous gas stream. When the gas is introduced into the liquid, the plasma pulse(s) can be generated within one or more gas bubbles.

[0022] Injection of plasma formed from a gas emitted for a short duration, particularly with synchronization with the gas emission, allows for better control and reproducibility of the initiation.

[0023] A virtually continuous gas injection with a plasma produced by a sequence of one or more electrical discharges allows for the production of a large quantity of nuclei, which can be advantageous for industrial-scale production. Furthermore, the fact that the process can be controlled without operator intervention in the crystallization reactor improves crystallization safety. This also makes it possible to impose atmospheric conditions within the crystallization reactor, which can be a closed chamber, that comply with strict safety standards, or to operate it in a sterile environment—something much more difficult to achieve with conventional seeding methods.

[0024] Preferably, the application of the plasma pulse(s) is a spatially localized application with the liquid.

[0025] Preferably, the process is devoid of a step involving the insertion of a crystallization primer of the solute into the solution.

[0026] Preferably, the plasma formed is an atmospheric pressure plasma, otherwise known as a cold plasma.

[0027] The process may include the formation of the plasma pulse(s). This formation may involve applying a sequence of one or more pulsed electrical discharges to the gas in a crystallization generator to generate the plasma pulse(s), particularly at the gas outlet of the crystallization generator. The pulsed electrical discharge(s) ionize the gas without a significant temperature change to form the plasma, including cold plasma. The process may also include emitting the gas from the crystallization generator outlet and applying the sequence of electrical discharge(s) to the gas to form the plasma pulse(s).

[0028] Each plasma pulse can be applied to a gas bubble formed in the liquid and generated under pressure conditions allowing its formation at the outlet of the crystallization generator.

[0029] In particular, the formation of the or each plasma pulse may involve the application, to the gas, in a crystallization generator, of a pressure pulse or volumetric gas flow rate pulse, and the application, to the gas, of one or more pulsed electrical discharges synchronized with the pressure pulse or volumetric gas flow rate pulse to generate the or each plasma pulse, notably at the outlet of the crystallization generator.

[0030] The pressure pulse applied to the gas can be at an overpressure of 50 mbar or less, preferably 20 mbar, preferably 10 mbar, or even better, 7 mbar. It can be between 1 and 20 mbar. Such an overpressure value for the pressure pulse allows the formation of one or more gas pulses intended to be ionized by electrical discharges, with sufficient size while limiting the contact area between the plasma and the liquid to reduce the risk of heterogeneous nucleation at the interface between the plasma pulse(s) and the liquid. The pressure pulse can have a predetermined duration, in particular 5 s or less, preferably 1 s or less, or even better, 0.5 s or less. It can be between 0.2 and 10 s, preferably between 0.05 and 3 s.Such a duration of the pressure pulse allows to have a plasma pulse or a train of plasma pulses of temporally short duration, which improves the reproducibility of the initiation and therefore the quality of the crystallization.

[0031] Alternatively, the process involves applying a plurality of plasma pulses formed in a substantially continuous gas flow for a predetermined duration by applying several pulsed electrical discharge sequences to the gas at the outlet of the crystallization generator with a duty cycle between 1 and 100%, the duty cycle being defined as the ratio between the duration of one electrical discharge sequence(s) and the duration between the start of two successive sequences.

[0032] The predetermined duration of the application of plasma pulses can be less than or equal to 10 min.

[0033] Each sequence may consist of one or more pulsed electrical discharges, typically between 1 and 200,000 discharges. The discharge frequency of each sequence may be fixed, preferably between 1 Hz and 200 kHz, ideally between 10 Hz and 50 kHz. The total duration of each sequence, corresponding to the duration of the discharge train, may be between 10 ns (for a single discharge) and 1 s (for 200,000 discharges).

[0034] Each electrical discharge can have a duration between 0.1 ns and 10 ps, ​​ideally between 1 and 100 ns, ideally between 1 and 50 ns, and ideally between 5 and 20 ns. Each electrical discharge can have a peak voltage between 1 kV and 50 kV, ideally between 1 and 40 kV.

[0035] The frequency, number, duration, and peak voltage of the electrical discharges, as well as the frequency of each discharge in one or more sequences, can be predetermined, particularly experimentally, based on the characteristics of the crystals to be formed, including their average size, size distribution, and crystalline structure. The characteristics of the sequence(s) can be easily predetermined, particularly experimentally, for crystals exhibiting characteristics predetermined by testing.

[0036] Electrical discharges can be sinusoidal voltage discharges or, preferably, pulses of substantially constant positive or negative voltage. Electrical discharges can be of positive, negative, or bipolar polarity.

[0037] In the case of multiple sequences forming a plasma pulse, the sequences may all be identical. Alternatively, at least two of the sequences may differ from each other, particularly in one or more of the aforementioned parameters, especially in the case of a bipolar voltage.

[0038] The process may involve the application of several plasma pulses forming a plasma pulse train. The number of plasma pulses in this pulse train may be less than or equal to 1500, preferably less than or equal to 1000, and even better, less than or equal to 200. The pulse train may have a duration of less than 15 minutes, preferably less than or equal to 10 minutes. The pulses may all be identical; in particular, the plasma of the pulses may be formed under the same conditions for all pulses, notably with an identical sequence of electrical discharges for each plasma pulse. Alternatively, at least two pulses may differ with respect to the plasma they contain, notably by plasmas formed by different sequences of one or more electrical discharges.

[0039] The process may include a step to control the gas temperature upstream of the formation of the plasma pulse(s), at a temperature less than 25°C below the solution temperature, and in particular less than 10°C below the solution temperature. Preferably, the temperature control step is present when the gas flow rate is greater than or equal to IL / min. This helps to limit the risk of thermal shock that could potentially trigger crystallization, especially at this flow rate, which could disrupt crystallization control and thus reduce crystallization performance or prevent the production of crystals with the desired characteristics.

[0040] The process may involve applying a variable or fixed ballast resistor to the electrical circuit. This helps to reduce the current during gas ionization and limit heating by Joule heating. In this case, the electrical discharges can be longer, on the order of a second or less.

[0041] Crystallization generator

[0042] The process can be implemented using at least one generator for crystallizing the solute in the solution.

[0043] The crystallization generator may include:

[0044] ■ A gas inlet, including a connector to a gas source,

[0045] ■ An electrical input, specifically a connector to a power source,

[0046] ■ A gas outlet,

[0047] ■ A gas transmission line connecting the gas inlet to the gas outlet,

[0048] ■ An application electrode for the sequence of pulsed electrical discharges is electrically connected to the electrical input and configured to subject the gas to the sequence of one or more pulsed electrical discharges at the gas outlet to form the plasma pulse.

[0049] ■ An electrical insulation configured to electrically isolate the electrode from the outside.

[0050] The process may involve connecting the gas inlet to a gas source and / or a pressure source.

[0051] The process may involve connecting the electrical input to an electrical source, including a voltage and / or current source, configured to generate pulsed electrical discharges at the electrode.

[0052] The process may involve controlling the pressure or gas source and the electrical source. This control can be performed according to a predetermined operating sequence, with synchronization of the electrical source and the pressure or gas source to generate the plasma pulse(s). The control can be implemented by an internal control unit or, preferably, external to the crystallization generator, notably by a processor connected to a human-machine interface.

[0053] With such a generator, the operator can generate or program a pressure pulse via the gas inlet. The gas subjected to this pressure pulse then propagates along the gas transport line to the gas outlet, where it is subjected to a sequence of electrical discharges from the electrode, synchronized with the pressure pulse. The generated plasma then forms one or more plasma pulses at the gas outlet, which are brought into contact with the solution.

[0054] Gas transmission line and electrode

[0055] The gas outlet can have a larger cross-sectional dimension between 0.1 and 30 mm, preferably between 0.5 and 2 mm. This allows for both short plasma pulses to make contact with the solution at a precise position and plasma pulses of sufficient length to contain a quantity of plasma enabling the initiation of crystallization with a plasma pulse or a train of plasma pulses.

