Processes and apparatus for crystallization and separation of substances

Abstract

This invention relates to a method for crystallizing substances from solution, and particularly to a method and apparatus for separating racemic mixtures.

Description

TECHNICAL FIELD

[0001] The present invention relates to a crystallization process and a crystallization apparatus for crystallizing a substance from a solution, in particular for the resolution of racemates. BACKGROUND

[0002] In many fields, it is advantageous to crystallize specific substances from a solution in order to separate these substances, in particular pure substances. One example is the resolution of optical antipodes, in which different antipodes have to be separated from an antipode mixture, preferably in the form of an antipode pure substance. The resolved optical antipodes are used for the manufacture of active pharmaceutical ingredients. It is therefore of fundamental importance to resolve optical antipodes in a safe and efficient manner.

[0003] With regard to known methods for crystallizing a specified substance from a solution, such as the resolution of antipodes, a variety of solutions exist in the prior art.

[0004] For example, Xichong Ye et al., Enantiomer-selective magentization of conglomerates for quantitative chiral separation, Nature Communications, (2019) 10: 1964 (https: / / doi.org / 10.1038 / s41467-019-09997-y) describes a separation method for resolving conglomerate crystals by using enantiomer-selective magnetization of magnetic fragments. However, this method has the following disadvantages: the magnetic fragments used consist of a copolymer and an optically antipode pure substance as an auxiliary agent. The polymer and the magnetic particles as experimental substrates have to be prepared in several stages over several days at temperatures of 0°C to 300°C. The subsequent separation process also takes several days.

[0005] US 2019 / 0345098 A1 describes the separation of enantiomers from a racemic mixture by a method called preferential crystallization. The antipodes are obtained by a crystallization process guided by the addition of seed crystals.

[0006] Andrew S. Dunn et al., Resolution control in a continuous preferential crystallization process, Organic Process Research & Development, DOI: 0.1021 / acs.oprd.9b00275, also describe a preferential crystallization process for separating antipodes.

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

[0008] AT 357501 describes a method and apparatus for removing excess salts, in particular potassium bicarbonate and calcium salts, from a beverage. Here the beverage is contacted with crystals to crystallize out the excess salts. The crystals can be fixed on a support surface. The method and apparatus are used to remove solids from a solution, the crystallized salts are not pure substances but mixtures of several different substances. Thus the disclosure of this document contributes to the production of salt-free beverages, but is not suitable for separating pure crystalline substances from a solution.

[0009] US 2,994,593 describes a crystallization apparatus for holding a large number of seed plates in a small volume.

[0010] US 2,495,024 describes a crystallizer for growing crystals from a supersaturated solution.

[0011] JPS 4940234 A describes a crystallization process using seed plates.

[0012] The principle of preferential crystallization known in principle involves the use of seed crystals, either by adding seed crystals to the solution or by crystallizing seed crystals from an excess of one enantiomer in the racemic solution before the crystallization process begins. In the above-mentioned prior art, in particular seed crystals floating in the solution are used. The seed crystals are suspended in the solution by stirring. In order to keep the distribution of the seed crystals in the solution as uniform as possible, while also avoiding sedimentation to the bottom of the container, the stirring speed should be optimized according to the particle size and adjusted as the crystals grow in size. High stirring speeds can achieve a uniform distribution, but high flow intensities can lead to the breakage of the crystals due to collisions with other crystals, the container wall or the stirrer, resulting in a high rate of secondary nucleation. The resulting crystals are thus small and have a broad Gaussian particle size distribution, which makes it difficult to separate the solid product from the solution in subsequent processing. Since a high content of solution adheres to the crystals, more impurities result, so more washing agents and more washing processes are required, and often longer drying times are necessary. In addition, when the crystal product of a drug is used directly in a drug, different particle sizes can lead to different bioavailability, which means that the direct usability of the resulting product is reduced.

[0013] The separation of crystals from a solution, for example by filtration or centrifugation, is usually complex, as appropriate means for separating the crystals from the solution must be provided. In addition, when the solution is separated from the crystals, the problem arises that the solution is recontaminated, which is a particular problem when resolving enantiomeric mixtures. In particular when there is a wide range of distribution of the crystalline particles, it is difficult to separate the crystals, for example by filtration.

[0014] In the prior art, in order to separate the crystals after crystallization, the suspension containing the crystals is transferred to another vessel in which the crystals are separated from the solution, in particular by filtration or centrifugation. In this process, the entire solution has to flow through the new vessel of the filter or through the centrifuge bowl. In industrial processes, the suspension has to be transferred from the pipe with a pump. Each new contact, for example with the pipe, the pump, the filter vessel or the centrifuge bowl, means an additional possible source of contamination, and the temperature of the suspension is difficult to regulate. The filtration or centrifugation of the entire suspension also requires a long time.

[0015] The three factors, new contact area, longer separation time and temperature drop, bring the risk of crystallization of impurities, in particular the risk of crystallization of the opposite enantiomer in the workup after the resolution. This is because in the preferential crystallization the opposite enantiomer is often supersaturated in the solution, and the solution temperature drop, the contact with a new surface and / or the longer residence time further promote its nucleation and crystallization.

[0016] In a coupled continuous process, there is an additional problem that floating fine particles of one enantiomer can be transferred from one process vessel to another process vessel of the opposite enantiomer by the circulating stream. As a result, there are two different enantiomer crystals in both process vessels, which destroys the final enantiomeric separation. In this case, the process has to be aborted or another step has to be performed. The process of separating the already formed crystals from the solution after the stop and the return to the starting point can take a long time.

[0017] Therefore, the solutions known in the prior art are not satisfactory in all respects, and there is a need to develop new methods and devices for crystallization and separation of substances from a mixture of substances. SUMMARY

[0018] It is an object of the present application to provide an improved method and an improved device for crystallization and / or separation of substances from a solution, in particular for crystallization and / or separation of enantiomers from a racemic mixture in a solution, which overcomes at least some of the disadvantages of the prior art.

[0019] The present application relates to a method for crystallization and separation of a substance from a solution, in particular from a supersaturated solution, in which the substance is located, comprising the following process steps:

[0020] a) introducing a solution containing the substance into a receiving volume of a process vessel of a crystallization device, the solution having a temperature T1 after the introduction;

[0021] b) providing a crystallization insert having at least one carrier in the process vessel, the surface of the carrier being provided with seeds of the substance for crystal growth, the seeds being fixed on the surface of the carrier of the crystallization insert, wherein at least one carrier has a helical structure;

[0022] c) positioning the crystallization insert in the vessel of the crystallization apparatus in such a way that the carrier is in contact with the solution;

[0023] d) optionally cooling the seed crystals while adjusting the seed crystal temperature to a temperature T2, wherein T2 is lower than T1 ;

[0024] e) crystallization of the substance on the surface of the seed crystals, and

[0025] f) optionally separating the resulting crystalline substance in the process vessel.

[0026] The crystallization process described is thus particularly suitable for crystallizing a substance from a solution in which the substance is present in particular together with one or more further substance components, in order to separate and isolate the substance, in particular to obtain the substance in pure form. The crystallization process described here is thus in particular a separation process for separating mixtures of substances.

