JP4813495B2 - Micro crystallization apparatus and micro crystallization system - Google Patents

Description

  The present invention relates to a crystallization apparatus and a crystallization system, and in particular, enables a highly accurate crystallization of a compound even if a sample containing a compound and a solvent is in a very small amount, and in turn enables a highly efficient multi-sample processing. The present invention relates to a crystallization apparatus and a microcrystallization system.

  Generally, a compound such as a pharmaceutical has a plurality of crystal forms (crystal polymorphs). And depending on each crystal form, its stability and the like may be different, and particularly in the case of a pharmaceutical, its therapeutic effectiveness may be different. Therefore, when evaluating a newly developed compound, the compound is crystallized under various conditions, and the stability of each crystal form generated thereby is measured using a measuring device such as an X-ray diffractometer or a thermal analyzer. It is necessary to select and determine a useful crystal form and crystallization conditions for obtaining the crystal form after evaluation by using it. Further, in order for the developer to monopolize the crystal polymorph of the new compound, it is necessary to find out all the crystal forms possessed by the new compound by testing by changing various crystallization conditions.

  Crystallization of the above compound is generally carried out by cooling the solution after dissolving the compound in a solvent. Then, the amount of the solvent with respect to the type of the solvent and the amount of the compound, in the case of the mixed solvent, the composition ratio, the cooling process after dissolution (temporal change in temperature), and the various crystallization condition parameters such as pressure are generated. Different crystal forms are obtained. Since the combinations of these parameters are extremely large, it has been very troublesome to perform separate tests according to various conditions, and the amount of compounds that can be used is limited. For this reason, various proposals regarding so-called multi-analyte processing in which a plurality of samples are used to simultaneously perform tests under a large number of conditions have been made (for example, Japanese Special Table 2003-519698, Japanese Special Table). 2004-504596 publication, Japanese special table 2005-502861 publication).

  In the conventionally proposed multi-analyte processing relating to crystallization, a plate-like member provided with a plurality of (for example, 96) recesses (wells) arranged in a matrix form called a well plate is used. It is common to use a crystallizer provided. When such a well plate is used, a sample containing a compound and a solvent is accommodated in each well of the well plate, heated with a heating device arranged at the bottom of the well plate, and the compound is dissolved in the solvent. Crystallization is carried out by cooling the solution (stopping heating or reducing the heating temperature) to crystallize the compound. According to the crystallizer equipped with such a well plate, a small number of samples (amount of sample used for one sample) can be tested simultaneously by reducing the amount of samples contained in each well. Is possible. In addition, the said prior art literature discloses that a vial can be used in addition to a well plate.

  However, the crystallizer equipped with the well plate has the following problems. That is, when a solvent having a low boiling point is used, the solvent is volatilized by heating, so that the test according to the assumed amount of solvent and the composition ratio of the mixed solvent is not performed. There is a problem of getting worse. In other words, if the expected amount of solvent and the composition ratio of the mixed solvent can be used, there is a problem that the crystal form that should have been produced cannot be obtained. Alternatively, since the volatilization amount is too large, there is a problem that the crystallization test itself cannot be performed for a specific solvent having a low boiling point, and the types of solvents that can be selected are limited. In addition, even if a useful crystal form is obtained, the amount of solvent used to actually dissolve the compound and the composition ratio of the mixed solvent cannot be accurately grasped, so that the reproducibility of the crystallization conditions is poor. There is.

  The problem of deterioration in the accuracy of the crystallization becomes more apparent as the amount of the sample becomes smaller. This is because the smaller the amount of solvent used in the test, the greater the proportion of the volatilized solvent amount, and the influence cannot be ignored. For this reason, even if it is possible to test a large number of samples at the same time with a small amount of sample in the conventional crystallizer, the test is actually repeated many times due to the poor crystallization accuracy. As a result of repeated situations, there is a problem that the efficiency of multi-sample processing is poor.

  There is also known a crystallizer configured to contain a compound and a solvent in a well provided in a well plate and then close the opening of the well with a plate-like lid. According to such a crystallization apparatus, since the volatilized solvent does not leak out of the well, it can be said that the deterioration of the accuracy of the crystallization can be improved as compared with the case where no lid is provided. However, since most of the volatilized solvent is present as a gas between the liquid surface of the solution in the well and the lid without being used for dissolving the compound, the problem of deterioration in the accuracy of the crystallization is sufficiently prevented. It cannot be solved. In addition, when the well opening is closed with a plate-shaped lid, the inside is in a pressurized state, and thus the crystal form obtained may be different from the case where the well is not closed. Furthermore, the boiling point of the solvent rises when pressurized. As a result, the solubility of the compound changes, and there is a problem that accurate crystallization conditions cannot be obtained.

