METHOD AND DEVICE FOR CRYSTALIZING AND SEPARATEING SUBSTANCES

Description

[0001] The present invention relates to a method and a device for crystallizing and separating substances from a mixture of substances, in particular from a supersaturated solution of the mixture of substances.

[0002] In many areas, it is advantageous to crystallize defined substances from a solution in order to isolate them, especially in pure form. One example is enantiomer separation, in which the different enantiomers must be separated from a mixture of enantiomers, ideally in enantiomerically pure form. Enantiomer separation is used, for example, in the production of active pharmaceutical ingredients. It is therefore clear that safe and effective enantiomer separation is often of fundamental importance.

[0003] With regard to known processes for the crystallization of defined substances from solutions, for example for enantiomer separation, there are already a variety of state-of-the-art solutions.

[0004] For example, Xichong Ye et al., Enantiomer-selective magnetization of conglomerates for quantitative chiral separation, Nature Communications, (2019) 10:1964 (https: / / doi.org / 10.1038 / s41467-019-09997-y), describe a method for separating crystals from conglomerates using magnetic splitters through enantiomer-selective magnetization. However, this method has the following disadvantages: The magnetic splitters used consist of a copolymer with an enantiomerically pure substance as an auxiliary agent. The polymer and the magnetic particles as the matrix for the experiment must be produced in several steps, over several days, at temperatures ranging from below 0 °C to 300 °C. The subsequent separation processes take several more days.

[0005] US 2019 / 0345098 A1 describes the separation of enantiomers from a racemic mixture by processes known as preferential crystallization. The enantiomers are obtained through targeted crystallization processes using seed crystals.

[0006] Andrew S. Dunn et al., Resolution control in a Continuous Preferential Crystallization Process, Organic Process Research & Development, DOI: 10.1021 / acs.oprd.9b00275, also describes a preferential crystallization process to separate enantiomers.

[0007] US 2012 / 0197040 A1 also describes the resolution of a racemic mixture. At least two crystallization units are used to crystallize at least one enantiomer in one crystallization unit.

[0008] AT 357501 describes a method and device for removing excess salts, particularly tartar and calcium salts, from beverages. The beverage is brought into contact with crystals to crystallize the excess salts. The crystals can be fixed to support surfaces. The method and device serve to remove solids from a solution, whereby the crystallized salts are not a pure substance, but rather a mixture of several different substances. Therefore, the disclosure of this document is suitable for the production of a salt-free beverage, but not for the separation of a pure crystalline solid from a solution.

[0009] US 2,994,593 describes a crystallization device which is intended to arrange a large number of seed plates in a small volume.

[0010] US 2,495,024 describes a crystallization device for growing crystals from supersaturated solutions.

[0011] JPS4940234 A describes a crystallization process using seed crystal carriers.

[0012] Basically, the known principle of preferential crystallization involves the use of a seed crystal, which is formed either by adding it to a solution or by adding an excess of one enantiomer of a racemate to the solution before the start of crystallization. In the prior art, as mentioned above, seed crystals floating in the solution are used. The seed crystals are suspended in the solution by stirring. To maintain the distribution of the seed crystals as homogeneous as possible in the solution and also to avoid sedimentation at the bottom of the container, the stirring speed should be optimized depending on the particle size and adjusted further during the process, since crystals sometimes grow.While high stirring speeds can achieve the desired dispersion, high flow rates can lead to crystal breakage due to collisions with other crystals, the vessel walls, or the stirrer, resulting in high secondary nucleation rates. The resulting fine crystals have a broad Gaussian particle size distribution, which complicates the separation of the solid product from the solution during subsequent processing. This is because a high concentration of the solution adheres to the crystals, causing more impurities to adhere to them. More detergent or washing steps are required, and a longer drying time is usually necessary. If the crystal product of an active ingredient is used directly for pharmaceuticals, the different particle sizes can also lead to different bioavailabilities, which reduces the usability of the resulting product.

[0013] Separating crystals from a solution, for example by filtering or centrifuging, is often very complex because appropriate devices must be provided to separate the crystals from the solution.

[0014] Furthermore, the solution may become contaminated again when separating the crystals, which is particularly problematic when separating enantiomeric mixtures. Separating the crystals, for example, by filtration, can be particularly problematic when the crystalline particles are widely distributed.

[0015] In the prior art, for isolation after crystallization, the suspension containing the produced crystals is transferred to another container, where the crystals are separated from the solution, particularly by filtration or centrifugation. During this process, the entire solution must flow through the new filter container or through the centrifuge drum. In industrial processes, the suspension is also transferred by the pump and piping. Each new contact, for example, with the piping, pump, filter container, or centrifuge drum, represents additional potential sources of contamination and complicates the control of the temperature of the suspension. Furthermore, the process of filtering or centrifuging the entire suspension requires a relatively long time.

[0016] These three factors—new contact surface, longer separation time, and decreasing temperature—pose the risk that impurities, especially the corresponding enantiomer antipode, will crystallize during workup. In the preferred crystallization, the antipode is often supersaturated in the solution, which is why nucleation is further stimulated by decreasing temperature, contact with new surfaces, and / or longer residence time.

[0017] In a coupled continuous process, an additional problem arises: floating fine particles of one enantiomer could be transferred from one process vessel to the other process vessel of the antipode by circulating flow. As a result, two different enantiomer antipodes exist in both process vessels, which torpedoes the final enantiomer separation. In this case, the process must be terminated or a subsequent step must be performed. After termination, the workup, including separating the crystals from the solution and regenerating them to the starting point, can take a considerable amount of time.

[0018] Such solutions known from the prior art are therefore not satisfactory in all respects and there is a need for new methods and devices for crystallizing and separating substances from a mixture of substances.

[0019] It is therefore the object of the present invention to provide an improved method and an improved device for the crystallization and / or separation of substances from a solution, in particular of enantiomers from a racemic mixture in the solution, which are able to at least partially overcome at least one disadvantage of the prior art.

[0020] The object is achieved according to the invention by a method having the features of claim 1. The object is further achieved according to the invention by a crystallization arrangement having the features of claim 10. Preferred embodiments of the invention are disclosed in the subclaims, in the description, the examples and in the figures, wherein further features described or shown in the subclaims or in the description or the figures or the examples can represent an object of the invention individually or in any combination, unless the context clearly indicates the opposite.

[0021] The present invention relates to a method for crystallizing and separating a substance from a solution in which the substance is present, in particular in a supersaturated solution, comprising the method steps: a) introducing the solution containing the substance into a receiving volume of a process vessel of a crystallization arrangement, wherein the solution has a temperature T1 after introduction; b) providing a crystallization insert with at least one support for insertion into the process vessel, wherein the surface of the support is provided with seed crystals for the substance for crystal growth such that the seed crystals are immobilized on the surface of the support of the crystallization insert; c) positioning the crystallization insert in a receptacle of the crystallization device such that the support can be brought into contact with the solution; d) optionally cooling the seed crystals while adjusting the temperature at the seed crystals to a temperature T2, wherein T2 is lower than T1; e) crystallizing the substance on the surface of the seed crystals; and f) optionally isolating the formed crystals of the substance in the process vessel. wherein at least one carrier is a spiral carrier.

