JP4813495B2 - Micro crystallization apparatus and micro crystallization system - Google Patents
Micro crystallization apparatus and micro crystallization system Download PDFInfo
- Publication number
- JP4813495B2 JP4813495B2 JP2007537661A JP2007537661A JP4813495B2 JP 4813495 B2 JP4813495 B2 JP 4813495B2 JP 2007537661 A JP2007537661 A JP 2007537661A JP 2007537661 A JP2007537661 A JP 2007537661A JP 4813495 B2 JP4813495 B2 JP 4813495B2
- Authority
- JP
- Japan
- Prior art keywords
- container
- compound
- solvent
- elongated container
- wall surface
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0004—Crystallisation cooling by heat exchange
- B01D9/0013—Crystallisation cooling by heat exchange by indirect heat exchange
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N2035/00346—Heating or cooling arrangements
Landscapes
- Physics & Mathematics (AREA)
- Thermal Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Sampling And Sample Adjustment (AREA)
- Analysing Materials By The Use Of Radiation (AREA)
Description
本発明は、晶析装置及び晶析システムに関し、特に化合物及び溶媒を含む試料が微量であっても精度の高い化合物の晶析を可能とし、ひいては効率の良い多検体処理を可能とする微量晶析装置及び微量晶析システムに関する。 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.
医薬等の化合物は、複数の結晶形(結晶多形)を有するのが一般的である。そして、各結晶形に応じて、その安定性等が異なったり、特に医薬の場合には治療上の有効性等が異なる場合がある。従って、新規に開発した化合物を評価するにあたっては、各種条件下で該化合物を晶析させ、これにより生成された各結晶形の安定性等をX線回折装置や熱分析装置等の計測装置を用いて評価した上で、有用な結晶形及びこの結晶形を得るための晶析条件を選択、決定する必要がある。また、新規化合物の結晶多形を開発者が独占するには、晶析の条件を種々変更して試験することにより、新規化合物が有する全ての結晶形を探し出す必要がある。 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.
上記化合物の晶析は、一般に化合物を溶媒に加熱溶解させた後、この溶液を冷却することにより実施される。そして、溶媒の種類や化合物の量に対する溶媒の量、混合溶媒の場合にはその組成比、溶解後の冷却過程(温度の時間的変化)、圧力といった晶析の各種条件パラメータに応じて、生成される結晶形が異なるものとなる。これらパラメータの組合せは極めて多数となるため、各種の条件に応じた試験を別個に実施していたのでは非常に手間を要する他、用いることのできる化合物の量にも限りがある。このため、従来より、複数の試料を用いて多数の条件での試験を同時に行ういわゆる多検体処理に関する種々の提案がなされている(例えば、日本国特表2003−519698号公報、日本国特表2004−504596号公報、日本国特表2005−502861号公報参照)。 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).
従来提案されている晶析に関する多検体処理には、いわゆるウェルプレートと称されるマトリックス状に配置された複数(例えば、96個)の凹部(ウェル)が上面に設けられたプレート状の部材を備えた晶析装置を用いるのが一般的である。そして、斯かるウェルプレートを用いる場合、ウェルプレートの各ウェル内に化合物及び溶媒を含む試料を収容し、ウェルプレートの下部に配置された加熱装置で加熱して化合物を溶媒に溶解させた後、この溶液を冷却(加熱を停止、或いは加熱温度を低減)して化合物を結晶化させることで晶析が実行される。斯かるウェルプレートを備えた晶析装置によれば、各ウェル内に収容する試料を少量とすることにより、少量の検体量(一検体に使用する試料の量)で多くの検体数を同時に試験することが可能である。なお、上記従来文献の中には、ウェルプレートの他にバイアルを用いることができる旨が開示されている。 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.
しかしながら、上記ウェルプレートを備えた晶析装置には、以下のような問題点が存在する。すなわち、沸点の低い溶媒を用いる場合、加熱により溶媒が揮発してしまうため、想定していた溶媒量や混合溶媒の組成比に応じた試験が行われないことになる結果、晶析の精度が悪化するという問題がある。換言すれば、想定通りの溶媒量や混合溶媒の組成比を用いることができたとすれば本来生成されていたはずの結晶形が得られないというような問題がある。或いは、揮発量が多すぎるために、沸点の低い特定の溶媒については晶析試験そのものを実施できず、選択できる溶媒の種類が限定されるというような問題がある。また、たとえ有用な結晶形が得られたとしても、実際に化合物を溶解するのに供された溶媒量や混合溶媒の組成比を正確に把握できないため、晶析条件の再現性が悪いといった問題がある。 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.
上記晶析の精度悪化の問題は、検体量が少量になればなるほど顕在化することになる。なぜならば、試験に供する溶媒量が少なくなればなるほど、揮発した溶媒量の占める割合が大きくなり、その影響を無視できなくなるからである。このため、従来の晶析装置では、少量の検体量で多くの検体数を同時に試験すること自体は可能であったとしても、晶析の精度が悪いために、実際には試験を何度も繰り返すような事態が生じる結果、多検体処理の効率が悪いという問題もある。 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.
