JP3755908B2 - Crystallization of cephalosporin compounds - Google Patents
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Description
【０００１】
【産業上の利用分野】
本発明は、セファロスポリン化合物の晶析法に関するものであり、医薬製造の分野で利用される。
【０００２】
【従来技術】
経口セファロスポリン製剤は、通常、カプセル剤として提供されているが、活性成分であるセファロスポリン化合物の分離、精製、乾燥、並びにカプセルへの充填を含む全操作を円滑に行い、品質の安定した製剤を得ることは、製造効率の面のみならず、治療面での信頼性を確保する上でも重要である。この操作性には、セファロスポリン化合物の結晶の形や大きさ（比表面積）が極めて大きい影響を及ぼすことが分かっている。即ち、一定の比表面積を有する均一な結晶の集合晶は、圧縮率が小さく、流動性、充填性、耐圧性に優れており、ろ過、乾燥等の製造段階から、カプセル充填に至る全工程を通して良好な操作性を有する。
【０００３】
従来、セファロスポリン化合物の塩酸塩水和物の晶析法として、セファロスポリン化合物のアルカリ金属塩水溶液または有機溶媒溶液を塩酸で処理する方法が開示されている（特開平６−９２９７０)。また、晶析操作において、媒晶剤を少量添加することにより、結晶形や結晶粒径を変える技術が知られており、例えば、セファロスポリン化合物のアルカリ金属塩を晶析させるための媒晶剤としてアミノ酸または該セファロスポリン化合物と類似構造を有する、アミノ基とカルボキシル基を有する化合物を使用する方法も開示されている（特開平第４−２４７０８９号)。
【０００４】
【発明が解決しようとする課題】
しかしながら、セファロスポリン化合物の製造方法や品質等が異なると、含まれる不純物の種類や量の違いにより、晶析で得られる結晶の形や大きさが異なるという問題点があった。また、アミノ酸またはその類似体を媒晶剤として用いる前記公報には、セファロスポリン化合物の酸付加塩への適用は開示されておらず、酸付加塩に対しても適用できるさらに効率的で操作性の良い晶析法の開発が望まれていた。
【０００５】
【課題を解決する手段】
本発明は上記の問題点を解決し、原料の由来や品質が異なる場合、または、媒晶剤ともなり得る不純物の含有量が異なる場合でも、一定の晶癖で、セファロスポリン化合物、その塩または塩水和物の結晶を得ることができる晶析法を提供するものである。
即ち、本発明は、水溶性セルロース誘導体、水溶性澱粉誘導体およびポリビニル化合物からなる群から選択される１種または２種以上の媒晶剤の存在下で晶析させることを特徴とする、セファロスポリン化合物の晶析法を提供するものである。
【０００６】
本発明方法によって得られる結晶を解析した結果、比表面積が１０4ｃｍ2／ｇ以下の集合晶を構成しており、圧縮率が小さく、流動性、充填性、耐圧性に優れ、操作性が極めて向上していることが明らかになった。
本発明の晶析法を適用することができるセファロスポリン化合物としては、例えば、７β−［（Ｚ）−２−（２−アミノ−４−チアゾリル）−２−ヒドロキシイミノアセトアミド］−３−（１，２，３−トリアゾール−４−イル）チオメチルチオ−３−セフェム−４−カルボン酸（以下、Ｓ−１０９０と略称する；特開平５−０５９０６６）およびその塩酸塩水和物（特開平６−９２９７０：33rd Interscience Conference on Antimicrobial Agents and Chemotherapy New Orleans, Louisiana 17-20, October 1993, Abstract No. 416)、セファクロル、セファトリジン、セファドロキシル、セファレキシン、セフラジン、セフロキサジン、セファロリジン、セフォチアム、セフィキシム、セフテラム、セフポドキシム、セフメノキシム、セフォテタン、セフタジジム、セファゾリン、セファピリン、セファロチン、セフテゾール、セファマンドール、セフォキシチン、セフメタゾール、セフロキシム、セフォタキシム、セフォペラゾン、セフチゾキシム、セフトリアキソン、セフピミゾール、セフピラミド、セフブペラゾン、セフゾナム、セフミノクス、セフォジジム、ラタモキセフ、フロモキセフ、セフスロジン等、およびこれらの塩または塩水和物が挙げられるが、必ずしもこれらに限定されない。
【０００７】
本発明方法に用いるセファロスポリン化合物の塩類としては、ナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、塩酸塩、硫酸塩などの無機酸との塩などが挙げられるが、無機酸付加塩またはその水和物が好ましい。
好適な化合物は、Ｓ−１０９０、セファクロル、セファトリジン、セファドロキシル、セファレキシン、セフラジン、セフロキサジン、セファロリジン、セフォチアム、セフロキシム、セフィキシム、セフテラム、セフポドキシム、セフメノキシム、セフォテタンおよびセフタジジム並びにこれらの無機酸付加塩またはその水和物であり、Ｓ−１０９０一塩酸塩水和物が特に好ましい。