  In order to reduce the internal pressure in the container, an apparatus for releasing steam to the outside has been proposed, but the amount of solvent changes more severely as the amount of the sample decreases. For this reason, crystallization is usually performed at a temperature lower than the boiling point of the solvent, but when the nucleation temperature is close to the boiling point, the crystals cannot be precipitated.

  The present invention has been made to solve such problems of the prior art, and enables crystallization of a compound with high accuracy even if a sample containing a compound and a solvent is in a very small amount, and thus efficient multi-sample processing. It is an object of the present invention to provide a microcrystallizer and a microcrystallizer system that make it possible.

  In order to solve the above-mentioned problems, the present invention provides a heating device for heating a lower wall surface of one or a plurality of elongate containers detachably installed to accommodate a sample containing a compound and a solvent, and the elongate And a cooling device for cooling a predetermined wall surface of the elongate container located above the lower wall surface to be heated of the container.

  The microcrystallization apparatus according to the present invention includes a heating device for heating the lower wall surface of one or a plurality of elongate containers that are detachably provided. When adopting a configuration in which a plurality of elongate containers are erected, each elongate container accommodates a small amount of compound and solvent by varying the conditions such as the type of solvent and the amount of solvent relative to the amount of compound for each elongate container. Can be attached to the apparatus, and the lower wall surface can be heated and cooled (stopping heating or reducing the heating temperature) in a predetermined temperature pattern. As a result, it is possible to simultaneously perform a crystallization test on a small number of samples and a large number of samples corresponding to the number of elongated containers. Further, even when a configuration in which one elongated container is erected is employed, it is possible to crystallize a compound with high accuracy as will be described later. For this reason, it is not necessary to repeat the test under the same conditions as before. In addition, by repeating the crystallization test under different conditions by repeating the desorption of the elongated container, it is possible to perform the crystallization test with the same efficiency as the multi-sample treatment as a result. . Or, even when adopting a configuration in which one elongated container is installed, by preparing multiple microcrystallizers, crystallization tests can be simultaneously performed on the number of samples according to the number of microcrystallizers. Is possible.

  The microcrystallization apparatus according to the present invention includes a cooling device for cooling a predetermined wall surface of the elongated container positioned above the lower wall surface to be heated of the elongated container. According to such a configuration, the solvent that volatilizes and rises in the elongated container is cooled by heat transfer from the wall surface of the elongated container cooled by the cooling device, so that the solvent returns to the liquid (particularly in the elongated container). It will descend (along the inner wall of the container) and will be subjected to dissolution of the compound. Moreover, when the compound and the solvent are stored in the elongated container, even if the compound adheres to the inner wall surface of the container located above the liquid level of the solvent, it returns to the liquid and descends along the inner wall surface of the elongated container. Since the adhering compound can be dissolved by the solvent to be used, there is no possibility that the compound itself adhering to the inner wall surface of the container becomes a seed to form crystals. The position of the cooling device (the position of the wall surface of the elongated container cooled by the cooling device) is such that the sample accommodated in the elongated container is not cooled by the cooling device (the wall surface of the elongated container cooled by the cooling device). It is preferable that the temperature of the container is separated upward from the lower wall surface of the elongated container (from the upper surface of the heating device) so that the temperature of the container does not substantially affect the temperature of the lower wall surface of the elongated container and thus the temperature of the sample. As described above, since the microcrystallizer according to the present invention is configured to recirculate the volatilized solvent in the elongated container by the cooling device, the solvent amount and the composition ratio of the mixed solvent as expected while keeping the pressure constant. Therefore, even if the amount of the sample containing the compound and the solvent is very small, it is possible to crystallize the compound with high accuracy, and thus, it is possible to efficiently perform multi-sample processing.

  The phrase “standing” in the present invention is not limited to a mode in which the lower portion of the elongated container is supported by a predetermined support means (for example, the heating device in the present invention), and the longitudinal direction of the elongated container is in the vertical direction. As long as it is attached to the microcrystallizer so as to extend, it is used as a concept including various aspects such as hanging an elongated container.

