JP3532558B2 - Method for producing L-calcium aspartate trihydrate crystals - Google Patents
Method for producing L-calcium aspartate trihydrate crystalsInfo
- Publication number
- JP3532558B2 JP3532558B2 JP2003130622A JP2003130622A JP3532558B2 JP 3532558 B2 JP3532558 B2 JP 3532558B2 JP 2003130622 A JP2003130622 A JP 2003130622A JP 2003130622 A JP2003130622 A JP 2003130622A JP 3532558 B2 JP3532558 B2 JP 3532558B2
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- Japan
- Prior art keywords
- calcium
- organic solvent
- hydrophilic organic
- crystals
- aspartate
- 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.)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、カルシウム剤等の
医薬として有用なＬ−アスパラギン酸カルシウムの工業
的製造方法に関し、特に、Ｌ−アスパラギン酸カルシウ
ム３水和物の製造方法に関する。TECHNICAL FIELD The present invention relates to a method for industrially producing calcium L-aspartate useful as a medicine such as a calcium agent, and more particularly to a method for producing L-calcium aspartate trihydrate.
【０００２】[0002]
【従来の技術】Ｌ−アスパラギン酸カルシウムは、低カ
ルシウム血症に起因するテタニーおよびテタニー関連症
状の改善、骨粗鬆症および骨軟化症等の代謝性骨疾患に
おけるカルシウム補給、発育期におけるカルシウム補
給、妊娠・授乳時におけるカルシウム補給等に有効な医
薬の有効成分であり、現在、日本で販売されている。日
本薬局方外医薬品規格によれば、Ｌ−アスパラギン酸カ
ルシウム(カルシウム Ｌ−アスパルテートとも称され
る)は、式：
で表され、換算した脱水物に対し、Ｌ−アスパラギン酸
84.8〜90.2％及びカルシウム12.5〜13.4％を含み、水分
は12.0〜16.0％であるとされている。さらに、同書に
は、Ｌ−アスパラギン酸カルシウムについての性状、確
認試験、旋光度、ｐＨ、純度試験、定量法、貯法の種々
の規格等が記載されている。Ｌ−アスパラギン酸カルシ
ウム無水物に関しては、Ｌ−アスパラギン酸カルシウム
水溶液を調製した後、噴霧乾燥することで製造する方法
が知られている（例えば、特許文献１）。しかし、この
方法では、医薬として使用しうる程度に高い純度で一定
の品質のＬ−アスパラギン酸カルシウムを安定して製造
することはできない。また、Ｌ−アスパラギン酸カルシ
ウムに関しては、その水溶液から３水和物として再結晶
されること、およびその３水和物の理化学的性質が非特
許文献１に記載されている。しかし、この方法では、結
晶回収率が高くなく、また結晶同士が付着して固化する
ために一定の純度の乾燥品を得ることが困難であり、作
業時間・作業効率の面で問題があった。2. Description of the Prior Art Calcium L-aspartate is used to improve tetany and tetany-related symptoms caused by hypocalcemia, calcium supplementation in metabolic bone diseases such as osteoporosis and osteomalacia, calcium supplementation during development, pregnancy and pregnancy. It is an active ingredient of medicine that is effective for supplementing calcium during breastfeeding and is currently sold in Japan. According to the Japanese Pharmacopoeia Standard, L-calcium aspartate (also called calcium L-aspartate) has the formula: The converted dehydrated product represented by the formula is L-aspartic acid
It contains 84.8-90.2% and calcium 12.5-13.4% and has a water content of 12.0-16.0%. Further, the same document describes various specifications of L-calcium aspartate such as properties, confirmation test, optical rotation, pH, purity test, quantitative method and storage method. Regarding L-calcium aspartate anhydrous, a method is known in which an aqueous L-calcium aspartate solution is prepared and then spray-dried (for example, Patent Document 1). However, this method cannot stably produce calcium L-aspartate of a certain quality with a purity high enough to be used as a medicine. Non-Patent Document 1 describes that L-calcium aspartate is recrystallized from its aqueous solution as a trihydrate and the physicochemical properties of the trihydrate. However, in this method, the crystal recovery rate is not high, and it is difficult to obtain a dried product of a certain purity because the crystals adhere to each other and solidify, and there is a problem in terms of working time and working efficiency. .
