JP5734369B2 - N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体形態 - Google Patents
N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体形態 Download PDFInfo
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- JP5734369B2 JP5734369B2 JP2013173750A JP2013173750A JP5734369B2 JP 5734369 B2 JP5734369 B2 JP 5734369B2 JP 2013173750 A JP2013173750 A JP 2013173750A JP 2013173750 A JP2013173750 A JP 2013173750A JP 5734369 B2 JP5734369 B2 JP 5734369B2
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- carboxamide
- dimethylethyl
- dihydro
- hydroxyphenyl
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Description
本願は、米国特許法第119条第(e)項のもと、2005年12月28日付、米国特許出願番号第60/754381号に対して優先権を主張しており、その全内容を出典明示により援用する。
本発明は、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体形態、例えば結晶およびアモルファス(非晶質)形態、その医薬組成物およびそれを用いる方法に関する。
ロタウイルス感染の症状には、水様便の排泄、脱水症および衰弱がある。コロナウイルスは、生まれたての動物ではさらに深刻な疾患を誘発し、ロタウイルス感染よりも死亡率は高い。しかしながら、多くの場合、若年動物は、一時に複数のウイルスまたはウイルスおよび細菌性微生物の組合せに感染し得る。このことによって、病気の重症度は劇的に増大する。
CFTR活性の上記モジュレーターを用いたCFTR介在疾患の処置方法が必要とされている。
アモルファスN−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミド粒子および医薬上許容される担体を含む水性懸濁液
を含む医薬組成物である。
いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約22.4〜約22.8、例えば約22.6での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約23.2〜約23.6、例えば約23.4での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約23.7〜約24.1、例えば約23.9での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約24.7〜約25.1、例えば約24.9での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約25.3〜約25.7、例えば約25.5での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約26.5〜約26.9、例えば約26.7での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約27.3〜約27.7、例えば約27.5での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約29.4〜約29.8、例えば約29.6での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約33.3〜約33.7、例えば約33.5での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、さらに約36.6〜約37.0、例えば約36.8での後続ピークを特徴としている。いくつかの態様において、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの結晶形態は、図7と実質的に類似しているCu Kアルファ放射線を用いて得られるX線粉末回折パターンを特徴としている。
化合物1の固体形態
形態A