[0027] The process described here comprises the following process steps:

[0028] First, according to process step a), a solution comprising the substance is introduced into a receiving volume of a process vessel (also referred to as separation vessel) of a crystallization apparatus, the solution having a temperature T1 after introduction into the process vessel. The solution is introduced into the process vessel according to this, which can be designed as a liquid vessel, the solution comprising the substance to be crystallized and separated or preferably isolated by the process. For example, the substance is dissolved in the solution in a suitable concentration, in particular the substance is present in the solution in supersaturated form.

[0029] In principle, any vessel in which the process described here can be carried out can be selected as the process vessel of the crystallization apparatus. The materials that can be used include in particular non-oxidizing materials, such as glass, or non-oxidizing metals, such as stainless steel or enamel metal, or plastic materials. In principle, the material of the process vessel should be inert to the solution.

[0030] In addition, 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 it is introduced into the process vessel, or it can be adjusted to the temperature T1 after it has been introduced. In particular, however, the temperature should be set before process step c).

[0031] The temperature T1 of the solution can preferably be up to 20°C, preferably up to 10°C, in particular preferably up to 5°C, below the saturation temperature. The saturation temperature is in particular under the conditions generally prevailing in the solution, for example at a pressure of about 1 bar. For example, the temperature T1 can be the saturation temperature and the substance can be a saturated solution.

[0032] Subsequently, process step b) is carried out, providing the crystallization insert with at least one carrier, the surface of the carrier being provided with seeds of the substance for crystal growth, the seeds being fixed on the carrier surface of the crystallization insert, wherein the at least one carrier has a helical shape structure.

[0033] The crystallization insert is used to cause the substance to be separated from the solution to crystallize on the crystallization insert. For this purpose, a carrier is provided, which has at least one or in particular a large number of seeds, which are suitable for the substance to be crystallized to crystallize on the seeds. Furthermore, the crystallization insert and the carrier and the process vessel are designed in such a way that the crystallization insert and the carrier can be positioned in the receiving volume, optionally in a liquid, which is optionally located in the receiving volume. In particular, the crystallization device can be designed with a lid of the process vessel and is sealed against the liquid. The lid can thus be exchanged, for example, for a component for filtration, which will be described in more detail below.

[0034] The carrier can be part of the crystallization insert or attached or mounted thereon. In particular, the carrier or the carrier assembly is oriented vertically.

[0035] The seeds can be fixed on the carrier surface by various methods, for example, by placing the carrier in a solution of the high-purity substance for obtaining the respective seeds. In particular, the carrier can be immersed in the respective supersaturated solution and then taken out and dried. It is also possible to spray the solution onto the carrier and dry it or to wet the carrier with a melt, in which case the carrier can be immersed in the melt or the carrier can be sprayed or otherwise coated with the melt. Likewise, the carrier can be inoculated by providing the solvent-treated carrier with fine crystals of the substance to be inoculated on the carrier, in principle by any other suitable method. The amount of seeds can be controlled by, for example, the duration of the immersion or by the duration of the spraying.

[0036] It is also possible to place the carrier in a solution and then to cool the solution to crystallize, forming seeds of the substance on the carrier.

[0037] Furthermore, the carrier can in principle be selected to have various shape structures, preferably in such a way as to provide a large surface area with which the seeds come into contact with the solution. Furthermore, it can be advantageous if the solution can flow through the carrier with the seeds, so that the solution can move relative to the carrier or the solution can flow around the carrier and thus around the seeds.

[0038] The carrier has a helical shape, in particular can be an Archimedean helical shape structure. This structural shape allows particularly effectively, due to the helical shape of the carrier, for the seeds to be distributed uniformly in the solution throughout the separation process, for example when the carrier is rotated in the process vessel or is supported by the helical shape of the carrier when it is stationary in the process vessel.

[0039] Furthermore, the carrier is preferably at least partially formed from a material selected from the group consisting of metals, plastics, textiles, paper, renewable raw materials, ceramics, glass and carbon materials. Depending on the solvent, these materials can have the advantage of being inert to the solution and can also be well suited to the growth of the seed crystals.

[0040] Rough surfaces or surfaces with a granular substrate facilitate wetting with the solution and the formation of seed crystals thereon. The surface of the carrier with hydrophilic properties facilitates aqueous solutions.

[0041] In principle, the fixed seed crystals can be distributed in a dense and uniform fine manner. The result is a rapid and at least largely complete crystallization of the substance on the seed crystals of the large surface, which makes it possible to realize an efficient and highly efficient process, which will be described below.

[0042] According to process step c), the crystallization insert is accordingly positioned in the container of the crystallization device, for example the process container, so that the carrier can be brought into contact with the solution. The crystallization insert or the carrier and the solution are thus brought together, for example by immersing the carrier in the solution, for example movement of the carrier in the solution, for example rotation, but also a flow of the solution through the carrier. The latter is achieved by conveying the solution, for example when the carrier is positioned above the stationary solution.

[0043] In general, it is possible to first add the solution with the substance to the process container and then to position the carrier accordingly, or vice versa, or to first fill a portion of the solution into the process container and then to position the carrier accordingly and then to add another portion of the solution to the process container. The substance can be present only in the first portion of the solution, only in the other portion or in both the first and the other portion. Process step a) can thus at least partially be carried out before process step c), or process step a) can at least partially be carried out after process step c). Process step a) can thus also be carried out before and after process step c) and / or at least partially simultaneously with process step c).

[0044] The carrier or its extension in the volume of the liquid is preferably arranged in such a way that the seed crystals in the crystallization insert are uniformly, densely and finely statically distributed in the solution in all volume elements of the solution. This can be constant or the movement of the carrier in the process container. According to the amount of supersaturation, a large number of seed crystals are statically present in each 1 cubic centimeter volume unit. In principle, the surface of the provided seed crystals, i.e. the crystallization surface, is in the range of 0.5 cm 3 to 5 cm 2 per 1 cm 2The carrier can have a corresponding crystallization surface in each volume element of the solution, or there can also be regions in the solution volume in which no such crystallization surface is present. It is correspondingly preferred that there is a crystallization surface of 0.5 cm 3 to 5 cm 2 per 1 cm 2 volume in at least part of the solution volume.

[0045] In a stationary medium, the molecules arrange themselves more quickly and better by van der Waals forces on the surface of the seed crystals than in a flowing solution without external influences. Stationary solution can be preferred for crystallization. However, as described elsewhere, this is by no means necessary.

[0046] In step d) of the crystallization method described here, the seed crystals can optionally be cooled and their temperature adjusted to a temperature T2, which is lower than T1. In other words, the crystallization insert or carrier with the seed crystals is adjusted in such a way that the temperature of the seed crystals is lower than the solution temperature of process step a).

[0047] The temperature T2 of the seed crystals can preferably be the same as or at most 5°C lower than the temperature T1 of the supersaturated solution or substance-rich solution. The temperature of the solution in the process vessel can be regulated, for which various known temperature regulation devices can be used. In principle, the temperature T2 can preferably be at most 20°C, preferably at most 10°C, particularly preferably at most 5°C lower than the temperature T1.