【０００３】[0003]
【特許文献１】特開昭５４−７９２２６[Patent Document 1] JP-A-54-79226
【非特許文献１】薬学研究 Vol. 36 (No. 8), p. 243-
253 (1965)[Non-Patent Document 1] Pharmaceutical Research Vol. 36 (No. 8), p. 243-
253 (1965)
【０００４】[0004]
【発明が解決しようとする課題】本発明が解決しようと
する課題は、医薬として使用しうる程度に高い純度で一
定の品質を確保したＬ−アスパラギン酸カルシウムを工
業的に製造する方法を提供することにある。The problem to be solved by the present invention is to provide a method for industrially producing calcium L-aspartate having a high purity and a certain quality and a certain quality. Especially.
【０００５】[0005]
【課題を解決するための手段】前記課題を解決するため
に本発明者等は鋭意研究の結果、Ｌ−アスパラギン酸カ
ルシウム水溶液に親水性有機溶媒又は親水性有機溶媒と
水の混合溶媒を滴下することにより、残留有機溶媒が検
出されず、一定の品質を有する結晶性Ｌ−アスパラギン
酸カルシウムが安定して製造されることを見出して本発
明を完成した。[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have earnestly studied, and as a result, dropped a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water into an aqueous solution of calcium L-aspartate. As a result, the present invention has been completed by finding that the residual organic solvent is not detected and crystalline L-aspartate having a certain quality is stably produced.
【０００６】［１］ Ｌ−アスパラギン酸カルシウム水
溶液に親水性有機溶媒又は親水性有機溶媒と水の混合溶
媒を滴下することによる、下記式で表されるＬ−アスパ
ラギン酸カルシウム３水和物結晶の製造方法。
［２］ 親水性有機溶媒がアルコール系有機溶媒である
［１］記載の製造方法。
［３］ 親水性有機溶媒がメタノールである［１］記載
の製造方法。
［４］ メタノール又は約40％〜約99％(v/v)メタノー
ル水溶液を滴下することによる［１］記載の製造方法。
［５］ Ｌ−アスパラギン酸カルシウム水溶液のｐＨが
約6〜約8である［１］〜［４］のいずれか記載の製造方
法。
［６］ Ｌ−アスパラギン酸カルシウム水溶液のｐＨが
約7.0〜約7.3である［１］〜［４］のいずれか記載の製
造方法。
［７］ ［１］〜［６］のいずれか記載の製造方法にお
いて、親水性有機溶媒又は親水性有機溶媒と水の混合溶
媒を滴下して結晶を析出させ、得られた結晶を濾取後、
その結晶を親水性有機溶媒で洗浄することによるＬ−ア
スパラギン酸カルシウム３水和物結晶の製造方法。
［８］ かさ密度が約0.2〜約0.5 g/mLの範囲にある
［１］〜［７］のいずれか記載の製造方法で製造された
Ｌ−アスパラギン酸カルシウム３水和物結晶。
［９］ ［１］〜［７］のいずれか記載の製造方法によ
って、Ｌ−アスパラギン酸カルシウム水溶液からＬ−ア
スパラギン酸カルシウム３水和物結晶を製造し、必要に
応じて粉砕し、薬学上許容される担体と混合し、製剤化
することによる経口用Ｌ−アスパラギン酸カルシウム製
剤の製造方法。[1] L-calcium L-aspartate trihydrate crystals represented by the following formula are prepared by dropping a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water into an aqueous L-calcium aspartate solution. Production method. [2] The production method according to [1], wherein the hydrophilic organic solvent is an alcoholic organic solvent. [3] The production method according to [1], wherein the hydrophilic organic solvent is methanol. [4] The production method according to [1], wherein methanol or about 40% to about 99% (v / v) aqueous methanol solution is added dropwise. [ 5 ] The production method according to any one of [1] to [ 4 ], wherein the pH of the L-calcium aspartate aqueous solution is about 6 to about 8. [ 6 ] The production method according to any one of [1] to [ 4 ], wherein the pH of the L-calcium aspartate aqueous solution is about 7.0 to about 7.3. [ 7 ] In the production method according to any one of [1] to [ 6 ], a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water is added dropwise to precipitate crystals, and the obtained crystals are collected by filtration. ,
A method for producing L-calcium aspartate trihydrate crystals by washing the crystals with a hydrophilic organic solvent. [ 8 ] L-calcium aspartate trihydrate crystals produced by the production method according to any one of [1] to [ 7 ], having a bulk density in the range of about 0.2 to about 0.5 g / mL. [ 9 ] A L-calcium L-aspartate trihydrate crystal is manufactured from the L-calcium aspartate aqueous solution by the manufacturing method according to any one of [1] to [ 7 ], and crushed as necessary, and pharmaceutically acceptable. A method for producing an oral L-calcium aspartate preparation by mixing with a carrier to be formulated.