【０００８】
本発明の晶析法に用いうる媒晶剤としては、水溶性セルロース誘導体、水溶性澱粉誘導体およびポリビニル化合物を挙げることができ、それらに属する化合物を１種またはそれ以上を用いる。具体的には、水溶性セルロース誘導体として、メチルセルロース、エチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシブチルセルロース等の非イオン性セルロースエーテルおよび、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシブチルメチルセルロース等の混合非イオン性セルロースエーテル等；水溶性または、極性有機溶媒溶解性ポリビニル化合物として、ポリビニルピロリドン、ポリビニルアルコール、ポリビニルアセタールジエチルアミノアセテート等；水溶性澱粉誘導体として、ヒドロキシプロピルスターチ等が例示される。好ましい媒晶剤は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、メチルセルロースおよびポリビニルピロリドンである。
【０００９】
本発明の晶析法では、まず、例えば晶析させるべきセファロスポリン化合物またはその酸付加塩を水、有機溶媒、またはその混液に溶解するか、もしくは、セファロスポリン化合物を水に懸濁した後、例えば、水酸化ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、水酸化カリウム、炭酸カリウム、炭酸水素カリウムなどの塩基を加えて該セファロスポリン化合物を溶解し、セファロスポリン化合物の溶液を調製する等、適宜、公知の方法を採用すればよい。
晶析は、例えば以下の方法のいずれかにより行う。媒晶剤の存在下、１）セファロスポリン溶液に水または有機溶媒を注入して直接晶析させる。２）セファロスポリン溶液を水または有機溶媒中に注入して直接晶析させる。
【００１０】
必要に応じて、当業者既知の任意の方法、例えば、種晶の使用、濃縮、温度調節、ｐＨ調節などを採用してもよい。ｐＨ調節は、例えばセファロスポリン溶液中に無機酸（塩酸、硫酸等）を注入するか、または、無機酸中にセファロスポリン溶液を注入することにより行う。媒晶剤は関与する溶液のいずれに加えても良い。即ち、セファロスポリン溶液、混合用の水や有機溶媒、もしくは、ｐＨ調節用の塩酸水、硫酸水などの無機酸のいずれかに溶解させる。
本発明方法に用いられる有機溶媒の例として、低級アルコ−ル、ケトン、ニトリル、エステルなど、常用の工業用有機溶媒を挙げることができ、メタノール、エタノール、アセトン、イソプロピルアルコールなどが好ましいがこれらに限定されない。溶媒は、単独または２種類以上の混合溶媒として用いられる。
【００１１】
本発明方法においては、特にセファロスポリン化合物の酸付加塩又はその水和物を得るためには、有機溶媒が含まれていてもよい酸性水溶液から晶析させることが好ましい。好ましい態様の１つとして酸性水溶液のｐＨは約６以下である。媒晶剤の添加量はセファロスポリン化合物に対して約０.００５〜５重量％、好ましくは０.１〜２重量％であるが、対象化合物および目的の結晶形などにより、適宜、調節することができる。晶析温度は，通常、約０〜９０℃または氷冷下、好ましくは５〜５０℃である。このような条件下、目的の結晶が晶析するまで、放置又は撹拌する。
【００１２】
晶析した結晶は遠心分離等の通常の方法で分離し、加温、常温、低温、加圧、常圧、減圧、送風、温風、乾燥剤による除湿、流動乾燥など、通常の乾燥条件を用いて乾燥する。ただし、水和物結晶を得る場合は水分子が完全には離脱しない乾燥条件を選択するかまたは、脱水した結晶を例えば、温度１０〜３０℃、湿度５０〜９０％の加湿条件下で放置して、再吸水させてもよい。本発明法により得られる結晶の含水量は、基質により異なることもあり必ずしも限定されないが、例えば、Ｓ−１０９０の場合には、通常の乾燥により、一塩酸塩の１〜２水和物（含水率約３.１〜６.３％）として安定化する傾向にある。また、得られた塩酸塩水和物結晶の比表面積は、この含水率の範囲においては、ほとんど変化が見られない。
【００１３】
【実施例】
以下に実施例を挙げ、本発明をさらに詳しく説明するが、これらは、本発明の範囲を制限するものではない。
製造例 粗Ｓ−１０９０塩酸塩水和物
７β-[(Ｚ)-２-(２-ｔ-ブトキシカルボニルアミノ-４-チアゾリル)-２-トリチルオキシイミノアセトアミド]-３-(１,２,３-トリアゾ−ル-５-イルチオメチル チオ)-３-セフェム-４-カルボン酸ジフェニルメチルエステル２６.０ｇをジクロルメタン２７０mlとアニソ−ル５１mlの混液に懸濁し、０〜５℃で撹拌しつつ、塩化アルミニウム１７.０ｇのアニソ−ル６０ml溶液を滴下後、１時間５０分撹拌する。生成するＳ−１０９０を含む反応液をメタノ−ル２２０ml、水１１４mlおよび塩酸２９.８ｇの混液（０〜１５℃で撹拌下）中に注入する。水層を分取し、ジクロルメタン１００mlで２回洗った後、種晶３０mgを加え、２０〜２８℃で１.５時間撹拌後、約１５０mlまで減圧濃縮する。晶析する結晶を取り、水２ ６０mlで洗えば、粗Ｓ−１０９０塩酸塩水和物２４.５ｇを得る。