化合物1の形態Aは、Cu Kアルファ放射線(2θ)を用いて得られたX線粉末回折パターンにおける約4.8〜約5.2、例えば約5.0、例えば約4.99、および約15.4〜約15.8、例えば約15.6、例えば15.58度での1個以上のピークを特徴とする。形態Aに特有なものであり得る他のピーク(2θ)は以下のものを含む:約7.6〜約8.0、例えば約7.8、例えば7.75;約8.3〜約8.7、例えば約8.5、例えば8.46;約9.0〜約9.4、例えば約9.2、例えば9.21;約9.7〜約10.1、例えば約9.9、例えば9.92;約11.7〜約12.1、例えば約11.9、例えば11.93;約12.4〜約12.8、例えば約12.6、例えば12.64;約13.7〜約14.1、例えば約13.9、例えば13.88;約14.7〜約15.1、例えば約14.9、例えば14.91;約16.3〜約16.7、例えば約16.5、例えば16.46;約17.9〜約18.3、例えば約18.1、例えば18.09;約18.3〜約18.7、例えば約18.5、例えば18.52;約21.5〜約21.9、例えば約21.7、例えば20.65;約21.8〜約22.2、例えば約22.0、例えば21.95;約23.1〜約23.7、例えば約23.5、例えば23.49;約25.1〜約25.5、例えば約25.3、例えば25.26;約27.8〜約28.2、例えば約28.0、例えば28.02;約29.2〜約29.6、例えば約29.4、例えば29.35;および約30.7〜約31.1、例えば30.9、例えば30.85。例えば、形態Aは、図4と実質的に類似しているCu Kアルファ放射線を用いて得られたX線粉末回折パターンを特徴とし得る。
化合物1の固体結晶形態Bは、Cu Kアルファ放射線(2θ)を用いて得られたX線粉末回折パターンにおける約6.0〜約6.4、例えば約6.2、例えば、6.17、約7.4〜約7.8、例えば約7.6、例えば7.61、約12.1〜約12.5、例えば約12.3、例えば12.33、および約17.8〜約18.2、例えば約18.0、例えば17.96度での1個以上のピークを特徴とする。形態Bに特有なものであり得る他のピーク(2θ)は以下のものを含む:約8.2〜約8.6、例えば約8.4、例えば8.40;約10.8〜約11.2、例えば約11.0、例えば11.02;約14.6〜約15.0、例えば約14.8、例えば14.83;約15.9〜約16.3、例えば約16.1、例えば16.14;約16.9〜約17.3、例えば約17.1、例えば17.11;約18.4〜約18.8、例えば約18.6、例えば18.55;約19.2〜約19.6、例えば約19.4、例えば19.43;約20.9〜約21.3、例えば約21.1、例えば21.05;約22.4〜約22.8、例えば約22.6、例えば22.56;約23.2〜約23.6、例えば約23.4、例えば23.37;約23.7〜約24.1、例えば約23.9、例えば23.94;約24.7〜約25.1、例えば約24.9、例えば24.86;約25.3〜約25.7、例えば約25.5、例えば25.50;約26.5〜約26.9、例えば約26.7、例えば26.72;約27.3〜約27.7、例えば約27.5、例えば27.51;約29.4〜約29.8、例えば約29.6、例えば29.60;約33.3〜約33.7、例えば約33.5、例えば33.48;および約36.6〜約37.0、例えば約36.8、例えば36.78。さらに形態Bは、例えば、図7と実質的に類似しているCu Kアルファ放射線を用いて得られたX線粉末回折パターンを特徴とし得る。
化合物1は、アモルファス固体として存在し、例えばアモルファス化合物1は実質的にニートの調製物として、または一成分としてのアモルファス化合物1は分散体、例えば固体アモルファス分散体として存在し得る。
アモルファス化合物1およびポリマー(または固体担体)を含む固体分散体も本発明に包含される。例えば、化合物1は、固体アモルファス分散体の一成分としてアモルファス化合物として存在する。固体アモルファス分散体は、概して化合物1およびポリマーを含む。ポリマーの例としては、セルロースポリマー、例えばHPMCまたはHPMCASおよびピロリドン含有ポリマー、例えばPVP/VAがある。固体アモルファス分散体は、1種以上の追加的賦形剤、例えば界面活性剤を含む。
ポリマーは、化合物1の物理的および/または化学的安定性を高めるべきである。
ポリマーは、化合物1の製造可能性を改善するべきである。
ポリマーは、化合物1の取扱い、投与または貯蔵特性の一つまたはそれ以上を改善するべきである。
ポリマーは、他の医薬成分、例えば賦形剤と不利な形で相互作用するべきではない。
