JP2010159264A - 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムを2.5水和物又は1水和物として選択的に結晶化する方法 - Google Patents
3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムを2.5水和物又は1水和物として選択的に結晶化する方法 Download PDFInfo
- Publication number
- JP2010159264A JP2010159264A JP2010030081A JP2010030081A JP2010159264A JP 2010159264 A JP2010159264 A JP 2010159264A JP 2010030081 A JP2010030081 A JP 2010030081A JP 2010030081 A JP2010030081 A JP 2010030081A JP 2010159264 A JP2010159264 A JP 2010159264A
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- JP
- Japan
- Prior art keywords
- monohydrate
- hydrate
- hydroxyethylidene
- pyridyl
- sodium
- 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.)
- Granted
Links
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- 239000011734 sodium Substances 0.000 title claims abstract description 23
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Abstract
【解決手段】本発明は、3−ピリジル−1−ヒドロキシエチリデン−1.1−ビスホスホン酸ナトリウム2.5水和物及び1水和物と、核形成温度及び結晶化速度を制御することにより2.5水和物又は1水和物を調製する方法、及び水和物の一方又は両方の形態を含有する医薬組成物を開示する。
【選択図】なし
Description
本出願は、米国特許法(35USC)119(e)に基づき、2000年2月1日出願の仮出願番号60/179,505号からの優先権を請求するものである。
本出願は、特願2001−556833号に基づく分割出願である。
本発明は、3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物及び1水和物、及び前記2.5水和物及び1水和物を含有する組成物を対象にする。また、ジェミナルビスホスホネート、リセドロン酸ナトリウム、3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムを2.5水和物及び1水和物として選択的に結晶化するための新しい方法を開示する。
リセドロン酸ナトリウム、即ちリセドロネート(risedronate)の1ナトリウム塩は、3つの結晶性水和物の状態、つまり無水物、1水和物、及び2.5水和物で存在する。1水和物及び2.5水和物が好ましい。
以下のリストは本明細書において使用する用語の定義である。
「リセドロネート(risedronate)」という用語は本明細書で使用するとき、3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸を意味し、次の構造を有する。
本発明による方法は、本明細書に記述された方法が工業生産に容易に適応されることを特徴とする。以下の非限定例は本発明の方法を説明するものである。
3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液は、0〜75℃、好ましくは25〜75℃、更に好ましくは45〜75℃において、結晶化の条件に依存して1水和物又は2.5水和物のいずれかの結晶形を選択的に生成すると考えられる。核形成温度及び結晶化速度は水和物を制御し、水対イソプロパノールの割合、並びに水溶液の温度及び冷却温度の勾配(cooling ramp)を変更することにより、形成された水和物の状態の割合を制御する。
25〜70℃、好ましくは50〜70℃の核形成条件と、0.1〜5℃/分、好ましくは0.1〜2℃/分の勾配で冷却することにより2.5水和物を生成する。3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸を約60℃で水に懸濁し、pHを水酸化ナトリウムで4.7〜5.0に調整して、得られた溶液にイソプロパノールを加え、懸濁液を冷却し、生成物を濾過して収集することにより、2.5水和物を生成する。
約45℃以上、好ましくは約55℃以上の核形成条件と、この温度で適切な時間保持し、冷却を行わないか又は急速に冷却することにより1水和物を生成する。3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を70℃で保持すると1水和物が徐々に結晶化し、この熱溶液から濾過により結晶を単離する。また、対照的に、70℃の水溶液を0℃のイソプロパノール中で直接冷却することにより、結晶性1水和物を得る。
本明細書において作成される化合物は、医薬組成物に使用することができる。「医薬組成物」という用語は、安全且つ有効な量の有効成分、及び医薬品として許容される賦形剤から構成される剤形を意味する。本明細書に記述する医薬組成物は、約0.1〜約99%、好ましくは約0.5〜約95%のビスホスホネート活性成分、及び約1〜約99.9%、好ましくは5.00〜約99.90%の医薬品として許容される賦形剤から構成される。リセドロン酸ナトリウム1水和物又は2.5水和物について、経口組成物は、好ましくは0.25〜40%、好ましくは約0.5〜約30%のリセドロネート活性成分、及び約60〜約97%、好ましくは約70〜約99.5%の医薬品として許容される賦形剤を含む。
Claims (6)
- 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物を製造する方法であって、
(a)3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を供給する工程、
(b)前記水溶液を45℃−70℃に加熱する工程、
(c)前記水溶液に、アルコールを加える工程、及び
(d)前記水溶液を0.1℃−5℃/分の割合で冷却する工程
を含むことを特徴とする方法。 - 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物を製造する方法であって、
(a)3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を供給する工程、
(b)前記水溶液を50℃−70℃に加熱する工程、
(c)前記水溶液に、アルコールを加える工程、及び
(d)前記水溶液を0.1℃−2℃/分の割合で冷却する工程
を含むことを特徴とする方法。 - 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物を製造する方法であって、
(a)3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を供給する工程、
(b)前記水溶液を60℃に加熱する工程、
(c)前記水溶液に、アルコールを加える工程、及び
(d)前記水溶液を0.1℃−2℃/分の割合で冷却する工程
を含むことを特徴とする方法。 - 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物を製造する方法であって、
(a)3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を供給する工程、
(b)前記水溶液を60℃に加熱する工程、
(c)前記水溶液に、アルコールを加える工程、及び
(d)前記水溶液を2時間で25℃まで冷却する工程
を含むことを特徴とする方法。 - 3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウム2.5水和物を製造する方法であって、
(a)3−ピリジル−1−ヒドロキシエチリデン−1,1−ビスホスホン酸ナトリウムの水溶液を供給する工程、
(b)前記水溶液を60℃に加熱する工程、
(c)前記水溶液に、アルコールを加える工程、及び
(d)前記水溶液を60℃で4時間保持した後、2時間で25℃まで冷却する工程
を含むことを特徴とする方法。 - 前記アルコールがイソプロパノールであることを特徴とする請求項1乃至5のいずれか1項に記載の方法。
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