JP5452492B2 - 選択的アンドロゲン受容体調節因子の固体形態 - Google Patents
選択的アンドロゲン受容体調節因子の固体形態 Download PDFInfo
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- JP5452492B2 JP5452492B2 JP2010524998A JP2010524998A JP5452492B2 JP 5452492 B2 JP5452492 B2 JP 5452492B2 JP 2010524998 A JP2010524998 A JP 2010524998A JP 2010524998 A JP2010524998 A JP 2010524998A JP 5452492 B2 JP5452492 B2 JP 5452492B2
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- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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Description
a.X線粉末回折パターンが約5.6(15.9),7.5(11.8),8.6(10.3),9.9(8.9),12.4(7.1),15.0(5.9),16.7(5.3),17.3(5.1),18.0(4.9),18.5(4.8),19.3(4.6),19.8(4.5),20.6(4.3),21.8(4.1),22.3(4.0),23.4(3.8),23.9(3.7),24.6(3.6),24.9(3.6),25.4(3.5),26.0(3.4),26.5(3.4),27.8(3.2)の°2θ(d値Å)の角度でピークを含むこと;および
b.融点が約80℃であること
によって特徴付けられる。
a.X線粉末回折パターンが15ないし25 °2θの範囲に2つの高調波ピーク(harmonic peak)を伴う幅広のハロー(halo)を示すこと、および
b.ガラス転移点が約55℃であること
によって特徴付けられる。
a.X線粉末回折パターンが15ないし25 °2θの範囲に2つの高調波ピークを伴う幅広のハロー(halo)を示すこと、および
b.ガラス転移点が約55℃であること
によって特徴付けられる。
a.X線粉末回折パターンが約6.9(12.8)、9.5(9.3)、13.5(6.6)、16.0(5.6)、22.8(3.9)の°2θ(d値Å)の角度で固有のピークを含むこと、
によって特徴付けられる。
a.X線粉末回折パターンが約4.4(19.9),8.5(10.4),8.8(10.0),11.3(7.8),12.7(6.9),13.8(6.4),14.4(6.1),14.6(6.0),15.1(5.8),16.1(5.5),16.6(5.3),16.9(5.2),18.0(4.9),18.7(4.7),19.0(4.6),19.4(4.55),20.8(4.25),22.1(4.0),22.7(3.9),23.1(3.8),23.4(3.8),24.7(3.6),24.9(3.56),25.3(3.51),27.8(3.2),29.3(3.0)の°2θ(d値)の角度で固有のピークを含むこと;および
b.融点が約130℃であること
によって特徴付けられる。
(a)HBrの存在下で、式2の環式化合物の開環によって式1のカルボン酸を調製すること、
(c)式4のアミドを式5の化合物:
ここで、ステップ(c)は炭酸カリウムおよびテトラヒドロフランの存在下で実行される。
(a)HBr12の存在下で、式2の環式化合物の開環によって式1のカルボン酸を調製すること、
(c)式4のアミドを式5の化合物:
(a)HBrの存在下で、式2の環式化合物の開環によって式1のカルボン酸を調製すること、
(c)式4のアミドを式10の化合物:
(a)HBrの存在下で、式2の環式化合物の開環によって式1のカルボン酸を調製すること、
(c)式4のアミドを式13の化合物:
XはO、NH、Se、PR、またはNR;
TはOH、OR、NHCOCH3、またはNHCOR;
Zは、NO2、CN、COOH、COR、NHCOR、またはCONHR;
Yは、CF3、F、I、Br、Cl、CN、CR3、またはSnR3;
Qは、アルキル、ハロゲン、CF3、CN、CR3、SnR3、NR2、NHCOCH3、NHCOCF3、NHCOR、NHCONHR、NHCOOR、OCONHR、CONHR、NHCSCH3、NHCSCF3、NHCSR NHSO2CH3、NHSO2R、OR、COR、OCOR、OSO2R、SO2R、SR;