[0022] The crystallization process described here thus serves, in particular, to crystallize a substance from a solution in which the substance is present, in particular, in combination with one or more other substances, in order to separate and, if necessary, isolate the substance and thus, in particular, to obtain it in pure form. Thus, the crystallization process described here can, in particular, be a separation process for separating a mixture of substances.

[0023] The procedure described here comprises the following steps.

[0024] First, according to process step a), the solution containing the substance is introduced into a receiving volume of a process vessel, which can also be referred to as a separation vessel, of a crystallization device, wherein the solution has a temperature T1 after being filled into the process vessel. Thus, a solution is introduced into the process vessel, which can be designed as a liquid container, wherein the solution contains the substance that is to be crystallized and separated, or preferably isolated, by the process. For example, the substance is dissolved in the solution at a suitable concentration, wherein the substance is particularly present in a supersaturated form in the solution.

[0025] The process vessel of the crystallization device is generally selectable, as long as the process described here is feasible with it. Advantageous materials include, in particular, non-oxidizing materials such as glass, or non-oxidizing metals, such as stainless steel or enameled metals, or plastic. In principle, the material of the process vessel should be inert to the solution.

[0026] Furthermore, the solution has a temperature T1. This temperature T1 is preferably selected such that the substance is completely dissolved in the solution. The solution can already have the temperature T1 before being poured into the process vessel, or the temperature T1 can be adjusted after introduction. However, the temperature should be adjusted, in particular, before process step c).

[0027] The temperature T1 of the solution can preferably be a maximum of 20°C, preferably a maximum of 10°C, and particularly preferably a maximum of 5°C below the saturation temperature. The saturation temperature is particularly present under the conditions under which the solution exists, for example, approximately 1 bar. For example, the temperature T1 can be the saturation temperature, and the substance can be present as a saturated solution.

[0028] Subsequently, according to method step b), a crystallization insert with at least one support is provided for insertion into the process vessel, wherein the surface of the support is provided with seed crystals for the substance, for example, with seed crystals of the substance, for crystal growth in such a way that the seed crystals are immobilized on the surface of the support of the crystallization insert, and wherein at least one support has a spiral shape. In other words, the invention provides for at least one support to be a spiral-shaped support.

[0029] The crystallization insert serves to crystallize the substance to be separated from the solution in such a way that the substance crystallizes on the crystallization insert. For this purpose, a carrier is provided which is equipped with at least one or in particular with a plurality of seed crystals which are adapted to the substance in such a way that the substance can crystallize on the seed crystals. Furthermore, the crystallization insert and the carrier and also the process vessel are designed such that they can be positioned in the receiving volume, optionally in the liquid that can optionally be present in the receiving volume. In particular, the crystallization arrangement can be designed with a lid for the process vessel and can seal it in a liquid-tight manner. The lid can thus be replaceable, for example with a filtration insert, as described in more detail below.

[0030] For example, the support can be part of the crystallization insert or can be attached or mounted to it. In particular, the support or support parts can run vertically.

[0031] The immobilization of the seed crystals on the surface of the support can be achieved, for example, by exposing the support to a solution of the corresponding high-purity substance from which the seed crystals are to consist. In particular, the support can be immersed in a corresponding supersaturated solution and the support can then be partially dried. Furthermore, spray-drying the solution on the support is possible, or wetting the support with a melt is also possible, whereby the support can be immersed in a melt or the support can be sprayed with a melt or coated in some other way. Likewise, the support can be coated with seed crystals by providing the solvent-treated support with fine crystals of the substance with which the support is to be coated, or by basically any other suitable method.The mass of the seed crystals can be varied, for example, by the duration of immersion or the duration of spraying.

[0032] The carrier can also be placed in the solution and the solution can then be cooled so that seed crystals of the substance form on the carrier.

[0033] Furthermore, the support can generally have a selectable shape, which is preferably selected to provide a large surface area through which the seed crystals come into contact with the solution. Furthermore, it is advantageous if the solution can flow through the support with the seed crystals, so that a relative movement of the solution relative to the support is possible, or the solution can flow around the support and thus the seed crystals.

[0034] The support is a spiral-shaped support, with an Archimedean spiral shape being particularly suitable. Such a shape particularly effectively allows for a homogeneous distribution of the seed crystals in the solution throughout the separation, for example, when the support is rotated in the process vessel, or when the supports are rotated in the process vessel, or even when the support(s) are stationary in the process vessel, which is facilitated by the spiral shape of the support.

[0035] Furthermore, the carrier can advantageously be formed at least partially from a material selected from the group consisting of metal, plastic, textile, paper, renewable raw materials, ceramic, glass, and carbon. Depending on the solvent, these materials can have the advantage of being inert to the solution and also be well suited for seed crystals to settle.

[0036] A rough surface or a surface with grainy substrates promotes wetting with the solution and the formation of seed crystals. For aqueous solutions, a support surface with hydrophilic properties is advantageous.

[0037] In principle, it may be preferable for the seed crystals to be densely and homogeneously immobilized in a finely distributed manner. This allows for rapid and, in particular, at least largely complete crystallization of the substance on the large surface of the seed crystals, which can enable an effective and efficient process, as described below.

[0038] Accordingly, according to process step c), the crystallization insert is positioned in a receptacle of the crystallization device, such as the process vessel, such that the support can be brought into contact with the solution. The crystallization insert or the support and the solution are thus brought together, for example, by immersing the support in the solution, for example while moving, such as rotating, the support in the solution, but can also be brought together by flowing the solution over the support. The latter can be achieved, for example, if the support is located above the solution while the solution is stationary and the solution is conveyed, for example, to flow over the support.

[0039] Accordingly, it is fundamentally possible for the solution containing the substance to first be poured into the process vessel and then the carrier is positioned accordingly, or vice versa, or for a portion of the solution to first be poured into the process vessel, then the carrier is positioned accordingly, and then another portion of the solution is poured into the process vessel. The substance can be present only in the first portion, only in the further portion, or in the first portion and the further portion of the solution. Thus, process step a) can take place at least in part before process step c), or process step a) can take place at least in part after process step c). It is also possible for process step a) to take place before and after process step c) and / or at least in part simultaneously with process step c).

[0040] Preferably, the support or its extension in the liquid volume is arranged such that the seed crystals in the crystallization insert are homogeneously, densely, and finely statically distributed in the solution in all volume elements of the solution. This can be the case permanently or through movement of the support in the process vessel. Depending on the supersaturated concentration, a large number of seed crystals can be statically present in each individual volume element of 1 cm³. In principle, a surface provided with seed crystals, i.e. a crystallization surface, can be present in a range of 0.5 cm² to 5 cm² per 1 cm³ of the receiving volume on the crystallization insert for rapid crystallization, at least in part of the receiving volume.It may be possible for the support to have a corresponding crystallization surface in each volume of the receiving vessel, or there may also be regions in the receiving volume in which the above-described crystallization surface is not realized. Accordingly, it may be preferred for a crystallization surface of 0.5 cm2 to 5 cm2 per 1 cm3 of the receiving volume to be present in at least part of the receiving volume.

[0041] In a static medium, the molecules can attach to the surface of the seed crystals through diffusion without external influences more quickly and effectively through van der Waals forces than in a flowing solution. Accordingly, it may be preferable for the solution to remain still for crystallization to occur. However, as described elsewhere, this is by no means mandatory.

