JP2004130201A - Method for granulating organic substance - Google Patents
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- JP2004130201A JP2004130201A JP2002296790A JP2002296790A JP2004130201A JP 2004130201 A JP2004130201 A JP 2004130201A JP 2002296790 A JP2002296790 A JP 2002296790A JP 2002296790 A JP2002296790 A JP 2002296790A JP 2004130201 A JP2004130201 A JP 2004130201A
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【０００１】
【発明の属する技術分野】
本発明は、有機物の造粒方法に関する。
【０００２】
【従来の技術】
近年、物質の精製手段である晶析操作によって結晶を析出させると同時に析出した結晶を凝集させ、圧密して球形造粒物を得る晶析造粒技術がさかんに研究されるようになっている。この晶析造粒では得られる結晶の粉体特性を改善できるほか、１つのプロセスで晶析と造粒をおこなうためコスト削減なども期待できる。また対象となる物質が薬物の場合、凝集している１次粒子が微細であるため、溶解性を改善し、吸収性を高めるなどの効果も期待できる。
【０００３】
晶析造粒で球形造粒物を得る方法としては、晶析に供する有機物を良く溶解できる溶媒（良溶媒）の溶液とし、その溶液を当該有機物をほとんど溶解しない溶媒（貧溶媒）中に滴下することで結晶を析出させる際に、貧溶媒と混和しない液体架橋剤を添加することで粒子を凝集させ、機械的せん断力を加え圧密して球形の造粒物を得る方法（以下、球形造粒法という）が知られている（非特許文献１：化学装置，２００２年５月号，第４６〜５１頁）。
【０００４】
また、液体架橋剤（凝集溶剤）を使用して造粒を行う方法としては、粉体を懸濁させた状態から凝集させる液中造粒（以下、湿式造粒法という）も知られている（特許文献１：特開平８−２９１０７２号公報）。
【０００５】
しかしながら、上記の球形造粒法は、有機物の溶液を貧溶媒に滴下するという晶析方法であるため、晶析槽のほかに有機物の溶液を調製するタンクや、滴下する液滴の大きさをコントロールする必要から薬物溶液を定量的に送液するポンプなどの付帯設備が必要となり、厳密な品質管理の必要な薬物等の物質を扱う場合、管理すべき対象が広がることも合わせてコスト高となる。
【０００６】
また、上記の球形造粒法および湿式造粒法のいずれも、液体架橋剤として貧溶媒（粉体の液中造粒法の場合は懸濁溶媒）と混和しない物質を使用しており、良好な造粒物を得るためには、液体架橋剤の液滴が均一に分散するように制御する必要があった。
【０００７】
【特許文献１】
特開平８−２９１９７２号公報
【０００８】
【非特許文献１】
化学装置，２００２年５月号、４６〜５１頁
【０００９】
【発明が解決しようとする課題】
上記課題に鑑み、本発明は、簡単な設備及び簡便な操作で有機物を晶析造粒する方法を提供することを目的とする。
【００１０】
【課題を解決するための手段】
上記課題を解決するために鋭意検討を行った結果、有機物を晶析するに際し、晶析溶媒と容易に混和し且つ有機物に親和性を有する補助溶剤を共存させることにより、簡単な設備、簡便な操作で有機物を造粒しうることを見出し、本発明を完成するに至った。
【００１１】
即ち、本発明は、有機物が溶媒に溶解された溶液から当該有機物を晶析するに際し、溶媒と容易に混和し且つ有機物と親和性を有する補助溶剤を共存させることにより、有機物を凝集、造粒することを特徴とする有機物の造粒法である。
【００１２】
【発明の実施の形態】
本発明の方法により造粒できる有機物としては、晶析可能なものであれば特に制限されないが、例えば、ユビキノン等のように通常の晶析法では結晶が微細になりがちな有機物が特に好適である。
【００１３】
本発明の方法においては、有機物溶液からの当該有機物の晶析は、従来の球形造粒法のように溶液を貧溶媒に滴下することなく、溶液の冷却（冷却晶析）や溶媒の蒸発（濃縮晶析）等の方法により行う。従って、有機物を溶解する溶媒としては、これら晶析法に適した溶媒を用いる。特に冷却晶析の場合は、ジャケット付きの槽のみで操作が可能なことから、冷却晶析に適した溶媒を用いるのがより好ましい。
【００１４】
有機物が上記のような溶媒に溶解した溶液は、別途製造された有機物を上記溶媒に溶解して調製しても良いし、有機物を合成した反応液から、上記溶媒を用いて有機物を抽出した抽出液であっても良い。
【００１５】
本発明の方法は、有機物の晶析に際し、溶媒と容易に混和し且つ有機物を親和性を有する補助溶剤を共存させることを特徴とする。ここで、「溶媒と容易に混和する」とは、晶析溶媒と補助溶媒が相溶し均一系となることを指す。従って、本発明方法においては、従来の球形造粒法や湿式造粒法のように液滴の分散状態を考慮する必要はなく、簡便な操作で有機物の造粒を行うことができる。また、「有機物と親和性を有する」とは、補助溶剤が本発明に用いる有機物を溶解し得ることを指す。
【００１６】
上記補助溶剤としては、溶媒と容易に混和し且つ有機物と親和性を有する限り特に制限されないが、有機物との親和性が高いほど好適であり、有機物の補助溶剤に対する溶解度が、溶媒に対する溶解度よりも高くなるような溶媒と補助溶剤の組合せがより好ましい。
