JP2022500456A - キナゾリン化合物及びその塩酸塩の結晶形 - Google Patents
キナゾリン化合物及びその塩酸塩の結晶形 Download PDFInfo
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Abstract
Description
本出願は、その開示全体が参照により本明細書に組み込まれる2018年9月14日に出願された米国特許仮出願第62/731,500号の利益を主張するものである。
[化学式(1)]
1)化学式(1)のキナゾリン化合物の水和物結晶形、及び
2)化学式(1)のキナゾリン化合物の無水物結晶形、
である。
1)化学式(1)のキナゾリン化合物の塩酸塩の水和物結晶形、
2)化学式(1)のキナゾリン化合物の塩酸塩の無水物結晶形、
である。
Cu−Kα光源で照射されたときに、9.4、13.0、及び18.5°の回折角(2θ±0.2°)でのピークを含む粉末X線回折(XRPD)パターンを有する化学式(1)の化合物の二水和物(2H2O)結晶形、
Cu−Kα光源で照射されたときに、6.0、18.3、及び22.7°の回折角(2θ±0.2°)でのピークを含むXRPDパターンを有する化学式(1)の化合物の無水物結晶形I、
Cu−Kα光源で照射されたときに、4.9、5.9、及び11.8°の回折角(2θ±0.2°)でのピークを含む粉末X線回折パターンを有する化学式(1)の化合物の無水物結晶形II、
Cu−Kα光源で照射されたときに、8.9、13.4、21.1、及び23.5°の回折角(2θ±0.2°)でのピークを含む粉末X線回折パターンを有する化学式(1)の化合物の一塩酸塩一水和物(1HCl・1H2O)結晶形、及び
Cu−Kα光源で照射されたときに、9.5、23.0、23.2、及び23.5°の回折角(2θ±0.2°)でのピークを含むXRPDパターンを有する化学式(1)の化合物の一塩酸塩無水物(1HCl)結晶形、及びまた、
13C CP/MAS TOSS ssNMRスペクトルにおける165.4、156.2、及び147.7ppmの化学シフト(ppm±0.5ppm)を含む13C CP/MAS TOSS(交差分極/マジック角回転TOSS)固体核磁気共鳴(ssNMR)スペクトルを有する化学式(1)の化合物の二水和物(2H2O)結晶形、
13C CP/MAS TOSS固体核磁気共鳴スペクトルにおける156.7、146.9、127.3、及び54.3ppmの化学シフト(ppm±0.5ppm)を含む13C CP/MAS TOSS固体核磁気共鳴スペクトルを有する化学式(1)の化合物の無水物結晶形I、
13C CP/MAS TOSS固体核磁気共鳴スペクトルにおける165.2、156.7、153.1、及び129.2ppmの化学シフト(ppm±0.5ppm)を含む13C CP/MAS TOSS ssNMRスペクトルを有する化学式(1)の化合物の無水物結晶形II、
13C CP/MAS TOSS固体核磁気共鳴スペクトルにおける164.5、157.8、及び145.8ppmの化学シフト(ppm±0.5ppm)を含む13C CP/MAS TOSS固体核磁気共鳴スペクトルを有する化学式(1)の化合物の一塩酸塩一水和物(1HCl・1H2O)結晶形、及び
13C CP/MAS TOSS固体核磁気共鳴スペクトルにおける163.0、158.7、及び146.9ppmの化学シフト(ppm±0.5ppm)を含む13C CP/MAS TOSS固体核磁気共鳴スペクトルを有する化学式(1)の化合物の一塩酸塩無水物(1HCl)結晶形。
本明細書で具体的に定義されない用語は、技術及び文脈に照らして当業者によって認識される意味を有する。しかしながら、特に明記しない限り、本明細書全体を通して、以下の用語は以下に示す意味を有する:
本発明は、以下の化学式(1)の化合物1−(4−(4−(3,4−ジクロロ−2−フルオロフェニルアミノ)−7−メトキシキナゾリン−6−イルオキシ)ピペリジン−1−イル)プロパ−2−エン−1−オン及びその塩酸塩の結晶形を提供する:
[化学式(1)]
化学式(1)の化合物の塩は、結晶形、アモルファス形態、又はその混合物で調製され得るが、塩は結晶形であることが好ましい。化学式(1)の化合物の塩酸塩の結晶形は、処方が容易な、優れた安定性及び物理化学的特性を有するという点で好ましい。