  As a more specific configuration of the microcrystallization apparatus according to the present invention, for example, the heating device includes at least one of a pedestal member provided with a recess for fitting a lower portion of the elongated container, and a pedestal member. A heater for heating the vicinity of the recess, and the cooling device adopts a configuration including a cooling member that is disposed above the pedestal member and configured to allow refrigerant to flow therethrough. Is possible.

  Preferably, a capillary used as a container for containing the compound when analyzing the crystal form of the compound with an X-ray diffractometer or the like can be detachably installed as the elongated container.

  Conventionally, when analyzing the crystal form of the crystallized compound with an X-ray diffractometer or the like, the solvent in the well of the well plate provided in the crystallizer is filtered and dried, and then the remaining crystal form is taken out. There has been a problem that it is necessary to transfer to a dedicated container or the like that can be mounted on an X-ray diffractometer or the like, and these series of analysis operations require much labor. According to the preferred configuration, since a so-called capillary can be used as the elongated container, the capillary after the crystallization test is completed can be detached from the apparatus according to the present invention and directly attached to an X-ray diffraction apparatus or the like. The advantage is that extremely efficient analysis work becomes possible.

  Preferably, a support that is disposed above the cooling member and is detachably suspended as the elongate container used as a container for containing the compound when analyzing the crystal form of the compound with an X-ray diffractometer or the like. A member is further provided, and the length of the lower region of the capillary fitted into the concave portion of the pedestal member can be adjusted by changing the vertical relative position of the support member and the capillary.

  When a capillary is used as the elongate container, since the outer diameter of the capillary is extremely small, the liquid level of the solvent varies greatly depending on the volume of the solvent accommodated in the capillary. Therefore, in the configuration in which the bottom surface of the capillary is fitted until it contacts the bottom surface of the recess of the pedestal member, if the lower wall surface of the region that approximately matches the liquid level of the solvent stored in the capillary is heated, the capillary is stored in the capillary. Depending on the volume of the solvent to be prepared, it is necessary to prepare a pedestal member having recesses of various depths and replace them appropriately. Further, when a plurality of capillaries are erected and the crystallization test is performed simultaneously, it is difficult to vary the volume of the solvent accommodated for each capillary. According to the preferable configuration, since the length of the lower region of the capillary to be fitted into the recess a can be adjusted, it is necessary to prepare a pedestal member having recesses of various depths according to the volume of the solvent accommodated in the capillary There is no. In the case where a plurality of capillaries are erected and the crystallization test is performed simultaneously, the volume of the solvent accommodated for each capillary can be easily varied.

  Preferably, the heating device is configured to heat the lower wall surface of the plurality of elongate containers and to control the temperature of the heated lower wall surface independently for each of the elongate containers.

  A conventional crystallizer equipped with a well plate has a configuration in which all wells are controlled with the same temperature pattern by a heating device arranged at the bottom of the well plate. Therefore, it is necessary to select a solvent having a close boiling point as a solvent to be accommodated in each well of one well plate, and there is a problem that the efficiency of multi-sample processing is poor. According to said preferable structure, the temperature of a lower wall surface is controllable independently for every elongate container. In other words, it is possible to control the temperature of the sample accommodated in each elongated container with different temperature patterns. Therefore, for example, there is an advantage that the crystallization test can be simultaneously performed using different types of solvents having different boiling points. In addition, if the type and amount of the solvent to be stored are set to a constant value in all elongated containers, and the heating process and the cooling process after dissolution are changed for each elongated container and tested, an appropriate heating process and cooling process can be performed. The advantage that it is easy to find the crystallization conditions to be included is obtained.

  Moreover, in order to solve the said subject, this invention is provided not only as the said microcrystallization apparatus but as a microcrystallization system provided also with the said elongate container attached to the said microcrystallization apparatus. That is, the present invention comprises the microcrystallizer and one or a plurality of elongated containers detachably installed on the microcrystallizer to accommodate a sample containing a compound and a solvent. It is also provided as a microcrystallization system.

  Preferably, the elongated container is formed using a glass material.

  According to such a preferable configuration, compared to the case of using a metal or plastic container, the type of solvent that can be accommodated is not limited, and is not affected by the acid or alkali added as necessary. Thus, there is an advantage that the crystallization conditions can be studied from various aspects.

  Preferably, the elongate container is made of a transparent material and has a flat bottom surface.