[0048] The temperature adjustment can be achieved by direct adjustment of the crystallization insert or carrier. The crystallization insert or carrier therefore preferably has a temperature regulation unit by means of which the seed crystals can be heated and / or cooled. In this way, the temperature of the crystallization insert or carrier can be regulated directly, in particular independently of the temperature regulation of the solution.

[0049] Within the scope of the present application, both the temperature of the solution and the temperature of the carrier or seed crystals can be regulated. In principle, it is preferred that the temperature of the seed crystals is lower than the temperature of the solution.

[0050] After the process steps described above, according to step e), the substance crystallizes on the seed crystals, i.e. on their surface and thus on the carrier. Because of the temperature regulation described above, for example, the substance dissolved in the solution can come into contact with the relatively low-temperature carrier, i.e. the relatively low-temperature seed crystals, and thus crystallize. The crystals grow on the carrier, so that the concentration of the substance in the solution becomes diluted or depleted.

[0051] Because both the seed crystals and the subsequently crystallized substance are fixed on the carrier, the substance can advantageously be separated off. In particular, the substance can thus be detached from the carrier and obtained in high-purity form.

[0052] To this end, the crystals of the formed substance are separated in the process vessel according to the optionally planned process step f). Thus, as will be described in more detail below, it is possible to use a process vessel in which high-purity crystals of the substance are formed from the solution by appropriate processing steps.

[0053] The described method allows the targeted removal of substances from the solution and thus their separation or isolation in an efficient manner from a mixture of substances. Because, for example, by the targeted temperature regulation possibilities allow the substances to be separated from the solution in a set and reproducible manner. This can make the substances as completely isolated as possible, for example by setting a very low temperature. Alternatively, it is also possible to crystallize the substances only to a certain extent, for example by choosing a relatively high temperature. Thus, it is always possible to create suitable conditions for the desired crystallization to occur.

[0054] In addition, the method can be adapted to a large extent to different substances to be isolated by using a carrier with suitable seed crystals and corresponding temperatures. Thus, a targeted and efficient separation of a plurality of substances from the solution is possible without major conversions, only with a small number of modifications.

[0055] The adaptability can be further improved due to the temperature controllability of the carrier, i.e. the seed crystals, since a suitable temperature regulation of the respective substance to be isolated is possible.

[0056] In addition, the process can be carried out in a continuous or batch manner, the process can also be very well suited to be designed custom-made, which will be described in more detail later.

[0057] For non-racemic resolution, there is no risk of enantiomeric crystallization. Thus, the solution can be slowly cooled, preferably uniformly cooled, the temperature continuously reduced, the seed crystals from the supersaturated solution occur controlled crystallization. The uniform cooling is preferably characterized by a temperature deviation of at most 1 °C throughout the solution. The crystallization on the carrier can occur by, for example, Ostwald ripening. In this case, the crystallization is in particular supported by the temperature change of the solution. To this end, the solution is preferably heated in such a way that the temperature change in the solution is rapid and short-lived by at most 2 °C, wherein small crystalline particles possibly present on the bottom and / or walls of the process vessel are dissolved, which, after dissolution, preferentially adhere to the larger crystalline particles on the carrier and recrystallize. Finally, the substance is completely crystallized from the solution with a uniform crystal particle size. This makes it possible to achieve very high yields, for example at least 95% by weight, preferably at least 99% by weight, based on the theoretical yield of the substance initially present or dissolved in the solution.

[0058] In addition, it is possible to choose a very simple setup until the separation of the crystals is obtained, and it is also possible to reduce the risk of contamination of the crystals. In this regard, it is possible to ultimately obtain a high-purity substance by the process described here, which is essential for many applications.

[0059] In order to separate the crystals and thus to carry out process step f), the process can have a further process step:

[0060] f1 ) peeling off the substance crystallized on the seed from the carrier in the process vessel.

[0061] Process step f1 ) serves to separate the crystals formed and in particular to bring the crystals into free form so that further process steps can be carried out and particularly efficient purification can be achieved.

[0062] To this end, a scraper can be provided, for example, a relative movement between the carrier and the scraper can be carried out in order to mechanically strip off the crystals. In this case, the crystals are initially retained in the solution, can then be separated from the solution and can continue to be isolated. Likewise, other methods of peeling off the crystals from the carrier are also included within the scope of the present application. For example, the process vessel can be centrifuged after the isolation of the free liquid, i.e. the free solution, wherein the crystals are peeled off from the carrier by the centrifugal force and at the same time the residual solution adhering to the crystals is separated from the process vessel.

[0063] Thus, when process step f) is carried out, the method can comprise a further process step:

[0064] f1 ) peeling off the substance crystallized on the seed from the carrier in the process vessel; and

[0065] f2) separating the crystals formed from the solution;

[0066] f3) optionally washing the crystals formed; and

[0067] f4) drying the crystals.

[0068] In order to remove the solution from the crystals formed, it can be provided, for example, that the free solution is discharged from the process vessel without a filter or, if necessary, the crystallization insert is removed and the free solution is decanted from the process vessel.

[0069] To this end, for example, the process vessel can be centrifuged with or without the carrier. In this way, the supernatant of the crystal solution can be removed and the centrifugation can be repeated after additional addition of solvent. In this way, the crystals can be washed. Accordingly, at least one of process steps f2) and f3) can comprise centrifugation of the solution in the process vessel.

[0070] However, it is particularly preferred that at least one of the process steps f2) and f3) involves a filtration for jointly removing the solution and the crystals in the solution by collecting the crystals on a filter, in particular in the process vessel, wherein the filter can be arranged preferably in or on the process vessel. This allows to decant the solution from the process vessel and the crystals remain in the process vessel. For example, the filter can be arranged on or between the outlets of the process vessel.

[0071] In principle, also supernatant can be drawn off, for example using a suction device. This can occur at the first removal of the solution and during the washing or cleaning process.

[0072] Subsequently, the crystals can be dried and then the crystals can be isolated. The crystals can be dried using a gas stream of particularly high purity or using a vacuum.

[0073] The crystals can also be detached from the carrier by centrifugation, so that the same device can be used for isolating the crystals and for washing the crystals.

[0074] Therefore, in principle at least one of the process steps f2) and f3), for example both, can comprise at least one of centrifugation and filtration. For example, both process steps f2) and f3) can comprise centrifugation and filtration. As a result, the operating procedure can be simplified and still the crystals can be washed very effectively and thus high-purity crystals can be obtained.

[0075] After crystallization, the crystals produced can be separated from the solvent or free liquid, for example by 90%, in a very short time, for example by decanting or draining the solution or removing the crystallization insert. This is a great increase in efficiency compared to prior art methods and can reduce the risk of contamination with the mother liquor. Therefore, in this step, the solution can be removed from the process vessel when the crystals formed are fixed on the seed, i.e. without the need for centrifugation and / or filtration.

[0076] For example, this can be carried out by having the following process steps:

[0077] f1) peeling the crystallized substance from the carrier in the process vessel from the seed; and

[0078] f2) removing the solution from the crystals formed;

[0079] f3) optionally washing the crystals formed; and

[0080] f4) drying the crystals, wherein

[0081] Both process steps f2) and f3) comprise filtering the solution together with the crystals in the solution to collect the crystals on a filter arranged in or at the opening of the process vessel, on the counter side of the process vessel filter a collection vessel for collecting the solution, i.e. the mother liquor, is provided, wherein process steps f2) and f3) comprise centrifuging the solution in the process vessel.