あるいはQは、それが結合しているベンゼン環とともに、構造A、B、またはCによって表される縮合環系;
R1は、CH3、CH2F、CHF2、CF3、CH2CH3、またはCF2CF3であり;
上記方法は、
a)HBrの存在下で、式16の環式化合物の開環によって式15のカルボン酸を調製すること
(b)式17のアミンを
カップリング試薬の存在下で、式17のカルボン酸と反応させて、式18:
(c)式19の化合物:
と式IIのアミドとを、カップリングさせることを含み、ここで、ステップ(c)は炭酸カリウムおよびテトラヒドロフランの存在下で実行される。
医薬組成物
[0126]一態様では、本発明は、無水(R)または(S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミドの結晶形態と適当な担体または希釈剤とを含む組成物を提供する。
カプセルは、SARMの任意の他の多形体または非晶質SARMとともに、所望の比率の結晶形態Aからなる混合物を含むものであってもよい。所望の百分率組成の所望の結晶形態のカプセルまたは錠剤もまた、他の活性化合物または不活性の充填剤および/もしくは希釈剤、例えば医薬的に許容し得るスターチ(例えばコーン、ポテト、またはタピオカスターチ)、糖、人工甘味料、粉末セルロース(例えば結晶質および微晶性のセルロース)、小麦粉、ゼラチン、ガム等の混合物と組み合わせることも可能である。
(Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein、同書, pp. 317-327を参照せよ;一般に同書を参照せよ)。
[0156]本明細書中に提供される固体形態およびそれを生産する方法は、いくつかの態様において、予期しない生体内(in vivo)のアンドロゲン活性および同化活性を有する経口テストステロン補充療法に有用である、選択的アンドロゲン受容体修飾因子(SARM)に関する。
いくつかの態様では、適切に置換された化合物は前立腺癌を治療するのに効果的で、前立腺癌の画像診断に有用である。
[0170](2R)−1−メタクリロイルピロリジン−2−カルボキシル酸。D−プロリン(14.93g、0.13mol)を71mLの2N NaOHに溶解し、氷浴中で冷やした。結果として得られたアルカリ溶液をアセトン(71mL)で希釈した。メタクリロイルクロリド(13.56g、0.13mol)のアセトン溶液(71mL)および2N NaOH溶液(71mL)を、氷浴中でD−プロリンの溶液に対して、40分以上かけて同時に添加した。メタクリロイルクロリドの添加中、混合物のpHを10〜11℃で保った。撹拌後(3時間、室温)、減圧下(in vacuo)で、混合物を35ないし45℃の温度で蒸発させることで、アセトンを除去した。結果として生じた溶液をエチルエーテルで洗い、濃HClによってpH2に酸性化した。酸性混合物をNaClで飽和させ、EtOAc(100mLx3)で抽出した。合わせた抽出物をNa2SO4上で乾燥させ、セライトによってろ過し、減圧下(in vacuo)で蒸発させることで、無色のオイルとして粗生成物を得た。エチルエーテルおよびヘキサンからのオイルの再結晶化によって、無色の結晶として16.2(68%)の所望の化合物が得られた。融点(mp)102〜103℃(lit.[214]mp102.5〜103.5℃);この化合物のNMRスペクトルは、表題化合物の2つの回転異性体の存在を実証した。1H NMR(300MHz,DMSO−d6)第1の回転異性体に関してはδ5.28(s)および5.15(s)、第2の回転異性体に関しては5.15(s)および5.03(s)(全体として両回転異性体の2H、ビニルCH2)、第1の回転異性体に関して4.48−4.44、第2の回転異性体に関して4.24−4.20(m)(全体として両回転異性体の1H、キラル中心のCH),3.57−3.38(m,2H,CH2),2.27−2.12(1H,CH),1.97−1.72(m,6H,CH2,CH,Me);13C NMR(75MHz,DMSO−d6)δ メジャー回転異性体に関して173.3,169.1,140.9,116.4,58.3,48.7,28.9,24.7,19.5:マイナー回転異性体に関して174.0,170.0,141.6,115.2,60.3,45.9,31.0,22.3,19.7;IR(KBr)3437(OH),1737(C=O),1647(CO,COOH),1584,1508,1459,1369,1348,1178cm−1;[α]D 26+80.8°(c=1,MeOH);C9H13NO3について計算値:C 59.00,H 7.15,N 7.65.実測値:C 59.13,H 7.19,N 7.61.