なお、ウェルプレートに設けられたウェルに化合物及び溶媒を収容した後、ウェルの開口をプレート状の蓋体で閉塞するように構成された晶析装置も知られている。斯かる晶析装置によれば、揮発した溶媒がウェルの外部に漏れ出さないため、蓋体を設けない場合に比べれば、上記晶析の精度悪化を改善することができるといえる。しかしながら、揮発した溶媒の多くは、化合物の溶解に供されることなく、ウェル内の溶液の液面と蓋体との間に気体として存在するため、上記晶析の精度悪化の問題を十分に解決することはできない。また、ウェルの開口をプレート状の蓋体で閉塞した場合、内部が加圧状態になるため、蓋体で閉塞しない場合とは、得られる結晶形が異なる可能性が考えられる。さらに、加圧されることにより溶媒の沸点が上昇する。これにより化合物の溶解度が変化してしまい、正確な晶析条件を得ることができなくなるという問題もある。 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.
容器内の内部圧力を低減させるため、蒸気を外部に放出させる装置も提案されているが、試料の量が少量になるほど溶媒量の変化が激しくなる。このため、通常、溶媒の沸点よりも低い温度で晶析が行われているが、核形成温度が沸点に近い場合には、その結晶を析出させることはできない。 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.
本発明は、斯かる従来技術の問題を解決するべくなされたものであり、化合物及び溶媒を含む試料が微量であっても精度の高い化合物の晶析を可能とし、ひいては効率の良い多検体処理を可能とする微量晶析装置及び微量晶析システムを提供することを課題とする。 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.
前記課題を解決するべく、本発明は、化合物及び溶媒を含む試料を収容するために脱着自在に立設される一つ又は複数の細長容器の下部壁面を加熱するための加熱装置と、前記細長容器の加熱される下部壁面に対して上方に位置する前記細長容器の所定の壁面を冷却するための冷却装置とを備えることを特徴とする微量晶析装置を提供するものである。 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.
本発明に係る微量晶析装置は、脱着自在に立設される一つ又は複数の細長容器の下部壁面を加熱するための加熱装置を備える。複数の細長容器を立設する構成を採用する場合、各細長容器毎に溶媒の種類や化合物の量に対する溶媒の量等の条件を異ならせて、微量の化合物及び溶媒を収容し、各細長容器を装置に取り付けて、下部壁面を所定の温度パターンで加熱・冷却(加熱の停止、或いは、加熱温度の低減)することができる。これにより、少量の検体量で且つ細長容器の個数に応じた多くの検体数について、同時に晶析試験を実施することが可能である。また、一つの細長容器を立設する構成を採用する場合であっても、後述するように精度の高い化合物の晶析が可能である。このため、従来のように同じ条件での試験を何度も繰り返す必要が無い。また、細長容器の脱着を繰り返して条件の異なる晶析試験を順次実施することにより、結果的に多検体処理を行っているのと同程度の効率で晶析試験を実施することが可能である。或いは、一つの細長容器を立設する構成を採用する場合であっても、微量晶析装置を複数用意することにより、微量晶析装置の台数に応じた検体数について、同時に晶析試験を実施することが可能である。 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.
そして、本発明に係る微量晶析装置は、細長容器の加熱される下部壁面に対して上方に位置する細長容器の所定の壁面を冷却するための冷却装置を備えることを特徴としている。斯かる構成によれば、揮発して細長容器内を上昇した溶媒が、冷却装置によって冷却された細長容器の壁面からの熱伝達により冷却される結果、液体に戻って細長容器内を(特に細長容器の内壁面に沿って)下降し、化合物の溶解に供されることになる。また、細長容器に化合物及び溶媒を収容した際に、たとえ溶媒の液面よりも上方に位置する容器内壁面に化合物が付着したとしても、上記液体に戻って細長容器の内壁面に沿って下降する溶媒によって、前記付着した化合物を溶解させることが可能となるため、容器内壁面に付着した化合物自体が種となって結晶を形成するというおそれもなくなる。なお、冷却装置の位置(冷却装置によって冷却される細長容器の壁面の位置)は、当該冷却装置によって細長容器内に収容された試料が冷却されない程度に(冷却装置によって冷却された細長容器の壁面の温度が細長容器の下部壁面の温度ひいては試料の温度に実質的な影響を及ぼさない程度に)、細長容器の下部壁面から(加熱装置の上面から)上方に離間させることが好ましい。以上のように、本発明に係る微量晶析装置は、冷却装置によって、揮発した溶媒を細長容器内で還流させる構成であるため、圧力を一定にしながら想定通りの溶媒量や混合溶媒の組成比に応じた試験を行うことができ、化合物及び溶媒を含む試料が微量であっても精度の高い化合物の晶析が可能であり、ひいては効率の良い多検体処理が可能である。 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.
なお、本発明における「立設」の語句は、細長容器の下部を所定の支持手段(例えば、本発明における加熱装置)で支持する態様に限るものではなく、細長容器の長手方向が上下方向に延びるように微量晶析装置に取り付けられる限りにおいて、細長容器を懸吊するなどの種々の態様を含む概念として用いている。 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.