【００１７】
具体的には、有機物がユビキノンのような脂溶性物質である場合、補助溶剤としてイソブタン、ノルマルヘキサン、シクロヘキサン、ヘプタンなどの炭素数が４以上の炭化水素化合物；大豆油、コーン油、オリーブ油などの食用油；ｄｌ−α−トコフェロール（ビタミンＥ）などの脂溶性ビタミン類が好ましく、晶析溶媒としてはメタノール、エタノール、イソプロパノール、ペンタノール（アミルアルコール）など炭素数が１〜５のアルコールが好ましい。
【００１８】
特に好ましい補助溶剤はノルマルヘキサン、ｄｌ−α−トコフェロール（ビタミンＥ）であり、特に好ましい晶析溶媒はエタノールである。なお、溶媒に用いられるアルコールには補助溶剤との混和性を妨げない程度の水を含んでも何ら問題はない。
【００１９】
補助溶剤の使用量としては、晶析溶媒の０．１〜７ｖｏｌ％であることが好ましく、さらに好ましくは０．５〜５ｖｏｌ％である。添加物質の量が多すぎると有機物の溶解度が上昇し、収率低下を招くとともに、補助溶剤が食用油や脂溶性ビタミンの場合には結晶化せず、油状の沈殿物となる。また補助溶剤の量が少なすぎると十分に凝集、造粒がおこなわれず、球形の造粒物を得ることができなくなる。
【００２０】
予め補助溶剤を含んだ溶媒に有機物を溶解して晶析を行ってもよく、また、有機物の溶液に、結晶が析出するまでに補助溶剤を添加してもよい。
【００２１】
晶析は攪拌下に行い、機械的せん断力を与えて、凝集した結晶を圧密するのが好ましい。
【００２２】
以上の方法により、有機物の溶液を貧溶媒に滴下するという方法のように調製タンクや定量送液ポンプのような付帯設備を必要とせず、簡便な操作で有機物を造粒することができる。
【００２３】
【実施例】
次に本発明を実施例により具体的に説明する。
【００２４】
（実施例１）
内容積５００ｍｌの撹拌装置付きセパラブルフラスコにユビキノン１０を１０ｇ、エタノールを２００ｍｌ仕込み、補助溶剤としてノルマルヘキサン１０ｍｌを加えて４５℃で完全に溶解したあと、毎分０．２℃の冷却速度で１０℃まで冷却した。ろ過乾燥後得られた結晶をマイクロスコープ（キーエンス製デジタルマイクロスコープＶＨ−６２００、以下同じ）で観察したところ、直径約２００ミクロンの球状の凝集結晶となっていた。
【００２５】
（実施例２）
内容積３００ｍｌの撹拌装置付き４ツ口フラスコにユビキノン１０を５ｇ、エタノールを１００ｍｌ仕込み、補助溶剤として大豆油５ｍｌを加えて４０℃で完全に溶解したあと、１０℃まで冷却した。ろ過乾燥後得られた結晶をマイクロスコープで観察したところ、直径２００〜３００ミクロンの凝集結晶となっていた。
【００２６】
（実施例３）
内容積５００ｍｌの撹拌装置付きセパラブルフラスコにユビキノン１０を１０ｇ、エタノールを２００ｍｌ仕込み、補助溶剤としてｄｌ−α−トコフェロール（ビタミンＥ）４ｍｌを加えて４５℃で完全に溶解したあと、毎分０．２℃の冷却速度で１０℃まで冷却した。ろ過乾燥後得られた結晶をマイクロスコープで観察したところ、直径約１００ミクロンの球状の凝集結晶となっていた。
【００２７】
（比較例１）
内容積３００ｍｌの撹拌装置付き４ツ口フラスコにユビキノン１０を５ｇ、エタノールを１００ｍｌ仕込み、補助溶剤を加えずに４０℃で完全に溶解したあと、１０℃まで冷却した。得られた結晶は５０ミクロン以下の板状結晶として分散し、微粉となって、球状の造粒物は得られなかった。
【００２８】
【発明の効果】
有機物の晶析造粒法として従来からある球形造粒法に比して、
（１）薬物の溶液を貧溶媒に滴下するという球形造粒法のように調製タンクや定量送液ポンプのような付帯設備を必要とせず、特に冷却による方法の場合ジャケット付きの槽のみでの操作が可能である。
（２）溶媒と容易に混和する物質を有機物結晶が析出する前に添加し、混和しておくだけで有機物の凝集結晶が得られることから、従来の液体架橋剤のように分散状態を考慮する必要がない。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method for granulating organic matter.
[0002]
[Prior art]
In recent years, crystallization and granulation techniques for obtaining crystals by condensing crystals at the same time as precipitating crystals by a crystallization operation, which is a means for purifying substances, and consolidating the crystals have been actively studied. . In this crystallization granulation, the powder characteristics of the obtained crystal can be improved, and crystallization and granulation can be performed in one process, so that cost reduction can be expected. When the target substance is a drug, since the aggregated primary particles are fine, effects such as improvement in solubility and absorption can be expected.