[0082] A device usable for the separation is designed as an arrangement of a process vessel, a collection vessel and a filter unit with a filter, wherein the process vessel and the collection vessel are attached to the filter unit in a fluid tight manner and are fluidly connected to each other by the filter in such a way that the solution in the process vessel is filtered through the filter to the collection vessel under vacuum or centrifugal force, the solids are retained by the filter in the process vessel and separated from the solution.

[0083] The method can preferably be an enantiomeric resolution, in which case the substance is an enantiomer of a racemic mixture, in particular a conglomerate forming system of the substance, and the solution contains a supersaturated solution of the racemic mixture, in particular the racemate. In this embodiment, the method described here can thus be used in particular for separating a racemate, in particular a conglomerate forming system of the substance. This can be advantageous for many industrial technical processes, since racemates can be obtained in chemical reactions, but usually only one enantiomer separated from the racemate or the enantiomeric mixture is required. The crystallization process described here can be very advantageous, in particular for enantiomeric separation, in particular because the conglomerate of the enantiomeric mixture can usually be separated by the crystallization process.

[0084] For the resolution of one enantiomer, it can be sufficient to use the carrier with one seed each time, so that the desired enantiomer can be separated by crystallization, while the other, undesired enantiomer remains in the solution.

[0085] If two enantiomers are to be separated, two different carriers, i.e. different seeds of the enantiomers, can be used, for example in a batch process by exchanging the crystallization insert in one process vessel, i.e. alternating use of the different carriers, or in a continuous process by interconnecting, i.e. coupling, different process vessels with crystallization inserts containing different seeds. For separating and isolating two enantiomers from a racemic mixture, for example in particular a conglomerate forming enantiomeric material system, for example, the carrier of a first crystallization insert is applied with a seed of a first enantiomer, and the carrier of a second crystallization insert is applied with a seed of a second enantiomer. This will be described in more detail below.

[0086] The isothermal crystallization in the enantiomeric resolution of the racemic mixture is preferred, in particular the enantiomeric resolution of the conglomerate-forming system. The crystallization time in the batch process and the residence time in the continuous process depend on the supersaturation. The residence time is preferably not more than 90 minutes, preferably not more than 60 minutes, particularly preferably not more than 30 minutes. In this way an enantiomeric excess of more than 90 %, preferably more than 95 %, particularly preferably more than 99 % can be achieved.

[0087] By measuring the optical rotation of the solution during the process, the ideal residence time for the optimal separation of the racemate resolution can be determined exactly, i.e. at the turning point of the optical rotation, the crystals on the carrier can be separated from the solution quickly.

[0088] It should be noted that with regard to the crystallization temperature set in process step d), this should be selected in such a way that only the desired enantiomer is allowed to crystallize out on the seed crystals, while the opposite enantiomer remains in solution.

[0089] It can also be preferred that the process steps a) to e) are repeated as a common sequence in one process vessel, wherein two crystallization inserts are replaced in the process vessel in the repeated sequence, wherein the carriers of the first sequence have a first type of seed crystals and the carriers of the second sequence have a second type of seed crystals which is different from the first type.

[0090] In such a design, more than one substance can thus be separated from the solution. It is thus possible to separate from a mixture of dissolved substances in such a way that the respective dissolved substance is separated individually in crystalline form. This can be achieved in such a way that the carriers, i.e. the different carriers each equipped with mutually different seed crystals, are used alternately, so that the substances to be separated each selectively crystallize out on the seed crystals.

[0091] Such a design can be used, in particular, in the so-called batch process.

[0092] It is also possible, moreover, to separate different substances from the solution in a continuous process. In this case, the process steps a) to e) can be repeated as a common sequence in different process vessels, wherein the carriers of a first process vessel have a first type of seed crystals and the carriers of a second process vessel connected thereto, in particular downstream of the first process vessel and coupled or fluidically connected to the first process vessel, have a second type of seed crystals which is different from the first type.

[0093] Thus, first the solution is fed into the first process vessel and stays there until the desired amount of the first substance has crystallized out on the carrier, i.e. its seed crystals, which are located in the first liquid vessel. Then the second substance can be fed into the second process vessel, in which a carrier with another seed crystal is provided. Here, too, the solution can stay until the desired amount of the second substance has crystallized out on the carrier, i.e. its seed crystals, which are located in the process vessel. This can be achieved by regulating the flow in the continuous process.

[0094] Thus, in this design it is specifically provided that the outlet pipe of the first process vessel is connected to the inlet pipe of the second process vessel, and the two process vessels are thus coupled to each other. In the connection between the first and the second process vessel, one or more further process vessels can be provided, in which a substance mixture saturated solution can be added.

[0095] In principle, thus at least two coupled process vessels are operated simultaneously and continuously, wherein the carriers in the two process vessels have different seed crystals, e.g. different enantiomers of a racemate.

[0096] Thus, the solution mixture can be separated in this efficient and easy-to-implement manner. According to this, two different substances can be separated, either in a batch process or in a continuous process, or, if more carriers are used, more than two substances can be separated.

[0097] A further advantage of the continuous process described here is that the risk of contamination of the two process vessels with each other is very small or non-existent, since there are no fine crystal particles floating in the solution. The risk can be further reduced by providing a filter.

[0098] In an exemplary embodiment of the design, the method can be carried out as follows, all the following steps or partial steps, either on their own or in combination with other steps, are also part of the method:

[0099] A) removing the solution without formed crystals from the process vessel, e.g. by at least one

[0100] A1 ) by discharge through the outlet of the process vessel, in particular in the presence of a

[0101] A2) taking out the crystallization insert, pouring out the solution through the opening;

[0102] A3a) centrifuging the process vessel with the crystallization insert, or optionally applying a vacuum to the process vessel; wherein the lid of the process vessel is equipped with or is equipped with a filter unit with a filter disc, the process vessel is closed, and wherein in the centrifugation the process vessel is placed upside down in a centrifuge for centrifugation, whereby the crystals are detached from the crystallization insert by the centrifugal force and the crystals are separated from the adhering solution by the filter; wherein:

[0103] A3b) if necessary, using a set-up in the centrifugal separation, which set-up comprises a process vessel, a collection vessel and a filter unit with a filter, the process vessel and the collection vessel being connected to the filter unit in a fluid-tight manner and being fluidically connected to one another via the filter, such that the solution can be filtered from the process vessel to the collection vessel through the filter under vacuum or centrifugal force, the solids being retained by the filter in the process vessel and separated from the solution.

[0104] B) optionally removing the crystals from the crystallization insert in a further step.

[0105] C) removing the crystallization insert, which has been freed of crystals, from the process vessel.

[0106] D) washing and drying the crystals in the same process vessel.

[0107] Further technical features and advantages of the method are described with regard to the crystallization apparatus, the use, the equipment, the embodiments, the figures and the description of the figures, and vice versa.