本発明に係る微量晶析装置のより具体的な構成としては、例えば、前記加熱装置は、前記細長容器の下部を嵌入するための凹部が上面に設けられた台座部材と、前記台座部材の少なくとも前記凹部近傍を加熱するためのヒーターとを具備し、前記冷却装置は、前記台座部材の上方に配置され、内部に冷媒が流通するように構成された冷却部材を具備する構成を採用することが可能である。 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.
好ましくは、X線回折装置等で化合物の結晶形を解析する際に化合物を収容するための容器として用いられるキャピラリーを前記細長容器として脱着自在に立設可能とされる。 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.
従来、晶析した化合物の結晶形をX線回折装置等で解析する際には、晶析装置が備えるウェルプレートのウェル内の溶媒を濾過して乾燥させた後、残存する結晶形を取り出してX線回折装置等に装着できる専用容器等に移し替える作業が必要であり、これら一連の解析作業に非常に手間を要するという問題があった。上記好ましい構成によれば、細長容器としていわゆるキャピラリーを用いることができるため、晶析試験終了後のキャピラリーを本発明に係る装置から取り外して、そのままX線回折装置等に装着することができるため、極めて効率の良い解析作業が可能になるという利点が得られる。 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.
好ましくは、前記冷却部材の上方に配置され、X線回折装置等で化合物の結晶形を解析する際に化合物を収容するための容器として用いられるキャピラリーを前記細長容器として脱着自在に懸吊する支持部材を更に備え、前記支持部材と前記キャピラリーとの上下方向の相対位置を変更することにより、前記台座部材の凹部に嵌入する前記キャピラリーの下部領域の長さを調整可能に構成される。 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.
細長容器としてキャピラリーを用いる場合、キャピラリーの外径は極めて小さいため、キャピラリー内に収容する溶媒の体積に応じて、溶媒の液面高さは大きく変動する。従って、キャピラリーの底面が台座部材の凹部の底面に当接するまで嵌入する構成では、キャピラリー内に収容される溶媒の液面高さに略一致する領域の下部壁面を加熱しようとすると、キャピラリーに収容する溶媒の体積に応じて各種深さの凹部を有する台座部材を用意し、適宜交換する必要が生じる。また、複数のキャピラリーを立設して同時に晶析試験を行う場合、各キャピラリー毎に収容する溶媒の体積を異ならせることは困難である。上記好ましい構成によれば、凹部aに嵌入させるキャピラリーの下部領域の長さを調整することができるため、キャピラリーに収容する溶媒の体積に応じて各種深さの凹部を有する台座部材を用意する必要がない。また、複数のキャピラリーを立設して同時に晶析試験を行う場合において、各キャピラリー毎に収容する溶媒の体積を容易に異ならせることが可能である。 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.
好ましくは、前記加熱装置は、複数の細長容器の下部壁面を加熱すると共に、前記各細長容器毎に独立して前記加熱される下部壁面の温度を制御可能に構成される。 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.
従来のウェルプレートを備えた晶析装置は、ウェルプレートの下部に配置された加熱装置によって、全てのウェルを同一の温度パターンで制御する構成であった。従って、1枚のウェルプレートの各ウェル内に収容する溶媒としては、その沸点が近いものを選択する必要が生じ、多検体処理の効率が悪いという問題があった。上記の好ましい構成によれば、各細長容器毎に独立して下部壁面の温度を制御可能である。換言すれば、各細長容器に収容された試料の温度をそれぞれ異なる温度パターンで制御することが可能である。このため、例えば、沸点の異なる種類の溶媒を用いて同時に晶析試験を実施することが可能となる利点を有する。また、収容する溶媒の種類や量を全ての細長容器で一定の値にして、加熱過程や溶解後の冷却過程を各細長容器毎に変更して試験すれば、適切な加熱過程、冷却過程を含む晶析条件を見出し易いといった利点が得られる。 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.
また、前記課題を解決するべく、本発明は、前記微量晶析装置のみならず、前記微量晶析装置に取り付けられる前記細長容器をも備えた微量晶析システムとしても提供される。すなわち、本発明は、前記微量晶析装置と、化合物及び溶媒を含む試料を収容するために前記微量晶析装置に脱着自在に立設される一つ又は複数の細長容器とを備えることを特徴とする微量晶析システムとしても提供される。 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.
好ましくは、前記細長容器は、ガラス材料を用いて形成される。 Preferably, the elongated container is formed using a glass material.
斯かる好ましい構成によれば、金属製やプラスチック製の容器を用いる場合に比べて、収容できる溶媒の種類が限定されず、また、必要に応じて添加される酸やアルカリの影響を受けないので、晶析条件を多面的に検討できるという利点が得られる。 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.
好ましくは、前記細長容器は、透明材料から形成され、底面が平坦に成形される。 Preferably, the elongate container is made of a transparent material and has a flat bottom surface.