  According to such a preferable configuration, since the elongate container is formed of a transparent material (a material having a transparency that allows the inside of the container to be visually recognized), the inside of the container can be observed. Thus, for example, if the compound is not dissolved, a solvent can be added during the test. In addition, since the crystallization state can be observed, for example, it is possible to detect the crystal precipitation start temperature. Further, even if the crystal form of the crystallized compound is not transferred to another container or the like, the elongated container after the completion of the crystallization test is removed from the apparatus according to the present invention, and the crystal form is directly viewed from the bottom side of the elongated container with a microscope. It is possible to observe. That is, since the elongate container is transparent, the crystal shape in the container can be observed with a microscope and is observed from the flat bottom surface side, so that the image is not deformed by the lens effect.

  Alternatively, the elongated container may be a capillary used as a container for containing a compound when the crystal form of the compound is analyzed by an X-ray diffractometer or the like.

  According to the above preferred configuration, by using a so-called capillary as the elongated container, as described above, the capillary after completion of the crystallization test can be detached from the apparatus according to the present invention and directly attached to an X-ray diffractometer or the like. Therefore, there is an advantage that extremely efficient analysis work becomes possible.

  Further preferably, the elongated container includes a lid member for closing the top opening after the sample is accommodated.

  According to such a preferable configuration, since the volatilized solvent does not leak out of the elongated container, the volatilized solvent is surely cooled and refluxed by the cooling device, thereby further improving the accuracy of crystallization of the compound. It is possible.

FIG. 1 is a perspective view showing a schematic configuration of a microcrystallization system according to an embodiment of the present invention. FIG. 2 is an enlarged cross-sectional view showing the configuration around the elongated container constituting the microcrystallization system shown in FIG. FIG. 3 is a diagram schematically showing a schematic configuration inside the heating apparatus shown in FIG. 1. 4 is an enlarged cross-sectional view showing another configuration example around the elongated container constituting the microcrystallization system shown in FIG. FIG. 5 is an enlarged cross-sectional view showing still another configuration example around the elongated container constituting the microcrystallization system shown in FIG. FIG. 6 is a perspective view showing a schematic configuration of a microcrystallization system according to another embodiment of the present invention. FIG. 7 is a perspective view showing a schematic configuration of a microcrystallization system according to still another embodiment of the present invention.

  Hereinafter, a microcrystallization system according to an embodiment of the present invention will be described with reference to the accompanying drawings.

  FIG. 1 is a perspective view showing a schematic configuration of a microcrystallization system according to an embodiment of the present invention. FIG. 2 is an enlarged cross-sectional view showing the configuration around the elongated container constituting the microcrystallization system shown in FIG. Further, FIG. 3 is a diagram schematically showing a schematic configuration inside the heating apparatus shown in FIG. As shown in FIG. 1, a microcrystallization system 100 according to this embodiment includes a plurality of elongated containers 1 for storing a sample containing a compound and a solvent, and a microcrystallization apparatus 10. The microcrystallizer 10 includes a heating device 2 for heating the lower wall surface of each elongated container 1 detachably installed on the microcrystallizer 10 and the heated lower part of each elongated container 1. And a cooling device 3 for cooling a predetermined wall surface of each elongated container 1 positioned above the wall surface.

  In the present embodiment, the lower portion of the elongated container 1 is fitted into the heating device 2 (specifically, a recess 21a of the heating device 2 described later), while the cooling device 3 (specifically, a cooling member 31 described later). ), The elongated containers 1 are inserted in the vertical direction so that the elongated containers 1 are detachable in the vertical direction. However, the present invention is not limited to this. For example, a predetermined support member is provided above the cooling device 3, and the elongated container 1 is suspended by the support member, so that the microcrystallizer 10 stands. It is also possible to adopt a configuration that is provided.

  The elongated container 1 can accommodate a small amount (for example, about several mg) of the compound C and a small amount (for example, about several tens of μL) of the solvent L, and can perform a crystallization test, and has a small heat capacity. In order to perform efficient temperature control, the outer diameter is about several mmφ (for example, 9 mmφ) and the length is about several tens mm (for example, 50 mm). Moreover, the elongate container 1 is formed using transparent glass material (for example, borosilicate glass) as a preferable structure, and as shown in FIG. 2, the bottom face is shape | molded flatly. Furthermore, it is good also as a structure provided with the cover member (not shown) for obstruct | occluding the top opening after accommodating the compound C and the solvent L as needed. In addition, as the lid member, in addition to a lid body (for example, a silicon stopper) fitted into the top opening of the elongated container 1, a sealing member (for example, Parafilm (registered trademark)) for sealing the top opening is applied. It is also possible to do. Since the microcrystallization system 100 according to the present embodiment includes the cooling device 3, even if a configuration including a lid member is employed, unlike the case where the conventional well opening is closed with a plate-shaped lid, an elongated container is used. It is possible to obtain accurate crystallization conditions without excessively pressing the inside of 1. This is because, when a configuration including a lid member is adopted, although a slight pressure increase may occur inside the elongate container 1, the volatilized solvent is cooled by the cooling device 3 and returned to the liquid. This is because it can be suppressed.