化学式(1)の化合物の二水和物(2H2O)結晶形は、Cu−Kα光源で照射されたときに、9.4、11.4、13.0、16.1、18.5、19.3、24.9、及び26.3°の回折角(2θ±0.2°)でのピークを含むXRPDスペクトルを有する。これらのピークは、相対強度が約10%〜20%またはそれを超えるピークであり得る。
上記の結晶形は、13C CP/MAS TOSS固体核磁気共鳴(交差分極/マジック角回転TOSS固体核磁気共鳴ssNMR)スペクトルにおいて、147.7、156.2、及び165.4ppmの化学シフト(ppm±0.5ppm)を有し得る。
上記の結晶形は、約7.5%の含水率(6.83%の理論含水率)、約117〜122℃の凝縮温度、及び約190〜195℃の融点を有し得る。
上記の結晶形は、DSC(10℃/分)で測定すると、約79℃の開始点から実行したとき約111℃に最低点の吸熱ピークを有し得る。
上記の結晶形は、DVSで測定すると、0〜90%の相対湿度範囲で約2%〜5%の吸湿度を有すると測定され得る。
化学式(1)の化合物の無水物結晶形Iは、Cu−Kα光源で照射されたときに、6.0、10.6、10.9、12.1、16.0、17.5、18.3、19.2、20.3、22.7、23.7、及び26.3°の回折角(2θ±0.2°)でのピークを含むXRPDスペクトルを有する。これらのピークは、相対強度が約10%〜20%またはそれを超えるピークであり得る。
上記の結晶形は、13C CP/MAS TOSS固体核磁気共鳴(ssNMR)スペクトルにおいて、54.3、127.3、146.9、及び156.7ppmの化学シフト(ppm±0.5ppm)を有し得る。
上記の結晶形は、約0.1%の含水率及び約190〜195℃の融点を有し得る。
上記の結晶形は、DSC(10℃/分)で測定すると、約186℃の開始点から実行したとき約191℃に最低点の吸熱ピークを有し得る。
上記の結晶形は、DVSで測定すると10〜50%の範囲の相対湿度範囲で約0.5%の吸湿度及び50〜90%の範囲の相対湿度範囲で約3%の吸湿度を有すると測定され得る。
化学式(1)の化合物の無水物結晶形IIは、Cu−Kα光源で照射されたときに、4.9、5.9、11.8、18.8、及び19.9°の回折角(2θ±0.2°)でのピークを含むXRPDスペクトルを有し得る。これらのピークは、相対強度が約10%〜20%またはそれを超えるピークであり得る。
上記の結晶形は、13C CP/MAS TOSS固体核磁気共鳴(ssNMR)スペクトルにおいて、129.2、153.1、156.7、及び165.2ppmの化学シフト(ppm±0.5ppm)を有し得る。
上記の結晶形は、約0.3%の含水率及び約183〜185℃の融点を有し得る。
上記の結晶形は、DSC(10℃/分)で測定すると、約181℃の開始点から実行したとき約185℃に最低点の吸熱ピークを有し得る。
上記の結晶形は、DVSで測定すると0〜90%の相対湿度範囲で非常に低い吸湿度を有すると測定され得る。
化学式(1)の化合物の一塩酸塩一水和物(1HCl・1H2O)結晶形は、Cu−Kα光源で照射されたときに、8.9、13.4、14.1、16.0、19.8、21.1、21.7、23.5、25.7、及び32.7°の回折角(2θ±0.2°)でのピークを含むXRPDスペクトルを有し得る。これらのピークは、相対強度が約10%〜20%またはそれを超えるピークであり得る。
上記の結晶形は、13C CP/MAS TOSS固体核磁気共鳴(ssNMR)スペクトルにおいて、145.8、157.8、及び164.5ppmの化学シフト(ppm±0.5ppm)を有し得る。
上記の結晶形は、DSC(10℃/分)で測定すると、約127℃の開始点から実行したとき約151℃に最低点の吸熱ピーク、及び約178℃に吸熱ピークを有し得る。
上記の結晶形は、約3.2%の含水率(理論含水率3.30%)及び約187〜193℃の融点を有し得る。
上記の結晶形は、DVSで測定すると10〜90%の相対湿度範囲で非常に低い吸湿度を有すると測定され得る。