固体分散体または他の組成物は、界面活性剤を含み得る。界面活性剤または界面活性剤混合物は、一般に固体分散体と水性媒質間の界面張力を減少させる。適当な界面活性剤または界面活性剤混合物はまた、固体分散体からの化合物1の水溶性および生物学的利用能を向上させ得る。本発明に関して使用される界面活性剤には、ソルビタン脂肪酸エステル類(例えば、Spans(登録商標))、ポリオキシエチレンソルビタン脂肪酸エステル類(例えば、Tweens(登録商標))、ラウリル硫酸ナトリウム(SLS)、ドデシルベンゼンスルホン酸ナトリウム(SDBS)ジオクチルナトリウムスルホサクシネート(ドキュセート)、ジオキシコール酸ナトリウム塩(DOSS)、ソルビタンモノステアレート、ソルビタントリステアレート、ヘキサデシルトリメチルアンモニウムブロミド(HTAB)、N−ラウロイルサルコシンナトリウム、オレイン酸ナトリウム、ミリスチン酸ナトリウム、ステアリン酸ナトリウム、パルミチン酸ナトリウム、Gelucire 44/14、エチレンジアミン四酢酸(EDTA)、ビタミンEd−アルファトコフェリルポリエチレングリコール1000サクシネート(TPGS)、レシチン、MW677−692、グルタン酸一ナトリウム一水和物、ラブラソール、PEG8カプリル/カプリン酸グリセリド、トランスクトール、ジエチレングリコールモノエチルエーテル、ソルトールHS−15、ポリエチレングリコール/ヒドロキシステアレート、タウロコール酸、プルロニックF68、プルロニックF108、およびプルロニックF127(または他のいずれかのポリオキシエチレン−ポリオキシプロピレンコポリマー類(Pluronics、登録商標)または飽和ポリグリコール化グリセリド(Gelucirs 、登録商標))があるが、これらに限定はされない。本発明に関して使用され得る上記界面活性剤の具体例には、Span 65、Span 25、Tween20、Capryol90、Pluronic F108、ラウリル硫酸ナトリウム(SLS)、ビタミンE TPGS、プルロニックおよびコポリマーがあるが、これらに限定はされない。SLSが一般的には好ましい。
化合物1の固体形態は、化合物1の製造に使用する方法により異なり得る。例えば、化合物1は、結晶性化合物1、例えば形態Aまたは形態Bを提供する方法を用いて製造され得るか、または化合物1は、例えばニート(純)調製物として、または化合物1が分散体、例えば固体アモルファス分散体(例えば、化合物1およびポリマー、例えばセルロースポリマー、例えばHPMCまたはHPMCASまたはピロリドンポリマー、例えばPVP/VAの分散体)における一成分である場合、アモルファス化合物1を提供する方法を用いて製造され得る。
化合物1の形態Aは、例えば化合物1をその融点またはそれより高温、例えば約250℃に加熱し、次いで化合物を冷却して、形態Aの固体を有する化合物1を生成させることにより製造され得る。形態Aは、XRPDを用いて測定される1個以上の特有のピークを特徴とし得る。例えば、形態Aとしての化合物1は、約5.0、例えば4.99、約7.8、例えば7.75、約8.5、例えば8.46、約9.2、例えば9.21、約9.9、例えば9.92、約11.9、例えば11.93、約12.6、例えば12.64、約13.9、例えば13.88、約14.9、例えば14.91、約15.6、例えば15.58、約16.5、例えば16.46、約18.1、例えば18.09、約18.5、例えば18.52、約21.7、例えば20.65、約22.0、例えば21.95、約23.5、例えば23.49、約25.3、例えば25.26、約28.0、例えば28.02、約29.4、例えば29.35、および約30.9、例えば30.85またはその前後でのピークの1個以上を含む、2θでの1個以上のピークの存在により同定され得る。
化合物1の形態Bは、例えば、溶媒中の化合物1のスラリーを加熱および冷却サイクルにかけることにより製造され得る。
アモルファス化合物1は、例えば、化合物1の溶液の噴霧乾燥によりアモルファス化合物1を例えばニート固体または固体分散体の一成分として得る方法を含む様々な技術を用いて製造され得、上記方法では、噴霧乾燥手段を用いて上記変換を行わせる。例えば、アモルファス化合物1は、化合物を溶液中に溶かし、化合物1の溶液を噴霧乾燥することにより、化合物1の一形態、例えば化合物1の結晶形態、例えば形態Aまたは形態Bを、化合物1の実質的アモルファス形態に変換することにより製造することができ、それによって化合物1の一形態、例えば結晶性化合物1はアモルファス化合物1に変換され得る。形態Bを化合物1の実質的アモルファス形態に変換することによるアモルファス化合物1の製造方法の一例を実施例で記載する。
医薬上許容される組成物
本発明の別の特徴は、医薬上許容される組成物であり、これらの組成物は、本明細書記載の化合物のいずれかを含み、さらに所望により医薬上許容される担体、補助薬またはビヒクルを含んでいてもよい。ある種の態様において、これらの組成物は、所望によりさらに1種以上の追加的治療薬を含んでいてもよい。