斯かる好ましい構成によれば、細長容器が透明材料(容器内部を視認できる程度の透過性を有する材料)から形成されているため、容器内部の様子を観察することが可能である。従って、例えば、化合物が溶解されていない場合には、試験中に溶媒を追加することができる。また、晶析状態を観察することもできるため、例えば、結晶の析出開始温度を検知することが可能である。さらに、晶析した化合物の結晶形を別の容器等に移し替えなくても、晶析試験終了後の細長容器を本発明に係る装置から取り外し、細長容器の底面側から結晶形を顕微鏡でそのまま観察することが可能である。すなわち、細長容器が透明であるため、容器内の結晶形を顕微鏡で観察できると共に、平坦な底面側から観察するので、レンズ効果によって像が変形することもない。 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.
或いは、前記細長容器は、X線回折装置等で化合物の結晶形を解析する際に、化合物を収容するための容器として用いられるキャピラリーとしても良い。 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.
上記好ましい構成によれば、細長容器としていわゆるキャピラリーを用いることにより、前述のように、晶析試験終了後のキャピラリーを本発明に係る装置から取り外して、そのままX線回折装置等に装着することができるため、極めて効率の良い解析作業が可能になるという利点が得られる。 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.
さらに、好ましくは、前記細長容器は、試料を収容した後の頂部開口を閉塞するための蓋部材を具備する。 Further preferably, the elongated container includes a lid member for closing the top opening after the sample is accommodated.
斯かる好ましい構成によれば、揮発した溶媒が細長容器の外部に漏れ出さないため、揮発した溶媒が冷却装置によって確実に冷却されて還流することになり、化合物の晶析の精度をより一層高めることが可能である。 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.
以下、添付図面を参照しつつ、本発明の一実施形態に係る微量晶析システムについて説明する。 Hereinafter, a microcrystallization system according to an embodiment of the present invention will be described with reference to the accompanying drawings.
図1は、本発明の一実施形態に係る微量晶析システムの概略構成を示す斜視図である。また、図2は、図1に示す微量晶析システムを構成する細長容器周辺の構成を拡大して示す断面図である。さらに、図3は、図1に示す加熱装置内部の概略構成を模式的に示す図である。図1に示すように、本実施形態に係る微量晶析システム100は、化合物及び溶媒を含む試料を収容するための複数の細長容器1と、微量晶析装置10とを備えている。微量晶析装置10は、該微量晶析装置10に対して脱着自在に立設された各細長容器1の下部壁面を加熱するための加熱装置2と、各細長容器1の前記加熱される下部壁面に対して上方に位置する各細長容器1の所定の壁面を冷却するための冷却装置3とを備えている。 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.
なお、本実施形態では、加熱装置2(具体的には、後述する加熱装置2の凹部21a)に細長容器1の下部を嵌入する一方、冷却装置3(具体的には、後述する冷却部材31)に細長容器1を嵌通させることによって、各細長容器1を上下方向に脱着自在に立設する構成としている。しかしながら、本発明はこれに限るものではなく、例えば、冷却装置3の上方に所定の支持部材を設け、この支持部材によって細長容器1を懸吊することにより、微量晶析装置10に対して立設するような構成を採用することも可能である。 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.
細長容器1は、少量(例えば、数mg程度)の化合物Cと、少量(例えば、数十μL程度)の溶媒Lとを収容して晶析試験を行うことが可能であると共に、熱容量を小さくして効率的な温度制御を行うべく、外径数mmφ程度(例えば、9mmφ)、長さ数十mm程度(例えば、50mm)の寸法とされている。また、細長容器1は、好ましい構成として、透明なガラス材料(例えば、ホウケイ酸ガラス)を用いて形成されており、図2に示すように、底面が平坦に成形されている。さらに、必要に応じて、化合物C及び溶媒Lを収容した後の頂部開口を閉塞するための蓋部材(図示せず)を備える構成としても良い。なお、前記蓋部材としては、細長容器1の頂部開口に嵌め込む蓋体(例えば、シリコン栓)の他、頂部開口を封止するためのシール部材(例えば、パラフィルム(登録商標))を適用することも可能である。本実施形態に係る微量晶析システム100は冷却装置3を備えるため、たとえ蓋部材を備える構成を採用したとしても、従来のウェルの開口をプレート状の蓋体で閉塞する場合と異なり、細長容器1の内部が過度に加圧状態になることなく、正確な晶析条件を得ることが可能である。なぜならば、蓋部材を備える構成を採用した場合、細長容器1の内部にわずかな圧力上昇が生じる可能性があるものの、揮発した溶媒が冷却装置3により冷却されて液体に戻るため、圧力上昇を抑制できるからである。 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.