[0042] Furthermore, in the crystallization process described here according to step d), the seed crystals can optionally be cooled by adjusting the temperature at the seed crystals to a temperature T2, where T2 is lower than T1. In other words, the crystallization insert or the support with the seed crystals is tempered such that the temperature at the seed crystals is lower than the solution immediately after process step a).

[0043] Preferably, the temperature T2 of the seed crystals can be equal to or at most 5°C lower than the temperature T1 of the particularly supersaturated solution or the substance-depleted solution. For this purpose, the solution in the process vessel can be temperature-controlled, for which purpose known temperature control means can be used. In principle, the temperature T2 can preferably be at most 20°C, preferably at most 10°C, and particularly preferably at most 5°C lower than the temperature T1.

[0044] This can be achieved, in particular, by directly controlling the temperature of the crystallization insert or the support. Thus, the crystallization insert or the support preferably has a temperature control unit by means of which the seed crystals can be heated and / or cooled. This makes it possible to directly control the temperature of the crystallization insert or the support, particularly independently of the temperature control of the solution.

[0045] However, it is also possible within the scope of the invention to temperature-control the solution in order to also temperature-control the support or the seed crystals. In principle, however, it may be preferable for the temperature of the seed crystals to be lower than that of the solution.

[0046] Following the previously described process steps, the substance then crystallizes out on the seed crystals or on their surface, and thus on the support, according to step e). This is because, for example, through the temperature control specified above, the substance dissolved in the solution can come into contact with the comparatively cold support or with the comparatively cold seed crystals and thus crystallize. In this process, the crystals grow on the support, so that the solution is diluted or depleted of the substance.

[0047] Because the seed crystals and subsequently the crystallized substance are immobilized on the support, the substance can then be advantageously isolated. In particular, the substance can thus be removed from the support and obtained in a highly pure form.

[0048] For this purpose, according to process step f), it is optionally provided that the formed crystals of the substance are isolated in the process vessel. This makes it possible, as described in more detail below, to use a process vessel in which high-purity crystals of the substance are formed from the solution through appropriate process steps.

[0049] The described method effectively allows for the targeted removal of substances from a solution and thus from a mixture of substances, thus separating or isolating them. For example, the possibility of targeted temperature control allows the substance to be isolated from the solution in a defined and reproducible manner. This is possible in such a way that the substance is isolated as completely as possible, for example, by setting a very low temperature. Alternatively, it is also possible to crystallize substances only to a limited extent, for example, by selecting a comparatively high temperature. This always creates suitable conditions that allow for the desired crystallization.

[0050] Furthermore, the process is highly adaptable to the substance to be isolated by using carriers with suitable seed crystals and appropriate temperatures. This allows a wide variety of substances to be specifically and effectively isolated from a solution without major modifications and with only minor changes.

[0051] The adaptability can be further improved by the fact that the temperature control of the carrier or the seed crystals allows for a temperature control suitable for the respective substance to be isolated.

[0052] Furthermore, the process can be made very adaptable by carrying out the process continuously or batchwise, as described in more detail later.

[0053] For non-racemic separation, there is no risk of crystallization of the antipode. The solution can therefore be cooled slowly, preferably homogeneously, while continuously lowering the temperature, whereby controlled crystallization on the seed crystals takes place from the supersaturated solution. Homogeneous cooling is preferably characterized by a temperature deviation of no more than 1°C throughout the solution. Crystallization on the supports can occur, for example, by Ostwald ripening. Crystallization is particularly assisted by a change in the temperature of the solution. For this purpose, the solution is preferably heated in such a way that a change in the temperature of the solution quickly and briefly increases by a maximum of 2°C, whereby any small crystalline particles on the bottom and / or wall of the process vessel are dissolved, and their substance preferentially attaches to larger crystalline particles on the supports.Ultimately, the substance crystallizes completely from the solution in a homogeneous crystallite size. This enables very high yields, for example, in the range of at least 95 wt.%, preferably at least 99 wt.%, based on the theoretical yield of the substance originally present or dissolved in the solution.

[0054] Furthermore, by processing the crystals to the isolated crystal, a very simple structure can be chosen and the risk of contamination of the resulting crystals can be minimized. Therefore, the process described here can produce a highly pure substance, which is of key importance for many applications.

[0055] In order to isolate the crystals and thus, when process step f) is implemented, the process may comprise the further process step: f1) detaching substance crystallized on the seed crystals from the carrier within the process vessel.

[0056] Process step f1) serves to isolate the crystals formed and, in particular, to ensure that the crystals are present in free form so that further process steps can follow and enable particularly effective purification.

[0057] For this purpose, for example, a scraper can be provided, wherein a relative movement is possible between the carrier and the scraper in order to mechanically detach the crystals. In this case, the crystals initially remain in the solution and can then be removed from the solution, and the isolation can continue. However, other possibilities for removing the crystals from the carrier are also encompassed by the present invention. For example, the crystals can be detached from the carrier by centrifuging the process vessel, for example after separation of the free solution mass or the free solvent. The crystals are detached due to centrifugal force, while the solution residues adhering to the crystalline elements are simultaneously separated from the process vessel.

[0058] Thus, when implementing step f), the method can comprise the following further steps: f1) detaching substance crystallized on the seed crystals from the support within the process vessel; and f2) removing solution from the formed crystals; f3) optionally cleaning the formed crystals; and f4) drying the crystals.

[0059] In order to remove the solution from the crystals formed, it can be provided, for example, that the produced crystals are separated from the mass of the free solution without a filter by draining the solution from the process vessel or, if necessary, removing the crystallization insert and decanting the solution from the process vessel.

[0060] For this purpose, for example, the process vessel can be centrifuged with or without a support. The solution above the crystals can then be removed, and centrifugation can be repeated, optionally with the addition of additional solvent. This allows the crystals to be purified. Accordingly, at least one of process steps f2) and f3) can comprise centrifuging the solution in the process vessel.

[0061] However, it can particularly preferably be provided that at least one of process steps f2) and f3) comprises filtering the solution together with the crystals present in the solution to collect the crystals on the filter, in particular in the process vessel. The filter can preferably be arranged in or on the process vessel. This allows the solution to be decanted from the process vessel, while the crystals can remain in the process vessel. For example, the filter can be arranged on or in an outlet of the process vessel.

[0062] In principle, however, it is also possible to remove the excess solution, for example, using a syringe. This can be done both during the initial removal of the solution and during a washing or cleaning process.

[0063] The crystals can then be dried so that they can be isolated. Drying the crystals can be achieved using a particularly high-purity gas stream or a vacuum.

[0064] Separation of the crystals from the support can also be achieved by centrifugation, so that the same setup is possible for separating the crystals and for cleaning the crystals.

[0065] In principle, at least one, for example both, of process steps f2) and f3) can thus comprise at least one of centrifugation and filtration. For example, both of process steps f2) and f3) can comprise centrifugation and filtration. This can simplify the process while still enabling very effective purification of the crystals and thus the obtaining of high-purity crystals.

[0066] After crystallization, the produced crystals can be separated from, for example, 90% of the solvent or the free solution mass in a very short time, for example by decanting or draining the solution or removing the crystallization insert. This can be done significantly faster than with state-of-the-art processes and can reduce the risk of contamination of the mother liquor. In this step, the solution can be removed from the process vessel once the formed crystals are immobilized on the seed crystals, i.e., without centrifugation and / or filtration.