【００１４】
実施例１
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇをメタノール１００ｍｌに溶解して得た溶液に、ヒドロキシプロピルセルロース０.０３ｇを溶解した水溶液１０ｍｌを注入する。この溶液を４０℃に保温した３Ｎ塩酸３６０ｍｌに３０分かけて注入し、途中で種晶を加えて、Ｓ−１０９０一塩酸塩水和物を晶析させた。
析出した結晶を取り、水８０mlで洗い、室温下、通気乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶８.３ｇを得た。
【００１５】
実施例２
製造例で得た粗Ｓ−１０９０を塩酸水から一度再結晶することにより得た精製Ｓ−１０９０塩酸塩水和物１０ｇを用い、実施例１と同様に晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶８.５ｇを得た。
【００１６】
実施例３
製造例１で得た粗製のＳ−１０９０塩酸塩水和物１０ｇおよびポリビニルピロリドン０.０３ｇをメタノール１６０ｍｌに溶解して得た溶液に０.５Ｎ塩酸１００ｍｌを加えた後、種晶を加えて減圧濃縮し、Ｓ−１０９０塩酸塩水和物を晶析させた。析出した結晶を取り、水８０mlで洗い、乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶９.０ｇを得た。
【００１７】
実施例４
製造例で得た粗Ｓ−１０９０を塩酸水から一度再結晶することにより得た精製Ｓ−１０９０塩酸塩水和物１０ｇを用い、実施例３と同様に晶析操作を行い、Ｓ−１０９０塩酸塩水和物の淡黄色結晶９.０ｇを得た。
【００１８】
実施例５
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇを水に懸濁した後、ＩＮ水酸化ナトリウム水を加えて溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌにヒドロキシプロピルセルロース０.０３ｇを溶解する。この溶液を実施例１と同様４０℃の３Ｎ塩酸３６０ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させた。
析出した結晶を取り、水８０mlで洗い、乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶８.５ｇを得た。
【００１９】
実施例６
製造例で得た粗Ｓ−１０９０を塩酸水から一度再結晶することにより得た精製Ｓ−１０９０塩酸塩水和物１０ｇを用い、実施例５と同様に晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶８.４ｇを得た。
【００２０】
実施例７
粗製のＳ−１０９０塩酸塩水和物１０ｇを水に懸濁した後、ＩＮ水酸化ナトリウム水を加えて溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌに塩酸を加えてｐＨ４とし、この溶液にヒドロキシプロピルセルロース０.０３ｇを溶解する。この溶液を実施例１と同様４０℃の６Ｎ塩酸２００ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させた。晶析する 結晶を取り、水８０mlで洗い、乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶８.３ｇを得た。
【００２１】
実施例８
製造例で得た粗Ｓ−１０９０を塩酸水から一度再結晶することにより得た精製Ｓ−１０９０塩酸塩水和物１０ｇを用い、実施例７と同様に晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶８.５ｇを得た。
【００２２】
実施例９
製造例で得た粗Ｓ−１０９０を塩酸水から一度再結晶することにより得た精製Ｓ−１０９０塩酸塩水和物１０ｇを水に懸濁した後、ＩＮ水酸化ナトリウム水を加えて溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌに塩酸を加えてｐＨ４とし、この溶液にヒドロキシプロピルメチルセルロース０.０１５ｇを溶解する。この溶液を実施例１と同様６Ｎ塩酸２００ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させた。晶析した結晶を取り、水８０mlで洗い、乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶８.５ｇを得た。
【００２３】
実施例１０