[0056] The gas transport line may include a tube forming a gas circulation cavity extending between the gas inlet and the gas outlet. The tube may be formed at least partially by the electrode, the latter being a tubular electrode. The tubular electrode may be fluidically connected in a leak-proof manner at its proximal end to the gas inlet, particularly to the connector to a gas source, and extend to the gas outlet. The tube may have a polygonal or, preferably, circular cross-section. It may have a constant or continuously variable cross-section. The largest internal dimension of the section, particularly the internal diameter, of the electrode may be between 0.1 and 30 mm, preferably between 0.5 and 2 mm. It is preferably constant.

[0057] The gas outlet can be formed by the distal end of the gas transport line, particularly by the tubular electrode, or by a nozzle at the outlet of the gas transport line, particularly the tubular electrode, to guide the plasma pulse outward. The nozzle can be substantially frustoconical in shape. Preferably, the nozzle has a smaller outlet cross-section than its inlet cross-section.

[0058] The generator may include a tubular extension with a continuous cross-section along its longitudinal axis, incorporating the gas outlet. This tubular extension allows the gas to be transported to the gas outlet for the application of the plasma pulse(s) to the solution. It also allows for a gas outlet that is either close to the surface of the solution or immersed in the solution, as detailed later.

[0059] The generator may include a housing that incorporates the gas inlet and electrical input, along with their respective connections to the gas supply line and the electrode. The housing may extend from the end of the tubular extension opposite the gas outlet. The connection housing ensures that all connections are located away from the solution to facilitate handling.

[0060] The tubular extension can extend to a length greater than or equal to 10 cm, preferably greater than or equal to 20 cm, and even better, greater than or equal to 30 cm. Such a tubular extension allows the device to be immersed in a tank to bring the plasma pulse(s) into contact with the liquid in all types of processes, particularly in industrial processes, at a predetermined position.

[0061] The tubular extension may have a frustoconical external shape or, preferably, a cylindrical shape with a polygonal base or, even more preferably, a circular shape. Preferably, the tubular extension has a constant cross-section along its entire length. It may have a larger external dimension in cross-section, specifically an external diameter of 55 mm or less, preferably 20 mm or less, and even more preferably 15 mm or less. This allows for a tubular extension with a small cross-sectional footprint that extends into the tank, enabling the process to be applied to tanks and / or containers with small diameters. Furthermore, the small cross-sectional footprint of the tubular extension prevents it from obstructing the tank and provides space for the installation of other components.

[0062] The outlet may have a porous plug at the end.

[0063] The tubular extension may include at its distal end an insulator made of a low surface energy material, such as hydrophobic silicone. This helps to reduce the risk of obstruction of the gas outlet by the formation of crystals of the compound upstream of the gas outlet, particularly within the tube.

[0064] Connectors

[0065] The gas inlet can be connected to the gas supply line, specifically to the tubular electrode, via a hose made of an electrically insulating material. This helps to minimize the risk of electrical discharge between the electrode and the connector during the application of pulsed electrical discharges. The hose made of an electrically insulating material is preferably made of plastic, particularly a flexible plastic such as silicone or polytetrafluoroethylene (PTFE).

[0066] The connector to the power source can be configured to be connected to a high voltage source and to be in electrical contact with the electrode, specifically with the outer lateral surface of the tubular electrode.

[0067] Electromagnetic shielding

[0068] The generator may include a grounded metallic electromagnetic shield. The shield may completely cover the generator except for the connectors to the gas source, the power source, and the gas outlet. It then forms a Faraday cage around the electrode to limit electromagnetic coupling that would disrupt the pulsed electrical discharges and to limit the device's outward radiation. This improves the device's performance and prevents interference with surrounding electrical equipment.

[0069] Preferably, the electrical insulation extends between the electrode and the electromagnetic shielding. This prevents pulsed electrical discharges from occurring anywhere other than at the gas outlet and forces them to pass through the outlet gas.

[0070] Preferably, the metallic electromagnetic shielding includes a metallic layer covering at least the longitudinal extension.

[0071] Metallic electromagnetic shielding may include a metallic body covering the housing, the housing body and the metallic layer being electrically connected to each other by a metallic fitting ensuring electrical continuity between them.

[0072] Preferably, the metallic layer is made of a metal that is chemically resistant to the solution. The metallic layer can be a metallic tube, particularly stainless steel, titanium, or a metallic deposit on the electrical insulation.

[0073] Electrical insulation

[0074] Preferably, the electrical insulation comprises a first insulator filling the body of the housing and a second tubular insulator fitted onto the electrode.

[0075] The second insulator can extend at least partially into the casing.

[0076] The first insulator can be an insulating gel, particularly silicone. The second insulator can be a material with chemical resistance compatible with the solution, especially with solvents and temperatures between -20°C and 100°C, ideally between -40°C and 250°C, such as silicone, PTFE, PFA, polypropylene, ceramic, or glass. This helps limit its degradation by the solution and provides good resistance to plasma.

[0077] It can have a thickness of between 4 and 10 mm. Such insulation prevents any electrical discharge between the electrode and the metallic layer.

[0078] The crystallization generator may include a delay generator configured to temporally offset the generation of the pulsed electrical discharge(s) relative to the pressure pulse to form the plasma pulse(s).

[0079] Tank

[0080] The solution may be contained in a tank, in particular with a volume greater than or equal to 250 mL.

[0081] The tank can be double-jacketed, and the process can involve controlling the solution temperature by circulating a temperature-controlled liquid between the two jackets. This allows, in particular, control of the metastable state of the solution. Indeed, the crystallization threshold of the solution by plasma depends on the temperature. Therefore, by controlling the temperature, it is possible to control and / or improve the control of solute crystallization by the plasma.

[0082] The process may involve maintaining the solution at a crystallization initiation temperature during the application of the plasma pulse(s), with the solute present in the solution at a concentration that renders it metastable at the initiation temperature. This can be achieved by temperature control, by evaporating the solute until it reaches the metastable state, or by adding an antisolvent.

[0083] The process may also include a step of crystallizing the solute in solution.

[0084] Crystallization may involve cooling the solution after the plasma pulse(s) have been applied to it, notably using a condenser circulating between the two chamber walls. Maintaining the temperature ensures that the solution remains in a metastable state during initiation and cooling, which facilitates crystal growth after initiation and improves crystallization yield.

[0085] Crystallization may involve evaporating the solvent from the solution before and / or after applying the plasma pulse(s) with the solution, and removing the evaporated solvent from the cell. This allows for continuous evaporation of the solvent after initiation, which, in particular during crystallization, helps maintain the supersaturation of the solute and increases the yield. The process may also involve crystallizing the solute with an antisolvent before and / or after applying the plasma pulse(s) with the solution.

[0086] The volume of the solution can be greater than or equal to 250 mL.

[0087] The process may involve agitating the solution in the tank during the application of the plasma pulse(s). This helps to reduce the induction time.

[0088] The process may involve circulating the solution between an inlet and an outlet of the tank. In this case, the process may involve periodically applying plasma pulses to the solution at a fixed point within the tank, depending on the flow rate of the solution. This allows, in particular, the integration of the crystallization process into a continuous industrial flow process.

[0089] The solution temperature can be between a high temperature at which contacting plasma-free gas pulses with the solution under the same conditions induces crystallization of the compound in the solution, and a low temperature at which contacting plasma pulses with the solution under the same conditions does not initiate crystallization, at least within 2 hours. Preferably, the supersaturation, defined as the ratio of the concentration to the solubility limit at a given temperature, is less than a predetermined value.

[0090] The solution may be in a metastable state such that contacting the solution with one or more gas pulses, identical to the plasma pulses without the application of the sequence of pulsed electrical discharges generating the plasma, does not generate crystallization of the compound in the solution in less than 2 hours.

