JP4408700B2 - 結晶粒子を調製するための装置および方法 - Google Patents
結晶粒子を調製するための装置および方法 Download PDFInfo
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- JP4408700B2 JP4408700B2 JP2003561752A JP2003561752A JP4408700B2 JP 4408700 B2 JP4408700 B2 JP 4408700B2 JP 2003561752 A JP2003561752 A JP 2003561752A JP 2003561752 A JP2003561752 A JP 2003561752A JP 4408700 B2 JP4408700 B2 JP 4408700B2
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- B01D9/0059—General arrangements of crystallisation plant, e.g. flow sheets
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0081—Use of vibrations, e.g. ultrasound
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/20—Jet mixers, i.e. mixers using high-speed fluid streams
- B01F25/25—Mixing by jets impinging against collision plates
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/80—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations
- B01F31/85—Mixing by means of high-frequency vibrations above one kHz, e.g. ultrasonic vibrations with a vibrating element inside the receptacle
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/712—Feed mechanisms for feeding fluids
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/7174—Feed mechanisms characterised by the means for feeding the components to the mixer using pistons, plungers or syringes
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/7176—Feed mechanisms characterised by the means for feeding the components to the mixer using pumps
- B01F35/717611—Peristaltic pumps
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/71805—Feed mechanisms characterised by the means for feeding the components to the mixer using valves, gates, orifices or openings
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/75—Discharge mechanisms
- B01F35/754—Discharge mechanisms characterised by the means for discharging the components from the mixer
- B01F35/7547—Discharge mechanisms characterised by the means for discharging the components from the mixer using valves, gates, orifices or openings
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/18—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic using a vibrating apparatus