加熱装置2は、各細長容器1の下部をそれぞれ嵌入するための複数の凹部21aが上面に設けられた台座部材(アルミニウム製)21と、台座部材21の少なくとも凹部21a近傍を加熱するためのヒーター22とを具備している。斯かる構成により、ヒーター22によって台座部材21の凹部21a近傍が加熱され、さらに加熱された台座部材21の凹部21a近傍領域からの熱伝導によって各細長容器1の下部壁面が加熱される。そして、細長容器1の下部壁面からの熱伝達によって細長容器1に収容された試料が加熱されることになる。なお、本実施形態に係る加熱装置2は、細長容器1内に収容される溶媒Lの液面高さ(化合物Cも収容した後の液面高さ)に略一致する領域の下部壁面を加熱し得るように構成されている。具体的には、図2に示すように、細長容器1は、その底面が台座部材21の凹部21aの底面に当接するまで台座部材21に嵌入される。そして、台座部材21の凹部21aの深さDが、細長容器1内に収容される溶媒Lの液面高さに略一致する(例えば、溶媒Lの液面高さよりも若干浅い)ように設定されている。より具体的には、例えば、細長容器1の寸法が外径9mmφ、長さ50mmの場合、溶媒Lの体積と凹部21aの深さDとしては、下記の表1に示す組合せが好適に用いられる。斯かる構成により、凹部21aに嵌入された細長容器1の下部壁面が台座部材21からの熱伝導によって略均一に加熱され、ひいては均一に加熱された細長容器1の下部壁面からの熱伝達によって細長容器1に収容された試料が略均一な温度となり得る。
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.
また、加熱装置2は、好ましい構成として、各細長容器1毎に独立して前記加熱される下部壁面の温度を制御可能に構成されている。具体的には、図3に示すように、ヒーター22内の各細長容器1の下部近傍(台座部材21の凹部21a近傍)部位毎に、通電によって発熱する導電体221が配置されると共に、台座部材21内の各細長容器1の下部近傍(台座部材21の凹部21a近傍)部位毎に、熱電対等の温度センサ211が配置されている。そして、各細長容器1の下部近傍部位毎に配置された導電体221及び温度センサ211が、ヒーター22内に設けられた制御手段222にそれぞれ電気的に接続されている。なお、本実施形態では、各細長容器1の下部近傍部位毎に配置された各導電体221による発熱が、隣接する細長容器1の下部壁面温度に及ぼす影響を少なくするために、好ましい構成として、各細長容器1毎に台座部材21が分割されており(図1では図示の便宜上、台座部材21を一枚のプレート状の部材として図示しているが、実際には図3に示すように各細長容器1毎に分割されている)、台座部材21の各分割部分の間に適宜の冷却板又は断熱板4が配置されている。 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.
制御手段222には、予め設定した各細長容器1の下部近傍部位の所定の時間における目標温度に対応する電圧が記憶されている。そして、制御手段222は、前記目標温度に対応する電圧と、温度センサ211で検出した温度に対応する電圧とを所定時間毎に比較し、その大小関係に応じて導電体221に通電する電流をオン・オフする(或いは、電流値を増減する)ように構成されている。以上の構成により、前述のように、各細長容器1毎に独立して下部壁面の温度が制御可能(実際には、台座部材21における各細長容器1下部近傍部位の温度を制御することになる)である。なお、本実施形態では、ヒーター22内に導電体221を配置し、台座部材21内に温度センサ211を配置した構成について説明したが、本発明はこれに限るものではなく、温度センサ211もヒーター22内に配置する構成を採用することも可能である。また、台座部材21とヒーター22とを一体化した構成(すなわち、ヒーター22の上面に各細長容器1の下部をそれぞれ嵌入するための複数の凹部を設け、導電体221及び温度センサ211をヒーター22内に配置する構成)を採用することも可能である。 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.
また、本実施形態に係る加熱装置2は、好ましい構成として、回転可能な磁石を内蔵したいわゆるスターラーとしての機能も備えている。従って、均一な結晶形が得られるように、必要に応じて各細長容器1内に収容された磁性体からなる攪拌子Mを加熱装置2の磁石から供される磁力によって動かせば、各細長容器1内の溶液を攪拌することが可能である。 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.
冷却装置3は、台座部材21の上方に配置され、各細長容器1をそれぞれ嵌通させるための複数の開口部31aが設けられ、内部に冷媒が流通するように構成された冷却部材31(アルミニウム製)を具備している。具体的には、本実施形態に係る冷却装置3は、管状部材32を具備し、この管状部材32を通じて冷却部材31の内部に冷媒が流通(図1の白抜矢符の方向に流通)するように構成されている。より具体的には、冷却部材31の一の側面から他の側面に向けて、真直な又は開口部31aの周囲を適宜経由する挿通孔を設け、該挿通孔に管状部材32を挿通させる構成を採用することができる。或いは、冷却部材31全体を中空とし、その内部に連通する管状部材32を冷却部材31の一の側面と他の側面にそれぞれ取り付ける構成を採用してもよい。何れの構成を採用しても、管状部材32内に冷媒を流通させることにより、冷却部材31の内部に冷媒が流通し、開口部31aに嵌通された部位の細長容器1の壁面の熱量が、冷却部材31を介して冷媒に放熱されることになる。管状部材32内に流通させる冷媒としては、冷却温度に応じて種々の媒体を使用可能であり、例えば、水、エタノール、メタノール等を例示することができる。なお、本実施形態に係る冷却装置3は、冷却部材31に設けられた開口部31aに細長容器1を嵌通させる構成であるため、前述のように、細長容器1のぶれを防止し、安定した立設状態を維持するための支持部材としての機能も奏している。 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.