500mLの2−プロパノール中のブロモアミド((2R)−3−ブロモ−N−[4−シアノ−3−(トリフルオロメチル)フェニル]−2−ヒドロキシ−2−メチルプロパンアミド、50g、0.14mol)、無水K2CO3(59.04g、0.43mol)、および4−シアノフェノール(25.44g、0.21mol)からなる混合物を、3時間にわたって環流加熱し、次に減圧下で濃縮して固体を得た。結果として生じる残留物を500mLのH2Oで処理し、次にEtOAc(2×300mL)で抽出した。合わせたEtOAc抽出物を10%のNaOH(4×200mL)およびブラインで洗った。有機層をMgSO4上で乾燥させ、次に減圧下で濃縮することで、オイルを得た。このオイルを300mLのエタノールと活性炭とで処理した。反応混合物を1時間にわたって環流加熱し、次にこの熱い混合物をセライトで濾過した。濾液を減圧下で濃縮することで、オイルを得た。このオイルを、CH2Cl2/EtOAc(80:20)を用いたカラムクロマトグラフィーで精製し、オイルを得た。このオイルをCH2Cl2/ヘキサンで結晶化することで、無色の固体(綿タイプ)として33.2g(59.9%)の(S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミドを得た。
実施例2 S−1SARM化合物の結晶化
材料と方法
方法:
X線粉末回折(XRPD)
[0176]部分的に結晶化した混合物における液晶物質の結晶構造の決定または該液晶物質の認識に、XRPDを用いた。パナリティカル(PANalytical)X線回折装置PW1710(管状の陽極がCu−Ka線)を用いてXRPDを実施した。ステップ走査方式(ステップサイズ0.02°2θ、カウント時間2.4分/ステップ)でパターンを収集した。平坦な面を得るために僅かな圧力を与えること以外は、いかなる特別な処置をともなうことなく、試料の測定をおこなった。その測定を大気雰囲気下でおこなった。
[0177] FT−ラマンスペクトルを、1064nmで動作する近赤外Nd:YAGレーザーと液体窒素冷却ゲルマニウム検出器とを有するブルカー(Bruker)RFS100FT−ラマン・システム上に記録した。各試料について、分解能2cm−1の走査64回分を蓄積した。用いたレーザー出力は、100mWであった。ラマン測定を、室温でアルミニウム試料ホルダーまたは密閉ガラス管を用いて、おこなった。
[0178] TG−FTIR機器は、発生成分の特徴付けと組み合わせた、質量損失によって生ずる、H2Oガス等のガスを分析するためのフーリエ変換赤外分光(FTIR)に連結した熱重量分析器(TG)からなる。熱重量測定を、ブルカー(Bruker)FTIR分光器ベクター(Vector)22に連結されたネッチ(Netzsch) サーモマイクロバランス(Thermo-Microbalance )TG209を用いておこなった。N2雰囲気下、加熱速度10k/分、温度範囲25ないし250℃で、ピンホールを有する試料皿(sample pan)を用いた。種々の条件下で、TA機器Q500 TGAを用いて追加の熱重量分析をおこなった。
[0179]熱分析を、以下の実験条件、すなわち試料質量3ないし6mg、閉じた金製試料鍋(closed gold sample pan)、温度範囲−50℃ないし120℃、加熱速度20K/分により、パーキン・エルマー(Perkin Elmer)DSC7を用いておこなった。試料の秤量を、空気中または乾燥N2雰囲気中で、おこなった。追加の熱分析を、種々の条件下で気密アルミニウム鍋を用いてTAインストルメンツ(Instruments)Q1000DSCを使用して、実施した。
[0180]動的蒸気収着定量は結晶化方法の間に吸収かつ実施的に脱着された水の質量に関連する。バッチP1、P2、およびP4が水和された多形体であるかどうかを決定するために、DVS測定を実施した(図9)。試料(13ないし14mg)をPt鍋に置き、あらかじめ定義された湿度プログラムを開示する前に、25℃/50%RHで平衡化させた。(1.0時間50%、50%RHないし95%RH:5%RH/時間、95%RHで10時間、95%RHないし0%RH:5%RH/時間、0%RHで10時間、0%RHないし50%RH:5%RH/時間、50%RHで1時間。
[0181]S−1バッチP1、P2、およびP4の像(図8)をSEMカムスキャン(CamScan)CS24システムで得た。