[0091] The tank can be hermetically sealed and filled with a non-combustible gas, particularly an inert gas such as nitrogen, argon, or carbon dioxide, or mixtures thereof. This helps to limit the risk of explosions and ensures that the tank is placed in compliance with applicable regulations, including ATEX regulations.

[0092] The oxygen concentration in the tank can be less than or equal to the minimum oxygen concentration (MOC). Preferably, the gas supplying the probe and the tank should be free of oxidizers, particularly oxygen. This also helps to limit the risk of explosions and ensures that the tank is placed in compliance with relevant regulations, including ATEX regulations.

[0093] The process may include detecting the oxygen concentration upstream and / or downstream of the gas outlet. The process may include an alert to the operator or a process shutdown when the oxygen concentration exceeds a predetermined threshold, in particular exceeding the minimum oxygen concentration (MOC). The gas used to generate the plasma pulses may preferably be a non-oxidizing gas, in particular an inert gas, such as nitrogen, helium, argon, or a mixture of these gases. Alternatively, the gas may be air.

[0094] The solution can be insulating, specifically exhibiting an electrical conductivity of 10 pS / cm or less. In this case, the pulsed electrical discharge(s) preferably have a maximum voltage between 1 kV and 40 kV, a duration between 1 and 100 ns, and a repetition rate between 1 Hz and 200 kHz. Such discharges generate a stable, non-thermal plasma with low power consumption.

[0095] Ex Situ Implementation Method

[0096] The plasma pulse(s) can be applied to the surface of the solution. In this case, the gas outlet is preferably located at a distance of 50 mm or less from the solution surface, ideally 10 mm or less, ideally 5 mm or less, and ideally 3 mm or less. This prevents contact between the solution and the device, thus limiting obstruction of the device at its distal end and the risk of solution contamination.

[0097] In this case, the plasma pulse(s) are formed from a localized region of plasma within the gas emitted by the device at its distal end in the form of a short-duration plasma jet blown onto the surface of the solution.

[0098] Plasma can be discharged from the gas outlet at a velocity ranging from 1 cm / s to 100 m / s. The choice of gas discharge velocity results from a compromise between rapid transport of the plasma agents to the solution and minimizing the risk of mechanical shock that could trigger crystallization under uncontrolled conditions. The plasma pulse(s) can be ejected by adjusting the gas pressure in the crystallization generator or, preferably, by adjusting the volumetric flow rate in the crystallization generator.

[0099] The gas outlet is preferably formed by the distal end of a nozzle, preferably frustoconical. This allows, in particular, for guiding the transport of the plasma to a precise area of ​​the solution and / or for accelerating the plasma pulse exiting the nozzle towards the surface of the solution.

[0100] The solution may be conductive, in particular having an electrical conductivity greater than or equal to 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode and the solution. The process may then include grounding the solution.

[0101] The solution can be insulating, specifically having an electrical conductivity of less than 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode and the metallic structure, particularly the metallic layer. The electromagnetic shielding, especially the metallic layer, may include a transverse extension at the end of the longitudinal extension at the gas outlet. This is particularly useful when applying an insulating solution to the surface to facilitate the application of the discharges between the electrode and the metallic layer.

[0102] Implementation method: In Situ

[0103] The formation and application of the plasma pulse(s) to the solution can be performed directly within the solution. In this case, the gas outlet is immersed in the solution, and the application can be carried out via one or more gas bubbles containing plasma. Preferably, the aforementioned metallic structure, particularly the metallic layer, is in contact with the solution.

[0104] The gas bubble(s) containing the plasma can be formed by the application of one or more pressure pulses in the crystallization generator or by the substantially continuous application of gas in the crystallization generator followed by the application of the sequence of electrical discharge(s).

[0105] The process may involve applying a continuous constant pressure to the gas in the generator at a pressure compensating at least for the capillary pressure and the Archimedes' buoyant force, in particular at a pressure substantially equal to

[0106] 2o cos 0

[0107] Pstab = Patm H - - - 1- pgh

[0108] R

[0109] Where o is the interfacial tension, 9 the contact angle and R the capillary radius, P atm is the surface pressure of the solution in the tank, p is the density of the solvent, g is the gravitational constant, and h is the depth at which the gas outlet is immersed. Maintaining this pressure during a crystallization cycle limits the risk of crystallization at the gas outlet or further upstream in the crystallization generator, particularly in the gas transport line, which could obstruct the gas outlet. Furthermore, this increases the device's operating time before obstruction occurs.

[0110] The gas bubble(s) preferably have a volume less than or equal to 200 pL.

[0111] The process may involve the formation of a gas bubble at regular intervals without plasma formation. This helps to limit obstruction by crystallization by maintaining a meniscus oriented towards the solution at the gas outlet. The gas bubbles can be formed by applying a constant pressure between P stab and P s tab+50mbar, even better between P sta b and P stab+5 mbar. Preferably, the constant pressure required depends on the cross-section of the gas line. Alternatively, the gas bubbles can be formed by the regular application of a pressure pulse to the gas without a pulsed electrical discharge. The solution can be conductive, in particular having an electrical conductivity greater than or equal to 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode and the solution. The gas flow rate at the outlet for forming the plasma-containing gas bubble(s) is preferably configured so that the bubble formed is small enough not to be in contact with the metallic structure, in particular the metallic layer, and large enough to extend between the electrode and the solution, covering the electrode at the gas outlet.At the outlet of the crystallization generator, the plasma-containing gas bubble(s) can extend transversely across the gas outlet to a width greater than the cross-sectional diameter of the electrode at the gas outlet and less than the cross-sectional diameter of the electrical insulation at the gas outlet. The electromagnetic shielding, particularly the metallic layer, preferably covers the entire longitudinal extension except for the distal end. This limits the contact between the gas bubble formed in the solution and the metallic layer, ensuring that pulsed electrical discharges occur between the electrode and the solution within the gas bubble.

[0112] It is possible for the electromagnetic shielding to extend to the distal end by continuing along the grounded metal tube. Openings are then necessary to allow for proper flow of the solution and the evacuation of gas and plasma bubbles. Preferably, such openings have a diameter of 5 mm or less. This notably improves the shielding's effectiveness.

[0113] The solution can be insulating, in particular having an electrical conductivity of less than 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode and the metallic structure, in particular the metallic layer. In this case, preferably, the gas flow rate at the outlet for forming the plasma-containing gas bubble(s) is configured so that the gas bubble formed is either large enough to be in contact with the metallic structure, in particular the metallic layer, or at a sufficiently small distance from the metallic structure, in particular less than 3 mm, so that the pulsed electrical discharge(s) can occur with the metallic structure, in particular the metallic layer.At the outlet of the crystallization generator, the plasma-containing gas bubble can extend transversely across the gas outlet to a width greater than 80%, and ideally 90%, of the outer diameter of the electrical insulation at the gas outlet. It can also extend transversely across the gas outlet to a width less than or equal to 150% of the generator's width at the gas outlet.

[0114] Detection

[0115] The process may include detecting the formation of the gas bubble or bubbles at the gas outlet, in particular by an optical method, for example using a laser. The detection of the formation of the gas bubble or bubbles at the gas outlet may include emission by an optical source, in particular a laser or light-emitting diode, at one or more wavelengths far removed from the plasma emission bands, in particular at a wavelength greater than or equal to 100 nm, preferably greater than or equal to 500 nm, and optically detecting the light at the gas outlet.

[0116] The process may involve the detection of plasma and / or its properties, in particular with a photoelectric sensor such as a photodiode or one or more electrical measurements.