なお、本実施形態では、冷却装置3として、内部に冷媒が流通するように構成された冷却部材31を具備する構成を例示したが、本発明はこれに限るものではなく、通常使用される冷却部材、例えば、ペルチェ素子を備えた冷却部材を具備する構成を採用してもよい。この場合、冷媒を流通させるための管状部材32は不要である。 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.
冷却部材31の位置は、冷却部材31によって細長容器1内に収容された試料が冷却されない程度に(冷却部材31によって冷却された細長容器1の壁面の温度が細長容器1の下部壁面の温度ひいては試料の温度に実質的な影響を及ぼさない程度に)、加熱装置2の上面から(台座部材21の上面から)上方に離間させることが好ましい。本実施形態では、長さ50mmの細長容器1を用いる場合において、冷却部材31と台座部材21との離間距離を、細長容器1の長さの約半分である27mmとしている。これにより、冷却部材31によって細長容器1内に収容された試料の温度に影響が及ぶことなく、精度の良い温度制御を行うことが可能である。また、冷却部材31と台座部材21とが離間して配置され、なお且つ細長容器1が透明材料を用いて形成されているため、晶析試験中に容器1内部の様子を観察することが可能である。さらには、各細長容器1毎に、晶析試験の途中で塩の形で晶析するように、酸(無機酸、有機酸)やアルカリ金属、アルカリ土類金属、アミン類等の塩基を追加したり、溶媒Lを追加したりすることも可能である。 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.
斯かる冷却装置3を備えることにより、図2の矢符で示すように、揮発して細長容器1内を上昇した溶媒Lが、冷却装置3(冷却部材31)によって冷却された細長容器1の壁面からの熱伝達により冷却される結果、液体に戻って細長容器1の内壁面に沿って下降し、化合物Cの溶解に供されることになる。また、細長容器1に化合物C及び溶媒Lを収容した際に、たとえ溶媒Lの液面よりも上方に位置する容器1内壁面に化合物Cが付着したとしても、上記液体に戻って細長容器1の内壁面に沿って下降する溶媒Lによって、前記付着した化合物Cを溶解することが可能となるため、容器1内壁面に付着した化合物C自体が種となって結晶を形成するというおそれもなくなる。このように、細長容器1の加熱される下部壁面に対して上方に冷却装置3を備えることにより、加熱装置2の台座部材21、ひいては細長容器1の下部壁面の温度が一時溶媒Lの沸点近くに上昇したとしても、溶媒Lが気化することも加圧状態になることもない。 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.
以上のように、本実施形態に係る微量晶析システム100によれば、冷却装置3によって、揮発した溶媒Lを細長容器1内で還流させる構成であるため、一定圧力のもと、想定通りの溶媒量や混合溶媒の組成比に応じた試験を行うことができ、化合物C及び溶媒Lを含む試料が微量(例えば、25〜50μL程度)であっても、又は数時間に及ぶ晶析温度の制御を行ったとしても、精度の高い化合物Cの晶析が可能であり、ひいては効率の良い多検体処理が可能である。 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.
なお、本実施形態では、細長容器1として、図2に示すような容器を用いたが、本発明はこれに限るものではなく、例えば、図4に示すようなキャピラリー1Aを用いても良い。キャピラリー1Aには、例えば、0.1〜3mmなど種々の外径を有するものが存在するが、本実施形態に係るキャピラリー1Aとしては、0.5〜1mmの外径を有するものが好適に用いられる(キャピラリー1Aに収容する試料は、例えば、数μL〜20μL程度で、好ましくは10〜20μL程度。化合物Cの量は、数μg〜数mg程度で、好ましくは数十μg〜数百μg程度)。斯かる構成によれば、より少量の化合物Cで晶析試験を行うことができ、また、晶析試験終了後のキャピラリー1Aを微量晶析装置10から取り外して、そのままX線回折装置等に装着することができるため、濾過作業が不要となるばかりでなく、濾過による結晶試料の損失もなく、極めて効率の良い解析作業が可能になる。 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.
ここで、細長容器1として特にキャピラリー1Aを用いる場合、上記のようにキャピラリー1Aの外径は極めて小さいため、キャピラリー1A内に収容する溶媒Lの体積に応じて、溶媒Lの液面高さは大きく変動する。従って、図4に示すように、キャピラリー1Aの底面が台座部材21の凹部21aの底面に当接するまで嵌入する構成では、キャピラリー1A内に収容される溶媒Lの液面高さに略一致する領域の下部壁面を加熱しようとすると、キャピラリー1Aに収容する溶媒Lの体積に応じて各種深さの凹部21aを有する台座部材21を用意し、適宜交換する必要が生じる。また、複数のキャピラリー1Aを立設して同時に晶析試験を行う場合、各キャピラリー1A毎に収容する溶媒Lの体積を異ならせることは困難である。 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.