実施例９と同様、一度再結晶を行った精製のＳ−１０９０塩酸塩水和物１０ｇを水に懸濁した後、ＩＮ水酸化ナトリウム水を加えて溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌに塩酸を加えてｐＨ４とし、この溶液を、ヒドロキシプロピルセルロース０.０３ｇを溶解した６Ｎ塩酸２００ｍｌ（４０℃）に注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させた。晶析した結晶を取り、水８０mlで洗い、乾燥して、Ｓ−１０９０塩酸塩水和物の白色結晶８.５ｇを得た。
【００２４】
実施例１１
ヒドロキシプロピルメチルセルロースに代えてメチルセルロース０.００３ｇを用い、実施例９と同様に晶析操作を行うことにより、Ｓ−１０９０塩酸塩水和物の淡黄色結晶８.０ｇを得た。
【００２５】
実施例１２
ヒドロキシプロピルメチルセルロースに代えてポリビニルピロリドン０.００５ｇを用い、実施例９と同様に晶析操作を行うことにより、Ｓ−１０９０塩酸塩水和物の淡黄色結晶８.０ｇを得た。
尚、上記実施例１〜１２にて得られた乾燥後の各結晶の含水率は、カールフィッシャー法で約３.０〜３.５％の範囲内であった。
【００２６】
以下の、比較例では、上記の実施例と同様の条件下、媒晶剤を用いずに、晶析操作を行った。
比較例１
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇをメタノール１００ｍｌに溶解して得た溶液を３Ｎ塩酸３６０ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させ、乾燥してＳ−１０９０塩酸塩水和物の白色結晶９.０ｇを得た。
【００２７】
比較例２
粗製のＳ−１０９０塩酸塩水和物のかわりに、塩酸水から一度再結晶を行った精製のＳ−１０９０塩酸塩水和物１０ｇを用い、比較例１と同様の晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶８.７ｇを得た。
【００２８】
比較例３
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇをメタノール１６０ｍｌに溶解して得た溶液に０.５Ｎ塩酸１００ｍｌを加えた後、種晶を加えて減圧濃縮し、Ｓ−１０９０塩酸塩水和物を晶析させ、乾燥してＳ−１０９０塩酸塩水和物の淡黄色結晶８.２ｇを得た。
【００２９】
比較例４
粗製のＳ−１０９０塩酸塩水和物のかわりに、塩酸水から一度再結晶を行った精製のＳ−１０９０塩酸塩水和物１０ｇを用い、比較例３と同様の晶析操作を行い、Ｓ−１０９０塩酸塩水和物の淡黄色結晶８.０ｇを得た。
【００３０】
比較例５
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇを溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌを３Ｎ塩酸３６０ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させ、乾燥してＳ−１０９０塩酸塩水和物の白色結晶８.７ｇを得た。
【００３１】
比較例６
約１％の不純物を含む、一度再結晶を行った精製のＳ−１０９０塩酸塩水和物１０ｇを用い、比較例５と同様の晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶８.８ｇを得た。
【００３２】
比較例７
製造例で得た粗製のＳ−１０９０塩酸塩水和物１０ｇを溶解して得たＳ−１０９０ナトリウム塩水溶液２５０ｍｌに塩酸を加えてｐＨ４とし、この溶液を６Ｎ塩酸２００ｍｌに注入し、途中で種晶を加えて、Ｓ−１０９０塩酸塩水和物を晶析させ、乾燥してＳ−１０９０塩酸塩水和物の白色結晶８.９ｇを得た。
【００３３】
比較例８
粗製のＳ−１０９０塩酸塩水和物のかわりに一度再結晶を行った精製のＳ−１０９０塩酸塩水和物１０ｇを用い、比較例７と同様の晶析操作を行い、Ｓ−１０９０塩酸塩水和物の白色結晶９.０ｇを得た。
上記の実施例および比較例で得たＳ−１０９０塩酸塩水和物結晶を顕微鏡およびＳＳＳ法（サブシーブサイダー法）で解析した結果を表にまとめて示す。
【００３４】
【表１】
【００３５】
【発明の効果】
本発明方法によれば、原料の由来、製造方法、不純物の有無や種類、含有量の違いに関係なく、粗または精製セファロスポリン化合物より一定以上の大きさの優れた結晶を得ることができる。そのような結晶は、圧縮率が小さく、流動性、充填性、耐圧性に優れ、錠剤用又はカプセル剤充てん用の原料として極めて操作性が高く、製剤効率並びに製品の品質の向上に寄与する。[0001]
[Industrial application fields]
The present invention relates to a method for crystallizing a cephalosporin compound and is used in the field of pharmaceutical production.