[0117] The process may include the simultaneous detection of the formation of the gas bubble(s) at the gas outlet and the plasma using a single optical detector. The crystallization device may include a multispectral camera to simultaneously detect the optical emission from the plasma and the light from the optical source that has at least partially passed through the gas or plasma. The process may include an optical system for separating the light from the optical source from that from the plasma. This allows, in particular, the synchronization of the gas ejection and the application of the electrical discharge(s) to form the plasma at the gas outlet. It also allows confirmation of the gas ejection and plasma formation under conditions where no optical access is available for verification, such as in the case of an opaque tank. Furthermore, it allows for monitoring of the crystallization process.Alternatively, the crystallization device may include a spectral separation system, in particular comprising a filter wheel, a bandpass filter, and / or a bandstop filter to separate the optical emission from the plasma and the light from the optical source that has at least partially passed through the gas or plasma. The emission from the plasma may be transmitted to a spectral analysis system, in particular a spectrometer, and the emission from the optical source that has at least partially passed through the gas or plasma may be transmitted to a detector, in particular a camera, for detecting gas ejection from the gas outlet.

[0118] The process may include spectral analysis, notably using a spectrometer, of the light emitted from the plasma. This allows for monitoring the plasma intensity and ensuring the stability and repeatability of the plasma treatment, and / or diagnosing generator degradation, for example by detecting an emission band or line indicating possible contamination.

[0119] In the case where the generator is immersed in the solution, the process may include, by spectral analysis of the light from the plasma, the measurement of the presence or absence of metals in solution and their concentration.

[0120] The crystallization device may include an optical detection system comprising the optical source, in particular the laser or light-emitting diode, the multispectral camera, a set of optical transport elements, in particular mirror(s), optical fiber(s), window(s) and / or lens(es), enabling the transport of light from the diode to an output to the gas outlet and the transport of the received light to the camera, a spectral separation device to separate the light from the plasma from that from the optical source and having passed at least partially through the gas or plasma and / or an optical analysis system, in particular comprising a camera and / or a spectrometer.

[0121] The optical system can be independent of the crystallization generator. It can be arranged parallel to the generator so that the light emission output is at the same level as the generator's gas outlet.

[0122] Alternatively, the optical system can be integrated into the crystallization generator, specifically within the generator's electromagnetic shielding. This shielding may include an optical duct running its length, opening via an optical aperture opposite the gas outlet.

[0123] The method may involve adjusting the synchronization between the pulsed electrical discharge(s) and the pressure pulse by detecting a signal peak in the electrical measurement(s) or the photoelectric sensor signal. This allows for fine control and optimization of the synchronization between the pressure pulses and the pulsed electrical discharges.

[0124] The process may include the detection of crystallization, in particular by a solution turbidity detector, an infrared probe or calorimetric detection.

[0125] The process may include the detection of plasma energy, in particular by a voltage and / or current probe as described in the article Minesi N, Thermal spark formation and plasma-assisted combustion by nanosecond repetitive discharges, PhD thesis, Centrale Supélec, 2020.

[0126] The process may include measuring the gas flow rate. This allows, in particular, the detection of tube clogging, notably due to the accumulation of crystals within the tube. Measuring the gas pressure in the tubular extension can detect any leakage, especially if the measured pressure is below the Pstab value, which can be problematic, particularly when ATEX standards are required.

[0127] Generator

[0128] The invention also relates to a crystallization generator for a solute present in a solution at a concentration that gives it a metastable state, particularly for implementing the crystallization initiation process as defined above, comprising:

[0129] ■ A gas inlet, including a connector to a gas source,

[0130] ■ An electrical input, specifically a connector to a power source,

[0131] ■ A gas outlet,

[0132] ■ A gas transport line connecting the gas inlet to the gas outlet, ■ An application electrode for a sequence of one or more pulsed electrical discharges, electrically connected to the electrical input and configured to subject the gas to the sequence of pulsed electrical discharge(s) at the gas outlet to form the plasma pulse,

[0133] ■ An electrical insulation configured to electrically isolate the electrode from the outside, the generator comprising a tubular extension with a continuous cross-section along its longitudinal axis and comprising the gas outlet, the tubular extension having a length greater than or equal to 10 cm.

[0134] The features of the invention mentioned above in relation to the process apply individually or in combination to the crystallization generator.

[0135] A generator may include a gas heating element upstream of the gas outlet.

[0136] The generator may include a detector of the formation of the or each plasma pulse at the output, in particular a laser.

[0137] The generator may include a crystallization detector, in particular a solution turbidity detector, an infrared probe or a calorimetric detector.

[0138] The generator may include a plasma energy detector, in particular a voltage and / or current probe as described in the article Minesi N, Thermal spark formation and plasma-assisted combustion by nanosecond repetitive discharges, PhD thesis, Centrale Supélec, 2020.

[0139] A generator may include a gas flow sensor.

[0140] The invention also relates to a crystallization device comprising the crystallization generator as defined above, an electrical source, in particular a pulsed high voltage source, connected to the electrical input of the generator and a gas source connected to the gas inlet.

[0141] The features of the invention as defined above in relation to the process apply individually or in combination to the crystallization device.

[0142] A crystallization device may include a gas pressure or flow regulator configured to apply gas pulses to the gas inlet, including a gas pressure control device connected to the gas inlet.

[0143] A crystallization device may include a device control unit, specifically for the power supply, gas supply, and / or gas pressure regulator. The control unit may include a processor. The control unit may receive information from one or more sensors, including a gas temperature sensor upstream of the gas outlet, a plasma pulse formation detector at the gas outlet (e.g., a laser), a crystallization detector (e.g., a solution turbidity detector, an infrared probe, or a calorimetric detector), a plasma energy detector (e.g., a voltage and / or current probe as described in the article Minesi N, Thermal spark formation and plasma-assisted combustion by nanosecond repetitive discharges, PhD thesis, CentraleSupélec, 2020), a gas flow sensor, and / or a solution temperature detector.It can control the device, including the power supply, the gas supply, and the gas pressure regulator, and optionally the gas heating element upstream of the gas outlet, the delay generator, the aforementioned sensor(s), and / or a solution circulation device within the tank, at least based on information received from one or more of the aforementioned sensors and / or a user interface. The aforementioned sensors may be integrated into the generator or external to it.

[0144] The device may include a human-machine interface, with the control unit configured to receive information from the human-machine interface and control the device based on at least one or more of these pieces of information. This information may relate to the solution and / or the solute, including the nature of the solution or solute and / or the solute concentration in the solution, the temperature of the solution, the type of crystal to be formed, the pressure pulse(s) to be generated, the pulsed electrical discharge(s) to be sent to form the plasma, the distance between the end of the generator and the surface of the solution in the case of an end generator not immersed in the solution, the nature of the gas, the flow rate of the solution in the tank in the case of a circulating solution, and / or the period between two applications of a plasma pulse or a train of plasma pulses.

[0145] The invention further relates to a crystallization assembly comprising at least the crystallization generator as described above and a crystallization cell into which the crystallization generator is inserted. The cell may contain the solution containing the solute at a concentration that renders it metastable.

[0146] The assembly may include a solution agitator in the tank, in particular a magnetic stirrer at the bottom of the tank. Preferably, when the gas outlet of the crystallization generator is immersed in the solution in the tank, it is at a distance from the stirring impeller greater than or equal to 20 mm.

[0147] The tank can be a vacuum tank.

[0148] The tank may include a solution inlet and a solution outlet. The assembly may include a solution circulation device between the solution inlet and the solution outlet. The tank may be hermetically sealed during the application of the plasma pulse(s), with the optional exception of the solution inlet and / or outlet, and may be filled with an inert gas as described previously.

[0149] The invention will be better understood by reading examples of embodiments described in relation to the figures below.