The heating device 2 includes a pedestal member (aluminum) 21 provided with a plurality of recesses 21 a for fitting the lower portions of the respective elongated containers 1 on the upper surface, and a heater for heating at least the vicinity of the recesses 21 a of the pedestal member 21. 22. With this configuration, the heater 22 heats the vicinity of the recess 21a of the pedestal member 21, and further heats the lower wall surface of each elongated container 1 by heat conduction from the region near the recess 21a of the heated pedestal member 21. And the sample accommodated in the elongate container 1 is heated by the heat transfer from the lower wall surface of the elongate container 1. Note that the heating device 2 according to the present embodiment heats the lower wall surface in a region that approximately matches the liquid level height of the solvent L accommodated in the elongated container 1 (the liquid level height after accommodating the compound C). It is configured to be able to. Specifically, as shown in FIG. 2, the elongated container 1 is fitted into the pedestal member 21 until the bottom surface thereof abuts against the bottom surface of the recess 21 a of the pedestal member 21. And the depth D of the recessed part 21a of the base member 21 is set so that it may substantially correspond to the liquid level height of the solvent L accommodated in the elongate container 1 (for example, slightly shallower than the liquid level height of the solvent L). Has been. More specifically, for example, when the dimensions of the elongate container 1 are an outer diameter of 9 mmφ and a length of 50 mm, the combinations shown in Table 1 below are preferably used as the volume of the solvent L and the depth D of the recess 21a. . With such a configuration, the lower wall surface of the elongate container 1 fitted in the recess 21a is heated substantially uniformly by heat conduction from the pedestal member 21, and as a result, is elongated by heat transfer from the lower wall surface of the elongate container 1 heated uniformly. The sample stored in the container 1 can be at a substantially uniform temperature.

  Moreover, the heating apparatus 2 is comprised so that control of the temperature of the said lower wall surface heated independently for each elongate container 1 as a preferable structure is carried out. Specifically, as shown in FIG. 3, a conductor 221 that generates heat by energization is disposed in the vicinity of the lower part of each elongated container 1 in the heater 22 (near the recess 21 a of the base member 21), and the base A temperature sensor 211 such as a thermocouple is arranged in the vicinity of the lower portion of each elongated container 1 in the member 21 (in the vicinity of the recess 21a of the base member 21). A conductor 221 and a temperature sensor 211 arranged for each lower portion of each elongated container 1 are electrically connected to the control means 222 provided in the heater 22. In addition, in this embodiment, in order to reduce the influence which the heat_generation | fever by each conductor 221 arrange | positioned for every lower vicinity site | part of each elongate container 1 has on the lower wall surface temperature of the adjacent elongate container 1, as a preferable structure, A base member 21 is divided for each elongated container 1 (in FIG. 1, for convenience of illustration, the base member 21 is illustrated as a single plate-like member. An appropriate cooling plate or heat insulating plate 4 is disposed between the divided portions of the base member 21.

  The control means 222 stores a voltage corresponding to a target temperature at a predetermined time in a portion near the lower portion of each elongated container 1 set in advance. Then, the control means 222 compares the voltage corresponding to the target temperature with the voltage corresponding to the temperature detected by the temperature sensor 211 every predetermined time, and determines the current flowing through the conductor 221 according to the magnitude relationship. It is configured to turn on / off (or increase / decrease the current value). With the above configuration, as described above, the temperature of the lower wall surface can be controlled independently for each elongate container 1 (in practice, the temperature in the vicinity of the lower part of each elongate container 1 in the base member 21 is controlled. ). In the present embodiment, the configuration in which the conductor 221 is arranged in the heater 22 and the temperature sensor 211 is arranged in the pedestal member 21 has been described. However, the present invention is not limited to this, and the temperature sensor 211 is also a heater. It is also possible to employ a configuration that is arranged within 22. In addition, a configuration in which the base member 21 and the heater 22 are integrated (that is, a plurality of recesses for fitting the lower portions of the respective elongated containers 1 are provided on the upper surface of the heater 22, and the conductor 221 and the temperature sensor 211 are connected to the heater 22. It is also possible to adopt a configuration arranged inside.