化学式(1)の化合物の一塩酸塩無水物(1HCl)結晶形は、Cu−Kα光源で照射されたときに、9.5、12.3、13.0、13.5、14.2、21.4、23.0、23.2、23.5、27.2、及び27.5°の回折角(2θ±0.2°)でのピークを含むXRPDスペクトルを有し得る。これらのピークは、相対強度が約10%〜20%またはそれを超えるピークであり得る。
上記の結晶形は、13C CP/MAS TOSS固体核磁気共鳴(ssNMR)スペクトルにおいて146.9、158.7、及び163.0ppmの化学シフト(ppm±0.5ppm)を有し得る。
上記の結晶形は、DSC(10℃/分)で測定すると、約201℃の開始点から実行したとき約230℃に最低点の吸熱ピークを有し得る。
上記の結晶形は、約0.1%の含水率及び約238〜243℃の融点を有し得る。
上記の結晶形は、DVSで測定すると10〜90%の相対湿度範囲で非常に低い吸湿度を有すると測定され得る。
(a)溶媒系(極性、非プロトン性、又はこれらの混合)中の化学式(1)の化合物の溶液を提供することと、
(b)化学式(1)の化合物の結晶形(水和物又は無水物)の形成をもたらすために溶液を冷却することと、
(c)化学式(1)の化合物の結晶形(水和物又は無水物)を単離すること、
を含む。
(a)溶媒系(極性、非プロトン性、又はこれらの混合)中の化学式(1)の化合物の溶液を提供することと、
(b)溶液に塩酸を加えることと、
(c)化学式(1)の化合物の塩酸塩の結晶形(水和物又は無水物)の形成をもたらすために溶液を冷却することと、
(d)化学式(1)の化合物の塩酸塩の結晶形(水和物又は無水物)を単離すること、
を含む。
それらの全体が本明細書に組み込まれる韓国特許第1,013,319号及び米国特許第8,003,658号で開示されるように、化学式(1)の化合物は、抗癌活性などの増殖抑制活性を有し、チロシンキナーゼ又はその変異体により誘発される癌細胞の増殖及び薬剤耐性を選択的且つ効果的に阻害する作用を有することが証明された。
本発明の別の態様は、本明細書に記載の新規結晶形、その医薬組成物、1つ以上の薬剤との組み合わせ、又は新規結晶形を含むキットを、それを必要としている患者に投与することを含む、患者における新生物を治療する方法を提供する。
1.粉末X線回折(XRPD)
粉末X線回折(XRPD)分光法を、サンプルに対し3°2θ〜40°2θでD8 Advance(Bruker ASX、ドイツ)分析器で行った。サンプル量が<100mgのとき、約5〜10mgのサンプルを、サンプルホルダに嵌めたスライドガラス上に静かに押し付けた。サンプル量が>100mgのとき、約100mgのサンプルを、サンプル表面が滑らかでありかつサンプルホルダレベルの少し上であるように、プラスチック製のサンプルホルダ上に静かに押し付けた。
測定は以下のように行った:
アノード材料(Kα):Cu−Kα(1.54056A)
走査範囲:3〜40°
ジェネレータ設定:100mA、40.0kV
走査速度:1秒/ステップ
発散スリットサイズ(ダイバースリット):0.3°
散乱防止スリット:0.3°
温度:20℃
ステップサイズ:0.02°2θ
回転:使用
ゴニオメータ半径:435mm
示差走査熱量計(DSC)分析を、30〜350℃にてSTA−1000(Scinco、韓国)分析器で行った。5〜10mgのサンプルをアルミニウムDSCパンに秤量し、有孔アルミニウム蓋で非密閉的に蓋をし、次いでサンプルを30℃から350℃に加熱することにより生じる熱流反応(DSC)を10℃/分の走査速度で監視した。
動的蒸気吸脱着測定(DVS)分析を、25℃及び相対湿度0〜90%にてDVS advantage(Surface measurement system、英国)分析器で行った。
10mgのサンプルを金網蒸気収着バランスパンに入れ、Surface measurement systemのDVS−advantage動的蒸気吸着バランスに取り付けた。サンプルに、安定な重量が達成される(99.5%ステップ完了)まで各ステップでサンプルを維持しながら10%増分で相対湿度(RH)10〜90%のランピングプロファイルを適用した。収着サイクルの完了後に、同じ手順を用いてサンプルを乾燥させ、その間、相対湿度を常に0%未満の相対湿度に戻した。サンプルの吸湿性を求めるために、収着/脱着サイクル(3回繰り返し)中の重量の変化を記録した。