[0150] Brief description of the drawings

[0151] [Fig 1] represents the steps of an example of a crystallization initiation process,

[0152] [Fig 2] schematically represents an overall example for the implementation of the process shown in Figure 1,

[0153] [Fig 3] is a view of the crystallization generator from Figure 2,

[0154] [Fig 4] schematically represents in cross-section the crystallization generator of figure 3,

[0155] [Fig 5] schematically represents in cross-section the distal end of the crystallization generator of figure 4 with an in situ plasma pulse in the case of a conductive solution,

[0156] [Fig 6] schematically represents in cross-section the distal end of the crystallization generator of figure 4 with a plasma pulse in the case of an insulating solution,

[0157] [Fig 7] schematically represents in cross-section a variant of the crystallization assembly, [Fig 8] schematically represents in cross-section the distal end of the crystallization generator of figure 8 with a plasma pulse in the case of a conductive solution,

[0158] [Fig 9] schematically represents in cross-section the distal end of the crystallization generator of figure 4 with a plasma pulse in the case of an insulating solution,

[0159] [Fig 10] is a graph of the concentration of the solute in solution versus temperature representing the metastable state zone allowing initiation by the plasma pulse(s),

[0160] [Fig 11] is a graph of turbidity as a function of solution temperature for crystallization initiation by MZL plasma pulses pjasma , MZL gas pulses gaz or spontaneously MZL,

[0161] [Fig 12] representing the turbidity measured as a function of time for a glycine solution in water after initiation of crystallization by application of bubbles containing plasma, [Fig 13] is a graph representing the initiation time measured for initiations by gas pulses without plasma and by plasma pulses at different gas temperatures, [Fig 14] represent results for two tests, a first test with initiation according to the invention and a second test with initiation by injection of gas bubbles into the solution,

[0162] [Fig 15] is a graph representing the measured initiation time for initiations by plasma pulses formed with different peak voltages of electrical discharges,

[0163] [Fig 16] is a graph representing the measured initiation time for initiations by plasma pulses formed with electrical sequences exhibiting different numbers of discharges,

[0164] [Fig 17] schematically represents in cross-section the distal end of the crystallization generator with an adjacent endoscope-like detection organ, and

[0165] [Fig 18] schematically represents in cross-section the distal end of the crystallization generator with a detection element integrated into the generator's electromagnetic barrier. Detailed description

[0166] In the following description, identical elements or elements with identical functions 10 bear the same reference symbol. For the sake of brevity, they are not described alongside each figure; only the differences between the embodiments are described.

[0167] Figure 1 illustrates the steps of a process according to the invention for initiating the crystallization of a solute present in a solution S at a concentration giving it a metastable state.

[0168] The process comprises a first step 10 of plasma pulse formation and a step 20 of applying the plasma pulse to the solution. These two steps can be carried out successively n times over a short period by forming a train of plasma pulses and applying each plasma pulse to the same point in the solution. The number of plasma pulses formed in the pulse train can be less than or equal to 1500, preferably less than or equal to 1000.

[0169] The formation of each plasma pulse 10 may include a step 12 of applying a gas pressure, specifically a pressure pulse, to the gas in a crystallization generator, as described below, and a step 14 of applying a sequence of one or more pulsed electrical discharges to the gas to generate the plasma pulse, specifically at the outlet of the crystallization generator. The pulsed electrical discharge(s) ionize the gas without a significant temperature change to form the plasma, the plasma being a cold plasma. The pulsed electrical discharge(s) are synchronized with the gas pressure, specifically the gas pulse, so as to form the plasma pulse.Alternatively, the formation of each plasma pulse 10 may include an application step 14, to a gas emitted continuously for a predetermined duration, in particular for less than 10 min, in a crystallization generator which is described in the following sequence of one or more pulsed electrical discharges to generate the plasma pulse, in particular at the outlet of the crystallization generator in the continuous gas flow with a duty cycle between 1 and 100%, the duty cycle being defined as the ratio between the duration of a pulsed electrical discharge sequence(s) and the duration between the start of two successive sequences, i.e. the ratio between the duration of application of the plasma pulse and the repetition period of the pulses.For example, for a sequence of 100 discharges with a frequency of 10 kHz with a duty cycle of 10%, the sequence of 100 discharges can be applied for 10 ms followed by 80 ms without discharges and then a new sequence.

[0170] Once initiation has been achieved using this method, solute crystallization can be carried out in step 30 using known methods, and its yield can be improved by cooling, solvent evaporation, or the use of an anti-solvent agent. The double jacket of the cell allows for temperature control, enabling the implementation of cooling techniques.

[0171] Figure 2 illustrates a set 100 enabling the implementation of the crystallization initiation process.

[0172] The assembly 100 includes a crystallization device 110 and a tank 120.

[0173] The crystallization device includes a crystallization generator 130 electrically connected to an electrical source 140 and fluidically to a gas source 150.

[0174] The electrical source 140 is configured to emit the pulsed electrical discharge(s) and transmit them to the crystallization device 110.

[0175] The connection to the electrical source 140 can be made via a high-voltage electrical connector 132.

[0176] The connection to the gas source 150 can be made via a fluidic connector 134. Preferably, the device includes a gas pressure regulator 160 configured to vary the gas pressure at the inlet of the fluidic connector 134 and thus apply the gas pressure, specifically the pulse, to generate the plasma pulse(s). The gas pressure regulator 160 and the electrical source 140 can be connected to a delay generator 170 configured to temporally offset the generation of the pulsed electrical discharge(s) relative to the pressure pulse to generate the plasma pulse(s).

[0177] The crystallization device may include a control unit 180 configured to control the various elements of the device, including the power source 140, the gas source 150, the pressure regulator 160 and the delay generator 170, according to information received.

[0178] The gas can be an inert gas or air, preferably an inert gas. The 120 tank can have a volume greater than or equal to 250 mL

[0179] The tank 120 can be double-jacketed and can include a liquid circulation element between the two jackets and a temperature control element 190, controlled by the control unit 180. This control can be predetermined and / or a function of the temperature of the solution S in the tank in real time, the temperature of the solution being measured by a temperature detector 200.

[0180] The assembly may include a stirring system 210 configured to stir the solution during the priming process and during the subsequent crystallization. Stirring may be achieved by any means, including a mechanical or magnetic stirrer.

[0181] Preferably, the tank 120 is a substantially closed enclosure. This allows, in particular, for a precise ignition environment and, specifically, for compliance with ATEX safety standards. However, the invention is not limited to a closed enclosure; the tank 120 could be open, as illustrated in Figure 7.

[0182] The tank may include a gas outlet 220 to extract any gas emitted during the process, particularly to remove the solvent that evaporates during crystallization. The process may include monitoring the oxygen concentration in the tank 120. The system may include an oxygen concentration detector 230 in the tank, specifically at the gas outlet. Such a detector allows the oxygen concentration in the tank to be monitored at a level below the minimum oxygen concentration (MOC) and alerts the operator or stops the use of the pulsed electrical discharge(s) when this concentration exceeds a predetermined threshold.

[0183] The crystallization generator 130 is shown in detail in Figures 3 and 4. The crystallization generator 130 comprises a housing 300 forming a proximal portion and a longitudinal extension 400 forming a distal portion. The housing 300 carries all the connections, in particular the electrical connector 132 and the fluidic connector 134, and is configured to extend out of the vessel 120. It includes a grounded metal casing 310 forming electromagnetic shielding for the inside of the housing. The longitudinal extension 400 has a gas outlet 410 at its distal end. It has an elongated cylindrical shape and is configured to extend into the vessel 120. It has an external metal layer 420 covering it, except for the grounded distal end, and forming electromagnetic shielding around this longitudinal extension.The housing 300 and the longitudinal extension 400 are connected to each other by a metallic connection 350. Preferably, this metallic connection allows an electrical connection between the metallic housing 310 and the external metallic layer 420.

[0184] The longitudinal extension may have a length L greater than or equal to 10 cm, preferably greater than or equal to 30 cm, and an outside diameter D in cross-section less than or equal to 15 mm. The metal casing 310 and the metal layer 420 may be made of metal. The metal layer 420 may be specifically made of a metal chemically resistant to the solution, particularly the solvent. The metal layer 420 may be a stainless steel tube.