[0002]
[Prior art]
Oral cephalosporin preparations are usually provided as capsules, but the entire operation including separation, purification, drying, and filling of capsules is carried out smoothly to stabilize the quality. Obtaining such a preparation is important not only in terms of production efficiency, but also in ensuring reliability in terms of treatment. It has been found that the operability of the crystal and size (specific surface area) of the cephalosporin compound is extremely large. In other words, a uniform crystal aggregate having a specific surface area has a small compressibility and excellent fluidity, filling properties, and pressure resistance, and it passes through all processes from the production stage such as filtration and drying to capsule filling. Good operability.
[0003]
Conventionally, as a method for crystallizing a hydrochloride hydrate of a cephalosporin compound, a method of treating an alkali metal salt aqueous solution or an organic solvent solution of a cephalosporin compound with hydrochloric acid has been disclosed (JP-A-6-92970). In addition, a technique for changing the crystal form and crystal grain size by adding a small amount of a crystallizing agent in a crystallization operation is known. For example, a crystal for crystallization of an alkali metal salt of a cephalosporin compound is known. A method is also disclosed in which an amino acid or a compound having an amino group and a carboxyl group having a structure similar to that of the cephalosporin compound is used as an agent (Japanese Patent Laid-Open No. 4-247089).
[0004]
[Problems to be solved by the invention]
However, when the production method and quality of the cephalosporin compound are different, there is a problem that the shape and size of the crystal obtained by crystallization differ depending on the kind and amount of impurities contained. In addition, the above-mentioned publication using an amino acid or an analog thereof as a crystal clearing agent does not disclose application to an acid addition salt of a cephalosporin compound, and it is more efficient and applicable to an acid addition salt. The development of a good crystallization method has been desired.
[0005]
[Means for solving the problems]
The present invention solves the above problems, and even when the origin and quality of the raw materials are different, or even when the content of impurities that can also serve as a crystallizing agent is different, the cephalosporin compound and its salt have a constant crystal habit. Alternatively, the present invention provides a crystallization method capable of obtaining a salt hydrate crystal.
That is, the present invention provides a cephalospo which is characterized in that crystallization is performed in the presence of one or more kinds of crystallizing agents selected from the group consisting of water-soluble cellulose derivatives, water-soluble starch derivatives and polyvinyl compounds. A method for crystallizing a phosphorus compound is provided.
[0006]
As a result of analyzing the crystal obtained by the method of the present invention, it has formed an aggregate crystal having a specific surface area of 10 4 cm 2 / g or less, a small compressibility, excellent fluidity, filling property, pressure resistance, and operability. It became clear that it was extremely improved.
As a cephalosporin compound to which the crystallization method of the present invention can be applied, for example, 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamide] -3- ( 1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid (hereinafter abbreviated as S-1090; JP-A-5-059066) and its hydrochloride hydrate (JP-A-6-6 92970: 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy New Orleans, Louisiana 17-20, October 1993, Abstract No.416) Cefmenoxime, cefotetan, ceftazidime, cefazolin, cef Apilin, cephalothin, ceftorazole, cefamandol, cefoxitin, cefomethazole, cefuroxime, cefotaxime, cefoperazone, ceftizoxime, ceftriaxone, cefpimizole, cefpyramide, cefbuperazone, cefzonam, cefminox, cefodixefine, latamoxef Although salt hydrate is mentioned, it is not necessarily limited to these.
[0007]
The salts of the cephalosporin compound used in the method of the present invention include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and salts with inorganic acids such as hydrochloride and sulfate. An inorganic acid addition salt or a hydrate thereof is preferable.
Suitable compounds include S-1090, cefaclor, cephatridine, cephadroxyl, cephalexin, cefurazine, cefloxazine, cephaloridine, cefothiam, cefuroxime, cefixime, cefteram, cefpodoxime, cefmenoxime, cefotetan and ceftazidime and their hydrated acid addition salts or S-1090 monohydrochloride hydrate is particularly preferred.
[0008]
Examples of the crystallization agent that can be used in the crystallization method of the present invention include water-soluble cellulose derivatives, water-soluble starch derivatives, and polyvinyl compounds, and one or more compounds belonging to them are used. Specifically, as water-soluble cellulose derivatives, nonionic cellulose ethers such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxybutylcellulose, and mixed nonions such as hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, and hydroxybutylmethylcellulose Examples of water-soluble or polar organic solvent-soluble polyvinyl compounds include polyvinyl pyrrolidone, polyvinyl alcohol, and polyvinyl acetal diethylaminoacetate; examples of water-soluble starch derivatives include hydroxypropyl starch. Preferred crystallites are hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and polyvinylpyrrolidone.