[0003]
As a method for obtaining spherical granules by crystallization granulation, a solution of a solvent (good solvent) that can well dissolve the organic substance to be crystallized is dropped into a solvent (poor solvent) that hardly dissolves the organic substance. A method of obtaining a spherical granulated product by adding a liquid cross-linking agent that is immiscible with a poor solvent to precipitate the crystals, thereby aggregating the particles, applying mechanical shearing force, and consolidating the particles (hereinafter referred to as spherical The particle method is known (Non-Patent Document 1: Chemical Apparatus, May 2002, pp. 46-51).
[0004]
As a method of performing granulation using a liquid crosslinking agent (aggregation solvent), in-liquid granulation (hereinafter, referred to as wet granulation method) in which a powder is suspended and aggregated from a suspended state is also known. (Patent Document 1: Japanese Patent Application Laid-Open No. 8-291072).
[0005]
However, since the above-mentioned spherical granulation method is a crystallization method in which an organic substance solution is dropped into a poor solvent, a tank for preparing an organic substance solution in addition to a crystallization tank, and the size of the droplets to be dropped are limited. Ancillary equipment such as a pump that sends the drug solution quantitatively is necessary because of the need to control it.When handling substances such as drugs that require strict quality control, the costs to be controlled are increased, and the costs to be managed are increased. Become.
[0006]
In addition, in both the spherical granulation method and the wet granulation method, a substance that is immiscible with a poor solvent (in the case of a powder-in-liquid granulation method, a suspension solvent) is used as a liquid crosslinking agent. In order to obtain a fine granulated product, it was necessary to control the liquid crosslinking agent so that the droplets were uniformly dispersed.
[0007]
[Patent Document 1]
Japanese Patent Application Laid-Open No. 8-291972
[Non-patent document 1]
Chemical Equipment, May 2002, pp. 46-51
[Problems to be solved by the invention]
In view of the above problems, an object of the present invention is to provide a method for crystallizing and granulating an organic substance with simple equipment and simple operation.