上記のような問題を解決するには、図5に示すように、凹部21a(貫通孔としてもよい)に嵌入させるキャピラリー1Aの下部領域の長さを調整可能に構成することが好ましい。具体的に説明すれば、冷却部材31の上方にキャピラリー1Aを脱着自在に懸吊する支持部材6を配置し、支持部材6とキャピラリー1Aとの上下方向の相対位置を変更することにより、凹部21aに嵌入させるキャピラリー1Aの下部領域の長さを調整可能に構成すればよい。より具体的に説明すれば、図5に示す例では、キャピラリー1Aを挿通し得ると共に下方に抜け落ちないように形状が設定された挿通孔5aと下部に雄ねじ部5bとを具備する治具5を用意する。一方、冷却部材31の上方に、治具5の雄ねじ部5bを螺挿し得る雌ねじ部6aを具備する支持部材6を設置する。支持部材6は、微量晶析装置10を構成する所定の部材(例えば、加熱装置2)に対して取り付けられ、その位置が固定される。そして、治具5の挿通孔5aにキャピラリー1Aを挿通した状態で、この治具5の雄ねじ部5bを支持部材6の雌ねじ部6aに螺挿し、その螺挿量を調節することにより、凹部21aに嵌入させるキャピラリー1Aの下部領域の長さを調整することが可能である。 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.
図5に示すような好ましい構成によれば、凹部21aに嵌入させるキャピラリー1Aの下部領域の長さを調整することができるため、キャピラリー1Aに収容する溶媒Lの体積に応じて各種深さの凹部21aを有する台座部材21を用意する必要がない。また、複数のキャピラリー1Aを立設して同時に晶析試験を行う場合において、各キャピラリー1A毎に収容する溶媒Lの体積を容易に異ならせることが可能である。なお、図5に示す好ましい構成は、細長容器1として外径の小さなキャピラリー1Aを用いる場合に特に有効であるが、これに限るものではなく、図2に示すような一般的な細長容器1に対して適用することも無論可能である。 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.
図6は、細長容器1としてキャピラリー1Aを用い、複数のキャピラリー1Aのそれぞれを前述した図5に示す構成を用いて立設する微量晶析システムの概略構成例を示す斜視図である。図5に示す微量晶析システムは、一定数のキャピラリー1Aが立設される各ブロック(図6に示す例では6つのブロック)毎に台座部材21が分割(さらには、分割された台座部材21の各ブロックに対応して、冷却部材31及び支持部材6も分割)されており、各ブロック毎に独立してキャピラリー1Aの加熱される下部壁面の温度を制御可能とされている。ただし、本発明はこれに限るものではなく、前述した図3に示す構成と同様に、各キャピラリー1A毎に下部壁面の温度を制御可能とするため、各キャピラリー1A毎に台座部材21を分割する構成とすることも可能である。 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.
なお、本実施形態では、複数の細長容器1を立設する構成について説明したが、本発明はこれに限るものではなく、例えば、図7に示すように、一つの細長容器1を立設する構成を採用することも可能である。図7に示す微量晶析システム100Aは、台座部材21に凹部21aが一つだけ設けられている点、冷却部材31に開口部31aが一つだけ設けられている点、導電体や温度センサ(図5では図示せず)が一つだけ設けられている点を除き、図1に示す微量晶析システム100と同様の構成を有する。図7に示す微量晶析システム100Aのように、一つの細長容器1を立設する構成であっても、精度の高い化合物の晶析が可能である。このため、従来のように同じ条件での試験を何度も繰り返す必要が無い。また、細長容器1の脱着を繰り返して条件の異なる晶析試験を順次実施することにより、結果的に多検体処理を行っているのと同程度の効率で晶析試験を実施することが可能である。或いは、図7に示す微量晶析システム100Aを複数用意することにより、微量晶析システム100Aの台数に応じた検体数について、同時に晶析試験を実施することが可能である。 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.
以上に説明した本発明に係る微量晶析装置によれば、化合物及び溶媒を含む試料が微量であっても精度の高い化合物の晶析が可能であり、ひいては効率の良い多検体処理が可能であるという優れた効果を奏するものである。 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)
前記細長容器の加熱される下部壁面に対して上方に位置する前記細長容器の所定の壁面を冷却するための冷却装置とを備えることを特徴とする微量晶析装置。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.
前記冷却装置は、前記台座部材の上方に配置され、前記細長容器を嵌通させるための開口部が設けられ、内部に冷媒が流通するように構成された冷却部材を具備することを特徴とする請求項1に記載の微量晶析装置。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.
前記支持部材と前記キャピラリーとの上下方向の相対位置を変更することにより、前記台座部材の凹部に嵌入する前記キャピラリーの下部領域の長さを調整可能に構成されていることを特徴とする請求項2に記載の微量晶析装置。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.