[0009]
In the crystallization method of the present invention, first, for example, a cephalosporin compound to be crystallized or an acid addition salt thereof is dissolved in water, an organic solvent, or a mixture thereof, or a cephalosporin compound is suspended in water. Thereafter, for example, a base such as sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate is added to dissolve the cephalosporin compound, and a solution of the cephalosporin compound is prepared. A known method may be employed as appropriate.
Crystallization is performed, for example, by one of the following methods. 1) In the presence of a crystallizing agent, 1) Water or an organic solvent is injected into a cephalosporin solution to cause direct crystallization. 2) The cephalosporin solution is poured into water or an organic solvent and directly crystallized.
[0010]
If necessary, any method known to those skilled in the art, for example, use of seed crystals, concentration, temperature adjustment, pH adjustment, etc. may be employed. The pH is adjusted by, for example, injecting an inorganic acid (hydrochloric acid, sulfuric acid, etc.) into the cephalosporin solution or injecting a cephalosporin solution into the inorganic acid. The crystallizer may be added to any of the solutions involved. That is, it is dissolved in either a cephalosporin solution, water for mixing or an organic solvent, or an inorganic acid such as hydrochloric acid or pH for adjusting pH.
Examples of the organic solvent used in the method of the present invention include conventional industrial organic solvents such as lower alcohols, ketones, nitriles, esters, etc., and methanol, ethanol, acetone, isopropyl alcohol, etc. are preferable. It is not limited. The solvent is used alone or as a mixed solvent of two or more.
[0011]
In the method of the present invention, in order to obtain an acid addition salt of a cephalosporin compound or a hydrate thereof, it is preferable to crystallize from an acidic aqueous solution which may contain an organic solvent. In one preferred embodiment, the acidic aqueous solution has a pH of about 6 or less. The addition amount of the crystallizing agent is about 0.005 to 5% by weight, preferably 0.1 to 2% by weight, based on the cephalosporin compound, and is appropriately adjusted depending on the target compound and the target crystal form. be able to. The crystallization temperature is usually about 0 to 90 ° C or under ice cooling, preferably 5 to 50 ° C. Under such conditions, it is allowed to stand or stir until the target crystal is crystallized.
[0012]
Crystallized crystals are separated by ordinary methods such as centrifugation, and are subjected to normal drying conditions such as heating, normal temperature, low temperature, pressurization, normal pressure, reduced pressure, ventilation, hot air, dehumidification with a desiccant, and fluidized drying. Use to dry. However, when obtaining a hydrate crystal, the drying condition is selected so that water molecules are not completely removed, or the dehydrated crystal is left under humidified conditions of, for example, a temperature of 10 to 30 ° C. and a humidity of 50 to 90%. The water may be absorbed again. The water content of the crystals obtained by the method of the present invention may vary depending on the substrate and is not necessarily limited. For example, in the case of S-1090, monohydrochloride monohydrate (water content) is obtained by ordinary drying. The rate tends to stabilize as about 3.1 to 6.3%). In addition, the specific surface area of the obtained hydrochloride hydrate crystals hardly changes within this water content range.
[0013]
【Example】
The present invention will be described in more detail with reference to examples below, but these do not limit the scope of the present invention.
Preparation crude S-1090 hydrochloride hydrate 7β - [(Z) -2- ( 2-t- butoxycarbonylamino-4-thiazolyl) -2-trityloxyiminoacetamido] -3- (1,2,3 26.0 g of triazol-5-ylthiomethyl thio) -3-cephem-4-carboxylic acid diphenylmethyl ester is suspended in a mixture of 270 ml of dichloromethane and 51 ml of anisole and stirred at 0 to 5 ° C., while containing aluminum chloride 17 After dropwise addition of 60 g of anisole 60 ml solution, the mixture is stirred for 1 hour 50 minutes. The resulting reaction solution containing S-1090 is poured into a mixed solution of 220 ml of methanol, 114 ml of water and 29.8 g of hydrochloric acid (stirring at 0 to 15 ° C.). The aqueous layer is separated, washed twice with 100 ml of dichloromethane, added with 30 mg of seed crystals, stirred at 20-28 ° C. for 1.5 hours, and concentrated under reduced pressure to about 150 ml. The crystallized crystals are taken and washed with 260 ml of water to obtain 24.5 g of crude S-1090 hydrochloride hydrate.
[0014]
Example 1
Into a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 100 ml of methanol, 10 ml of an aqueous solution in which 0.03 g of hydroxypropylcellulose is dissolved is poured. This solution was poured into 360 ml of 3N hydrochloric acid kept at 40 ° C. over 30 minutes, and seed crystals were added on the way to crystallize S-1090 monohydrochloride hydrate.