[0067] For example, a method can be carried out by comprising the following steps: f1) detaching substance crystallized on the seed crystals from the support within the process vessel; and f2) removing solution from the crystals formed; f3) optionally cleaning the crystals formed; and f4) drying the crystals, wherein both of the process steps f2) and f3) comprise filtering the solution together with crystals present in the solution to collect the crystals on the filter in the process vessel, wherein the filter is arranged in or at an opening of the process vessel, wherein a collecting vessel for collecting the solution or mother liquor is provided on the side of the filter opposite the receiving volume, and wherein both of the process steps f2) and f3) comprise centrifuging the solution in the process vessel.

[0068] In one embodiment, an arrangement comprising a process vessel, a collecting vessel and a filter unit having a filter, wherein the process vessel and the collecting vessel are attached to the filter unit in a fluid-tight manner and are fluidly connected to one another by the filter such that solution is filtered from the process vessel into the collecting vessel under vacuum or centrifugal force through the filter, wherein solids are retained by the filter in the process vessel and separated from the solution.

[0069] The process can preferably be a resolution of enantiomers, wherein the substance is an enantiomer of a racemic mixture, in particular of a conglomerate-forming substance system, and the solution comprises the racemic mixture, in particular as a supersaturated solution of the racemate. In this embodiment, the process described here can thus be used in particular to resolve a racemate, in particular a conglomerate-forming substance system. This is advantageous for many industrial processes, since chemical reactions may produce racemates, but often only an isolated enantiomer of the racemate or of the enantiomer mixture is required. The crystallization process described here can be particularly advantageous for a resolution of enantiomers, since conglomerates of an enantiomer mixture, in particular, can often be separated by crystallization processes.

[0070] To isolate one enantiomer, it may be sufficient to use the support with a seed crystal so that the desired enantiomer can be crystallized and isolated, but the other undesired enantiomer remains in solution.

[0071] If both enantiomers are to be isolated, different supports or different seed crystals of the enantiomers can be used, for example by using different supports one after the other in a batch process in a process vessel by exchanging the crystallization insert, or in a continuous process by connecting different and interconnected or coupled process vessels with differently equipped crystallization inserts in series. For the separation and isolation of two enantiomers from a racemic mixture, such as in particular a conglomerate-forming substance system, the support of a first crystallization insert is loaded with the seed crystal of the first enantiomer, for example, and the support of the second crystallization insert with the seed crystal of the second enantiomer. This is described in more detail below.

[0072] For the enantiomeric separation of a racemic mixture, especially a conglomerate-forming system, isothermal crystallization is preferred. The crystallization time in a batch process and the residence time in a continuous process depend on the degree of supersaturation. The residence time is preferably a maximum of 90 minutes, approximately a maximum of 60 minutes, particularly preferably a maximum of 30 minutes. This allows an enantiomeric excess of over 90%, preferably over 95%, and especially preferably over 99% to be achieved.

[0073] The ideal residence time for optimal separation for the resolution of racemates can be determined precisely by measuring the rotation value of the solution in the process, whereby at the inflection point of the rotation value the crystalline on supports can be quickly separated from the solution.

[0074] With regard to the crystallization temperature set in process step d), it should be noted that it should be chosen such that only the desired enantiomer crystallizes on the seed crystals, but the antipode remains in solution.

[0075] It may further be preferred that the process steps a) to e) are carried out repeatedly as a common sequence in a process vessel, wherein the crystallization insert of the process vessel is exchanged between two repeating sequences, wherein in a first sequence the carrier has a first type of seed crystals and wherein in a second sequence the carrier has a second type of seed crystals different from the first type.

[0076] In this embodiment, more than one substance can be isolated from the solution. This makes it possible, for example, to separate a mixture of dissolved substances in such a way that each dissolved substance is individually isolated in crystallized form. This can be achieved by equipping the support, or even different supports used one after the other, with different seed crystals, on which the substance to be isolated selectively crystallizes.

[0077] In particular, this design can form a so-called batch process.

[0078] Alternatively or additionally, it is also possible to carry out a separation of different substances from the solution in a continuous process. In this case, process steps a) to e) can be carried out as a common sequence repeatedly in different process vessels, wherein the support of a first process vessel comprises a first type of seed crystals and wherein the support of a second process vessel, in particular connected downstream of the first process vessel and connected or coupled to the first process vessel by a fluid connection, comprises a second type of seed crystals different from the first type.

[0079] Thus, the solution is first conveyed into a first process vessel and can remain there until a desired amount of a first substance crystallizes on the carrier or its seed crystals located in the first liquid container. The solution, which is supersaturated, particularly with regard to the second substance, can then be conveyed into a second process vessel, where a carrier with a different seed crystal is provided. Here, too, the solution can remain until a desired amount of a second substance crystallizes on the carrier or its seed crystals located in the first process vessel. This can be achieved, for example, continuously at an adjustable flow rate.

[0080] Thus, in this embodiment, it is particularly provided that the outlet of a first process vessel is connected to the inlet of a second process vessel, thus coupling the process vessels to one another. One or more additional process vessels can be provided in the connection between the first and second process vessels, into which a saturated substance mixture solution can be introduced.

[0081] In principle, at least two coupled process vessels are operated simultaneously and continuously, with different seed crystals, for example of the enantiomer antipodes of a racemate, being immobilized on the support in both process vessels.

[0082] This allows for the effective and easy separation of solution mixtures. Two different substances can be isolated using either a batch or a continuous process, or more than two substances can be isolated if a larger number of carriers are used.

[0083] Another advantage of a continuous process is that there is little or no risk of contamination between the two process vessels, as there are no fine crystal particles floating in the solution. This risk can be further reduced by providing a filter.

[0084] In an exemplary embodiment, the process can proceed as follows, whereby all of the following steps or sub-steps can also be part of the process on their own or in combination with other steps: A) The solution free of formed crystals is removed from the process vessel, for example by at least one of A1) decanting through an outlet of the process vessel, in particular with a crystallization insert inserted, A2) removing the crystallization insert and decanting the solution through an opening thereby created; A3a) centrifuging the process vessel with the crystallization insert and, if appropriate, applying a vacuum to the process vessel; wherein the process vessel, the lid of which is or will be equipped with a filter insert with a filter disc, is tightly closed, and wherein, during centrifugation, the process vessel is inserted into a centrifuge with the opening facing downwards and centrifuged, whereby the crystals are simultaneously detached from the crystallization insert by centrifugal force, and the crystals are freed from adhering solution by the solution passing through the filter;wherein A3b) optionally an arrangement is used during centrifugation, wherein the arrangement consists of the process vessel, a collecting vessel and a filter unit with a filter, wherein the process vessel and the collecting vessel are attached fluid-tight to the filter unit and fluidly connected to one another by the filter such that solution from the process vessel into the collecting vessel can be filtered through the filter under vacuum or centrifugal force, wherein solids are retained in the process vessel by the filter and separated from the solution. B) The crystals are optionally removed from the crystallization insert in a further step. C) The crystallization insert freed of crystals can be removed from the process vessel. D) The crystals are washed and dried in the same process vessel. ;

[0085] With regard to further technical features and advantages of the process, reference is hereby made to the description of the crystallization arrangement, the use, the arrangement, the examples, the figures and the description of the figures, and vice versa.