[0108] The present application describes a crystallization apparatus for crystallizing at least one substance from a solution, in particular for carrying out the method as described above, having a process vessel for receiving the solution and having a container for receiving a crystallization insert with at least one carrier, which is equipped with a carrier surface with seed crystals for the crystal growth of the substance, wherein the at least one carrier has a spiral shape, wherein the process vessel has a container for receiving the crystallization insert with the carrier, the detachable crystallization insert can be removed from the container without damage, and the crystallization insert is positioned in the container such that the seed crystals can be brought into contact with the solution.

[0109] With such a crystallization apparatus the described crystallization method can in particular be carried out and thus be used in particular for crystallizing at least one substance from a solution.

[0110] To this end, the crystallization apparatus comprises a process vessel for receiving the solution in which the substance is located. In principle, the process vessel of the crystallization apparatus can be selected arbitrarily here, as long as it can be used for the method described. Advantageous materials include in particular non-oxidizing materials, such as glass or plastic, or non-oxidizing metals, such as stainless steel or enamel metal. In principle, the material of the process vessel and any other components which come into contact with the solution should be inert to the solution, in particular to the substance.

[0111] Furthermore, the crystallization apparatus comprises a crystallization insert with at least one carrier for insertion into the process vessel, the carrier surface of which has seed crystals for the crystal growth of the substance and is present in such a way that the seed crystals are fixed on the carrier surface of the crystallization insert.

[0112] The carrier or seed crystal is thus advantageously adapted to the method to be carried out, i.e. the substance to be separated. The carrier can be designed and produced in particular in accordance with the method as described above, and the seed crystal can also be fixed in such a way that the substance crystallizing on the carrier can be separated from the carrier.

[0113] It is particularly preferred that the carrier has a helical shape, in particular an Archimedean helical shape. Such a shape can provide a uniform distribution of the seed crystals in the solution for an effective separation, for example if the carrier is rotated in the process vessel, or even if the carrier is constant in the process vessel, the latter can be achieved by its helical shape.

[0114] It is particularly preferred that the carrier is configured in an Archimedean helical shape, for example made of a rigid film, wherein the distance between the helical shapes, i.e. the distance of the individual winding intervals, is less than 2 cm, preferably less than 1 cm, particularly preferably less than 0.5 cm. A rigid film can also be understood as a film that is sufficiently stable, i.e. the helical shape is empty, and free, even without external influences, the helical shape maintains its shape at the process temperature and when the surface carries crystals.

[0115] Alternatively or additionally, it can be preferred that the carrier is a film or a fabric, wherein the film or fabric is preferably provided with channel openings. This arrangement allows the solution to flow effectively around the carrier-fixed seed crystals, making it possible for the substance to crystallize more effectively in the solution.

[0116] With regard to the positioning of the crystallization insert, the process vessel has a volume for receiving the crystallization insert with the carrier. Furthermore, the carrier can be detached from the vessel without being destroyed, preferably this makes it possible for the process vessel and the carrier to be used several times. The vessel can achieve a defined position of the crystallization insert and also ensure that the crystallization insert is fixed in a stable manner.

[0117] Furthermore, the carrier is positioned or positionable in the vessel in such a way that the seed crystals can be brought into contact with the solution. Bringing it into contact can mean immersing the carrier in the solution or possibly flowing it down from above the carrier or also immersing the carrier in the solution, see the above more detailed description of the method.

[0118] Furthermore, it is preferred to provide a temperature regulation unit for directly or indirectly regulating the temperature of the carrier and thus of the seed crystals. For example, the temperature of the solution in the process vessel can be regulated, thereby indirectly regulating the temperature of the carrier or the seed crystals.

[0119] In order to directly regulate the temperature of the carrier, for example, it can have one or more channels through which a corresponding, in particular liquid, temperature regulating medium can be passed in order to regulate the temperature of the carrier, in particular to cool it. In this case, the one or more channels can be connected to a cooling and / or heating device which can be set to the desired temperature of the carrier and / or of the seed crystals fixed on the carrier for the growth of crystals of a substance as required.

[0120] For example, the temperature of the solution in the container and / or the carrier can be regulated separately from one another.

[0121] In the crystallization apparatus described here, it is also possible to provide a filter for filtering the solution in the process container or a centrifuge for centrifuging the process container in a configuration of the crystallization apparatus. For example, it can be advantageous if the process container has a filter for filtering the solution present in the process container and if the crystallization apparatus has a centrifuge for centrifuging the process container.

[0122] With regard to the filter, for example, this can be positioned at the liquid outlet of the process container. The filter can be used to prevent the solution discharged from the liquid outlet from entraining already formed crystals, which can be lost or have to be further separated. This can be independent of whether the solution is poured, returned to the container or fed into a coupled process container with another carrier. The filter is therefore used in particular to isolate the crystals from the solution and thus to separate the crystals.

[0123] The filter or filter insert is thus designed for the filtration of the liquid medium and the retention of the resulting crystals. It can be embodied as a filter disc, or a filter mesh, or a filter cloth, or a filter membrane or filter paper, or other materials known to the person skilled in the art which have this function. The mesh size can be selected depending on the desired crystal particle size to be obtained.

[0124] For example, after removal of the free liquid, the lid of the process container can be equipped with a filter unit and the container can be placed on a centrifuge like a conventional centrifuge bottle, but with the opening facing downwards, so that the adhering residual solution can be centrifuged out of the container through the filter. The resulting crystals are detached from the carrier by the centrifugal force.

[0125] The centrifuge can also be used to separate the crystals in the process container. In this regard, it should be mentioned that the container can be connected to the centrifuge. For example, the process container can be designed in a cylindrical shape and / or have a wide mouth opening, in particular with a filter mounted thereon and on which, for example, a centrifuge or a vacuum pump can be configured, as described below.

[0126] For example, the crystals can be detached from the carrier or seed crystal by centrifugation, or the supernatant solution can be removed from the process vessel. This can be without or with a filter receptacle. It can be more advantageous to provide a collection volume in the process vessel for collecting the crystals that settle out when the process vessel is centrifuged. In this arrangement, the solution can be centrifuged together with the crystals that have been detached from the carrier in order to separate the crystals from the solution. For example, the collection volume can be a region of reduced diameter, for example a V-shaped region. For example, the solution can be filtered out by centrifugation.

[0127] More preferably, the crystallization apparatus can be connected to at least one vacuum pump and a protective gas source, wherein the process vessel can be connected to the protective gas source or vacuum pump in such a way that an inert gas flow can be conducted or a vacuum can be applied in the process vessel. In this configuration, it can be particularly advantageous to make possible the drying of the formed crystals, since the solvent adhering to the crystals can be carried away by the protective gas flow through the process vessel. In addition, the solvent can also be evaporated by vacuum.

[0128] The protective gas of the present application is to be understood as not reacting with the crystallized-out substance, whereby for example argon or nitrogen.

[0129] In this case, the outlet of the protective gas flow or the interface of the vacuum pump can preferably be arranged on the filter of the process vessel, since this can prevent the crystals that have formed from being discharged from the process vessel.

[0130] In addition, it can be advantageous to provide a mixing device for mixing the solution in the process vessel. Such a device can be in particular a stirrer or a device that introduces oscillatory waves, for example sound waves, into the solution. In addition, it can also be that the carrier moves in the vessel, for example rotates. This allows the solution to move relative to the carrier, so that the crystallization of the solution on the carrier can be significantly improved.