核磁気共鳴分光計を用いて固体状態での結晶多形を比較する目的で、固体核磁気共鳴(ssNMR)分析を、100mgのサンプルを4mmのサンプルチューブに入れた後にBruker Avance II 500MHz固体NMRシステム(Bruker、ドイツ)分析器を用いて室温で行った。13C NMRスペクトル(13C CP/MAS TOSS ssNMR)の分析条件は以下の通りである。
周波数:125.76MHz
スペクトル幅:20kHz
マジック角でのサンプル回転速度:5kHz
パルスシーケンス:デカップリング付きCP(交差分極)SPINAL 64(デカップリングパワー80kHz)
繰り返し遅延:5秒
接触時間:2ms
走査数:4096
外部標準:アダマンタン
高速液体クロマトグラフィ(HPLC)を、安定性試験などを含む純度及び含有量の分析を目的として、Agilent 1100/1200シリーズHPLCシステム(Agilent、米国)分析器で行った。HPLCの分析条件は以下の通りである。
純度及び含有量の分析条件:化学式(1)のチエノピリミジン化合物
カラム:Hydrosphere C18(YMC)、5μm(150mm×4.6mm)
カラム温度:30℃
検出器:紫外吸光光度計
検出波長:254nm
流量:1.0mL/分
分析時間:35分
溶離液:NaClO4−NaH2PO4−リン酸緩衝液(pH2.5±0.1)/CH3CN=40/60(v/v%)
イオンクロマトグラフ(IC)分析を、塩酸塩中の塩酸の含有量分析を目的として、Thermo Fisher Scientific ICS−2500シリーズICシステム(Thermo Fisher Scientific、米国)分析器で行った。ICの分析条件は以下の通りである。
含有量の分析条件:化学式(1)のチエノピリミジン化合物
カラム:IonPac AS19(Dionex)、(250mm×4mm)、Guard(50mm×4mm)
カラム温度:30℃
検出器:電気伝導度検出器(CD)
サプレッサ:ASRS 4mm、電流40mA
流量:1.0ml/分
分析時間:30分
溶離液:10mM水酸化カリウム溶液
水分測定を、795KFT Titrino(Metrohm、スイス)Karl−Fischer水分計を用いて行った。
融点測定を、IA9200(Electrothermal、英国)融点装置を用いて行った。
本明細書で引用した韓国特許登録番号第1,013,319号及び米国特許第8,003,658号の方法又は同様の方法に従い調製した化学式(1)の化合物100gを、300mlのジクロロメタンと300mlのメタノールの混合溶液に溶解し、40℃で30分間攪拌し、不溶性固体を、濾紙を用いて濾過した。減圧下での蒸留は、93g(収率93%)の表題化合物をもたらした。
含水率:2.1%
参考実施例で調製した化学式(1)の化合物のXRPD、ssNMR、DSC、及びDVSの分析結果を、それぞれ図1G、図2G、及び図4Gに示す。
また、参考実施例の化合物は、ssNMRスペクトルにおいてブロードなピークを示し、これはアモルファス構造の典型的なピークパターンである。
また、参考実施例の化合物は、DSC(10℃/分)で測定したとき、どのような特定の吸熱発熱曲線も呈さなかった。
また、参考実施例の化合物は、DVSで測定したとき、10〜90%の相対湿度範囲で1〜3%の水分を継続的に吸収する傾向を示した。
また、アモルファス形態の含水率は、Karl−Fischer水分計で測定したとき、2.1%であり、特徴的な融点は観察されなかった。
実施例1.化学式(1)の化合物の二水和物(2H2O)結晶形の調製
参考実施例の化学式(1)の化合物10.0gに、80mLのアセトンと20mlの水を加え、続いて、還流下で加熱することにより化学式(1)の化合物を完全に溶解させ、次いで20〜25℃に冷却し、4時間攪拌した。得られた固体を濾過し、20mLの4:1のアセトン:水の混合溶媒で洗浄した。濾過した固体を50℃で乾燥させて10g(収率:93%)の表題化合物を得た。
含水率:7.5%(二水和物の理論値:6.83%)