【０００７】Ｌ−アスパラギン酸カルシウム水溶液は通
常の方法で調製することができる。例えば、Ｌ−アスパ
ラギン酸と消石灰(水酸化カルシウム)又は生石灰(酸化
カルシウム)とを水中で反応させることで得ることがで
きる(特開昭54-79226、特開昭62-116693等)。Ｌ−アス
パラギン酸カルシウム水溶液の濃度(w/w)としては、特
に限定はないが、結晶性Ｌ−アスパラギン酸カルシウム
の収量、工業上の操作性、費用等から、例えば、Ｌ−ア
スパラギン酸カルシウム３水和物量として約15％〜約40
％の範囲の濃度が挙げられ、好ましくは約20％〜約35％
の濃度が挙げられる。調製されたＬ−アスパラギン酸カ
ルシウム水溶液は、脱色、不純物等の除去等のため、活
性炭処理を行うこともできる。Ｌ−アスパラギン酸カル
シウム水溶液の好ましいｐＨとしては、例えば約6〜約8
が挙げられ、さらに好ましくは約6.5〜約7.6が挙げら
れ、特に好ましくは約7.0〜約7.3が挙げられる。このｐ
Ｈの調節においては、酸性化するにはＬ−アスパラギン
酸を添加することで、塩基性化するには消石灰、生石灰
等を添加することで実施することができる。The L-calcium aspartate aqueous solution can be prepared by a usual method. For example, it can be obtained by reacting L-aspartic acid with slaked lime (calcium hydroxide) or quick lime (calcium oxide) in water (JP-A-54-79226, JP-A-62-116693, etc.). The concentration (w / w) of the L-calcium aspartate aqueous solution is not particularly limited, but from the viewpoint of the yield of crystalline calcium L-aspartate, industrial operability, cost, etc., for example, L-calcium aspartate 3 About 15% to about 40 as hydrate
% In the range of about 20% to about 35%.
The concentration of The prepared L-calcium aspartate aqueous solution may be treated with activated carbon for decolorization, removal of impurities and the like. The preferred pH of the L-calcium aspartate aqueous solution is, for example, about 6 to about 8
And more preferably about 6.5 to about 7.6, and particularly preferably about 7.0 to about 7.3. This p
The adjustment of H can be carried out by adding L-aspartic acid for acidification and adding slaked lime, quick lime, etc. for basification.
【０００８】親水性有機溶媒としては、例えばケトン系
有機溶媒、アルコール系有機溶媒、ニトリル系有機溶
媒、エーテル系有機溶媒等またはこれらの混合溶媒が挙
げられる。ケトン系有機溶媒としては、例えば直鎖又は
分枝鎖のＣ３〜Ｃ６ケトン系有機溶媒が挙げられ、具体
的にはアセトン、２−ブタノン、３−ペンタノン、４−
メチル−２−ペンタノン等が挙げられ、好ましくはアセ
トンが挙げられる。アルコール系有機溶媒としては、例
えば直鎖又は分枝鎖のＣ１〜Ｃ６アルコール系有機溶媒
が挙げられ、具体的にはメタノール、エタノール、１−
プロパノール、２−プロパノール等が挙げられ、好まし
くはメタノール、エタノール、２−プロパノールが挙げ
られる。ニトリル系有機溶媒としては、例えば直鎖又は
分枝鎖のＣ ２〜Ｃ６ニトリル系有機溶媒が挙げられ、具
体的にはアセトニトリル、プロピオニトリル等が挙げら
れ、好ましくはアセトニトリルが挙げられる。エーテル
系有機溶媒としては、直鎖又は分枝鎖のＣ４〜Ｃ６エー
テル系有機溶媒、５又は６員の環状エーテル系有機溶媒
等が挙げられ、具体的にはジエチルエーテル、メチルｔ
−ブチルエーテル、テトラヒドロフラン、１，４−ジオ
キサン等が挙げられる。親水性有機溶媒の好ましい例と
しては、アルコール系有機溶媒が挙げられ、さらに好ま
しくはメタノール、エタノール、２−プロパノールが挙
げられ、特に好ましい例として、メタノールが挙げられ
る。親水性有機溶媒と水の混合溶媒としては、例えば、
上記親水性有機溶媒と水の混合溶媒が挙げられる。該混
合溶媒中の親水性有機溶媒の含有率(v/v)としては、親
水性有機溶媒の種類によって変化するが、例えば約40％
〜約99％が挙げられる。親水性有機溶媒と水の混合溶媒
を滴下した場合、一般に餅状結晶の生成を抑え、乾燥時
の残留有機溶媒を無くし易くなるので好ましい。The hydrophilic organic solvent is, for example, a ketone-based solvent.