[0182]以下の実験、すなわち懸濁液平衡、析出実験、再結晶、相対的安定度実験、および水溶解性実験の過程で、濾過ステップを実施した。遠心濾過機装置:ウルトラフリー(Ultrafree)−CL(0.22|a,m)、ミリポア(Millipore);遠心(Centrifuge)型またはエッペンドルフ(Eppendorf)5804Rを温度22℃かつ2分3000rpmの遠心プログラムで使用した。
[0183]S−1の純度を分析するために、HPLCを用いた。HP1090M HPLC装置を以下の条件で用いた。すなわち、
カラム:シンメトリーシールド(Symmetry Shield)RP18,3.9x150mm,5μm
カラム温度:35℃
注入量:10μL
溶媒:アセトニトリル+水1:1v/v
移動相A:0.1%TFA−水
移動相B:0.1%TFA−アセトニトリル
流速:1mL/分
検出:UV(271nm)
実行時間:21分
保持時間(S−1):10.7分
材料:
溶媒
[0184]すべての実験について、フルカ(Fluka)またはメルク(Merck)等級の溶媒を用いた。水:脱イオン化(フルカ(Fluka)no.95305)。
[0186]特徴付けのために、S−1化合物の4つのバッチ、すなわち(S−1−P1)、(S−1−P2)、(S−1−P3)、および(S−1−P4)を、選択した。S−1−P1、S−1−P2、およびS−1−P3は、実施例1に記述された合成方法によって調製された個々のバッチであった。バッチS−1−P4は、保存中、40℃/75%RHに曝露したバッチS−1−P1の試料であった。S−1化合物の異なる固体形態の安定度、溶解性、および特性を決定するために、以下の実験をおこなった。
[0194]室温の湿度室内96%RH(相対湿度)下で、化合物をガラス管に保存した。異なる時間で保存後、密閉ガラス管を用いてラマン測定をおこなった。結果を表1にまとめる。
[0195] 室温での近似溶解度(approximate solubility)を測定するために、溶媒を段階的に固形材料に添加した。毎回添加した後に、試料を十分撹拌した。溶媒の添加は完全溶解まで継続されたか、あるいは15mlの溶媒まで加えられた。23℃で固体形態AおよびB’の溶解度を表2に示す。
[0196]懸濁液平衡実験(suspension equilibration experiment)を81〜128mgの化合物を用いて実施した。懸濁液をマグネットスターラーで撹拌した。不安定な水和物または溶媒和物の起こり得る脱溶媒化を防ぐためにのみ、濾過後に得られた試料を周囲温度で短時間にわたり空気乾燥した。固体形態AおよびB’の懸濁液平衡実験の結果を表3に示す。
[0197]蒸気拡散実験を異なる溶媒中で化合物の溶液を用いておこなった。溶液を、混和性で揮発性の貧溶媒を含む大きな容器に貯蔵された、小さな蓋なし容器に入れた。次に、大きな容器を密閉した。貧溶媒は溶液の中に気相を介して拡散して、飽和または過飽和が達成された。固体形態AおよびB’の蒸気拡散実験の結果を表4に示す。
[0198]化合物の溶液を、撹拌することなく室温(乾燥窒素流)で乾燥させた。固体形態Aの蒸発実験の結果を表5に示す。
[0199]析出実験(preceipitation experiment)を42ないし79mgの化合物を用いておこなった。非溶媒を溶液に加えた。不安定な水和物または溶媒和物の脱溶媒を防ぐためにのみ、濾過(ガラス濾過器孔隙率(glass filter porosity)P4)後に得られた試料を周囲温度かつ短時間で空気乾燥させた。固体形態Aの析出実験の結果を表6に示す。
[0200]化合物を室温で異なる溶媒系に溶かし、+5℃または−20℃に冷やした。不安定な水和物または溶媒和物の起こり得る脱溶媒化を防ぐためにのみ、濾過(ガラス濾過器孔隙率P4)後に得られた試料を周囲温度で短時間にわたり空気乾燥した。
[0202]化合物を1,4−ジオキサンに溶かし、この溶液を−50℃に冷やした。溶媒の昇華中に、固体の温度を表8に示すように、<0℃にした。
[0203] DSC試料鍋を閉じる前に、乾燥N2雰囲気中室温で試料を一晩乾燥させた。
[0205]DSCで120℃に加熱した後、試料を−50℃に冷却し、さらに120℃に再加熱した。結果を表10にまとめる。
[0206]懸濁液実験を130ないし145mgの化合物でおこなった。懸濁液をマグネットスターラーで撹拌し、所定の時間後に濾過した。濾過(ガラス濾過器孔隙率P4)後に得られた試料を、周囲温度で空気乾燥した。結果を表11にまとめる。