[0131] The process vessel can preferably have at least one liquid inlet and one liquid outlet that is different from the liquid inlet. In this configuration, it can be particularly advantageous to use a continuous process with two coupled process vessels. This is because the solution depleted of the crystallized-out substance can be removed through the outlet, while new solution can be added through the inlet. Downstream of the outlet, the solution can be discarded, or returned to the inlet, or passed from one feed to another, in particular coupled, process vessel, in which further substance is crystallized out.

[0132] The present application also encompasses a crystallization apparatus with more than two process vessels. In this case, the carriers can have different seed crystals on their faces, and the process vessels can be connected to one another by fluid connections and thus coupled to one another.

[0133] In particular, the crystallization apparatus can provide at least two process vessels which are connected in series and the carriers in the process vessels are equipped with seed crystals which differ from each other.

[0134] In this design, the two process vessels provided can be used, inter alia, not only for separating one substance from a solution, but also for removing two substances from a solution by crystallization. This can be done in a continuous process, first the solution is added to the first process vessel of the crystallization apparatus and the first substance crystallizes out on the respective carriers, i.e. seed crystals. The solution can then be fed into the second process vessel, where it comes into contact with the seed crystals of the second carrier.

[0135] Then, as described in the method, the crystals can be detached from the carriers or seed crystals and separated.

[0136] The construction design described above thus enables the described crystallization process to be carried out in a very efficient manner and thus also describes the advantages described above with regard to the efficient separation of substances in a solution.

[0137] For example, a crystallization apparatus for crystallizing and separating at least one substance from a solution is described, in particular for carrying out the method described above, having a process vessel, in particular a cylindrical process vessel, for receiving the solution, having a process vessel for receiving carriers, wherein the carriers have seed crystals fixed on the carriers for the crystallization of the substance and can be separated from the vessel without being destroyed, and wherein the carriers can be positioned in the vessel in such a way that the seed crystals come into contact with the solution, further preferably a temperature control unit is provided for the direct or indirect temperature control of the seed crystals, and wherein the crystallization apparatus has a filter for filtering the solution present in the process vessel, or wherein the crystallization apparatus has a centrifuge for the centrifugation of the process vessel.

[0138] Further technical features and advantages of the crystallization apparatus are described with regard to the method, the use, the apparatus, the embodiments, the figures and the description of the figures, and vice versa.

[0139] Further, exemplary use of at least one of the crystallization processes and crystallization apparatuses described above for the enantiomeric resolution of racemic mixtures.

[0140] Thus in this design, in particular racemates, preferably aggregate-forming substance mixtures or substance systems, can be separated.

[0141] This is advantageous for many industrial processes, since racemates can be obtained in chemical reactions, but often only one separated enantiomer of the racemate or the enantiomeric mixture is needed. The crystallization processes described here can have a great advantage, in particular for enantiomeric resolution, since enantiomers can often be separated by crystallization processes.

[0142] For separating one enantiomer, it can be sufficient to use a carrier with a seed, so that the desired enantiomer can be crystallized and separated.

[0143] If two enantiomers are to be separated, different carriers, i.e. different seeds, can be used, for example in a batch process different carriers are used alternately, while in a continuous process different carriers are used as described in detail above.

[0144] It has been shown here that the crystallization apparatus, the method and the crystallization apparatus as described above are particularly suitable for efficiently and unambiguously separating the corresponding bodies from each other and highly selectively separating the individual enantiomers and thus performing enantiomeric resolution.

[0145] For further technical features and advantages of use, see the description of the crystallization process, the crystallization apparatus, the assembly, the embodiments, the figures and the figure description, and vice versa.

[0146] It is further described an assembly consisting of a process container, a collection container and a filter unit with a filter, which process container and collection container are fluidically connected to the filter unit and to each other through the filter, so that under vacuum or centrifugal force the solution can be filtered through the filter from the process container into the collection container, while the solids are retained by the filter in the process container and separated from the solution.

[0147] Such an assembly allows the filtration in a particularly advantageous manner without or at least significantly reduced risk of contamination of the filtrate. Furthermore, it can be used in a particularly simple manner, since the process container after removal of the lid can be connected to the filter unit and the collection container in a simple manner.

[0148] It is further advantageous that the process container and the collection container are in the same structural form. In this configuration, the collection container can also be used as a process container with the possibility of using a crystallization insert.

[0149] For easy mounting and dismounting, the process container or the collection container on the filter unit is preferably detachably fastened. This includes for example screw connections, clamp connections, etc.

[0150] For further technical features and advantages of the apparatus, see the description of the crystallization process, the crystallization apparatus, the use, the embodiments, the figures and the figure description, and vice versa. BRIEF DESCRIPTION OF DRAWINGS

[0151] Figure 1 The crystallization apparatus of the application is schematically shown;

[0152] Figure 2 The apparatus for centrifuging a solution is schematically shown;

[0153] Figure 3A centrifuge for the crystallization apparatus of the present invention is shown; and

[0154] Figure 4 A device for the continuous crystallization and separation of various substances from a solution according to the present invention is shown.

[0155] In the figure: 10, crystallization apparatus; 12, process vessel; 13, bottom; 14, receiving volume; 16, carrier; 18, seed crystal; 20, holder; 21, crystallization insert; 22, temperature control unit; 24, filter; 26, centrifuge; 28, assembly; 30, collection vessel; 31, filter cake; 32, filtration unit; 33, filtrate; 34, holding arm; 36, drive hub; 38, source of protective gas; 40, vacuum pump. DETAILED DESCRIPTION

[0156] The present invention is explained below with the aid of examples, in which the features presented below can represent an aspect of the invention, both individually and in combination, and the invention is not limited to the following figures, the following description and the following exemplary embodiments.

[0157] In Figure 1 partially schematically, a crystallization apparatus 10 for crystallizing at least one substance from a solution is shown.

[0158] The crystallization apparatus 10 comprises a process vessel 12, which is designed according to Figure 1 as a cylindrical process vessel. The process vessel 12 serves to accommodate the solution and thus the substance dissolved in the solution. Furthermore, the process vessel 12 comprises a receiving volume 14 for receiving a carrier 16, i.e. a crystallization insert with the carrier 16. The receiving volume 14 is in particular the inner volume of the process vessel 12, so that the carrier 16 can be accommodated in the process vessel 12. The carrier 16 contains seed crystals 18 for the substance to be fixed on the carrier 16 and can be separated from the receiving volume 14 without interference. The carrier 16 is positioned in the receiving volume 14 in such a way that the seed crystals 18 can come into contact with the solution. As Figure 1 is shown, a holder 20 is also provided, with which the carrier 16 can be introduced into the vessel and removed from the vessel. The carrier 16 forms a crystallization insert 21 together with the holder 20.

[0159] It is further shown that the carrier 16 is formed as an Archimedean spiral. In Figure 1 the form shown, the carrier 16, which can in particular be composed of a rigid film, is morphologically stable under working or separation conditions. In general, it is advantageous to use a carrier 16 regardless of the specific carrier shape. Thereby, the solution can be effectively caused to flow around the carrier 16, i.e. the seed crystals 18, and the substance can thus be effectively crystallized out on the seed crystals 18. This arrangement provides a dense, uniform and static distribution of the seed crystals 18 and thus promotes a rapid and uniform crystallization precipitation.