Organic solvent, alcohol organic solvent, nitrile organic solvent
Media, ether organic solvents, etc., or mixed solvents thereof.
You can Examples of the ketone-based organic solvent include linear or
Branched chain CThree~ C6Specific examples include ketone-based organic solvents.
Acetone, 2-butanone, 3-pentanone, 4-
Methyl-2-pentanone and the like are mentioned, and preferably acetone
There are tons. Examples of alcohol-based organic solvents
For example, straight chain or branched chain C1~ C6Alcohol organic solvent
And specifically, methanol, ethanol, 1-
Propanol, 2-propanol and the like are mentioned and preferred.
For example, methanol, ethanol, and 2-propanol are listed.
To be Examples of the nitrile organic solvent include linear or
Branched chain C Two~ C6Nitrile-based organic solvents are included.
Physically, acetonitrile, propionitrile, etc.
And preferably acetonitrile is used. ether
Examples of the organic solvent include linear or branched CFour~ C6A
Tellurium-based organic solvent, 5- or 6-membered cyclic ether-based organic solvent
And the like. Specifically, diethyl ether, methyl t
-Butyl ether, tetrahydrofuran, 1,4-dio
Examples include xanthan. Preferred examples of hydrophilic organic solvents and
Examples include alcohol organic solvents, and more preferred
Methanol, ethanol and 2-propanol are recommended.
And a particularly preferable example is methanol.
It As a mixed solvent of a hydrophilic organic solvent and water, for example,
A mixed solvent of the above hydrophilic organic solvent and water may be mentioned. The mixture
As the content rate (v / v) of the hydrophilic organic solvent in the mixed solvent,
It depends on the type of aqueous organic solvent, but it is about 40%
~ About 99%. Mixed solvent of hydrophilic organic solvent and water
In general, the formation of rice cake-like crystals is suppressed when the
This is preferable because it is easy to eliminate the residual organic solvent.
【０００９】親水性有機溶媒又は親水性有機溶媒と水の
混合溶媒の滴下量としては、親水性有機溶媒の種類によ
り異なるが、滴下終了時の結晶懸濁液において、その溶
媒中の親水性有機溶媒の含有率(v/v)が、例えば約3％〜
約50％となる範囲になるように調整される量が挙げられ
る。例えば、アルコール系有機溶媒の場合は、この親水
性有機溶媒の含有率の好ましい範囲は、約5％〜約40％
が挙げられ、さらに好ましくは約10％〜約30％が挙げら
れる。親水性有機溶媒又は親水性有機溶媒と水の混合溶
媒は、連続して１回に滴下してもよいが、結晶を熟成し
ながら２回以上に分けて滴下することも好ましい。親水
性有機溶媒又は親水性有機溶媒と水の混合溶媒の滴下時
の温度としては、結晶化に支障が無い限り、いかなる温
度でもよいが、例えば約10℃〜約70℃の範囲が挙げら
れ、好ましくは約20℃〜約60℃の範囲が挙げられ、さら
に好ましくは約30℃〜約50℃の範囲が挙げられる。滴下
時間としては、特に制限はないが、例えば約10分間〜約
2時間が挙げられる。親水性有機溶媒又は親水性有機溶
媒と水の混合溶媒の滴下後、Ｌ−アスパラギン酸カルシ
ウムの種晶を加えるのが好ましい。種晶の量としては、
いかなる量でも良いが、例えば、結晶化するＬ−アスパ
ラギン酸カルシウムの量の0.01％〜5％の量、好ましく
は0.5％〜2％の量が挙げられる。結晶熟成温度として
は、親水性有機溶媒又は親水性有機溶媒と水の混合溶媒
の滴下時の温度と同じでよいが、変えることもできる。
結晶が生成した後、加温することも好ましく、それによ
って、結晶を成長させることができ、あるいは壁面に付
着した結晶がある場合はその結晶を脱離させることがで
きる。結晶熟成時間としては、無くてもよいが、例えば
約1時間〜約5時間を挙げることができる。The dropping amount of the hydrophilic organic solvent or the mixed solvent of the hydrophilic organic solvent and water varies depending on the kind of the hydrophilic organic solvent, but in the crystal suspension at the end of the dropping, the hydrophilic organic solvent in the solvent is added. The solvent content (v / v) is, for example, about 3% to
The amount is adjusted so that it is in the range of about 50%. For example, in the case of an alcohol organic solvent, the preferable range of the content of the hydrophilic organic solvent is about 5% to about 40%.