  Moreover, the heating apparatus 2 which concerns on this embodiment is also provided with the function as what is called a stirrer which incorporated the magnet which can rotate as a preferable structure. Accordingly, if the stirrer M made of a magnetic material accommodated in each elongated container 1 is moved by the magnetic force provided from the magnet of the heating device 2 as necessary, a uniform crystal form can be obtained. It is possible to stir the solution in 1.

  The cooling device 3 is arranged above the pedestal member 21, provided with a plurality of openings 31 a for allowing the respective elongated containers 1 to be inserted thereinto, and configured to allow a coolant to flow therein. Made). Specifically, the cooling device 3 according to the present embodiment includes a tubular member 32, and the refrigerant flows through the tubular member 32 into the cooling member 31 (circulates in the direction of the white arrow in FIG. 1). It is configured as follows. More specifically, a configuration is provided in which an insertion hole that is straight or appropriately passes through the periphery of the opening 31a is provided from one side surface to the other side surface of the cooling member 31, and the tubular member 32 is inserted into the insertion hole. Can be adopted. Alternatively, a configuration may be adopted in which the entire cooling member 31 is hollow and the tubular member 32 communicating with the inside thereof is attached to one side surface and the other side surface of the cooling member 31. Regardless of which configuration is adopted, by circulating the refrigerant through the tubular member 32, the refrigerant flows through the cooling member 31, and the amount of heat on the wall surface of the elongated container 1 at the portion inserted through the opening 31 a is reduced. Then, heat is radiated to the refrigerant through the cooling member 31. As the refrigerant to be circulated in the tubular member 32, various media can be used according to the cooling temperature, and examples thereof include water, ethanol, methanol, and the like. In addition, since the cooling device 3 according to the present embodiment has a configuration in which the elongate container 1 is fitted into the opening 31a provided in the cooling member 31, as described above, the elongate container 1 is prevented from shaking and stable. It also functions as a support member for maintaining the standing state.

  In the present embodiment, the configuration including the cooling member 31 configured to allow the refrigerant to flow therein is exemplified as the cooling device 3, but the present invention is not limited to this, and cooling that is normally used. You may employ | adopt the structure which comprises the member, for example, the cooling member provided with the Peltier device. In this case, the tubular member 32 for circulating the refrigerant is not necessary.

  The position of the cooling member 31 is such that the sample housed in the elongate container 1 is not cooled by the cooling member 31 (the temperature of the wall surface of the elongate container 1 cooled by the cooling member 31 is It is preferable that the heating device 2 is separated upward (from the upper surface of the base member 21) so as not to substantially affect the temperature of the sample. In the present embodiment, when the elongated container 1 having a length of 50 mm is used, the separation distance between the cooling member 31 and the pedestal member 21 is set to 27 mm, which is approximately half the length of the elongated container 1. Thereby, accurate temperature control can be performed without affecting the temperature of the sample accommodated in the elongate container 1 by the cooling member 31. Further, since the cooling member 31 and the pedestal member 21 are arranged apart from each other and the elongated container 1 is formed using a transparent material, it is possible to observe the inside of the container 1 during the crystallization test. It is. Furthermore, bases such as acids (inorganic acids, organic acids), alkali metals, alkaline earth metals, amines, etc. are added to each elongated container 1 so as to crystallize in the form of salt during the crystallization test. It is also possible to add a solvent L.

  By providing such a cooling device 3, as indicated by the arrow in FIG. 2, the solvent L that has volatilized and has risen in the elongated container 1 is cooled by the cooling device 3 (cooling member 31). As a result of cooling by heat transfer from the wall surface, the liquid returns to the liquid and descends along the inner wall surface of the elongated container 1 to be used for dissolving the compound C. Further, when the compound C and the solvent L are stored in the elongated container 1, even if the compound C adheres to the inner wall surface of the container 1 located above the liquid level of the solvent L, the elongated container 1 returns to the liquid. Since the adhering compound C can be dissolved by the solvent L descending along the inner wall surface, there is no possibility that the compound C itself adhering to the inner wall surface of the container 1 will become a seed to form crystals. . Thus, by providing the cooling device 3 above the lower wall surface of the elongated container 1 to be heated, the temperature of the pedestal member 21 of the heating device 2 and the lower wall surface of the elongated container 1 is close to the boiling point of the temporary solvent L. The solvent L will not vaporize nor be pressurized.