さらなる特徴として、本発明は、CFTRが関与する状態、疾患または障害の処置方法を提供する。ある態様において、本発明は、CFTR活性の欠損が関与する状態、疾患または障害の処置方法であって、本明細書記載の化合物1の固体形態(例えば、形態A、形態B、またはアモルファス化合物1、例えばニートまたは分散体における一成分として)を含む組成物を、それを必要とする対象、好ましくは哺乳類に投与することを含む方法を提供する。
方法および原材料
示差走査熱量測定(DSC)
DSC Q100 V9.6 Build 290(TA Instruments、ニューキャッスル、デラウェア)を用いて、形態A、形態Bおよびアモルファス化合物1の示差走査熱量測定(DSC)データを集めた。温度をインジウムで測定し、熱容量をサファイアで測定した。3〜6mgの試料を秤量してアルミニウムパンに入れ、1個のピンホールがあるリッドを用いてセットした。試料を25℃から350℃まで、10℃/分の加熱速度および50ml/分の窒素ガスパージにより走査した。データをThermal Advantage Q SeriesTM バージョン2.2.0.248ソフトウェアにより集め、Universal Analysis ソフトウェアバージョン4.1D(TA Instruments、ニューキャッスル、デラウェア)により分析した。記録された数は単分析結果を表す。
熱重量測定に使用されるTGA Q500 V6.3 Build 189(TA Instruments、ニューキャッスル、デラウェア)により熱重量測定(TGA)を実施した。温度をニッケルでキュリー点まで平衡させた。10〜20mgの試料を25℃から350℃まで10℃/分の加熱速度で走査した。10ml/分の窒素ガスバランスパージおよび90ml/分の試料パージを用いた。データをThermal Advantage Q SeriesTM バージョン2.2.0.248ソフトウェアにより集め、Universal Analysis ソフトウェアバージョン4.1D(TA Instruments、ニューキャッスル、デラウェア)により分析した。記録された数は単分析結果を表す。
形態A、形態B、およびアモルファス化合物1のX線回折(XRD)データを、HI−STAR 2次元検出装置および平型グラファイト製モノクロメーターを伴うGADDS粉末回折計を備えた Bruker D8 DISCOVERで収集した。K□線照射でのCuシールX線管を40kV、35mAで使用した。試料を25℃のゼロ−バックグラウンドのシリコンウェハー上に置いた。各試料について、各々2つの異なる2□角度:8°および26°で、2つのデータフレームを120秒で集めた。フレームデータをGADDSソフトウェアにより処理し、DIFFRACTplusEVAソフトウェアでマージした。
アニリン(25.6g、0.275mol)および2−(エトキシメチレン)マロン酸ジエチル(62.4g、0.288mol)の混合物を、140〜150℃で2時間加熱した。混合物を室温に冷却し、減圧下で乾燥することにより、2−フェニルアミノメチレン−マロン酸ジエチルエステルを固体として得て、それ以上精製せずに次の工程で使用した。1H NMR(DMSO−d6)δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H), 7.36−7.39 (m, 2H), 7.13−7.17 (m, 3H), 4.17−4.33 (m, 4H), 1.18−1.40 (m, 6H)。
撹拌装置を備えた1Lの三口フラスコに、2−フェニルアミノメチレン−マロン酸ジエチルエステル(26.3g、0.100mol)、ポリリン酸(270g)およびホスホリルクロリド(750g)を注いだ。混合物を70℃に加熱し、4時間撹拌した。混合物を室温に冷却し、濾過した。残留物をNa2CO3水溶液で処理し、濾過し、水で洗浄し、乾燥した。4−ヒドロキシキノリン−3−カルボン酸エチルエステルを淡褐色固体として得た(15.2g、70%)。粗生成物をそれ以上精製せずに次の工程で使用した。
4−ヒドロキシキノリン−3−カルボン酸エチルエステル(15g、69mmol)を、水酸化ナトリウム溶液(2N、150mL)に懸濁し、還流温度で2時間撹拌した。冷却後、混合物を濾過し、濾液を2NのHClによりpH4に酸性化した。生じた沈殿物を濾過により集め、水で洗浄し、真空乾燥することにより、青白い固体として4−オキソ−1,4−ジヒドロキノリン−3−カルボン酸を得た(10.5g、92%)。1H NMR (DMSO−d6) δ 15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d, J= 8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.60 (m, 1H)。