実施例1で調製した結晶形のXRPD、ssNMR、DSC、及びDVSの分析結果を、それぞれ図1A、図2A、図3A、及び図4Aに示す。
この結晶形は、Karl−Fischer水分計で約7.5%の含水率(6.83%の理論含水率)を呈し、約117〜122℃の凝縮温度及び約190〜195℃の融点を示した。
この結晶形の吸湿度は、DVSで測定したとき、10%〜90%の相対湿度範囲で約2%〜5%であった。
実施例1の方法によって得られた化学式(1)の化合物5.0gに、50mLのアセトンを加え、次いで20〜25℃で6時間攪拌した。得られた固体を濾過し、7.5mLのアセトンで洗浄した。濾過した固体を50℃で乾燥させて3.7g(収率:80%)の表題化合物を得た。
含水率:0.1%
実施例2で調製した結晶形のXRPD、ssNMR、DSC、及びDVSの分析結果を、それぞれ図1B、図2B、図3B、及び図4Bに示す。
この結晶形は、Karl−Fischer水分計で測定したとき、約0.1%の含水率を呈し、約190〜195℃で融点を示した。
この結晶形の吸湿度は、DVSで測定すると、10%〜50%の相対湿度範囲で約0.3〜0.5%のレベルであり、これは非常に低く、50〜90%の範囲での吸湿度は、約3%のレベルであると測定された。
実施例2の化学式(1)の化合物2.0gに、20mLのアセトニトリルを加え、続いて70〜80℃で2時間加熱及び攪拌し、次いで20〜25℃で12時間攪拌した。得られた固体を濾過し、5mLのアセトニトリルで洗浄した。濾過した固体を50℃で乾燥させて1.7g(収率:85%)の表題化合物を得た。
含水率:0.3%。
実施例3で調製した結晶形のXRPD、ssNMR、DSC、及びDVS分析結果を、それぞれ図1C、図2C、図3C、及び図4Cに示す。
この結晶形は、Karl−Fischer水分計で測定すると、約0.3%の含水率を呈し、約183〜185℃の融点を示した。
この結晶形の吸湿度は、DVSで測定すると、10%〜90%の相対湿度範囲で約0.7%のレベルであり、これは非常に低い。この結晶形は、長期保管条件(例えば、25℃で相対湿度60%)、加速条件(例えば、40℃で相対湿度75%)、及び過酷条件(例えば、60℃)で十分に安定であった。
参考実施例又は実施例1〜3の方法によって調製した化合物10gに、100mlのエタノール:水(9:1)の混合溶媒を加えた。4.9mLの35%濃塩酸を加え、室温で6時間攪拌した。得られた固体を濾過し、30mLのエタノールで洗浄した。濾過した固体を50℃で乾燥させて9.1g(収率:82%)の表題化合物を得た。
含水率:3.2%(一水和物の理論値:3.3%)
イオンクロマトグラフィ:6.5%(一塩酸塩の理論値:6.92%)
実施例4で調製した結晶形のXRPD、ssNMR、DSC、及びDVSの分析結果を、それぞれ図1D、図2D、図3D、及び図4Dに示す。
この結晶形は、Karl−Fischer水分計で測定すると約3.2%の含水率を呈し、約187〜193℃の融点を示した。
この結晶形の吸湿度は、DVSで測定すると、10%〜90%の相対湿度範囲で約0.4%のレベルであり、これは非常に低い。この結晶形は、長期保管条件(例えば、温度25℃及び相対湿度60%)及び加速条件(例えば、温度40℃及び相対湿度75%)で水分を吸収して一水和物結晶形を維持すると予想できる。
実施例2と同様の方法で調製した20gの無水化合物1に、60mLのDMSOを加えた。5.1mLの35%濃塩酸を加え、混合物を室温で6時間攪拌した。得られた固体を濾過し、40mLのDMSOで洗浄した。濾過した固体を50℃で乾燥させて18.3g(収率:85%)の表題化合物を得た。
含水率:0.1%
イオンクロマトグラフィ:6.6%(一塩酸塩の理論値:6.92%)
実施例5で調製した結晶形のXRPD、ssNMR、DSC、及びDVSの分析結果を、それぞれ図1E、図2E、図3E、及び図4Eに示す。
この結晶形は、Karl−Fischer水分計で約0.1%の含水率を呈し、約238〜243℃の融点を示した。
この結晶形の吸湿度は、DVSで測定すると、10%〜90%の相対湿度範囲で約0.35%のレベルであり、これは非常に低い。この結晶形は、長期保管条件(例えば、温度25℃及び相対湿度60%)及び加速条件(例えば、温度40℃及び相対湿度75%)で水分を吸収せずに、無水物の結晶形を維持した。