[0185] The crystallization generator 130 includes a gas transport line 430 extending from the fluidic connector 134 to the gas outlet 410 in the housing 300 and the longitudinal extension 400. The transport line 430 is formed laterally, at least along part of its length, by a tubular electrode 440 extending to the gas outlet 410 and electrically connected by an electrical link 445 to the electrical connector 132. In the illustrated example, the tubular electrode 440 extends along the entire length of the generator 130. However, it could extend only along part of the length to the gas outlet 410, the gas transport line 430 being able to be connected to the fluidic connector by a non-metallic tube, in particular made of an electrically insulating material into which the tubular electrode 440 is fitted.

[0186] The crystallization generator 130 also includes electrical insulation between the electromagnetic shielding 420 and 310 and the tubular electrode 440. The electrical insulation may comprise a first insulator 320 filling the body of the housing and a second tubular insulator 450 fitted onto the electrode 440. The second insulator 450 may extend at least partially over the electrode 440 in the housing 300 and up to the gas outlet 410.

[0187] The first insulator, 320, can be an insulating gel, and the second insulator, 450, can be a material with chemical resistance compatible with the solution, particularly the solvent(s), and with temperatures ranging from -20°C to 100°C, ideally from -40°C to 250°C. Suitable materials include silicone, PTFE, PFA, polypropylene, ceramic, or glass. The second insulator, 450, can be between 4 and 10 mm thick.

[0188] The gas outlet 410 can have a larger dimension d ranging from 0.5 to 30 mm. The largest internal dimension, specifically the internal diameter, of the electrode can be between 0.1 and 5 mm, preferably between 0.5 and 30 mm.

[0189] Thus, during the implementation of the process as described above, the gas pulse is emitted through the gas transport line 430 to the end forming the gas outlet 410. Simultaneously, as the gas reaches the outlet 410, a sequence of one or more pulsed discharges is emitted by the electrode 440 into the gas at the outlet 410, either towards the solution or towards the metal layer 420, depending on the situation. This pulsed electrical discharge, or these discharges, will ionize the gas at the outlet and generate a plasma pulse 500. The plasma comes into contact with the solution via the plasma pulse 500 to generate, alone or in combination with a train of plasma pulses, the initiation of crystallization.

[0190] As illustrated in Figure 2, the plasma pulse(s) can be brought into contact by generating them directly within the solution containing the solute to be crystallized, in the form of gas bubbles containing the plasma. In this case, the crystallization generator 130 is immersed in the solution by its longitudinal extension 400, and the gas outlet 410 extends into the solution. The metal layer 420 is also in contact with the solution. In this case, it is preferable that the metal layer and the second insulator be configured to be chemically resistant to the solution, particularly the solvent.

[0191] In this case, the process may involve applying a continuous constant pressure to the gas in the generator 130 at a pressure compensating at least the capillary pressure and the Archimedes' buoyant force, in particular at a pressure substantially equal to

[0192] 2cr cos 0

[0193] Pstab = Patm H - - - 1- pgh

[0194] R as indicated above. Maintaining this pressure during a crystallization cycle helps limit the risk of crystallization at the gas outlet 410 or further upstream in the crystallization generator 130, particularly in the gas transport line 430, which would obstruct the gas outlet 410. The process may involve the formation of a gas bubble at regular intervals without plasma formation using a constant pressure between P sta b and Pstab+50mbar, even better between P sta b and P sta b+5mbar or by the regular application to the gas of a pressure pulse without pulsed electrical discharge at that same pressure.

[0195] The electrical discharge sequence(s) can be synchronized with the formation of gas bubbles, particularly with pressure pulses, to generate plasma in a controlled manner within one or more gas bubbles. As described previously, plasma bubbles can be formed only when a plasma pulse is applied or continuously at a regular rate.

[0196] In cases where gas bubbles are formed continuously and regularly, plasma can form within some of these bubbles in sync with their formation without the application of any specific gas overpressure, or plasma formation can be synchronized with a gas overpressure in the generator. In both cases, there is an alternation of one or more plasma-containing bubbles with one or more successive gas bubbles without plasma. The number of plasma-containing bubbles is controlled and essentially identical for each plasma pulse.

[0197] Alternatively, the electrical discharge sequence(s) can be periodic without any particular synchronization. It is then possible to apply a continuous, constant gas pressure greater than P stab) and to apply, at regular time intervals, a sequence of one or more electrical discharges as described previously to form an alternation of one or more plasma-containing bubbles with one or more successive gas-free bubbles. Since the sequence(s) are not synchronized with the bubbles, the distribution of plasma within the bubbles is not controlled. Nevertheless, this allows for satisfactory control of crystallization and is easy to implement in an industrial setting. The number of plasma-containing bubbles is not perfectly controlled and can vary by one bubble, particularly between two plasma pulses.

[0198] The ratio of plasma-containing bubbles to plasma-free gas bubbles can be between 1 in 100 and 1 in 2.

[0199] Solution S can be conductive, as shown in Figure 5, specifically exhibiting an electrical conductivity greater than or equal to 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between electrode 440 and solution S. The pressure pulse to generate the plasma pulse 500 is preferably configured so that the gas bubble(s) formed by this pressure pulse have a width k small enough not to contact the metal layer 420 and large enough to extend between electrode 440 and the solution, covering electrode 440 at the gas outlet 410. The metal layer 420 can cover the entire longitudinal extension except for the distal end.

[0200] Solution S can be insulating, as shown in Figure 6, and in particular, it has an electrical conductivity of less than 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode 440 and the metal layer 420. In this case, preferably, the pressure pulse used to generate the plasma pulse is configured so that the gas bubble(s) formed by this pressure pulse have a width k large enough to be in contact with the metal layer 420, or a smaller distance p sufficiently small, in particular less than 3 mm, from the metal layer 420 so that the pulsed electrical discharge(s) can discharge into the metal layer 420.At the gas outlet 410, the plasma-containing bubble(s) can extend transversely across the gas outlet to a width k greater than 80%, and preferably 90%, of the outer diameter in cross-section of the electrical insulation at the gas outlet. They can also extend transversely across the gas outlet to a width less than or equal to 150% of the generator width D at the gas outlet.

[0201] In the variant illustrated in figures 7 to 9, the crystallization generator 130 is not immersed in the solution S. In this case, the plasma pulse(s) 500 are formed above the surface of the solution and the contact of the plasma pulse(s) 500 is made at the surface of the solution S. The gas outlet 410 is preferably spaced from the surface of the solution S by a distance m less than or equal to 10 mm, better less than or equal to 5 mm, even better less than or equal to 3 mm.

[0202] The plasma pulse(s) 500 can be ejected from the gas outlet 410 with a velocity between 1 cm / s and 100 m / s. The tank 120 can be as described previously or be open as illustrated.

[0203] The gas flow can be pulsed and synchronized with the electrical discharge sequence(s) or the gas flow can be substantially continuous and the electrical discharge sequence(s) pulsed with a duty cycle between 1 and 100% as described previously.

[0204] Solution S can be conductive, as illustrated in Figure 8, specifically exhibiting an electrical conductivity greater than or equal to 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between electrode 440 and solution S. The process may, in this case, involve grounding the solution. In this embodiment, it is preferable that the distance m be less than or equal to 3 mm.

[0205] Solution S can be insulating, as illustrated in Figure 9, specifically exhibiting an electrical conductivity of less than 10 pS / cm. In this case, preferably, the pulsed electrical discharge(s) are applied between the electrode 440 and the metal layer 420. The metal layer 420 may include a transverse extension 425 at the end of the longitudinal extension 400 at the gas outlet 410. This allows, in particular, the plasma bubble 500 formed to be directed towards the surface of solution S.