And more preferably about 10% to about 30%. The hydrophilic organic solvent or the mixed solvent of the hydrophilic organic solvent and water may be continuously added dropwise at once, but it is also preferable to add the hydrophilic organic solvent in two or more portions while aging the crystal. The temperature at the time of dropwise addition of the hydrophilic organic solvent or the mixed solvent of the hydrophilic organic solvent and water may be any temperature as long as it does not hinder crystallization, for example, a range of about 10 ° C. to about 70 ° C., The range is preferably about 20 ° C to about 60 ° C, more preferably the range of about 30 ° C to about 50 ° C. The dropping time is not particularly limited, but for example, about 10 minutes to about
2 hours. After dropping the hydrophilic organic solvent or a mixed solvent of the hydrophilic organic solvent and water, it is preferable to add seed crystals of calcium L-aspartate. As the amount of seed crystals,
Any amount may be used, and examples thereof include 0.01% to 5% of the amount of L-calcium L-aspartate to be crystallized, preferably 0.5% to 2%. The crystal aging temperature may be the same as the temperature at the time of dropping the hydrophilic organic solvent or the mixed solvent of the hydrophilic organic solvent and water, but may be changed.
It is also preferable to heat after the crystals have been formed, whereby the crystals can be grown or the crystals, if any, adhered to the wall surface can be desorbed. The crystal aging time may be, but is not limited to, for example, about 1 hour to about 5 hours.
【００１０】得られた結晶は、常法に従って、例えば、
吸引濾過、遠心濾過等により濾取することができる。濾
取された結晶は、常法に従い、洗浄することができる。
洗浄溶媒としては、親水性溶媒又は親水性有機溶媒と水
の混合溶媒が挙げられる。結晶のかさ密度を低下させる
ために、親水性有機溶媒で洗浄することも好ましい。濾
取された結晶を乾燥することで本発明の結晶性Ｌ−アス
パラギン酸カルシウムを得ることができる。乾燥方法と
しては、常法に従って実施することができるが、例え
ば、付着水の量を確認しながら、減圧下、加温して実施
することができる。また、製剤化に際して、必要に応じ
て粉砕することもできる。良好な溶出特性を有し、良好
な打錠性を有する経口製剤を製造するには、結晶性Ｌ−
アスパラギン酸カルシウムのかさ密度が、約0.2〜約0.5
の範囲、より好ましくは約0.25〜約0.4の範囲に入るも
のが望ましい。本発明の製造方法によれば、通常、この
範囲に入る結晶性Ｌ−アスパラギン酸カルシウムを製造
することができる。The obtained crystals are prepared according to a conventional method, for example,
It can be collected by suction filtration, centrifugal filtration or the like. The crystals collected by filtration can be washed according to a conventional method.
Examples of the washing solvent include a hydrophilic solvent or a mixed solvent of a hydrophilic organic solvent and water. It is also preferable to wash with a hydrophilic organic solvent in order to reduce the bulk density of the crystals. The crystalline L-aspartate of the present invention can be obtained by drying the crystals collected by filtration. The drying method can be carried out according to a conventional method, for example, it can be carried out by heating under reduced pressure while confirming the amount of attached water. In addition, it can be crushed if necessary during formulation. To prepare an oral preparation having good dissolution properties and good tableting properties, crystalline L-
The bulk density of calcium aspartate is about 0.2 to about 0.5.
Is preferred, more preferably in the range of about 0.25 to about 0.4. According to the production method of the present invention, it is possible to produce crystalline L-aspartic acid calcium which usually falls within this range.