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Description
(ii) 該物質に対する液体逆溶媒の第2の貯槽;
(iii) 第1および第2の流入口、および流出口を有している混合室;
(iv) 第1および第2の貯槽の内容物を独立制御の流量でそれぞれ第1および第2の流入口を経て混合室に送達するための手段であって、その第1および第2の流入口が、第1および第2の貯槽の内容物が混合室の中に平行接触流れで送達されるように配向している手段;
(v) 第1の流入口の近傍に配置された超音波放射発生源;
(vi) 流出口で混合室から排出される液体に懸濁している結晶粒子を回収するための手段。
(ii) 前記流入口の近辺に超音波放射を供給すること;
(iii) 前記流出口で混合室から排出される液体に懸濁している結晶粒子を回収すること。
(2R,3R,4S,5R)-2-[6-アミノ-2-(1S-ヒドロキシメチル-2-フェニル-エチルアミノ)-プリン-9-イル]-5-(2-エチル-2H-テトラゾール-5-イル)-テトラヒドロ-フラン-3,4-ジオールまたはその塩(例えばマレイン酸塩);
(2S)-3-[4-({[4-(アミノカルボニル)-1-ピペリジニル]カルボニル}オキシ)フェニル]-2-[((2S)-4-メチル-2-{[2-(2-メチルフェノキシ)アセチル]アミノ}ペンタノイル)アミノ]プロパン酸またはその塩(例えば遊離酸またはカリウム塩として);および
6α,9α-ジフルオロ-17α-[(2-フラニルカルボニル)オキシ]-11β-ヒドロキシ-16α-メチル-3-オキソ-アンドロスタ-1,4-ジエン-17β-カルボチオ酸S-フルオロメチルエステル。
幅:15cm
全高:約38cm
1リットル容量の印しのところにある1つの出口(これは、容器の底部出口から約12cm上のところである)。
IPA:イソプロピルアルコール
DMAc:ジメチルアセトアミド
IMS:工業用メチレーテッドスピリット
DMF:ジメチルホルムアミド
IPE:イソプロピルエーテル
DMSO:ジメチルスルホキシド
HFA134a:1,1,1,2-テトラフルオロエタン
HFA227:1,1,1,2,3,3,3-ヘプタフルオロ-n-プロパン。
実験手順
対象医薬物質(プロピオン酸フルチカゾン、FP)(1重量)をアセトン(実験では15〜20容量)に、56℃に加熱することで溶解させ、そのあと25〜35℃に冷却させた。このFP/アセトン溶液に第1の蠕動ポンプを連結し、第2の蠕動ポンプを水貯槽に連結したが、この水の温度は3〜30℃であった。ポンプを始動する前に、混合室をアセトンと水(それぞれの比は、対応する2つの貯槽からのポンプ送入速度比と同じにする)の溶液で満たした。こうすることで、混合室中の水対アセトンの相対濃度は、結晶化の間ずっと一定であった。混合室の温度は、容器ジャケットの中に、温調された熱伝達流体を通すことで約-10〜+30℃に維持した。FP/アセトン溶液の流入口と水の流入口は、同軸または平行に並べられた(図1a/1b/2a/2bに示されているように)ものとし、超音波プローブの先端は、それが流入口の直ぐ上に来るように配置した。超音波を強度2〜4 W/cm2(プローブの先端面領域において)で開始すると同時に、非磨り混ぜ式マグネチックスタラーバー(棒)または懸架式撹拌機による撹拌を開始した。超音波プローブは同じ位置に配置するが出力はゼロとする比較実験も行なった。実験デザインのところに掲載されているパラメーターにより決定されるアセトンと水の、いくつかの混合物(それぞれの流量を変えることによる)の再結晶化を行なった。そういうことで、ポンプを同時に始動させた。この再結晶化混合物中に生成した結晶の懸濁液は、オーバーフローを経て直接フィルターベッド上に流出させた。得られたスラリーは単離し、水で洗い、真空中約20〜50℃で乾燥させる。
*:FPの濃度は、溶媒(アセトン)mL中のFPグラムとして表わされている。
アルミニウム製キャニスターに、本発明に従って調製されたプロピオン酸フルチカゾンの粒子(例えば実施例1、実験4に記載のもの)を充填することが可能である。その上に計量バルブ(Valois)を圧接し、そのバルブを通して液化HFA134aを加えることも可能である。
吸入用乾燥粉末組成物を、本発明に従って調製されたプロピオン酸フルチカゾンの粒子(例えば実施例1、実験4に記載のもの)と粉砕ラクトースを混ぜることで調製することが可能である。
Claims (26)
- 物質の結晶粒子の調製方法であって、超音波放射が存在している連続フローセル中で、物質の液体溶媒中の流動溶液と、該物質に対する流動液体逆溶媒とを混合すること、および、その結果として得られる生成した結晶粒子を回収すること、を含んでなる物質の結晶粒子の調製方法において、前記溶液および逆溶媒を平行接触流れで前記連続フローセルの中に送達することを特徴とする上記方法。
- 次の(i)〜(vi)を有してなる、物質の結晶粒子を調製するための装置。
(i) 液体溶媒に溶解された該物質溶液の第1の貯槽;