[0206] In an unillustrated variant, the longitudinal extension 400 has a truncated cone-shaped nozzle, particularly at the distal end at the gas outlet.

[0207] The assembly may include a device for detecting the formation of the or each plasma pulse at the gas outlet, in particular a laser, a device for detecting plasma and / or its properties, in particular with a photodiode or one or more electrical measurements, and / or a device for detecting crystallization, in particular by a turbidity detector of the solution, an infrared probe or a calorimetric detection, and / or a device for detecting the energy of the plasma, in particular by a voltage and / or current probe as described in the article Minesi N, Thermal spark formation and plasma-assisted combustion by nanosecond repetitive discharges, PhD thesis, CentraleSupélec, 2020 and / or a flow meter at the inlet of the crystallization generator.

[0208] An example of a detection device is illustrated in Figures 17 and 18. It can consist of an optical detection system 600 comprising a tube 610 formed of a bundle of optical fibers 610 in a ring connecting a light source 650 to an emission end and a receiving structure connecting a detection window 620 to a filtering system 670 configured to direct a part of the received beam corresponding to the signal from the emission of the source 650 having passed at least partially through the plasma or gas to a camera 660 to identify the emission of the gas and, a part of the received beam corresponding to the signal emitted by the plasma to a spectral analysis system 680, in particular a spectrometer.

[0209] The receiving structure may include a 630 mirror or prism and / or a 640 objective and a series of bar lenses.

[0210] The 660 camera allows control of gas emission and plasma formation. This makes it possible to synchronize the gas ejection with the application of the electrical discharge(s) to form the plasma.

[0211] The 680 spectral analysis system can analyze the spectrum emitted by the plasma and thereby detect information about the plasma and the liquid in which crystallization takes place. For example, it is possible to monitor the plasma intensity, ensure the stability and repeatability of the plasma treatment, diagnose probe degradation, and detect the presence of one or more metals and their proportion in solution through spectral analysis of the plasma.

[0212] The detection unit 600 can be in the form of a rigid endoscope arranged along the generator and having a detection opening at the level of the opening, as illustrated in Figure 17 or integrated into the generator in the electromagnetic barrier 420, as illustrated in Figure 18.

[0213] Alternatively, not shown, the detection unit lacks a filtering system but includes a multispectral camera configured to simultaneously collect the plasma emission and the image of the gas ejection.

[0214] In implementing the process as described above using the aforementioned assembly, it is desirable that the solute to be crystallized in solution be in a metastable state such that its crystallization is possible by the application of plasma alone, without the influence of other factors, particularly the influence of the gas. Figures 10 and 11 illustrate graphs representing this metastable state. Figure 10 illustrates in color the region, in terms of solute concentration C in the solution and solution temperature, in which the solute is in a metastable state such that crystallization can be initiated by the application of a plasma in less than 2 hours. This region is delimited by a curve from which crystallization can be initiated by the gas without plasma MZL. gazin less than 2 hours, and the curve from which plasma crystallization initiation becomes possible in 2 hours. The MZL curve represents the spontaneous crystallization curve, which is not desired because it does not allow precise control of crystal characteristics. Crystallization initiation can be detected by measuring the turbidity T ur of the solution as illustrated in Figure 11. In this graph, the turbidity of the solution was measured by a turbidity probe or any other method allowing the detection of turbidity, including an infrared probe, as a function of the temperature of the solution and it can be seen that it is possible to initiate crystallization with the application of plasma at much lower temperatures than with gas without plasma or spontaneously.

[0215] For turbidity measurement, a camera can be aligned with a portion of the tank. Perpendicular to the camera's axis, an LED light source can illuminate the tank. When nuclei form, the light scattered by the particles is collected by the camera.

[0216] Examples of implementation of the invention are now described.

[0217] Example 1

[0218] A solution of glycine in water is formed. The concentration of glycine in water is 297 g / L. The supersaturation is 115%. The temperature of the solution is maintained at 32°C throughout the crystallization process.

[0219] The setup shown in Figure 2 is used. Twenty plasma-containing bubbles are introduced into the solution. Plasma is formed in each bubble by applying a sequence of pulsed electrical discharges synchronized with a pressure pulse. The discharge sequence consists of 50 electrical discharges with a frequency of 10 kHz. The discharges have a peak voltage of 7 kV and a duration of 10 ns.

[0220] The bubbles are formed by pressure pulses of 2.5 mbar amplitude and Pstab=7 mbar.

[0221] The gas is also heated upstream of the gas outlet to 32°C.

[0222] The application of the bubbles containing plasma is carried out at 23hl0 (vertical line on figure 12).

[0223] Turbidity is measured by a turbidity probe.

[0224] Figure 12, which shows the measured turbidity as a function of time, demonstrates that the application of plasma-containing bubbles at 23 hCl generates a progressive increase in the detected turbidity signal. This measurement is indicative of the formation of glycine crystals in the water and therefore of the initiation of crystallization by the plasma application.

[0225] Example 2

[0226] The same glycine-in-water solution is used in this example 2. The priming time t amor is detected for different bubble temperatures and with initiation by the application of gas bubbles without plasma and bubbles containing plasma. The initiation time t amor is the delay between the end of the plasma treatment and the moment from which the turbidity signal exceeds a predetermined threshold, here 3 times the noise signal.

[0227] The conditions for the formation of plasma-containing bubbles and the number of plasma-containing bubbles remain the same and are as described in Example 1. In the case of initiation with gas bubbles without plasma, the application conditions are the same as with plasma but without the pulsed electrical discharge sequence. The application is performed using the same crystallization generator.

[0228] The bubble temperature is controlled upstream of the gas outlet by controlling the gas temperature. Plasma formation under the conditions mentioned does not result in a significant increase in bubble temperature.

[0229] Figure 13 illustrates the initiation times t amorin minutes depending on the temperature of the bubbles. It is observed that bubbles containing plasma allow the initiation of crystallization in less than 2 hours at much higher temperatures, up to 30°C, than for gas bubbles which do not allow initiation above 25°C.

[0230] Example 3

[0231] The same glycine-in-water solution is used in Example 3 as in Example 1. Two hundred plasma-containing bubbles are introduced into the solution. The plasma is formed in each bubble by applying a sequence of 200 pulsed electrical discharges at a frequency of 10 kHz. The discharges have a peak voltage of 3 kV and a duration of 10 ns. The solution temperature is maintained at 32°C throughout the crystallization process.

[0232] In the first test, crystallization was carried out according to the method described in Example 1 with a constant temperature of 32°C for 4 hours. The glycine crystals formed had an average size of 2 mm and the size distribution of the crystals obtained was fine, as can be seen in the photo in Figure 14a.

[0233] In a second test, crystallization was carried out according to the method described in Example 1, with a constant temperature of 32°C for 2 hours. Cooling was then applied at 0.1°C / min to 25°C, followed by a 3-hour isotherm. The resulting glycine crystals exhibited twinning and an average size of 0.9 mm, with a broad crystal size distribution, as shown in Figure 14b.

[0234] This example shows that the cooling rate after initiation must be controlled to avoid further supersaturating the solution and triggering unwanted secondary nucleation.

[0235] Example 4

[0236] The same glycine-in-water solution is used in Example 4 as in Example 1. The solution temperature is 25°C. The priming time t amor is detected for different pulse peak voltages V. The conditions for the formation of plasma-containing bubbles and the number of plasma bubbles are always the same and are as described in Example 1, with the exception of the peak voltage In, which varies.

[0237] Figure 15 shows that varying the peak voltage between 3 and 10 kV reduces the initiation time by approximately 30%. It is therefore clear that the peak voltage influences the crystallization initiation time.

[0238] Example 5

[0239] The same glycine-in-water solution is used in Example 5 as in Example 1. The solution temperature is 25°C. The priming time t amoris detected for electrical discharges with varying numbers of pulses N. The discharges all have the same peak voltage of 3 kV. The frequency is the same for all electrical discharge sequences and is 10 kHz. The conditions for plasma bubble formation and the number of plasma bubbles are always the same and are as described in Example 1, except for the number of discharges, which varies.