クロロ蟻酸メチル(58mL、750mmol)を、氷水浴で0℃に冷却しておいたジクロロメタン(400mL)中の2,4−ジ−tert−ブチル−フェノール(103.2g、500mmol)、Et3N(139mL、1000mmol)およびDMAP(3.05g、25mmol)の溶液に滴下した。混合物を一晩撹拌しながら、そのまま室温に温め、次いで、溶離液として10%酢酸エチル−ヘキサン(〜4L)を用いてシリカゲル(約1L)により濾過した。濾液を合わせて濃縮することにより、黄色油状物として炭酸2,4−ジ−tert−ブチル−フェニルエステルメチルエステルを得た(132g、定量的)。1H NMR (400MHz, DMSO−d6) δ 7.35 (d, J=2.4 Hz, 1H), 7.29 (dd, J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H), 1.29 (s, 9H)。
氷水浴中で冷却しておいた、濃硫酸(2mL)中の炭酸2,4−ジ−tert−ブチル−フェニルエステルメチルエステル(4.76g、180mmol)の撹拌混合物に、硫酸(2mL)および硝酸(2mL)の冷却混合物を滴下した。反応温度が50℃を超えることのないように、滴下をゆっくりと行った。反応物をそのまま室温に温めながら2時間撹拌した。次いで、反応混合物を氷水に加え、ジエチルエーテル中に抽出した。エーテル層を乾燥(MgSO4)し、濃縮し、カラムクロマトグラフィー(0〜10%酢酸エチル−ヘキサン)により精製して、炭酸2,4−ジ−tert−ブチル−5−ニトロ−フェニルエステルメチルエステルおよび炭酸2,4−ジ−tert−ブチル−6−ニトロ−フェニルエステルメチルエステルの混合物を淡黄色固体として得て(4.28g)、次の工程で直接使用した。
炭酸2,4−ジ−tert−ブチル−5−ニトロ−フェニルエステルメチルエステルおよび炭酸2,4−ジ−tert−ブチル−6−ニトロ−フェニルエステルメチルエステルの混合物(4.2g、14.0mmol)を、MeOH(65mL)に溶かした後、KOH(2.0g、36mmol)を加えた。混合物を室温で2時間撹拌した。次いで、濃HClを加えることにより、反応混合物を酸性化(pH2〜3)し、水およびジエチルエーテル間に分配した。エーテル層を乾燥(MgSO4)し、濃縮し、カラムクロマトグラフィー(0〜5%酢酸エチル−ヘキサン)により精製して、2,4−ジ−tert−ブチル−5−ニトロ−フェノール(1.31g、2段階にわたって29%)および2,4−ジ−tert−ブチル−6−ニトロ−フェノールを得た。2,4−ジ−tert−ブチル−5−ニトロ−フェノール:1H NMR (400MHz, DMSO−d6) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H), 1.36 (s, 9H), 1.30 (s, 9H)。2,4−ジ−tert−ブチル−6−ニトロ−フェノール:1H NMR (400MHz, CDCl3) δ11.48 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.66 (d, J= 2.4 Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H)。
エタノール(75mL)中の2,4−ジ−tert−ブチル−5−ニトロ−フェノール(1.86g、7.40mmol)および蟻酸アンモニウム(1.86g)の還流溶液に、Pd−5重量%・活性炭(900mg)を加えた。反応混合物を還流温度で2時間撹拌し、室温に冷却し、セライトで濾過した。セライトをメタノールで洗浄し、濾液を合わせて濃縮することにより、灰色固体として5−アミノ−2,4−ジ−tert−ブチル−フェノールを得た(1.66g、定量的)。1H NMR (400 MHz, DMSO−d6) δ 8.64 (s, 1H, OH), 6.84 (s, 1H), 6.08 (s, 1H), 4.39 (s, 2H, NH2), 1.27 (m, 18H); HPLC保持時間 2.72 分、10−99 % CH3CN, 5分実施; ESI−MS 222.4 m/z [M+H]+。
化合物1に関する1H NMRデータを図2に示す。
化合物1のDSCトレースを図3に示す。
固体としての化合物1を250℃に加熱し、室温に冷却することにより、形態Aを得た。化合物1に関するDSC自記温度記録図(図6参照)は、化合物において195℃の開始温度では溶融が起こり、220℃の開始温度では再結晶化が起こることを示す。
形態Aに関するDSCデータを図5に示す。
形態Aに関するTGAトレースを図6に示す。
粗化合物1は、24時間還流しているアセトニトリル(27倍容量)中ではスラリーであった。24時間後、混合物を20℃に放冷した。形態Bが、濾過により白色〜オフホワイト色物質として単離された。湿ったケーキをアセトニトリル(5倍容量)ですすぎ、恒量となるまで50℃で真空乾燥することにより、形態Bを得た。