  As described above, according to the microcrystallization system 100 according to the present embodiment, the cooling device 3 is configured to recirculate the volatilized solvent L in the elongate container 1. Tests can be performed according to the amount of solvent and the composition ratio of the mixed solvent. Even if the amount of the sample containing Compound C and Solvent L is very small (for example, about 25 to 50 μL), the crystallization temperature can be several hours. Even if the control is performed, it is possible to crystallize the compound C with high accuracy, and thus, it is possible to efficiently perform multi-sample processing.

  In this embodiment, a container as shown in FIG. 2 is used as the elongated container 1, but the present invention is not limited to this, and for example, a capillary 1A as shown in FIG. 4 may be used. For example, those having various outer diameters such as 0.1 to 3 mm exist in the capillary 1A, but those having an outer diameter of 0.5 to 1 mm are preferably used as the capillary 1A according to this embodiment. (The sample accommodated in the capillary 1A is, for example, about several μL to 20 μL, preferably about 10 to 20 μL. The amount of the compound C is about several μg to several mg, preferably about several tens μg to several hundred μg. ). According to such a configuration, the crystallization test can be performed with a smaller amount of the compound C, and the capillary 1A after the crystallization test is removed from the microcrystallizer 10 and attached to the X-ray diffractometer as it is. Therefore, not only the filtering work becomes unnecessary, but also a very efficient analysis work can be performed without loss of the crystal sample due to the filtration.

  Here, particularly when the capillary 1A is used as the elongated container 1, since the outer diameter of the capillary 1A is extremely small as described above, the liquid surface height of the solvent L depends on the volume of the solvent L accommodated in the capillary 1A. It fluctuates greatly. Therefore, as shown in FIG. 4, in the configuration in which the bottom surface of the capillary 1A is fitted until it contacts the bottom surface of the recess 21a of the pedestal member 21, a region that substantially matches the liquid level of the solvent L accommodated in the capillary 1A. When the lower wall surface is to be heated, it is necessary to prepare the pedestal member 21 having the recesses 21a of various depths according to the volume of the solvent L accommodated in the capillary 1A and replace it appropriately. Further, when a plurality of capillaries 1A are erected and a crystallization test is performed simultaneously, it is difficult to vary the volume of the solvent L accommodated for each capillary 1A.

  In order to solve the above problems, it is preferable that the length of the lower region of the capillary 1A to be fitted into the recess 21a (which may be a through hole) is adjustable as shown in FIG. More specifically, the support member 6 for detachably suspending the capillary 1A is disposed above the cooling member 31, and the relative position in the vertical direction between the support member 6 and the capillary 1A is changed to thereby form the recess 21a. What is necessary is just to comprise so that the length of the lower area | region of 1 A of capillaries inserted in can be adjusted. More specifically, in the example shown in FIG. 5, a jig 5 having an insertion hole 5 a that can be inserted through the capillary 1 </ b> A and has a shape set so as not to fall down and a male screw portion 5 b at the lower part is provided. prepare. On the other hand, above the cooling member 31, the support member 6 which comprises the internal thread part 6a which can screw in the external thread part 5b of the jig | tool 5 is installed. The support member 6 is attached to a predetermined member (for example, the heating device 2) constituting the microcrystallization apparatus 10, and the position thereof is fixed. Then, in a state where the capillary 1A is inserted through the insertion hole 5a of the jig 5, the male screw portion 5b of the jig 5 is screwed into the female screw portion 6a of the support member 6, and the concave portion 21a is adjusted by adjusting the screwing amount. It is possible to adjust the length of the lower region of the capillary 1A to be inserted into the cap.

  According to a preferred configuration as shown in FIG. 5, since the length of the lower region of the capillary 1A to be fitted into the recess 21a can be adjusted, the recesses of various depths are selected according to the volume of the solvent L accommodated in the capillary 1A. There is no need to prepare the pedestal member 21 having 21a. Further, when a plurality of capillaries 1A are erected and the crystallization test is performed simultaneously, the volumes of the solvent L accommodated for each capillary 1A can be easily varied. The preferred configuration shown in FIG. 5 is particularly effective when a capillary 1A having a small outer diameter is used as the elongated container 1. However, the present invention is not limited to this, and the general elongated container 1 as shown in FIG. Of course, it is also possible to apply it.