[0086] Also described is a crystallization arrangement for crystallizing at least one substance from a solution, in particular for carrying out a method as described above, comprising a process vessel for receiving the solution and comprising a crystallization insert with at least one carrier for insertion into the process vessel, wherein the surface of the carrier is provided with seed crystals for the substance for crystal growth such that the seed crystals are immobilized on the surface of the carrier of the crystallization insert, and wherein at least one carrier is a spiral-shaped carrier, wherein the process vessel has a receptacle for receiving the crystallization insert with the carrier, wherein the crystallization insert can be detached from the receptacle in a non-destructive manner and wherein the crystallization insert can further be positioned in the receptacle such that the seed crystals can be brought into contact with the solution.

[0087] With such a crystallization device, in particular a described crystallization process can be carried out and it thus serves in particular for crystallizing at least one substance from a solution.

[0088] For this purpose, the crystallization arrangement comprises a process vessel for holding the solution containing the substance. The process vessel of the crystallization arrangement is generally selectable, as long as the process described here is feasible with it. Advantageous materials include, in particular, non-oxidizing materials, such as glass or plastics, or non-oxidizing metals, such as stainless steel or enameled metals. In principle, the material of the process vessel and any other components that come into contact with the solution should be inert to the solution and, in particular, to the substance.

[0089] Furthermore, the crystallization arrangement comprises a crystallization insert with at least one carrier for insertion into the process vessel, wherein the surface of the carrier is provided with seed crystals for the substance for crystal growth such that the seed crystals are immobilized on the surface of the carrier of the crystallization insert.

[0090] Thus, the support or seed crystals are advantageously adapted to the method to be performed or to the substance to be isolated. Such a support can be designed and produced, in particular, as described above with reference to the method, and the seed crystals can further be immobilized in such a way that substance crystallized on the support can be detached from the support while the seed crystals remain immobilized.

[0091] Particularly preferably, the support has a spiral shape, whereby an Archimedean spiral shape can be provided. Such a shape particularly effectively allows for a homogeneous distribution of the seed crystals in the solution throughout the separation, for example, when the support is rotated in the process vessel or when the supports are rotated in the process vessel, or even when the support is stationary in the process vessel, the latter being supported by the spiral shape.

[0092] Particularly preferably, the carrier is configured, for example, in an Archimedean spiral shape, for example made of rigid film, wherein the distances between the spiral shapes, i.e., the respective winding regions, are less than 2 cm, preferably less than 1 cm, and particularly preferably less than 0.5 cm. A rigid film can also be understood as a film that is so stable that the spiral shape retains its shape under the process temperature and when supporting the crystalline elements on the surfaces, even, for example, when the spiral shape is empty and stands freely without external influences.

[0093] Alternatively or additionally, it may be preferred for the carrier to be designed as a film or fabric, wherein the film or fabric is preferably provided with through-holes. This design allows the solution to flow effectively around the seed crystals immobilized on the carrier, thus enabling particularly effective crystallization of the substance from the solution.

[0094] With regard to positioning the crystallization insert, the process vessel has a receptacle for accommodating the crystallization insert with the support. Furthermore, the support can be removed from the receptacle without causing damage, which allows for the preferred applicability of the process vessel and support for multiple uses. The receptacle can enable a defined position of the crystallization insert and further ensure that the crystallization insert is securely fastened.

[0095] Furthermore, the carrier is positioned, or can be positioned, in the receptacle in such a way that the seed crystals can be brought into contact with the solution. Bringing the carrier into contact can mean immersing the carrier in the solution, as well as pouring or even immersing the carrier in the solution, as described in more detail above with reference to the method.

[0096] Furthermore, it is preferably provided that a temperature control unit is provided for directly or indirectly controlling the temperature of the support and thus the seed crystals. For example, the solution contained in the process vessel can be temperature-controlled, whereby the support or the seed crystals can thus be temperature-controlled indirectly.

[0097] For direct temperature control of the carrier, the carrier can, for example, have one or more channels through which a corresponding, in particular liquid, temperature control medium can be passed to thereby temperature control, in particular to cool, the carrier. In this case, the channel(s) can be connected to a cooling and / or heating unit, which adjusts the temperature control medium to a temperature by means of which the carrier can be temperature-controlled as desired or so that the temperature of the carrier and thus of seed crystals immobilized on the carrier for crystal growth of the substance can be set in a defined manner.

[0098] For example, the solution in the container and / or the carrier can be temperature controlled separately.

[0099] In the crystallization arrangement described here, it can further be provided in one embodiment that the crystallization arrangement has a filter for filtering the solution present in the process vessel, or that the crystallization arrangement has a centrifuge for centrifuging the process vessel. For example, it can be advantageous if the process vessel has a filter for filtering the solution present in the process vessel, and if the crystallization arrangement has a centrifuge for centrifuging the process vessel.

[0100] The filter can be positioned at a liquid outlet of the process vessel. This filter can prevent the solution discharged from the liquid outlet from entraining crystals that would then potentially be lost or require further isolation. This can be done regardless of whether the solution is dumped, returned to the container, or fed to another carrier in a coupled process vessel. Thus, the filter serves primarily to separate the crystals from the solution and, accordingly, to isolate the crystals.

[0101] The filter or filtration insert is thus designed to allow the liquid medium to pass through and retain the produced crystals. It can be designed as a filtration disc, filter sieve, filter fabric, filter foil, filter paper, or other materials known to those skilled in the art that serve such a function. The mesh size can be selected based on the desired crystal size to be obtained.

[0102] For example, after removing the free solvent mass, the lid of the process vessel can be equipped with a filter unit, and the container can be positioned on a centrifuge like a conventional centrifuge bottle, but with the opening facing down so that the adhering solvent residues are centrifuged out of the container through the filter. The produced crystals are detached from the carrier by centrifugal force.

[0103] The centrifuge can also be used to isolate the crystals in the process vessel. In this regard, it should be noted that the container can be connected to the centrifuge. For example, the process vessel can be cylindrical and / or have a wide-neck opening, in particular at which the filter is arranged and at which, for example, the centrifuge or a vacuum pump can be arranged, as described below.

[0104] By centrifuging, for example, the crystals can be detached from the support or from the seed crystals, or the supernatant solution can be removed from the process vessel. This can be done without or preferably with a filter. It can also be advantageous for a collection volume to be provided in the process vessel for collecting crystals that settle when the process vessel is centrifuged. In this embodiment, the solution can be centrifuged together with the crystals detached from the support in order to separate the crystals from the solution. For example, the collection volume can be an area with a reduced diameter, such as a V-shaped tapered area. For example, the solution can be discharged through the filter by centrifuging.

[0105] Further preferably, the crystallization arrangement can comprise at least one of a vacuum pump and a protective gas source, wherein the process vessel can be connected to the protective gas source or the vacuum pump in such a way that a protective gas flow can be conducted through the process vessel or that a vacuum can be applied in the process vessel. This configuration enables particularly advantageous drying of the resulting crystals, since any solvent adhering to the crystals can be entrained by a protective gas flow conducted through the process vessel. Furthermore, the solvent can evaporate due to the vacuum.

[0106] For the purposes of the present invention, protective gas is understood to mean a gas which does not react with the crystallized substance and is therefore inert in this regard, for example argon or nitrogen.

[0107] The outlet of the protective gas flow or the connection of the vacuum pump can preferably be arranged on the filter of the process vessel, since this can prevent formed crystals from being carried out of the process vessel.