実施例5で得られた式1の化合物の無水物結晶形5gを、150mLのメタノールに溶解した。溶液をフィルタで濾過して異物を除去し、濾過液を減圧下で濃縮して、固体として4.9g(収率:98%)の表題化合物を得た。
含水率:1.2%
実施例6で調製したアモルファス形態のXRPD、DVS、及びssNMRの分析結果を、それぞれ図1F、図2F、及び図4Fに示す。
加えて、アモルファス形態は、DVSで測定すると、10〜90%の相対湿度範囲で非常に高い吸湿度を呈した。これにより、それは長期保管条件(温度25℃及び相対湿度60%)及び加速条件(温度40℃及び相対湿度75%)下で水分を吸収することにより不安定であると予想される。実際に、7〜9%の水分吸収が、25℃で相対湿度60%の条件及び40℃で相対湿度75%の条件下で確認された。
加えて、アモルファス形態の含水率は、Karl−Fischer水分計で測定すると、1.2%であり、特徴的な融点は観察されなかった。
塩酸塩のアモルファス形態と塩酸塩の結晶多形の溶解度を比較するために、実施例4〜6で調製した化学式(1)の化合物の塩酸塩の多形及びアモルファス形態のそれぞれを用いて、脱イオン水及び酸性度(pH)による以下の条件下でサンプルを調製した。その後、各溶液を、高速液体クロマトグラフィ(HPLC)で化学式(1)の化合物の含有量の測定条件に従って分析して、化学式(1)の化合物に基づく溶解量(LOD:0.1μg/mL)を測定した。測定値から計算した結果を、以下の表11に示す。
したがって、化学式(1)の化合物の塩酸塩の無水物結晶形は、溶出などを考慮したとき、医薬組成物に関して最も有利であると予想される。
塩酸塩のアモルファス形態と塩酸塩の結晶多形の安定性を比較するために、実施例4〜6で調製した化学式(1)の化合物の塩酸塩の多形及びアモルファス形態のサンプルのそれぞれを、長期条件(例えば、温度25±2℃及び相対湿度60±5%)及び加速条件(例えば、温度40℃及び相対湿度75%)下で4週間おいた。各サンプルを、化学式(1)の化合物の純度測定条件に従い高速液体クロマトグラフィ(HPLC)により分析した。純度測定値(%)を、以下の表12に示す。
Claims (24)
- 化学式(1)の化合物の結晶形であって、
[化学式(1)]
かつ前記結晶形が、
(a)Cu−Kα光源で照射されたときに9.4°±0.2°、13.0°±0.2°及び18.5°±0.2°の回折角2θ値でのピークを含む粉末X線回折(XRPD)パターンを有する化学式(1)の化合物の二水和物(2H2O)結晶形、
(b)Cu−Kα光源で照射されたときに6.0°±0.2°、18.3°±0.2°及び22.7°±0.2°の回折角2θ値でのピークを含むXRPDパターンを有する化学式(1)の化合物の無水物形態I、
(c)Cu−Kα光源で照射されたときに4.9°±0.2°、5.9°±0.2°及び11.8°±0.2°の回折角2θ値でのピークを含むXRPDパターンを有する化学式(1)の化合物の無水物形態II、
(d)Cu−Kα光源で照射されたときに8.9°±0.2°、13.4°±0.2°、21.1°±0.2°及び23.5°±0.2°の回折角2θ値でのピークを含むXRPDパターンを有する化学式(1)の化合物の一塩酸塩一水和物(1HCl・1H2O)結晶形、及び
(e)Cu−Kα光源で照射されたときに9.5°±0.2°、23.0°±0.2°、23.2°±0.2°及び23.5°±0.2°の回折角2θ値でのピークを含むXRPDパターンを有する化学式(1)の化合物の一塩酸塩無水物の結晶形、
からなる群から選択される、結晶形。 - 前記結晶形の化学純度が、95%を超える、請求項1に記載の化学式(1)の化合物の結晶形。
- 前記結晶形が、前記(a)に記載のものである、請求項1に記載の結晶形。
- 前記結晶形が、前記(b)に記載のものである、請求項1に記載の結晶形。
- 前記結晶形が、前記(c)に記載のものである、請求項1に記載の結晶形。
- 前記結晶形が、前記(d)に記載のものである、請求項1に記載の結晶形。
- 前記結晶形が、前記(e)に記載のものである、請求項1に記載の結晶形。