The precipitated crystals were collected, washed with 80 ml of water, and dried by aeration at room temperature to obtain 8.3 g of white crystals of S-1090 hydrochloride hydrate.
[0015]
Example 2
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was carried out in the same manner as in Example 1 to obtain S-1090 hydrochloride water. 8.5 g of white crystals of the Japanese product was obtained.
[0016]
Example 3
To a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example 1 and 0.03 g of polyvinylpyrrolidone in 160 ml of methanol was added 100 ml of 0.5N hydrochloric acid, seed crystals were added, and the mixture was concentrated under reduced pressure. S-1090 hydrochloride hydrate was crystallized. The precipitated crystals were taken, washed with 80 ml of water, and dried to obtain 9.0 g of white crystals of S-1090 hydrochloride hydrate.
[0017]
Example 4
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 3 to obtain S-1090 hydrochloride water. 9.0 g of a pale yellow crystal of the Japanese product was obtained.
[0018]
Example 5
10 g of crude S-1090 hydrochloride hydrate obtained in the production example was suspended in water and dissolved by adding IN sodium hydroxide solution to 250 ml of an aqueous solution of S-1090 sodium salt to obtain 0.03 g of hydroxypropylcellulose. Dissolve. This solution was poured into 360 ml of 3N hydrochloric acid at 40 ° C. as in Example 1, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate.
The precipitated crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0019]
Example 6
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 5 to obtain S-1090 hydrochloride water. 8.4 g of white crystals of the Japanese product was obtained.
[0020]
Example 7
After 10 g of crude S-1090 hydrochloride hydrate was suspended in water, hydrochloric acid was added to 250 ml of an aqueous solution of S-1090 sodium salt obtained by dissolving by adding IN sodium hydroxide aqueous solution to pH 4. Dissolve 0.03 g of propylcellulose. This solution was poured into 200 ml of 6N hydrochloric acid at 40 ° C. as in Example 1, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate. The crystallizing crystals were taken, washed with 80 ml of water and dried to obtain 8.3 g of white crystals of S-1090 hydrochloride hydrate.
[0021]
Example 8
Using 10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing crude S-1090 obtained in Production Example once from hydrochloric acid water, the crystallization operation was performed in the same manner as in Example 7 to obtain S-1090 hydrochloride water. 8.5 g of white crystals of the Japanese product was obtained.
[0022]
Example 9
10 g of purified S-1090 hydrochloride hydrate obtained by recrystallizing the crude S-1090 obtained in the production example once from aqueous hydrochloric acid was suspended in water, and then dissolved by adding IN sodium hydroxide aqueous solution. Hydrochloric acid is added to 250 ml of an aqueous S-1090 sodium salt solution to adjust the pH to 4, and 0.015 g of hydroxypropylmethylcellulose is dissolved in this solution. This solution was poured into 200 ml of 6N hydrochloric acid in the same manner as in Example 1, and seed crystals were added along the way to crystallize S-1090 hydrochloride hydrate. The crystallized crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0023]
Example 10
In the same manner as in Example 9, 10 g of purified S-1090 hydrochloride hydrate which had been recrystallized once was suspended in water and then dissolved by adding IN sodium hydroxide aqueous solution to obtain 250 ml of an aqueous S-1090 sodium salt solution. Hydrochloric acid was added to adjust the pH to 4, and this solution was poured into 200 ml (40 ° C.) of 6N hydrochloric acid in which 0.03 g of hydroxypropylcellulose was dissolved, and seed crystals were added on the way to crystallize S-1090 hydrochloride hydrate. I let you. The crystallized crystals were collected, washed with 80 ml of water and dried to obtain 8.5 g of white crystals of S-1090 hydrochloride hydrate.
[0024]
Example 11
Crystallization operation was performed in the same manner as in Example 9 using 0.003 g of methylcellulose instead of hydroxypropylmethylcellulose to obtain 8.0 g of pale yellow crystals of S-1090 hydrochloride hydrate.
[0025]
Example 12
By using 0.005 g of polyvinylpyrrolidone instead of hydroxypropylmethylcellulose and performing the crystallization operation in the same manner as in Example 9, 8.0 g of pale yellow crystals of S-1090 hydrochloride hydrate were obtained.
In addition, the water content of each crystal after drying obtained in Examples 1 to 12 was in the range of about 3.0 to 3.5% by the Karl Fischer method.
[0026]
In the following comparative examples, the crystallization operation was performed under the same conditions as in the above examples without using a crystallization agent.
Comparative Example 1
A solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 100 ml of methanol was poured into 360 ml of 3N hydrochloric acid, seed crystals were added on the way, and S-1090 hydrochloride hydrate was crystallized. And dried to obtain 9.0 g of white crystals of S-1090 hydrochloride hydrate.