[0108] Furthermore, it may be advantageous to provide a mixing device for mixing the solution in the process vessel. Such a device can, in particular, be an agitator or a device for introducing waves, such as sound waves, into the solution. Furthermore, the support can also be movable, such as rotatable, within the container. This can enable relative movement of the solution to the support, which in turn can significantly improve the crystallization of the solution on the support.

[0109] Preferably, the process vessel can have at least one liquid inlet and one liquid outlet that is different from the liquid inlet. This configuration particularly advantageously enables a continuous process using two coupled process vessels. This is because solution depleted of the crystallized substance can be removed through the outlet, while additional solution can be added through the inlet. Downstream of the outlet, the solution can either be discarded, fed back to the inlet, or fed to another, particularly coupled, process vessel in which another substance is to be crystallized.

[0110] The invention further encompasses the crystallization arrangement having more than two process vessels. In this case, the supports can, in particular, have different seed crystals on the supports, and the process vessels can be connected to one another by a fluid connection and thus coupled to one another.

[0111] In particular, it can be provided that the crystallization arrangement has at least two process vessels, wherein the at least two process vessels are connected in series, and wherein the supports of the process vessels are equipped with seed crystals that are different from one another.

[0112] In this embodiment, the two provided process vessels can be used, in particular, not only to isolate one substance from the solution, but also to remove two substances from the solution by crystallization. This can be done in a continuous process such that the solution is first poured into the process vessels of the first crystallization arrangement, where the substance crystallizes on the corresponding support or on the seed crystals. The solution can then be transferred to the second process vessel, where it comes into contact with the seed crystals of the second support.

[0113] The crystals can then be removed from the carrier or from the seed crystals and isolated as described in the process.

[0114] The above-described embodiment thus enables the described crystallization process to be carried out effectively and thus also enables the advantages described above, in particular with regard to effective isolation of substances in the solution.

[0115] Thus, for example, a crystallization arrangement is described for crystallizing and separating at least one substance from a solution, in particular for carrying out a method as described above, comprising a process vessel, in particular a cylindrical process vessel, for receiving the solution, wherein the process vessel has a receptacle for receiving a carrier, wherein the carrier is provided with seed crystals for the substance immobilized on the carrier and can be detached from the receptacle without destruction, and wherein the carrier can further be positioned in the receptacle in such a way that that the seed crystals can be brought into contact with the solution, wherein further preferably a tempering unit is provided for directly or indirectly tempering the seed crystals, and wherein the crystallization arrangement has a filter for filtering solution present in the process vessel, or wherein the crystallization arrangement has a centrifuge for centrifuging the process vessel.

[0116] With regard to further technical features and advantages of the crystallization arrangement, reference is hereby made to the description of the method, the use, the arrangement, the examples, the figures and the description of the figures, and vice versa.

[0117] By way of example, the use of at least one crystallization process and one crystallization arrangement as described above for an enantiomer separation of a racemic mixture is furthermore provided.

[0118] In this embodiment, a racemate, preferably a conglomerate-forming substance mixture or system of substances, can be separated. This is advantageous for many industrial processes, since chemical reactions may produce racemates, but often only an isolated enantiomer of the racemate or enantiomer mixture is required. The crystallization process described here can be particularly advantageous for enantiomer separation, since enantiomers can often be separated through crystallization processes.

[0119] To isolate one enantiomer, it may be sufficient to use the support with a seed crystal so that the desired enantiomer can be crystallized and isolated.

[0120] If both enantiomers are to be isolated, different supports or different seed crystals can be used, for example by using different supports one after the other in a batch process or in a continuous process, as described in more detail above.

[0121] It has been shown that the crystallization arrangement, the method and the crystallization arrangement as described above are particularly well suited to effectively and precisely isolating the individual enantiomers separately from each other and highly selectively, thus carrying out an enantiomer separation.

[0122] For further technical features and advantages of use, reference is hereby made to the description of the crystallization process, the crystallization arrangement, the arrangement, the examples, the figures and the description of the figures, and vice versa.

[0123] Further described is an arrangement comprising a process vessel, a collecting vessel and a filter unit having a filter, wherein the process vessel and the collecting vessel are attached to the filter unit in a fluid-tight manner and are fluidly connected to one another by the filter such that solution from the process vessel into the collecting vessel can be filtered through the filter under vacuum or centrifugal force, wherein solid matter is retained by the filter in the process vessel and separated from the solution.

[0124] Such an arrangement advantageously allows filtration without, or at least with a significantly reduced risk of filtrate contamination. Furthermore, it can be particularly easy to use, since the process vessel can be easily connected to the filter unit and the collecting vessel, for example, after removing the lid.

[0125] Particularly advantageously, the process vessel and the collecting vessel can be designed identically. In this configuration, the collecting vessel can also be used as a process vessel using a crystallization insert.

[0126] For easy assembly and disassembly, detachable attachments of the process vessel or collecting vessel to the filter unit are also preferred. Examples include screw connections, clamp connections, and the like.

[0127] With regard to further technical features and advantages of the arrangement, reference is hereby made to the description of the crystallization process, the crystallization arrangement, the use, the examples, the figures and the description of the figures, and vice versa.

[0128] The invention is explained below by way of example with reference to the attached figures, wherein the features shown below can represent an aspect of the invention both individually and in combination, and wherein the invention is not limited to the following drawing, the following description and the following embodiment.

[0129] They show: Fig. 1 shows schematically a crystallization arrangement according to the present invention; Fig. 2 shows schematically an arrangement for centrifuging the solution; Fig. 3 shows a centrifuge for a crystallization arrangement according to the present invention; and Fig. 4 shows a setup for the continuous crystallization and separation of various substances from a solution.

[0130] In the Figure 1a crystallization arrangement 10 for crystallizing at least one substance from a solution is shown schematically and in part.

[0131] The crystallization arrangement 10 comprises a process vessel 12 which, according to Figure 1is designed as a cylindrical process vessel. The process vessel 12 serves to hold the solution and thus the substance dissolved in the solution. Furthermore, the process vessel 12 comprises a receptacle 14 for holding a carrier 16 or a crystallization insert having the carrier 16. The receptacle 14 is in particular an internal volume of the process vessel 12, so that the carrier 16 can be arranged in the process vessel 12. The carrier 16 is further provided with seed crystals 18 for the substance immobilized on the carrier 16 and can be removed from the receptacle 14 without destruction. The carrier 16 is further positioned in the receptacle 14 such that the seed crystals 18 can be brought into contact with the solution. This is shown in the Figure 1, wherein a holder 20 is also provided for the carrier 16, with which the carrier 16 can be inserted into and removed from the receptacle. The carrier 16 together with the holder 20 form the crystallization insert 21.

[0132] It is further shown that the carrier 16 is formed in an Archimedean spiral shape. In the Figure 1In the form shown, the carrier 16, which can be configured in particular from a rigid film, is dimensionally stable under the working or separation conditions. The latter is fundamentally advantageous for the carrier 16, regardless of the specific shape. This allows the solution to flow effectively around the carrier 16 or the seed crystals 18, thus effectively crystallizing the substance on the seed crystals 18. Such a configuration provides a dense, homogeneous, and static distribution of the seed crystals 18 and thus rapid and homogeneous crystallization.