- 前記結晶形が、前記(a)に記載のものであり、かつ前記結晶形が、147.7±0.5、156.2±0.5及び165.4±0.5ppmの化学シフトでのピークを含む13C固体核磁気共鳴(ssNMR)スペクトルを有する、請求項1に記載の結晶形。
- 前記結晶形が、前記(b)に記載のものであり、かつ前記結晶形が、54.3±0.5、127.3±0.5、146.9±0.5及び156.7±0.5ppmの化学シフトでのピークを含む13C ssNMRスペクトルを有する、請求項1に記載の結晶形。
- 前記結晶形が、前記(c)に記載のものであり、かつ前記結晶形が、129.2±0.5、153.1±0.5、156.7±0.5及び165.2±0.5ppmの化学シフトでのピークを含む13C ssNMRスペクトルを有する、請求項1に記載の結晶形。
- 前記結晶形が、前記(d)に記載のものであり、かつ前記結晶形が、145.8±0.5、157.8±0.5及び164.5±0.5ppmの化学シフトでのピークを含む13C ssNMRスペクトルを有する、請求項1に記載の結晶形。
- 前記結晶形が、前記(e)に記載のものであり、かつ前記結晶形が、146.9±0.5、158.7±0.5及び163.0±0.5ppmの化学シフトでのピークを含む13C ssNMRスペクトルを有する、請求項1に記載の結晶形。
- 請求項1〜請求項12のいずれか一項に記載の結晶形と、少なくとも1つの薬学的に許容される担体又は希釈剤とを含む医薬組成物。
- 前記医薬組成物が、チロシンキナーゼ又はその変異体によって誘発された癌を治療するために用いられる、請求項13に記載の医薬組成物。
- 前記癌が、固形癌である、請求項14に記載の医薬組成物。
- 前記結晶形の化学純度が、約95%を超える、請求項13に記載の医薬組成物。
- ベヘン酸グリセリル、パルミトステアリン酸グリセリル、モノステアリン酸グリセリル、トリミリスチン酸グリセリル、トリステアリン酸グリセリル、ショ糖脂肪酸エステル、パルミチン酸、パルミトイルアルコール、ステアリン酸、ステアリルアルコール、フマル酸、ポリエチレングリコール4000、ポリエチレングリコール6000、ポリテトラフルオロエチレン、デンプン、タルク、水添ヒマシ油、鉱油、水添植物油、二酸化ケイ素、及びこれらの任意の組み合わせからなる群から選択される非金属塩潤滑剤をさらに含む、請求項13に記載の医薬組成物。
- 金属塩潤滑剤をさらに含む、請求項13に記載の医薬組成物。
- 請求項3に記載の二水和物(2H2O)結晶形を調製する方法であって、
(a)化学式1の化合物をアセトンと水の混合物に加えることであって、前記アセトンと水が、前記化合物が室温で前記混合物中に完全に溶解できないような比率である、加えること
(b)前記化合物が完全に溶解する温度に前記混合物を加熱することと、
(c)前記混合物を冷却すること及びアセトンと水を除去して前記化合物の二水和物(2H2O)を得ること、
を含む、方法。 - 請求項4に記載の無水物形態Iを調製する方法であって、
(a)請求項3に記載の化合物の二水和物(2H2O)をアセトンと混合することと、
(b)前記化合物の無水物形態Iを単離すること、
を含む、方法。 - 請求項5に記載の無水物形態IIを調製する方法であって、
(a)請求項4に記載の化合物の無水物形態Iをアセトニトリルと混合することと、
(b)約80℃を超えるように加熱することと、
(c)冷却すること及び前記化合物の無水物形態IIを単離すること、
を含む、方法。 - 請求項6に記載の一塩酸塩一水和物(1HCl・1H2O)を調製する方法であって、
(a)化学式1の化合物をエタノール、水及び塩酸水溶液と混合することと、
(b)前記化合物の一塩酸塩一水和物(1HCl・1H2O)を単離すること、
を含む、方法。 - 請求項7に記載の一塩酸塩無水物の結晶形を調製する方法であって、
(a)化学式1の無水化合物を非プロトン性極性溶媒及び約30%以上の濃度を有する塩酸と混合することと、
(b)前記化合物の一塩酸塩無水物を単離すること、
を含む、方法。 - 前記非プロトン性極性溶媒が、DMSO又はDMFである、請求項23に記載の方法。
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