[0207]固体形態の懸濁液(3.5または7.0ml再蒸留水中、25または50mg)を振とう(800rpm)させて、0.5時間、1.5時間、4時間および20時間後に濾過した。濾過後、固形残渣をラマン分光によってチェックし、透明な溶液中の濃度をHPLCで測定した。
[0210]多形性(polymorphism)研究用の出発原料(バッチ番号S−1−P1)は、結晶かつ結晶形態Aである。TG−FTIRは、200℃までの質量損失がかなり低い(<0.2%)ことを示すことから、バッチ番号S−1−P1は水和物または溶媒和物ではない。バッチ番号S−1−P1は82℃(DSCピーク温度、加熱速度20K/分)で溶融する。DSCでの溶融および−50℃への急冷後、無水結晶形態が生じた。試料は、約52℃の相転移温度を示し、DSCでの加熱中に再結晶しなかった。S−1−P1は、少量(概算5%)の形態B’またはB”を含むと思われた。
[0212]DSCおよびXRPDによる研究は、40℃かつ相対湿度75%での固体形態Aの保存中に生じた固体形態(バッチS−1−P4;40℃/75%RH)が、低い範囲のオーダーに制限された準結晶形態であることを、示している。
[0214]高相対湿度で観察されたトランスフォーメーションに加えて、37℃で一晩、固体形態Aの懸濁液を撹拌することで、固体形態B’を生成することができる。
[0215]固体形態B”を生産するための経路は、溶解および溶融物の冷却、ならびにエタノール等の溶媒中での溶液のゆっくりとした蒸発である。多形形態B”は、多形態多形形態B”は、多形形態Aおよび多形形態Cを80℃および130℃の各々の融点よりも高く、加熱することで、これらの多形形態Aおよび多形形態Cから調製することができる。B’およびB”は、これまで用いた任意の分析法から識別可能ではなく、それらの形成のルートに基づいて決定される。B’はその溶媒媒介構造によりリオトロピック液晶形として割り当てられ、一方B’はその熱的方法由来のサーモトロピック結晶形態として割り当てられる。貧溶媒のないエタノール等の溶媒からの薬物の蒸発濃縮もまた、B”を生ずる。
[0216]多形形態Cは、溶解およびそれに続いて周囲温度でTHFから薬物を蒸発させることで、Aとの混合物としてのみ、得ることができる。
[0217]多形形態Dは、酢酸エチルおよびシクロヘキサンを溶媒および貧溶媒として各々用いて、50℃で溶媒/貧溶媒混合物から結晶化によって、最初に生産される。形態Dもまた、少量のDを含む試料を「播種(seeding)」し、110℃/0%RHで7日間にわたって、または水中で50℃、24時間にわたって保存し、乾燥することによって、他の多形から調製することができる。
[0218]トルエン溶媒和物を、貧溶媒としてトルエンを用いた任意の溶媒/貧溶媒結晶化方法によって、調製した。
[0219]22℃における水中での化合物S−1の形態AおよびB’の溶解度は、24.0±1.4mg/1000mlおよび27.3±0.8mg/1000ml(懸濁液平衡時間1.5時間後に得た値)である。これらの溶解度は、溶解度実験の過程で粒子状物質の表面上での形態Aから形態B’への急速なトランスフォーメーションにより、かなり類似している。
[0220]バッチS−1−P1、S−1−P2、およびS−1−P3の試料は、同様の回折パターンを示す。DSC測定は、50℃付近で熱容量の変化によって示されるように、数%の固体形態B’またはBを含む可能性が最も高いことを示す。試料S−1−P2は、最高レベルの固体形態B’またはB”(約20%)を示す。DSC結果をよりよく理解するために、試料S−1−P1およびS−1−P2の走査型電子顕微鏡写真(SEM)を作成した。試料S−1−P1の写真ではかなり形の良い粒子状物質が示されるが、試料S−1−P2の写真は、おそらくはかなり高い乾燥温度または水との部分的接触によって引き起こされる部分的トランスフォーメーションを示す。固体形態B’およびB”の部分的形成もまた、急速析出および析出後の相対的に高い貧溶媒/溶媒比率によって、引き起こすことができる。他の説明として、高温条件下での乾燥または高湿度条件下での貯蔵が考えられる。
[0221]結晶形態Aは、結晶化に一般に用いられるいくらかの溶媒において高い溶解性を有する。その高い可溶性により、溶媒/貧溶媒混合物は結晶化に必要である。
バッチP4は、上記に記述されるような、その広いXRPD、ラマン、TG FTIR、DVSおよびDSC結果によって特徴づけられる準結晶固体形態を明らかにした。