[0010]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, when crystallizing an organic substance, a simple facility, which is easily mixed with a crystallization solvent and coexists with an auxiliary solvent having an affinity for the organic substance, is used. It has been found that an organic substance can be granulated by an operation, and the present invention has been completed.
[0011]
That is, the present invention, when crystallizing an organic substance from a solution in which the organic substance is dissolved in a solvent, coagulates and granulates the organic substance by coexisting with an auxiliary solvent that is easily mixed with the solvent and has an affinity for the organic substance. This is a method for granulating organic substances.
[0012]
BEST MODE FOR CARRYING OUT THE INVENTION
The organic substance that can be granulated by the method of the present invention is not particularly limited as long as it can be crystallized.For example, an organic substance such as ubiquinone, which tends to be fine in a normal crystallization method, is particularly preferable. is there.
[0013]
In the method of the present invention, the crystallization of the organic substance from the organic substance solution can be performed by cooling the solution (cooling crystallization) or evaporating the solvent (droplet crystallization) without dripping the solution into a poor solvent as in the conventional spherical granulation method. Concentration crystallization) and the like. Therefore, a solvent suitable for these crystallization methods is used as a solvent for dissolving the organic matter. In particular, in the case of cooling crystallization, it is more preferable to use a solvent suitable for cooling crystallization because the operation can be performed only in a tank with a jacket.
[0014]
The solution in which the organic substance is dissolved in the solvent as described above may be prepared by dissolving the separately produced organic substance in the solvent, or extracting the organic substance from the reaction solution obtained by synthesizing the organic substance using the solvent. It may be a liquid.
[0015]
The method of the present invention is characterized in that in the crystallization of an organic substance, a co-solvent which is easily mixed with a solvent and has an affinity for the organic substance is coexisted. Here, “easily miscible with the solvent” means that the crystallization solvent and the auxiliary solvent are compatible with each other to form a homogeneous system. Therefore, in the method of the present invention, there is no need to consider the dispersion state of droplets as in the conventional spherical granulation method or wet granulation method, and the organic substance can be granulated by a simple operation. Further, "having an affinity with an organic substance" means that the auxiliary solvent can dissolve the organic substance used in the present invention.
[0016]
The auxiliary solvent is not particularly limited as long as it is easily miscible with the solvent and has an affinity for an organic substance.The higher the affinity for an organic substance is, the more preferable. The solubility of the organic substance in the auxiliary solvent is higher than the solubility in the solvent. More preferred combinations of solvents and co-solvents are higher.
[0017]
Specifically, when the organic substance is a fat-soluble substance such as ubiquinone, a hydrocarbon compound having 4 or more carbon atoms such as isobutane, normal hexane, cyclohexane, and heptane as an auxiliary solvent; soybean oil, corn oil, olive oil, and the like Edible oil; fat-soluble vitamins such as dl-α-tocopherol (vitamin E) are preferable, and alcohols having 1 to 5 carbon atoms such as methanol, ethanol, isopropanol and pentanol (amyl alcohol) are preferable as crystallization solvents.
[0018]
Particularly preferred co-solvents are normal hexane and dl-α-tocopherol (vitamin E), and a particularly preferred crystallization solvent is ethanol. In addition, there is no problem even if the alcohol used as the solvent contains water to such an extent that the miscibility with the auxiliary solvent is not impaired.
[0019]
The amount of the auxiliary solvent used is preferably 0.1 to 7 vol% of the crystallization solvent, and more preferably 0.5 to 5 vol%. If the amount of the added substance is too large, the solubility of the organic substance increases, resulting in a decrease in the yield. In addition, when the auxiliary solvent is an edible oil or a fat-soluble vitamin, it does not crystallize but forms an oily precipitate. On the other hand, if the amount of the auxiliary solvent is too small, coagulation and granulation are not sufficiently performed, and a spherical granulated product cannot be obtained.
[0020]
Crystallization may be performed by dissolving an organic substance in a solvent containing an auxiliary solvent in advance, or an auxiliary solvent may be added to a solution of the organic substance until crystals are precipitated.
[0021]
The crystallization is preferably performed with stirring, and a mechanical shear force is applied to compact the aggregated crystals.