[0027]
Comparative Example 2
Instead of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate once recrystallized from hydrochloric acid water was used, and the same crystallization operation as in Comparative Example 1 was performed. 8.7 g of white crystals of hydrochloride hydrate were obtained.
[0028]
Comparative Example 3
To a solution obtained by dissolving 10 g of crude S-1090 hydrochloride hydrate obtained in Production Example in 160 ml of methanol, 100 ml of 0.5N hydrochloric acid was added, seed crystals were added, and the mixture was concentrated under reduced pressure, and S-1090 hydrochloride water was added. The hydrate was crystallized and dried to obtain 8.2 g of pale yellow crystals of S-1090 hydrochloride hydrate.
[0029]
Comparative Example 4
Instead of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate, which was once recrystallized from hydrochloric acid water, was used for the same crystallization operation as in Comparative Example 3, and S-1090 8.0 g of pale yellow crystals of hydrochloride hydrate was obtained.
[0030]
Comparative Example 5
250 ml of an aqueous S-1090 sodium salt solution obtained by dissolving 10 g of the crude S-1090 hydrochloride hydrate obtained in the production example was poured into 360 ml of 3N hydrochloric acid, seed crystals were added on the way, and S-1090 hydrochloride hydrated. The product was crystallized and dried to obtain 8.7 g of white crystals of S-1090 hydrochloride hydrate.
[0031]
Comparative Example 6
Using 10 g of purified S-1090 hydrochloride hydrate that had been recrystallized once and containing about 1% of impurities, the same crystallization operation as in Comparative Example 5 was carried out to obtain white crystals of S-1090 hydrochloride hydrate 8 0.8 g was obtained.
[0032]
Comparative Example 7
Hydrochloric acid was added to 250 ml of an aqueous S-1090 sodium salt solution obtained by dissolving 10 g of the crude S-1090 hydrochloride hydrate obtained in the production example to adjust the pH to 4, and this solution was poured into 200 ml of 6N hydrochloric acid. Was added to crystallize S-1090 hydrochloride hydrate and dried to obtain 8.9 g of white crystals of S-1090 hydrochloride hydrate.
[0033]
Comparative Example 8
In place of the crude S-1090 hydrochloride hydrate, 10 g of purified S-1090 hydrochloride hydrate that had been recrystallized once was used, and the same crystallization operation as in Comparative Example 7 was performed to obtain S-1090 hydrochloride hydrate. Of white crystals was obtained.
The results of analyzing the S-1090 hydrochloride hydrate crystals obtained in the above Examples and Comparative Examples with a microscope and SSS method (sub-sieve cider method) are shown in a table.
[0034]
[Table 1]
[0035]
【The invention's effect】
According to the method of the present invention, it is possible to obtain crystals having a certain size or larger than the crude or purified cephalosporin compound regardless of the origin of the raw material, the production method, the presence or absence of impurities, the type, and the difference in content. . Such crystals have a small compressibility, excellent fluidity, filling properties, and pressure resistance, are extremely easy to operate as a raw material for tablets or capsules, and contribute to improvement in formulation efficiency and product quality.
Claims (9)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19305994A JP3755908B2 (en) | 1994-08-17 | 1994-08-17 | Crystallization of cephalosporin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19305994A JP3755908B2 (en) | 1994-08-17 | 1994-08-17 | Crystallization of cephalosporin compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0859671A JPH0859671A (en) | 1996-03-05 |
| JP3755908B2 true JP3755908B2 (en) | 2006-03-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19305994A Expired - Fee Related JP3755908B2 (en) | 1994-08-17 | 1994-08-17 | Crystallization of cephalosporin compounds |
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| Country | Link |
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| JP (1) | JP3755908B2 (en) |
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| KR101366216B1 (en) | 2010-09-03 | 2014-02-24 | 영진약품공업주식회사 | Method for purifying cephalosporin antibiotic |
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| DE19951418A1 (en) * | 1999-10-26 | 2001-05-03 | Merck Patent Gmbh | Process for the preparation of N- (4,5-bismethanesulfonyl-2-methyl-benzoyl) guanidine, hydrochloride |
| DE19958460A1 (en) * | 1999-12-03 | 2001-06-07 | Boehringer Ingelheim Pharma | Process for the preparation of epinastine hydrochloride in high-melting crystal modification |
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| KR101366216B1 (en) | 2010-09-03 | 2014-02-24 | 영진약품공업주식회사 | Method for purifying cephalosporin antibiotic |
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| JPH0859671A (en) | 1996-03-05 |
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