[0240] Figure 16 shows that varying the number of discharges between 10 and 200 discharges results in a reduction of approximately 55% in the initiation time.

[0241] It is therefore clear that the number of pulses influences the crystallization initiation time. The examples below show that when one or more plasma pulses are applied to the solution, crystallization can be initiated in a controlled and reproducible manner, particularly with regard to the morphological properties of the crystals formed. Similar results were obtained by applying plasma pulses to the surface of the solution.

Claims

Demands 1. Method for initiating the crystallization of a solute present in a solution (S) at a concentration giving it a metastable state, comprising the application of one or more plasma pulses to the solution (S).

2. Method according to claim 1, comprising the formation of the or each plasma pulse (500) by applying, to a gas, in a crystallization generator (130) a sequence of one or more pulsed electrical discharges to generate the or each plasma pulse (500), in particular at the gas outlet (410) of the crystallization generator (130).

3. Method according to claim 1 or 2, comprising the application of a plurality of plasma pulses (500) formed in a substantially continuous gas flow for a predetermined duration by the application of several pulsed electrical discharge sequence(s) to the gas at the outlet of the crystallization generator with a duty cycle between 1 and 100%, the duty cycle being defined as the ratio between the duration of one electrical discharge sequence(s) and the duration between the start of two successive sequences.

4. Method according to claim 1, comprising the formation of the or each plasma pulse by applying, to a gas, in a crystallization generator (130) a pressure pulse or volumetric gas flow rate pulse, and applying, to the gas, a sequence of one or more pulsed electrical discharges synchronized with the pressure pulse or volumetric gas flow rate pulse to generate the or each plasma pulse (500), in particular at the outlet of the crystallization generator (130).

5. Method according to claim 3, wherein the pressure pulse applied to the gas is at an overpressure less than or equal to 50 mbar, better 20 mbar, better 10 mbar, even better 7 mbar and has a predetermined duration less than or equal to 5 s, better less than or equal to 1 s, even better less than or equal to 0.5 s.

6. A method according to any one of claims 2 to 5, wherein the pulsed electrical discharge sequence(s) comprises one or more electrical discharges, in particular between 1 and 200,000 electrical discharges per pulse, at an electrical discharge frequency between 1 Hz and 200 kHz, the electrical discharges having in particular an electrical discharge duration between 0.1 ns and 10 ps, ​​better between 1 and 100 ns, better between 1 and 50 ns, even better between 5 and 20 ns and a peak voltage between 1 kV and 50 kV, better between 1 and 40 kV.

7. A method according to any one of the preceding claims, wherein the solution is contained in a vessel (120), in particular of a volume greater than or equal to 250 mL.

8. A method according to claim 7, wherein the tank is hermetically sealed and filled with a non-combustible gas, in particular an inert gas, in particular nitrogen, argon or carbon dioxide or mixtures thereof, the oxygen concentration in the tank being less than or equal to the minimum oxygen concentration (MOC), the gas enabling the formation of plasma pulses being a non-combustible gas, in particular an inert gas, in particular selected from nitrogen, helium, argon, or a mixture of these gases.

9. A method according to any one of the preceding claims, implemented using at least one crystallization generator (130) of the solute in the solution, the crystallization generator (130) comprising: ■ A gas inlet (134), including a connector to a gas source, ■ An electrical input (132), in particular a connector to an electrical source, ■ A gas outlet (410), ■ A gas transmission line (430) connecting the gas inlet to the gas outlet, ■ An electrode (440) for applying the pulsed electrical discharge(s) electrically connected to the electrical input (132) and configured to subject the gas to a sequence of one or more pulsed electrical discharges at the gas outlet (410) to form the plasma of the plasma pulse (500), ■ An electrical insulation (450) configured to electrically isolate the electrode from the outside.

10. Method according to claim 9, wherein the gas transport line (430) comprises a tube forming a gas circulation cavity extending between the gas inlet (134) and the gas outlet (410), the tube being formed at least partially by the electrode (440), the latter being a tubular electrode.

11. Method according to claim 9 or 10, wherein the crystallization generator (130) comprises a metallic electromagnetic shield (310, 420) connected to earth.

12. Method according to any one of claims 9 to 10, wherein the crystallization generator (130) comprises a tubular extension (400) with a continuous cross-section along its longitudinal axis and comprising the gas outlet (410) and a housing (300) including the gas inlet (134) and the electrical inlet (132) and their respective connections to the gas transport line (430) and the electrode (440).

13. Method according to claim 12, wherein the metallic electromagnetic shielding comprises a metallic layer (420) covering at least the longitudinal extension (400), the metallic layer (420) is made of a metal chemically resistant to solution.

14. A method according to any one of claims 9 to 13, wherein the application of the plasma pulse(s) (500) is made to the surface of the solution (S), a gas outlet (410) being in particular spaced from the surface of the solution by a distance less than or equal to 50 mm, better less than or equal to 10 mm, better less than or equal to 5 mm, even better less than or equal to 3 mm.

15. A method according to any one of claims 9 to 14 taken in combination with claim 2, wherein the formation and application to the solution of the plasma pulse(s) (500), in particular by means of one or more gas bubbles containing plasma, is carried out directly in the solution, the gas outlet (410) in particular being immersed in the solution.

16. A method according to claim 15, comprising applying a continuous constant pressure to the gas in the generator at a pressure compensating at least the capillary pressure and the Archimedes' buoyant force, in particular at a pressure substantially equal to 2o cos 0 Pstab = Patm 4 - I- pghQ where o is the interfacial tension, 0 the contact angle and R the radius of the capillary, Patm is the pressure at the surface of the tank, p is the density of the solvent, g is the gravitational constant and h is the depth at which the gas outlet is immersed.

17. A method according to any one of the preceding claims, comprising the detection of the formation of the gas bubble or of each gas bubble at the gas outlet, in particular by emission by an optical source (650) at one or more wavelengths far removed from the emission bands of the plasma, in particular at a wavelength greater than or equal to 100 nm, preferably greater than or equal to 500 nm, and the optical detection of the light at the gas outlet.

18. A method according to any one of the preceding claims, comprising the detection of plasma and / or its properties, in particular simultaneously with the detection of the formation of the or each gas bubble at the gas outlet.

19. A crystallization generator for a solute present in a solution at a concentration conferring a metastable state, in particular for implementing the crystallization initiation process according to any one of the preceding claims, comprising • A gas inlet (134), • An electrical inlet (132), • A gas outlet (410), • A gas transmission line (430) connecting the gas inlet to the gas outlet, • An electrode (440) for applying a sequence of one or more pulsed electrical discharges, electrically connected to the electrical input (132) and configured to subject the gas to a sequence of pulsed electrical discharges at the gas outlet (410) to form a plasma of a plasma pulse, • An electrical insulation (450) configured to electrically isolate the electrode from the outside, the generator (130) comprising a tubular extension (400) with a continuous cross-section along its longitudinal axis and comprising the gas outlet (410), the tubular extension (400) having a length greater than or equal to 10 cm.

20. Crystallization device comprising the crystallization generator (130) according to claim 19, an electrical source (140), in particular a pulsed high voltage source, connected to the electrical input (132) of the generator (130), a gas source (150) connected to the gas inlet (134), and a gas pressure or flow regulator configured to apply gas pulses to the gas inlet, in particular a gas pressure control element connected to the gas inlet.

21. Device according to claim 20, comprising a control unit (170) of the device, in particular of the electrical source, the gas source and the gas pressure regulator.

22. Crystallization assembly (100) comprising at least the crystallization generator (130) according to claim 19, or better the crystallization device according to claim 20 or 21, and a crystallization tank (120) in which the crystallization generator (130) is inserted.

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