[0022]
According to the above-described method, the organic substance can be granulated by a simple operation without requiring an additional facility such as a preparation tank or a constant-rate liquid sending pump unlike the method of dropping the organic substance solution into the poor solvent.
[0023]
【Example】
Next, the present invention will be described specifically with reference to examples.
[0024]
(Example 1)
10 g of ubiquinone 10 and 200 ml of ethanol were charged into a separable flask having an internal volume of 500 ml with a stirrer, 10 ml of normal hexane was added as an auxiliary solvent, and the mixture was completely dissolved at 45 ° C. Cooled to ° C. The crystals obtained after the filtration and drying were observed with a microscope (Digital Microscope VH-6200 manufactured by KEYENCE, the same applies hereinafter). As a result, spherical aggregated crystals having a diameter of about 200 microns were found.
[0025]
(Example 2)
5 g of ubiquinone 10 and 100 ml of ethanol were charged into a four-necked flask equipped with a stirrer having an inner volume of 300 ml, and 5 ml of soybean oil was added as an auxiliary solvent, completely dissolved at 40 ° C., and then cooled to 10 ° C. The crystals obtained after filtration and drying were observed with a microscope and found to be aggregated crystals having a diameter of 200 to 300 microns.
[0026]
(Example 3)
10 g of ubiquinone 10 and 200 ml of ethanol were charged into a separable flask with an internal volume of 500 ml with a stirrer, 4 ml of dl-α-tocopherol (vitamin E) was added as an auxiliary solvent, and the mixture was completely dissolved at 45 ° C. It was cooled to 10 ° C at a cooling rate of 2 ° C. Observation of the crystals obtained after filtration and drying with a microscope revealed spherical aggregated crystals having a diameter of about 100 μm.
[0027]
(Comparative Example 1)
5 g of ubiquinone 10 and 100 ml of ethanol were charged into a four-necked flask equipped with a stirrer having an inner volume of 300 ml and completely dissolved at 40 ° C. without adding an auxiliary solvent, followed by cooling to 10 ° C. The obtained crystals were dispersed as plate-like crystals of 50 μm or less, turned into fine powder, and spherical granules could not be obtained.
[0028]
【The invention's effect】
Compared with the conventional spherical granulation method as a crystallization granulation method for organic substances,
(1) No additional equipment such as a preparation tank or a fixed-rate pump is required as in the spherical granulation method in which a drug solution is dropped into a poor solvent. Particularly, in the case of a cooling method, only a jacketed tank is used. Operation is possible.
(2) A substance that is easily miscible with the solvent is added before the organic crystal is precipitated, and agglomerated crystals of the organic substance can be obtained only by mixing the organic substance with the substance. No need.
Claims (6)
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| JP2002296790A JP4467230B2 (en) | 2002-10-09 | 2002-10-09 | Granulation method of organic matter |
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| JP2002296790A JP4467230B2 (en) | 2002-10-09 | 2002-10-09 | Granulation method of organic matter |
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| JP4467230B2 JP4467230B2 (en) | 2010-05-26 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033054A1 (en) * | 2003-09-10 | 2005-04-14 | Kaneka Corporation | Reduced coenzyme q10 crystal excelling in stability and composition containing reduced coenzyme q10 crystal |
| US7358402B2 (en) | 2003-09-10 | 2008-04-15 | Kaneka Corporation | Reduced coenzyme Q10 crystal with excellent stability and composition containing said reduced coenzyme Q10 crystal |
| CN111661856A (en) * | 2020-05-12 | 2020-09-15 | 云南省盐业有限公司 | Preparation method of large-particle spherical sodium sulfate crystal |
-
2002
- 2002-10-09 JP JP2002296790A patent/JP4467230B2/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033054A1 (en) * | 2003-09-10 | 2005-04-14 | Kaneka Corporation | Reduced coenzyme q10 crystal excelling in stability and composition containing reduced coenzyme q10 crystal |
| US7358402B2 (en) | 2003-09-10 | 2008-04-15 | Kaneka Corporation | Reduced coenzyme Q10 crystal with excellent stability and composition containing said reduced coenzyme Q10 crystal |
| CN111661856A (en) * | 2020-05-12 | 2020-09-15 | 云南省盐业有限公司 | Preparation method of large-particle spherical sodium sulfate crystal |
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