形態Bに関するDSCトレースを図8に示す。
形態Bに関するTGAトレースを図9に示す。
1gの化合物1を、10mlのイソプロパノールアセテートに加えた。懸濁液を加熱し、3時間60℃で放置した。懸濁液を室温に冷却し、そのまま一晩撹拌した。懸濁固体を濾過し、イソプロパノールアセテートで洗浄した。集めた固体を室温で真空乾燥した。300mgの乾燥固体を5mlの10%酢酸エチル水溶液に溶かした。溶液を10分間70℃に加熱した後、室温に冷却した。時間経過に伴い、結晶はバイアル中で生長した。
形態Bの単晶を、MicroMount ループに載せ、シールした銅X線管および Apex II CCD検出器を備えた Bruker Apex II 回折計の中心に置いた。最初に、40フレームの3セットを集めて、予備的単位格子を測定した。それに続いて、15スキャンおよび6084フレームからなる完全データセットを得た。データ収集を100Kで実施した。Bruker AXS からの Apex II ソフトウェアを用いて、データを集中処理およびスケーリングした。集中処理およびスケーリングの結果、7528の反射データを得、そのうち3071はユニークであった[R(int)=0.0466]。SHELXTLソフトウェアを用いて、空間群P21における直接的方法により構造を分解した。同じくSHELXTLソフトウェアを用いて、F2でのフル−マトリックス最小二乗法により精密化を行った。375のパラメーターを合わせて精密化で用いることにより、8.19の対パラメーター反射比を得た。最終精密化により、0.0(3)のFlack パラメーターを有するキラル構造が得られた。最終精密化指数はwR2=0.1242およびR1=0.0663(I>2シグマ(I)の反射データについてはwR2=0.1137およびR1=0.0482)であった。
この方法では、下記の条件下で Buchi スプレードライヤーを用いた。
入口温度設定点:130℃
出口温度(開始時)55℃
出口温度(終了時):58℃
窒素圧:120psi
吸引装置:100%
ポンプ:40%
フィルター圧:11mbar
冷却器温度:10℃
実行時間:15分
収率:86.5%
24時間25℃真空中で乾燥。
4gの形態Bを、上記条件下で86.4gのアセトンおよび9.6gの水に溶解した。実行時間は15分であった。生成物を24時間にわたって25℃で真空乾燥することにより、アモルファス形態を生成した。
アモルファス形態に関するTGAトレースを図12に示す。
アモルファス形態に関するDSCトレースを図13に示す。
結晶形態B、85%アモルファス化合物1および化合物1のHPMCAS固体分散体の生物学的利用能をラットで評価することにより、下記表Aに示す結果を得た。これらの化合物形態を、0.5%メチルセルロース/0.5%SLS/99%水を含むビヒクルによる経口懸濁液で投与した。様々な固体形態の生物学的利用能を、化合物1の多成分IV溶液の場合と比べて評価した。結晶性多形Bの生物学的利用能は、アモルファス物質に関する61〜95%および固体分散体に関する109〜111%と比べて、3〜6%であった。FaSSIFでは、結晶性多形Bは、1.0μg/mlの実測溶解度を有し、85%アモルファス物質は、67.4μg/mlの溶解度を有する。結晶性物質は、PEG溶液として投与したとき、67〜74%の生物学的利用能を示したことから、吸収が溶解度制限されていることがわかる。
Claims (3)
- N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体アモルファス。
- 15%未満の割合で結晶性N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドを含む、N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体アモルファス。
- N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体アモルファスを含む、医薬組成物。
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JP2015096539A (ja) * | 2005-12-28 | 2015-05-21 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | N−[2,4−ビス(1,1−ジメチルエチル)−5−ヒドロキシフェニル]−1,4−ジヒドロ−4−オキソキノリン−3−カルボキサミドの固体形態 |
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