【００１１】本発明方法で得られる結晶性Ｌ−アスパラ
ギン酸カルシウムに薬学上許容される担体を添加し、通
常の製剤化方法（「日本薬局方・製剤総則」記載の方
法）等に従って、錠剤、散剤、顆粒剤等の経口製剤を製
造することができる。薬学上許容される担体としては、
賦形剤、崩壊剤、結合剤、滑沢剤、安定剤、着色剤等が
挙げられる。賦形剤としては、デンプン類、結晶セルロ
ース、炭酸カルシウム、ソルビトール、エリスリトー
ル、マルチトール、キシリトール、シクロデキストリ
ン、乳糖、ブドウ糖、マンニトール、白糖等が挙げられ
る。崩壊剤としては、カルボキシメチルスターチナトリ
ウム、部分α化デンプン、カルボキシメチルセルロース
カルシウム、カルボキシメチルセルロース、低置換ヒド
ロキシプロピルセルロース、クロスリンクカルボキシメ
チルセルロースナトリウム等が挙げられる。結合剤とし
ては、デキストリン、ゼラチン、アラビアゴム、ポリビ
ニルピロリドン、アルギン酸ナトリウム、ヒドロキシプ
ロピルセルロース、ヒドロキシプロピルメチルセルロー
ス、ヒドロキシエチルセルロース等が挙げられる。滑沢
剤としては、タルク、ステアリン酸、ステアリン酸マグ
ネシウム、ステアリン酸カルシウム、軽質無水ケイ酸、
マクロゴール、含水二酸化ケイ素、合成ケイ酸アルミニ
ウム等が挙げられる。その他、安定化剤や着色剤等とし
て、リン脂質、グリセリン脂肪酸エステル、ポリエチレ
ン硬化ヒマシ油、ポリエチレン脂肪酸エステル、ポリオ
キシエチレンアルキルエーテル、ショ糖脂肪酸エステ
ル、香料、第二酸化鉄、黄色三二酸化鉄、リボフラビ
ン、カラメル、アスパルテーム、サッカリン、クエン
酸、クエン酸ナトリウム等を添加することもできる。A tablet is prepared by adding a pharmaceutically acceptable carrier to the crystalline calcium L-aspartate obtained by the method of the present invention and following a usual formulation method (method described in "Japanese Pharmacopoeia / General Rules for Formulation") and the like. Oral preparations such as powders and granules can be manufactured. As a pharmaceutically acceptable carrier,
Excipients, disintegrants, binders, lubricants, stabilizers, colorants and the like can be mentioned. Excipients include starch, crystalline cellulose, calcium carbonate, sorbitol, erythritol, maltitol, xylitol, cyclodextrin, lactose, glucose, mannitol, sucrose and the like. Examples of the disintegrator include sodium carboxymethyl starch, partially pregelatinized starch, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium and the like. Examples of the binder include dextrin, gelatin, gum arabic, polyvinylpyrrolidone, sodium alginate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose and the like. Lubricants include talc, stearic acid, magnesium stearate, calcium stearate, light anhydrous silicic acid,
Macrogol, hydrous silicon dioxide, synthetic aluminum silicate and the like can be mentioned. In addition, as stabilizers and colorants, phospholipids, glycerin fatty acid esters, polyethylene hydrogenated castor oil, polyethylene fatty acid esters, polyoxyethylene alkyl ethers, sucrose fatty acid esters, fragrances, ferric dioxide, yellow ferric oxide, riboflavin , Caramel, aspartame, saccharin, citric acid, sodium citrate and the like can also be added.
【００１２】[0012]
【実施例】以下に、実施例、比較例をあげて本発明をさ
らに具体的に説明するが、本発明はこれらに限定される
ものではない。
実施例１
Ｌ−アスパラギン酸カルシウム水溶液(Ｌ−アスパラギ
ン酸37.5 g、酸化カルシウム8.25 gおよび水330 gから
調製)に、40℃でエタノール130 mLを滴下し、Ｌ−アス
パラギン酸カルシウム３水和物の種晶を添加し、18℃ま
で徐冷しながら3時間攪拌した。生成した結晶を遠心分
離機で濾取することで、Ｌ−アスパラギン酸カルシウム
を得た(収率83％)。得られたＬ−アスパラギン酸カルシ
ウムは、試験の結果、Ｌ−アスパラギン酸(脱水物換算)
84.4％、カルシウム(脱水物換算)13.1％、水分14.7％、
残留エタノールは0.1％であった。The present invention will be described in more detail below with reference to Examples and Comparative Examples, but the present invention is not limited thereto. Example 1 130 mL of ethanol was added dropwise at 40 ° C. to an aqueous L-calcium aspartate solution (prepared from 37.5 g of L-aspartic acid, 8.25 g of calcium oxide and 330 g of water) to obtain L-calcium aspartate trihydrate. Seed crystals were added, and the mixture was stirred for 3 hours while gradually cooling to 18 ° C. The produced crystals were collected by filtration with a centrifuge to obtain L-calcium aspartate (yield 83%). As a result of the test, the obtained L-aspartic acid calcium was L-aspartic acid (calculated as dehydrated product).