  FIG. 6 is a perspective view showing a schematic configuration example of a microcrystallization system in which a capillary 1A is used as the elongated container 1 and each of a plurality of capillaries 1A is set up using the configuration shown in FIG. 5 described above. In the microcrystallization system shown in FIG. 5, the pedestal member 21 is divided for each block (six blocks in the example shown in FIG. 6) in which a certain number of capillaries 1A are erected (further divided into pedestal members 21). Corresponding to each block, the cooling member 31 and the support member 6 are also divided), and the temperature of the lower wall surface heated by the capillary 1A can be controlled independently for each block. However, the present invention is not limited to this, and the base member 21 is divided for each capillary 1A so that the temperature of the lower wall surface can be controlled for each capillary 1A, as in the configuration shown in FIG. A configuration is also possible.

  In the present embodiment, the configuration in which a plurality of elongate containers 1 are erected has been described. However, the present invention is not limited to this, and for example, as shown in FIG. It is also possible to adopt a configuration. The microcrystallization system 100A shown in FIG. 7 includes a pedestal member 21 provided with only one recess 21a, a cooling member 31 provided with only one opening 31a, a conductor and a temperature sensor ( The configuration is the same as that of the microcrystallization system 100 shown in FIG. 1 except that only one (not shown in FIG. 5) is provided. Even with a configuration in which one elongated container 1 is erected as in the microcrystallization system 100A shown in FIG. 7, crystallization of a compound with high accuracy is possible. For this reason, it is not necessary to repeat the test under the same conditions as before. In addition, by repeatedly performing the crystallization test under different conditions by repeatedly desorbing the elongated container 1, it is possible to perform the crystallization test with the same efficiency as the multi-sample treatment as a result. is there. Alternatively, by preparing a plurality of microcrystallization systems 100A shown in FIG. 7, it is possible to simultaneously perform a crystallization test on the number of samples corresponding to the number of microcrystallization systems 100A.

  According to the microcrystallizer according to the present invention described above, it is possible to crystallize a compound with high accuracy even if the amount of the sample containing the compound and the solvent is very small, and thus, it is possible to perform efficient multi-sample processing. It has an excellent effect of being.

Claims (10)

A heating device for heating a lower wall surface of one or a plurality of elongate containers detachably installed to accommodate a sample containing a compound and a solvent;
A micro-crystallization apparatus comprising: a cooling device for cooling a predetermined wall surface of the elongate container located above the lower wall surface to be heated of the elongate container. The heating device comprises a pedestal member provided on the upper surface with a recess for fitting the lower portion of the elongated container, and a heater for heating at least the vicinity of the recess of the pedestal member,
The cooling device includes a cooling member disposed above the pedestal member, provided with an opening for fitting the elongated container, and configured to allow refrigerant to flow therethrough. The microcrystallization apparatus according to claim 1.   The capillary used as a container for containing the compound when analyzing the crystal form of the compound with an X-ray diffractometer or the like is detachably erected as the elongated container. 2. The microcrystallization apparatus according to 2. A support member that is disposed above the cooling member and detachably suspends a capillary used as a container for containing the compound when the crystal form of the compound is analyzed by an X-ray diffractometer or the like as the elongated container; Prepared,
The length of the lower region of the capillary that fits into the concave portion of the pedestal member can be adjusted by changing the vertical relative position of the support member and the capillary. 2. The microcrystallization apparatus according to 2.   2. The heating device is configured to heat a lower wall surface of a plurality of elongate containers and to control a temperature of the heated lower wall surface independently for each of the elongate containers. To 4. The microcrystallization apparatus according to any one of items 1 to 4. A microcrystallization apparatus according to any one of claims 1 to 5,
A microcrystallization system comprising: one or a plurality of elongate containers detachably installed on the microcrystallizer to accommodate a sample containing a compound and a solvent.   The micro crystallization system according to claim 6, wherein the elongated container is formed using a glass material.   The micro crystallization system according to claim 6 or 7, wherein the elongated container is formed of a transparent material and has a flat bottom surface.   The microscopic crystallization according to claim 6 or 7, wherein the elongated container is a capillary used as a container for containing a compound when the crystal form of the compound is analyzed by an X-ray diffractometer or the like. system.   10. The microcrystallization system according to claim 6, wherein the elongated container includes a lid member for closing a top opening after the sample is accommodated.