[0228]図19のAおよびBのDSCサーモグラムは、Aが80℃近傍で溶融する一方でDは130℃近傍に融点を有することを示す。Aの融解エンタルピーは40±5J/gである一方、融解エンタルピーは75±5J/gである。融解温度およびエンタルピーは、形態Aと比較してDの安定度が高いことを示唆している。
[0231]多形体AはそのA形態で、周囲温度/75%RH(相対湿度)、周囲温度/100%RH、30℃/75%RH、および50℃/0%RHの貯蔵条件下で、少なくとも7日間安定している。しかし、それは、50℃/75%RHで貯蔵した場合に、B’に変換する。結果のうちのいくつかを、図17Fに示す。実際、25℃/60%RHおよび30℃/65%RHで貯蔵された多形体Aは、それぞれ36ヶ月および9ヶ月のあいだ、安定している。一方40℃/75%RHで貯蔵された試料は1ヶ月のあいだにB’に変換される。これらの結果は、多形形態Aが、湿気がある状態でB’に変換されることを示す。
[0233]貧溶媒としてトルエンを用いる溶媒/貧溶媒システムからのS−1の再結晶によって、トルエン溶媒和物が生ずる。トルエン溶媒和物は、融解エンタルピーが70±5 J/gである100℃近傍の融点を有する。図20中のトルエン溶媒和物のTGAグラフによれば、溶媒和物中のトルエン含有量が、S−1の3つの分子ごとに1つのトルエン分子に相当する〜7%である。溶媒/薬物質量比は調製された各試料バッチについて同じ状態のままであり、トルエン分子が格子の外側の溝(channel)または層の中でではなく単位格子構造の内部に存在することが示唆される。トルエン中のS−1の溶解度が低い(<2mg/mL)ことから、形態Dからトルエン溶媒和物への顕著なトランスフォーメーションは周囲温度および50℃の両方で、4日間トルエン中で懸濁(50mg/mL)させた後では、観察されなかった。10分間にわたる懸濁液の超音波処理は、トルエン溶媒和物への部分的なトランスフォーメーションを生じた。
Claims (8)
- (S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミド化合物の結晶形態Dであって、
X線粉末回折パターンが4.4(19.9),8.5(10.4),8.8(10.0),11.3(7.8),12.7(6.9),13.8(6.4),14.4(6.1),14.6(6.0),15.1(5.8),16.1(5.5),16.6(5.3),16.9(5.2),18.0(4.9),18.7(4.7),19.0(4.6),19.4(4.55),20.8(4.25),22.1(4.0),22.7(3.9),23.1(3.8),23.4(3.8),24.7(3.6),24.9(3.56),25.3(3.51),27.8(3.2),29.3(3.0)の°2θ(d値Å)の角度における固有のピークを含むこと
によって特徴付けられる、前記結晶形態D。 - 融点が130℃であることによって特徴付けられる、請求項1に記載の結晶形態D。
- 前記結晶形態Dが、図18に示すX線回折パターンによって特徴付けられる、請求項1又は2に記載の結晶形態D。
- 請求項1〜3のいずれか1項に記載の結晶形態Dを調製する方法であって、
非晶質の(S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミドを溶媒/貧溶媒混合物中に、結晶化を可能とする条件下で50℃の温度で混合し、それにより該結晶形態を得る、前記方法。 - 前記溶媒/貧溶媒が酢酸エチル/シクロヘキサン混合物である、請求項4に記載の方法。
- 組成物であって、請求項1〜3のいずれか1項に記載の結晶形態Dと適当な担体または希釈剤とを含む、前記組成物。
- 請求項1〜3のいずれか1項に記載の結晶形態Dを調製する方法であって、
(S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミドの他の多形を、結晶形態Dの存在下で加熱することを含む、前記方法。 - 請求項1〜3のいずれか1項に記載の結晶形態Dを調製する方法であって、
少量の結晶形態Dを(S)−N−(4−シアノ−3−(トリフルオロメチル)フェニル)−3−(4−シアノフェノキシ)−2−ヒドロキシ−2−メチルプロパンアミドの他の多形の試料に播種し、該試料を高湿度で保管することを含む、前記方法。
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