84.4%, calcium (dehydrated equivalent) 13.1%, water 14.7%,
The residual ethanol was 0.1%.
【００１３】実施例２
Ｌ−アスパラギン酸カルシウム水溶液(Ｌ−アスパラギ
ン酸37.5 g、酸化カルシウム8.25 gおよび水470 gから
調製)に、35℃で２−プロパノール200 mLを滴下し、Ｌ
−アスパラギン酸カルシウム３水和物の種晶を添加し、
18℃まで徐冷しながら4時間攪拌した。生成した結晶を
遠心分離機で濾取することで、Ｌ−アスパラギン酸カル
シウムを得た(収率81％)。得られたＬ−アスパラギン酸
カルシウムは、試験の結果、Ｌ−アスパラギン酸(脱水
物換算)85.9％、カルシウム(脱水物換算)13.3％、水分1
4.8％であり、残留２−プロパノールは検出されなかっ
た。Example 2 To an aqueous solution of calcium L-aspartate (prepared from 37.5 g of L-aspartic acid, 8.25 g of calcium oxide and 470 g of water) was added dropwise 200 mL of 2-propanol at 35 ° C.
-Adding seed crystals of calcium aspartate trihydrate,
The mixture was gradually cooled to 18 ° C and stirred for 4 hours. The produced crystals were collected by filtration with a centrifuge to obtain L-calcium aspartate (yield 81%). As a result of the test, the obtained L-aspartic acid calcium was L-aspartic acid (dehydrated product) 85.9%, calcium (dehydrated product) 13.3%, water content 1
4.8%, no residual 2-propanol was detected.
【００１４】実施例３
Ｌ−アスパラギン酸カルシウム水溶液(Ｌ−アスパラギ
ン酸410 kg、酸化カルシウム85 kgおよび水1320 kgから
調製：ｐＨ 7.0〜7.3)1815 kgに46℃〜50℃で50％(v/v)
メタノール水溶液1294 kgをゆっくりと滴下した。32℃
に冷却し、Ｌ−アスパラギン酸カルシウム３水和物の種
晶約5 kgを添加して攪拌し、結晶がある程度生成した
後、40℃〜50℃に昇温し、約１時間攪拌した。約20℃ま
で冷却し、メタノール168 kgを添加してさらに約30分間
攪拌した。生成した結晶を遠心分離機で濾取し、メタノ
ール約68 kgで洗浄し、減圧下、乾燥することで、Ｌ−
アスパラギン酸カルシウム488.3 kgを得た。得られたＬ
−アスパラギン酸カルシウムは、日本薬局方外医薬品規
格の試験の結果、Ｌ−アスパラギン酸(脱水物換算)87.0
％、カルシウム(脱水物換算)13.0％、水分15.1％、旋光
度＋22.2°、ｐＨ値 6.5であり、またその他のいずれの
規格にも適合していた。さらに、残留溶媒は検出されな
かった。Example 3 L-calcium L-aspartate aqueous solution (prepared from L-aspartic acid 410 kg, calcium oxide 85 kg and water 1320 kg: pH 7.0 to 7.3) 1815 kg to 50% (v / v) at 46 ° C to 50 ° C v)
1294 kg of an aqueous methanol solution was slowly added dropwise. 32 ° C
After cooling, the seed crystals of L-calcium aspartate trihydrate (about 5 kg) were added and stirred. After some crystals were generated, the temperature was raised to 40 ° C to 50 ° C and the mixture was stirred for about 1 hour. The mixture was cooled to about 20 ° C, 168 kg of methanol was added, and the mixture was stirred for about 30 minutes. The crystals formed were collected by filtration with a centrifuge, washed with about 68 kg of methanol, and dried under reduced pressure to give L-
488.3 kg of calcium aspartate was obtained. Obtained L
-Calcium aspartate is 87.0 L-aspartic acid (as dehydrated product) as a result of the test of the Japanese Pharmacopoeia standard.
%, Calcium (calculated as dehydrated product) 13.0%, water content 15.1%, optical rotation + 22.2 °, pH value 6.5, and also conformed to all other standards. Furthermore, no residual solvent was detected.