化合物及び溶媒を含む試料を収容するために前記微量晶析装置に脱着自在に立設される一つ又は複数の細長容器とを備えることを特徴とする微量晶析システム。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.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2007537661A JP4813495B2 (en) | 2005-09-28 | 2006-09-28 | Micro crystallization apparatus and micro crystallization system |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005281592 | 2005-09-28 | ||
JP2005281592 | 2005-09-28 | ||
PCT/JP2006/319258 WO2007037304A1 (en) | 2005-09-28 | 2006-09-28 | Microcrystallization apparatus and microcrystallization system |
JP2007537661A JP4813495B2 (en) | 2005-09-28 | 2006-09-28 | Micro crystallization apparatus and micro crystallization system |
Publications (2)
Publication Number | Publication Date |
---|---|
JPWO2007037304A1 JPWO2007037304A1 (en) | 2009-04-09 |
JP4813495B2 true JP4813495B2 (en) | 2011-11-09 |
Family
ID=37899728
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007537661A Expired - Fee Related JP4813495B2 (en) | 2005-09-28 | 2006-09-28 | Micro crystallization apparatus and micro crystallization system |
Country Status (2)
Country | Link |
---|---|
JP (1) | JP4813495B2 (en) |
WO (1) | WO2007037304A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP7135582B2 (en) * | 2018-02-19 | 2022-09-13 | 住友金属鉱山株式会社 | Capillary holder and X-ray diffraction measurement method |
CN112213340B (en) * | 2020-10-16 | 2023-07-21 | 郑州大学 | Sample stage for on-line determination of crystal structure and determination method thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001113184A (en) * | 1999-10-19 | 2001-04-24 | Ichiro Kojima | Metallic block for heating test tube |
JP2002528701A (en) * | 1998-09-09 | 2002-09-03 | エメラルド バイオストラクチャー,インク. | Crystallization tray |
JP2002543955A (en) * | 1999-05-10 | 2002-12-24 | グラクソ グループ リミテッド | Crystal form screening workstation with high throughput and method of using same |
JP2004504596A (en) * | 2000-07-13 | 2004-02-12 | ユニフェルシタイト ライデン | Screening of crystallization conditions for organic compounds |
JP2004536306A (en) * | 2001-07-17 | 2004-12-02 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | Sublimation screening test and its apparatus |
-
2006
- 2006-09-28 JP JP2007537661A patent/JP4813495B2/en not_active Expired - Fee Related
- 2006-09-28 WO PCT/JP2006/319258 patent/WO2007037304A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002528701A (en) * | 1998-09-09 | 2002-09-03 | エメラルド バイオストラクチャー,インク. | Crystallization tray |
JP2002543955A (en) * | 1999-05-10 | 2002-12-24 | グラクソ グループ リミテッド | Crystal form screening workstation with high throughput and method of using same |
JP2001113184A (en) * | 1999-10-19 | 2001-04-24 | Ichiro Kojima | Metallic block for heating test tube |
JP2004504596A (en) * | 2000-07-13 | 2004-02-12 | ユニフェルシタイト ライデン | Screening of crystallization conditions for organic compounds |
JP2004536306A (en) * | 2001-07-17 | 2004-12-02 | イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー | Sublimation screening test and its apparatus |
Also Published As
Publication number | Publication date |
---|---|
WO2007037304A1 (en) | 2007-04-05 |
JPWO2007037304A1 (en) | 2009-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2011007804A (en) | High throughput crystal form screening workstation and method of use thereof | |
Talreja et al. | Screening and optimization of protein crystallization conditions through gradual evaporation using a novel crystallization platform | |
US11971377B2 (en) | Method and apparatus for temperature gradient microfluidics | |
JP4813495B2 (en) | Micro crystallization apparatus and micro crystallization system | |
JP2010220618A (en) | Protein crystallization method | |
US7137734B2 (en) | Device for measuring quantities of heat while simultaneously measuring the evaporation kinetics and/or condensation kinetics of the most minute amounts of liquid in order to determine thermodynamic parameters | |
CN100498255C (en) | Molten cryolitic bath probe | |
JPS6073346A (en) | Method and device for measuring speed of dissolution | |
KR102518245B1 (en) | Thermal cycler and real-time PCR device having the same | |
Arrondo et al. | Advanced techniques in biophysics | |
CN101008639B (en) | Method and device for accurately testing pour point of petroleum product | |
WO2005097325A1 (en) | Autonomous device with active temperature regulation | |
CN208420494U (en) | Temperature control stirred type dyeing apparatus | |
JP4572418B2 (en) | Crystal growth equipment | |
US9089850B2 (en) | Method and apparatus for separation of pharmaceutical materials on the basis of their density | |
US8357340B2 (en) | Materials analysis | |
CN213456549U (en) | Thrombelastogram instrument | |
CN220340143U (en) | Automatic titration intelligent instrument | |
CN113945505A (en) | Medical material biodegradability test device | |
JP3600868B2 (en) | Crystallization search plate | |
CN214636219U (en) | Chemical industry chemical analysis is with quantitative feeding device | |
CN112213340B (en) | Sample stage for on-line determination of crystal structure and determination method thereof | |
Briuglia | Primary and secondary crystal nucleation of pharmaceutics | |
US20230321649A1 (en) | Linear microfluidic array device and casette for temperature gradient microfluidics | |
SU1221547A1 (en) | Arrangement for determining density and surface tension of liquid solutions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20090306 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20110819 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20110824 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20140902 Year of fee payment: 3 |
|
LAPS | Cancellation because of no payment of annual fees |