[0160] The process vessel 12 can be temperature-regulated using methods known to the person skilled in the art.

[0161] In order to achieve the crystallization effectively, a temperature-regulating unit 22 is also provided for directly or indirectly regulating the temperature of the carrier 16, i.e. of the seed crystals 18. According to the representation in Figure 1 , a temperature-regulating unit 22 is shown schematically, which acts on the solution and thus indirectly regulates the temperature of the carrier 16 and of the seed crystals 18.

[0162] The crystallization apparatus 10 shown in the figure also has at least one filter 24 for filtering the solution present in the process vessel 12, in particular for removing the solution adhering to the crystals, and at least one centrifuge 26 for centrifuging the process vessel. This makes it possible to separate the crystals formed in the process vessel 12 in a more advantageous manner, to wash and to dry them. More precisely, the crystallization apparatus 10 has a filter 24 for filtering the solution present in the process vessel 12, and the crystallization apparatus 10 has a centrifuge 26 for centrifuging the process vessel 12.

[0163] Figure 2 An assembly 28 is shown, by means of which the process vessel 12 can be centrifuged in particular advantageously. In addition to the process vessel 12, a collection vessel 30 is provided, between the process vessel 12 and the collection vessel 30 a filtering unit 32 with the filter 24 is provided. This assembly 28 is centrifuged in the centrifuge 26, the crystals formed are retained by the filter 24, the remaining solution passes through the filter 24 and can be collected in the collection vessel 30. Thus, the crystals can be separated very quickly from the solution and are not contaminated. In particular for the resolution of racemates, for example in particular the separation of polytropic systems, a precise separation can be carried out according to the optical rotation value.

[0164] In this respect Figure 2 The filter 24 is shown with a filter cake 31 retained on the filter, the solution passes through the filter 24 as filtrate 33 and is collected in the collection vessel 30. The filter cake 31 or the crystals can thus be separated.

[0165] Figure 3 The centrifuge 26 is shown, in which four assemblies 28 with process vessels 12 are provided. The assemblies 28 are placed in the centrifuge rotor, the stationary arms 34 can be rotated by means of the motor-driven wheel hubs 36 for centrifugation. It is expressly pointed out here that in order to enable the solution to be removed effectively from the process vessels 12, the bottoms of the process vessels 12 are facing upwards, as is shown in Figure 2 .

[0166] The crystallization process for crystallizing and separating a substance from a solution, in particular from a supersaturated solution, in which the substance is present, using the crystallization apparatus 10 described above, comprises the process steps:

[0167] a) introducing a solution containing the substance into the receiving volume of the process vessel 12 of the crystallization apparatus 10, the solution having a temperature T1 after the introduction;

[0168] b) providing a crystallization insert 21 having at least one carrier 16 with a surface provided with seeds of the substance for crystal growth, the seeds 18 being fixed on the surface of the carrier 16 of the crystallization insert 21, wherein the at least one carrier 16 has a helical shape,

[0169] c) positioning the crystallization insert 21 in the receiving volume 14 of the crystallization apparatus 10 such that the carrier 16 can be in contact with the solution,

[0170] d) optionally cooling the seeds 18 while adjusting the temperature of the seeds 18 to a temperature T2, wherein T2 is lower than T1,

[0171] e) crystallization of the substance on the surface of the seeds 18, and

[0172] f) optionally separating the substance forming crystals in the process vessel 12.

[0173] Using the apparatus described above, it is possible to separate different substances from each other in addition to separating one substance from a solution. For this purpose, the solution can be treated successively with carriers 16 having different seeds 18.

[0174] For example, when the solution is collected in the receptacle 30 of the assembly 28, it can be reintroduced into the process vessel 12, wherein the carrier 16 or the seeds 18 are exchanged after the first crystallization process. The same procedure can then be performed again.

[0175] This can be simpler if the process vessel 12 and the collection vessel 30 have the same structural form. In this case, another crystallization insert 21 with other seeds 18 can be placed into the solution.

[0176] Alternatively, the crystallization apparatus 10 has at least two coupled process vessels 12, and the at least two process vessels 12 are connected in series, and the carriers 16 of the different process vessels 12 are equipped with different seeds 18 from each other. Such a configuration is shown in Figure 4 In this setup, a continuous process can be performed by slowly conveying the solution through the two process vessels 12. As a result, different substances are crystallized on different carriers 16, i.e. different seeds 18. This enables a separate separation without the risk of contamination in a particularly efficient manner.

[0177] A protective gas source 38 can be provided upstream of the first process vessel 12, through which residual solvent adhering to the crystals can be removed. Alternatively or additionally, a vacuum pump 40 can be provided downstream of the second process vessel 12. Thereby also residual solvent adhering to the crystals can be removed, whereby the crystals can be dried.

[0178] Example

[0179] In the following examples first the preparation of the seed crystals on the carrier 16 is shown. Then the corresponding obtained carrier 16 is used for the racemic separation.

[0180] Preparation of seed crystals on a carrier

[0181] Preparation of L-threonine seed crystals on a carrier 16:

[0182] In a cylindrical process vessel 12 with a screw cap, a 60°C saturated aqueous solution of L-threonine was prepared and cooled to 35°C. A crystallization insert 21 with an Archimedes screw carrier 16 made of rigid PP film with a distance between the screws of about 3 mm was briefly immersed into the solution and briefly dried after being separated from the solution. This process was repeated several times until a thin and uniformly issued seed crystal surface was obtained. The L-threonine seed crystals of the thus prepared crystallization insert 21 were used in the subsequent separation.

[0183] Preparation of D-threonine seed crystals on a carrier 16:

[0184] In a screw-capped cylindrical round-bottom flask, a 60°C saturated aqueous solution of D-threonine was prepared and cooled to 35°C. A crystallization insert 21 with an Archimedes screw carrier 16 made of rigid PP film with a distance between the screws of about 3 mm was briefly immersed into the solution and briefly dried after being separated from the solution. This process was repeated several times until a thin and uniformly issued seed crystal surface was obtained. The D-threonine seed crystals of the thus prepared crystallization insert 21 were used in the subsequent separation.

[0185] Batch separation of DL-threonine by seed crystal preferential crystallization on a carrier 16

[0186] 1.1 L-threonine:

[0187] A 50°C saturated aqueous solution of the DL-threonine racemic mixture was added to a screw-capped cylindrical round bottom flask and heated to 55°C under stirring for 60 minutes. The solution was cooled to 35°C and stirring was stopped. The crystallization insert 21 with L-threonine seed crystals, at the same temperature as the solution, 35°C, was carefully placed in the solution. The solution was kept at this temperature for 45 minutes. The supersaturated L-threonine in the solution statically crystallized on the surface of the seed crystals. After 45 minutes, the crystallization insert 21 with crystals was removed from the solution and transferred to a centrifuge container and centrifuged for 3 minutes using a 2-vessel system with a filter unit in the middle. The solution adhering to the crystals was collected in the lower vessel. The obtained L-threonine was dried and had an enantiomeric excess >99% ee.