【００１５】比較例１
99％(v/v)メタノール200 mLに30％(w/w)Ｌ−アスパラギ
ン酸カルシウム水溶液20 mLを40℃で滴下し、攪拌し
た。攪拌中に、餅状の固体が生成し、その後ザラザラし
た結晶へと変化した。結晶を濾取し、55℃で３日間、減
圧下、乾燥したが、結晶中にメタノールが4％程度残存
した。Comparative Example 1 To 200 mL of 99% (v / v) methanol, 20 mL of a 30% (w / w) L-calcium aspartate aqueous solution was added dropwise at 40 ° C. and stirred. During the stirring, a dough-like solid was formed, which then turned into gritty crystals. The crystals were collected by filtration and dried under reduced pressure at 55 ° C. for 3 days, but about 4% of methanol remained in the crystals.
【００１６】[0016]
【発明の効果】本発明により、医薬として使用しうる程
度に高い純度で一定の品質を確保し、日本薬局方外医薬
品規格に合致したＬ−アスパラギン酸カルシウムを工業
的に安定して製造する方法を提供することができた。INDUSTRIAL APPLICABILITY According to the present invention, a method for industrially stably producing L-calcium aspartate which has a certain degree of purity and a certain level of quality so that it can be used as a medicine, and which meets the Japanese Pharmacopoeia standards. Could be provided.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭61−83152（ＪＰ，Ａ) 特開 昭54−122216（ＪＰ，Ａ) (58)調査した分野(Int.Cl.7，ＤＢ名) C07C 227/00 A61K 31/00 C07C 229/00 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP 61-83152 (JP, A) JP 54-122216 (JP, A) (58) Fields investigated (Int.Cl. 7 , DB name) C07C 227/00 A61K 31/00 C07C 229/00 CA (STN) REGISTRY (STN)
Claims (9)
親水性有機溶媒又は親水性有機溶媒と水の混合溶媒を滴
下することによる、下記式で表されるＬ−アスパラギン
酸カルシウム３水和物結晶の製造方法。 1. Production of L-calcium aspartate trihydrate crystals represented by the following formula by dropping a hydrophilic organic solvent or a mixed solvent of a hydrophilic organic solvent and water into an aqueous L-calcium aspartate solution. Method.
である請求項１記載の製造方法。2. The production method according to claim 1, wherein the hydrophilic organic solvent is an alcoholic organic solvent.
項１記載の製造方法。3. The method according to claim 1, wherein the hydrophilic organic solvent is methanol.
ール水溶液を滴下することによる請求項１記載の製造方
法。4. The method according to claim 1, wherein methanol or a 40% to 99% (v / v) aqueous methanol solution is added dropwise.
ｐＨが6〜8である請求項１〜４のいずれか記載の製造方
法。5. The L- any method according aspartic acid aqueous calcium claim. 1 to 4 pH is 6 to 8.
ｐＨが7.0〜7.3である請求項１〜４のいずれか記載の製
造方法。6. L- method for producing a pH of aspartic acid calcium aqueous solution according to any one of claims 1-4 is 7.0 to 7.3.
において、親水性有機溶媒又は親水性有機溶媒と水の混
合溶媒を滴下して結晶を析出させ、得られた結晶を濾取
後、その結晶を親水性有機溶媒で洗浄することによるＬ
−アスパラギン酸カルシウム３水和物結晶の製造方法。7. A method according to any one of claims 1-6, was added dropwise a mixed solvent of a hydrophilic organic solvent or a hydrophilic organic solvent and water to precipitate crystals, after filtration the resulting crystals , L by washing the crystals with a hydrophilic organic solvent
A method for producing calcium aspartate trihydrate crystals .
請求項１〜７のいずれか記載の製造方法で製造されたＬ
−アスパラギン酸カルシウム３水和物結晶。8. A bulk density produced by the production method according to any one of claims 1 to 7 in the range of 0.2 to 0.5 g / mL L
-Calcium aspartate trihydrate crystals .
によって、Ｌ−アスパラギン酸カルシウム水溶液からＬ
−アスパラギン酸カルシウム３水和物結晶を製造し、必
要に応じて粉砕し、薬学上許容される担体と混合し、製
剤化することによる経口用Ｌ−アスパラギン酸カルシウ
ム製剤の製造方法。By 9. The method according to any one of claims. 1 to 7, L calcium solution L- aspartic acid
A method for producing an oral L-calcium aspartate preparation by producing calcium aspartate trihydrate crystals , crushing as necessary, mixing with a pharmaceutically acceptable carrier, and formulating.
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