[0133] The process vessel 12 can be tempered using methods known to those skilled in the art.

[0134] In order to enable crystallization effectively, a tempering unit 22 is also provided for direct or indirect tempering of the carrier 16 or the seed crystals 18. In the embodiment according to Figure 1a tempering unit 22 is schematically shown, which acts on the solution and thus indirectly tempers the carrier 16 and the seed crystals 18.

[0135] The crystallization arrangement 10 shown further comprises at least one of a filter 24 for filtering the solution present in the process vessel 12, in particular for removing the solution adhering to crystals, and a centrifuge 26 for centrifuging the process vessel 12. This makes it particularly advantageous to isolate the crystals formed in the process vessel 12, i.e., for example, to wash and dry them. More specifically, it is provided that the crystallization arrangement 10 comprises a filter 24 for filtering the solution present in the process vessel 12, and that the crystallization arrangement 10 comprises a centrifuge 26 for centrifuging the process vessel 12.

[0136] In the Figure 2An arrangement 28 is shown by means of which the process vessel 12 can be centrifuged in a particularly advantageous manner. In addition to the process vessel 12, a collecting vessel 30 is provided, wherein a filter unit 32 with a filter 24 is provided between the process vessel 12 and the collecting vessel 30. If this arrangement 28 is now centrifuged in a centrifuge 26, the crystals formed are retained by the filter 24 and the remaining solution passes through the filter 24 and can be collected in the collecting vessel 30. This allows the separation of the crystals from the solution to take place extremely quickly and free of contamination. Especially for the resolution of racemates, such as in particular conglomerate-forming systems, a separation can be carried out with pinpoint accuracy with regard to the rotation value.

[0137] In this regard, the Figure 2It has been shown that a filter cake 31 of crystals retained on the filter 24 forms, with the solution penetrating the filter 24 as filtrate 33 and collecting in the collecting vessel 30. The filter cake 31 or the crystals can then be isolated.

[0138] In the Figure 3 A centrifuge 26 is shown in which four assemblies 28 with process vessels 12 are provided. The assemblies 28 are pivotally mounted on a motor of the centrifuge 26 on mounting arms 34, wherein the mounting arms 34 can be rotated by a drive hub 36 of the motor to allow centrifugation. It should be noted that the Figure 3 shown upper area is the bottom 13 of the process vessel 12 to enable effective removal of the solution from the process vessel 12, as is also shown in the Figure 2 is shown.

[0139] By means of the crystallization arrangement 10 described above, a crystallization process for crystallizing and separating a substance from a solution in which the substance is located, in particular in a supersaturated solution, can be carried out, comprising the process steps: a) introducing the solution containing the substance into a receiving volume of a process vessel 12 of a crystallization arrangement 10, wherein the solution has a temperature T1 after introduction;b) providing a crystallization insert 21 with at least one carrier 16 for insertion into the process vessel 12, wherein the surface of the carrier 16 is provided with seed crystals of a substance for crystal growth such that the seed crystals 18 are immobilized on the surface of the carrier 16 of the crystallization insert 21 and wherein at least one carrier 16 has a spiral shape, c) positioning the crystallization insert 21 in a receptacle 14 of the crystallization arrangement 10 such that the carrier 16 can be brought into contact with the solution, d) optionally cooling the seed crystals 18 while adjusting the temperature at the seed crystals 18 to a temperature T2, wherein T2 is lower than T1, e) crystallizing the substance on the surface of the seed crystals 18, and f) optionally isolating the formed crystals of the substance in the process vessel (12).

[0140] Using the arrangement described above, in addition to isolating a single substance from the solution, different substances present in the solution can also be isolated separately. For this purpose, the solution can be treated successively with carriers 16 containing different seed crystals 18.

[0141] For example, once the solution has been collected in the collection container 30 of the assembly 28, it can be reintroduced into a process vessel 12 in which the carrier 16 or the seed crystals 18 have been changed after a first crystallization process. The same process can then be performed again.

[0142] This is easier if the process vessel 12 and the collecting vessel 30 are of identical design. In this case, an additional crystallization insert 21 containing different seed crystals 18 can be inserted into the solution.

[0143] Alternatively, the crystallization arrangement 10 may comprise at least two coupled process vessels 12, wherein the at least two process vessels 12 are connected in series, and wherein the supports 16 of the process vessels 12 are equipped with mutually different seed crystals 18. This embodiment is shown in the Figure 4 shown. In this embodiment, a continuous process is possible by slowly passing the solution through both process vessels 12. This causes the different substances to crystallize on the different carriers 16 or the different seed crystals 18. This enables separate isolation in a particularly efficient manner without the risk of contamination.

[0144] A protective gas source 38 can be provided upstream of the first process vessel 12, by means of which crystals formed in the process vessel 12 can be dried. Alternatively or additionally, a vacuum pump 40 can be provided downstream of the second process vessel 12. This can also be used to remove solvent residues adhering to the crystals and thus dry the crystals. Examples

[0145] The following examples first demonstrate the preparation of seed crystals on a support 16. Subsequently, a racemate separation is carried out using the correspondingly produced supports 16. Production of seed crystals on supports Preparation of L-threonine seed crystals on carriers 16:

[0146] A solution of L-threonine in water saturated at 60°C is prepared in a cylindrical process vessel 12 with a screw cap and cooled to 35°C. A crystallization insert 21 with an Archimedean spiral support 16 made of rigid PP film, with a distance between the spirals of approximately 3 mm, is briefly immersed in the solution and, after being separated from the solution, briefly dried. The process is repeated several times until a surface coated with a thin, homogenously distributed layer of seed crystals is obtained. The crystallization insert 21 thus produced is used with the resulting L-threonine seed crystals in a subsequent separation. Preparation of D-threonine seed crystals on carriers 16:

[0147] A saturated solution of D-threonine in water at 60°C is prepared in a cylindrical, round-bottomed flask with a screw cap and cooled to 35°C. A crystallization insert 21 with an Archimedean spiral support 16 made of rigid PP film, with a distance of approximately 3 mm between the spirals, is briefly immersed in the solution and, after being separated from the solution, briefly dried. The process is repeated several times until a surface is obtained that is thinly and homogeneously coated with seed crystals. The resulting crystallization insert 21 is used with the resulting D-threonine seed crystals in a subsequent separation. Batchwise separation of DL-threonine by preferential crystallization with seed crystals on supports 16 1.1 L-Threonine:

[0148] A solution of the racemic mixture of DL-threonine in water, saturated at 50°C, is introduced into a process vessel 12, namely a cylindrical round-bottom flask with a screw cap, while stirring, and stirred at 55°C for 60 minutes. The solution is cooled to 35°C, and the stirrer is turned off. A crystallization insert 21, as described above, containing L-threonine seed crystals, whose temperature is the same as the solution (35°C), is carefully placed in the solution. The solution is held at this temperature for 45 minutes. The supersaturated L-threonine in the solution crystallizes statically on the surface of the seed crystals. After 45 minutes, the crystallization insert 21 with the crystalline crystals is removed from the solution and transferred to a centrifuge container. The crystallization insert is centrifuged for 3 minutes using a two-bottle system with a filter insert between them.The solution adhering to the crystalline particles is collected in the lower bottle. The resulting L-threonine is dry and has an enantiomeric excess of > 99% ee. 1.2 D-Threonine:

[0149] The 1.1 The solution collected and filtered in the lower bottle is mixed with the remaining solution in the process vessel 12 from the experiment 1.1mixed and stirred at 55°C for 60 minutes and then cooled to 35°C. The stirrer is turned off. A crystallization insert 21 as described above with D-threonine seed crystals, the temperature of which is the same as the solution (35°C), is carefully placed in the solution. At this temperature, the supersaturated D-threonine crystallizes statically on the surface of the seed crystals. After 45 minutes, the solution is decanted. A centrifuge container is tightly and firmly connected to the opening of the process vessel 12 by means of a screw connection with a filter arrangement arranged in between. The solution adhering to the crystalline material is centrifuged and collected in the lower bottle. The obtained D-threonine has an enantiomeric excess of > 99% ee. Continuous separation of DL-threonine by preferential crystallization with seed crystals on supports 16

[0150] In 2 process vessels 12 A and BA supersaturated solution of the racemic mixture in water, saturated at 50°C and tempered to 38°C, is introduced separately. A crystallization insert 21 containing L-threonine seed crystals, also tempered to 38°C, is carefully placed in the solution of the process vessel 12. A At the same time, a crystallization insert 21 containing D-threonine seed crystals, heated to 38°C, is carefully placed into the solution in the process vessel 12 B positioned. In process vessel 12 A A supersaturated solution of the racemic mixture in water, saturated at 50°C and tempered to 38°C, is continuously introduced from process vessel 12 A the solution is fed into the process vessel at the same speed B discharged. From process vessel 12 BThe solution flows at the same rate into a process vessel 12, where the supersaturated solution of the racemic mixture in water, saturated at 50°C and tempered to 38°C, is prepared. Process vessels 12 A and B are tempered to 38°C. After 3 hours, the two process vessels 12 A and B as in the attempt 1.2 centrifuged. The isolated L-threonine and D-threonine each have an enantiomeric excess of >99% ee.

[0151] The present invention thus makes it possible to create a method and a device that can at least partially overcome the disadvantages of the prior art. The seed crystals of a substance, in particular of an enantiomer, which are homogeneously finely distributed, particularly in all volume elements of the solution, should appear statically immobilized on the support surface and not, as described in the prior art, as a crystal suspension. This allows crystallization to occur rapidly on the densely, homogeneously finely distributed surface of the seed crystals. The resulting crystals can be large and homogeneous in size and can be quickly and completely mechanically separated from the solution. Furthermore, highly pure substances can be obtained. Reference symbol

[0152] 10Crystallization assembly 12Process vessel 13Bottom 14Receptacle 16Carrier 18Seed crystals 20Holder 21Crystallization insert 22Temperature control unit 24Filter 26Centrifuge 28Assembly 30Collecting vessel 31Filter cake 32Filter unit 33Filtrate 34Mounting arm 36Drive hub 38Protective gas source 40Vacuum pump

Claims

1. Method for crystallizing and separating a substance from a solution in which the substance is present, in particular in supersaturated solution, comprising the method steps. a) introducing the solution containing the substance into a receiving volume of a process vessel (12) of a crystallization arrangement (10), wherein the solution has a temperature T1 after introduction; b) providing a crystallization insert (21) comprising at least one carrier (16) for insertion into the process vessel (12), wherein the surface of the carrier (16) is provided with seed crystals (18) for the substance for crystal growth in such a way that the seed crystals (18) are immobilized at the surface of the carrier (16) of the crystallization insert (21); c) positioning the crystallization insert (21) in a receptacle (14) of the crystallization device (10) in such a way that the carrier (16) can be brought into contact with the solution; d) optionally cooling the seed crystals (18) while adjusting the temperature at the seed crystals (18) to a temperature T2, wherein T2 is lower than T1; e) crystallizing the substance at the surface of the seed crystals (18); and f) optionally isolating the crystals of the substance formed in the process vessel (12), characterized in that at least one carrier (16) is a spiral-shaped carrier (16).

2. Method according to claim 1, characterized in that the method comprises method step f) and method step f) comprises the methos steps: f1) detaching substance crystallized at the seed crystals (18) from the carrier (16) within the process vessel (12); f2) removing solution from the formed crystals; f3) optionally purifying the formed crystals; and f4) drying the crystals.

3. Method according to claim 2, characterized in that at least one of method steps f2) and f3) comprises filtering the solution together with crystals present in the solution in order to collect the crystals on a filter (24), in particular in the process vessel (12).

4. Method according to any one of claims 1 to 3, characterized in that for separation an arrangement (28) consisting of a process vessel (12), a collection vessel (30) and a filter unit (32) comprising a filter (24) is used, wherein the process vessel (12) and the collection vessel (30) are attached to the filter unit (32) in a fluid-tight manner and are connected to each other fluidically by the filter (34) in such a way that solution from the process vessel (12) is filtered into the collection vessel (30) under vacuum or centrifugal force through the filter (24), whereby solid material is retained by the filter (24) in the process vessel (12) and separated from the solution.

5. Method according to any one of claims 1 to 4, characterized in that the method is an enantiomer separation, wherein the substance is an enantiomer of a racemic mixture and the solution comprises the racemic mixture.

6. Method according to any one of claims 1 to 5, characterized in that method steps a) to e) are carried out repeatedly as a common sequence in a process vessel (12), wherein between two repeated sequences the crystallization insert (21) of the process vessel (12) is exchanged, wherein in a first sequence the carrier (16) comprises a first type of seed crystals (18), and wherein in a second sequence the carrier (16) comprises a second type of seed crystals (18) different from the first type.

7. Method according to any one of claims 1 to 6, characterized in that the method steps a) to e) are carried out repeatedly as a common sequence in different process vessels (12), wherein the carrier (16) of a first process vessel (12) comprises a first type of seed crystals (18), and wherein the carrier (16) of a second process vessel (12) comprises a second type of seed crystals (18) different from the first type.

8. Method according to any one of claims 1 to 7, characterized in that method step a) is carried out at least in part prior to method step c).

9. Method according to any one of claims 1 to 8, characterized in that method step a) is carried out at least in part after method step c).

10. Crystallization arrangement (10) for crystallizing at least one substance from a solution, in particular for carrying out a method according to any one of claims 1 to 9, comprising a process vessel (12) for receiving the solution and comprising a crystallization insert (21) comprising at least one carrier (16) for insertion into the process vessel (12), wherein the surface of the carrier (16) is provided with seed crystals (18) for the substance for crystal growth in such a way that the seed crystals (18) are immobilized at the surface of the carrier (16) of the crystallization insert (21), wherein the process vessel (12) comprises a receptacle (14) for receiving the crystallization insert (21) with the carrier (16), wherein the crystallization insert (21) can be removed from the receptacle (14) in a non-destructive manner, and wherein the crystallization insert (21) is further positionable in the receptacle (14) such that the seed crystals (18) can be brought into contact with the solution, characterized in that at least one carrier (16) is a spiral-shaped carrier (16).

11. Crystallization arrangement (10) according to claim 10, characterized in that the crystallization arrangement (10) comprises a filter (24) for filtering solution present in the process vessel (12).

12. Crystallization arrangement according to claim 10 or 11, characterized in that the carrier (16) is designed as a foil or fabric.

13. Crystallization arrangement according to claim 12, characterized in that the foil or fabric is provided with through holes.