[0188] 1.2 D-threonine:

[0189] The filtered solution collected in the lower vessel from 1.1 was mixed with the remaining solution in the process vessel 12 of experiment 1.1 and stirred at 55°C for 60 minutes and then cooled to 35°C. Stirring was stopped. The crystallization insert 21 with D-threonine seed crystals, at the same temperature as the solution, 35°C, was carefully placed in the solution. The supersaturated D-threonine statically crystallized on the surface of the seed crystals at this temperature. After 45 minutes, the solution was decanted. At the opening of the process vessel 12, a 2-vessel system with a filter device in the middle and a tight and firm connection to a centrifuge container was connected and centrifuged for 3 minutes. The solution adhering to the crystals was centrifuged and collected in the lower flask. The obtained D-threonine had an enantiomeric excess >99% ee.

[0190] Continuous separation of DL-threonine by seed crystal preferential crystallization on a carrier 16

[0191] To the two process vessels 12A and 12B, a supersaturated aqueous solution of the racemic mixture was added, saturated at 50°C and thermostated at 38°C. A crystallization insert 21 with L-threonine seed crystals, at a temperature of 38°C, was carefully placed in the solution of process vessel 12A. At the same time, a crystallization insert 21 with D-threonine seed crystals, heated to 38°C, was carefully placed in the solution of process vessel 12B. The process vessel 12A was continuously fed with a 50°C saturated aqueous solution of the racemic mixture, supersaturated at 38°C. Process vessel 12A discharged the solution into process vessel B at the same rate. The solution flowed from process vessel 12B into process vessel 12 at the same rate, where a 50°C saturated aqueous solution of the racemic mixture, supersaturated at 38°C, was prepared. Process vessels 12A and 12B were thermostated at 38°C. After 3 hours, both process vessels 12A and 12B were centrifuged according to experiment 1.2. The L-threonine and D-threonine obtained after the separation each had an enantiomeric excess >99% ee.

[0192] According to this, the method and the device of the present application make it possible to at least partially overcome the disadvantages of the prior art. The seeds of the substance, in particular of the enantiomer, are uniformly finely distributed, in particular in all volume elements of the solution, and are represented as statically fixed on the surface of the carrier, and not, as described in the prior art, as a suspension of crystals. As a result, the crystallization can occur quickly on the surface of the seeds, which are densely, uniformly finely distributed. The obtained crystals can be large and uniformly granular, and can be quickly and completely mechanically separated from the solution. In addition, a high-purity substance can be obtained.

Claims

1. A method of crystallizing and separating a substance from a solution in which the substance is present, characterized in that, The method comprises the following steps: a) introducing a solution containing the substance into a receiving volume (14) of a process vessel (12) of a crystallization apparatus (10), the solution having a temperature T1 after the introduction; b) providing a crystallization insert (21) having at least one carrier (16) in the process vessel (12), the surface of the carrier (16) being provided with seeds (18) for the growth of crystals of the substance, the seeds (18) being fixed on the surface of the carrier (16) of the crystallization insert (21), and the at least one carrier (16) having a spiral shape; c) positioning the crystallization insert (21) in the receiving volume (14) of the crystallization apparatus (10) such that the carrier (16) can come into contact with the solution; d) optionally cooling the seeds (18) and adjusting the temperature of the seeds (18) to a temperature T2, wherein T2 is lower than T1; e) crystallization of the substance on the surface of the seeds (18), and f) optionally separating the crystals of the substance formed in the process vessel (12).

2. The method of claim 1, wherein, The solution in which the substance is located is a supersaturated solution.

3. The method of claim 1, wherein, at least 0.5 cm 3 of the crystalline surface is present in the at least partial receiving volume 2 of 0.5 cm 2 to 5 cm of the crystalline surface.

4. The method of claim 1, wherein, The method has a process step f) which comprises the following steps: f1) removing the substance crystallized on the seeds (18) from the carrier (16) in the process vessel (12); f2) removing the solution from the crystals formed; f3) optionally washing the crystals formed; and f4) drying the crystals.

5. The method of claim 4, wherein, At least one of the steps f2) and f3) comprises filtering the solution together with the crystals in the solution and collecting the crystals on a filter (24).

6. The method of claim 5, wherein, At least one of the steps f2) and f3) comprises filtering the solution together with the crystals in the solution in the process vessel (12) and collecting the crystals on a filter (24).

7. The method of claim 1, wherein, A set-up (28) consisting of the process vessel (12), a collection vessel (30) and a filter unit (32) having a filter (24) is used for the separation; wherein the process vessel (12) and the collection vessel (30) are connected to the filter unit (32) in a fluid-tight manner and are fluidically connected to each other by the filter (24) in such a way that the solution of the process vessel (12) can be filtered through the filter (24) under vacuum or centrifugal force into the collection vessel (30), wherein the solids are retained by the filter (24) in the process vessel (12) and separated from the solution.

8. The method of claim 1, wherein, The method is a separation of enantiomers, wherein the substance is an enantiomer of a racemic mixture and the solution comprises the racemic mixture.

9. The method of claim 1, wherein, The process steps a) to e) are repeated as a common sequence in the process vessel (12) and the crystallization insert (21) in the process vessel (12) is exchanged in the two repeated sequences, wherein the carriers have a first type of seeds in the first sequence and a second type of seeds different from the first type in the second sequence.

10. The method of claim 1, wherein, The process steps a) to e) are repeated as a common sequence in different process vessels (12), the carriers in the first process vessel having a first type of seeds and the carriers in the second process vessel having a second type of seeds different from the first type.

11. The method of claim 1, wherein, The process step a) is carried out at least partially before the process step c).

12. The method of claim 1, wherein, The process step a) is carried out at least partially after the process step c).

13. Crystallization apparatus (10) for crystallizing at least one substance from a solution by a method according to one of claims 1 to 12, having a process vessel (12) for receiving the solution and a crystallization insert (21) with at least one carrier (16) which is arranged in the process vessel (12), the surface of the carrier (16) being provided with seed crystals (18) for the growth of substance crystals, the seed crystals (18) being fixed on the surface of the carrier (16) of the crystallization insert (21), and wherein the at least one carrier (16) has a spiral shape, the process vessel (12) having a receiving volume (14) for receiving the crystallization insert (21) with the carrier (16), the crystallization insert (21) being detachable without damage from the receiving volume (14), and the crystallization insert (21) being positioned in the receiving volume (14) in such a way that the seed crystals (18) can come into contact with the solution.

14. The crystallization apparatus (10) of claim 13, characterized by The crystallization apparatus (10) has a filter (24) for filtering the solution in the process vessel (12).

15. The crystallization apparatus of any one of claims 13 or 14, wherein, The carrier (16) is designed as a membrane or a fabric.

16. The crystallization apparatus of claim 15, wherein, The membrane or fabric is provided with channel openings.

17. Assembly (28) for crystallizing at least one substance from a solution by a method according to one of claims 1 to 12, having a process vessel (12), a collection vessel (30) and a filter unit (32) with a filter (24), wherein the process vessel (12) and the collection vessel (30) are connected by a fluid-tight filter unit (32), are fluidically connectable to one another by the filter (24), the solution can be filtered from the process vessel (12) through the filter (24) into the collection vessel (30) under the action of a vacuum or centrifugal force, and solids are retained in the process vessel (12) by the filter (24) and separated from the solution.

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