(ii) 該物質に対する液体逆溶媒の第2の貯槽;
(iii) 第1および第2の流入口、および流出口を有している混合室;
(iv) 第1および第2の貯槽の内容物を独立制御の流量でそれぞれ第1および第2の流入口を経て混合室に送達するための手段であって、その第1および第2の流入口が、第1および第2の貯槽の内容物が平行接触流れで混合室の中に送達されるように配向している手段;
(v) 第1の流入口の近傍に配置された超音波放射発生源;
(vi) 流出口で混合室から排出される液体に懸濁している粒子を回収するための手段。 - 前記液体逆溶媒が前記液体溶媒と混和性である請求項1に記載の方法。
- 前記液体逆溶媒が前記液体溶媒と混和性である請求項2に記載の装置。
- 前記第1および第2の流入口が、液体が混合室中の液体本体の中に流出するようフローセルの中に突き出ている請求項2または4に記載の装置。
- 前記第1および第2の流入口からの流出液が前記超音波放射発生源に向かって向けられている請求項2、4および5のいずれか1項に記載の装置。
- 前記第1および第2の流入口が、それぞれの流入口から流出する液体の流れがその流れの1つの側面に沿って接触するよう互いに隣接している請求項2または4〜6のいずれか1項に記載の装置。
- 前記第1および第2の流入口が、一方の流入口が他方の流入口を完全に囲むように同軸的に配置されている請求項2または4〜6のいずれか1項に記載の装置。
- 前記内側流入口が第1の流入口(すなわち、物質の溶媒溶液のための流入口)である請求項8に記載の装置。
- さらに、前記第1および第2の流入口を経て混合室に送達される液体を混合するための手段を有してなる請求項2または4〜9のいずれか1項に記載の装置。
- 前記混合手段がスタラーを有している請求項10に記載の装置。
- 前記第1および第2の貯槽の内容物を独立制御の流量でそれぞれ第1および第2の流入口を経て混合室に送達するための手段が1つ以上のポンプを有している請求項2または4〜11のいずれか1項に記載の装置。
- 前記流出口が、混合室中の液体が混合室中の低い地点から高い地点に流れてから出て行くように混合室の流入口より上に配置されている請求項2または4〜12のいずれか1項に記載の装置。
- 前記混合室の横断面が円形である請求項2または4〜13のいずれか1項に記載の装置。
- 前記流出口で混合室から排出される液体に懸濁している粒子を回収するための手段がフィルターを有している請求項2または4〜14のいずれか1項に記載の装置。
- 次の(i)〜(iii)を含んでなる、請求項2または4〜15のいずれか1項に記載の装置を用いた請求項1または3に記載の方法。
(i) 第1および第2の貯槽の内容物を独立制御の流量でそれぞれ第1および第2の流入口を経て混合室に送達すること;
(ii) 前記流入口の近辺に超音波放射を供給すること;
(iii) 前記流出口で混合室から排出される液体に懸濁している結晶粒子を回収すること。 - 前記物質が、コデイン、ジヒドロモルフィン、エルゴタミン、フェンタニル、モルフィン、ジルチアゼム、クロモグリク酸塩、ケトチフェン、ネドクロミル、セファロスポリン、ペニシリン、ストレプトマイシン、スルホンアミド、テトラサイクリン、ペンタミジン、メタピリレン、ベクロメタゾン、フルチカゾン、フルニソリド、ブデソニド、ロフレポニド、モメタゾン、シクレソニド、トリアムシノロン、ノスカピン、アルブテロール、サルメテロール、エフェドリン、アドレナリン、フェノテロール、ホルモテロール、イソプレナリン、メタプロテレノール、フェニレフリン、フェニルプロパノールアミン、ピルブテロール、レプロテロール、リミテロール、テルブタリン、イソエタリン、ツロブテロール、(-)-4-アミノ-3,5-ジクロロ-α-[[[6-[2-(2-ピリジニル)エトキシ]ヘキシル]メチル]ベンゼンメタノール、シロミラスト、ロフルミラスト、モンテルーカスト、プランルーカスト、ザフィルルーカスト、アミロリド、イプラトロピウム、チオトロピウム、アトロピン、オキシトロピウム、コルチゾン、ヒドロコルチゾン、プレドニゾロン、アミノフィリン、テオフィリン酸コリン、テオフィリン酸リシン、テオフィリン、インスリン、グルカゴン、ならびにそれらの塩、エステルおよび溶媒和物;4-ヒドロキシ-7-[2-[[2-[[3-(2-フェニルエトキシ)プロピル]スルホニル]エチル]アミノ]エチル-2(3H)-ベンゾチアゾロン、ブチキシコルト、ならびにそれらの塩および溶媒和物;(2R,3R,4S,5R)-2-[6-アミノ-2-(1S-ヒドロキシメチル-2-フェニル-エチルアミノ)-プリン-9-イル]-5-(2-エチル-2H-テトラゾール-5-イル)-テトラヒドロ-フラン-3,4-ジオールおよびその塩;(2S)-3-[4-({[4-(アミノカルボニル)-1-ピペリジニル]カルボニル}オキシ)フェニル]-2-[((2S)-4-メチル-2-{[2-(2-メチルフェノキシ)アセチル] アミノ}ペンタノイル)アミノ]プロパン酸およびその塩;6α,9α-ジフルオロ-17α-[(2-フラニルカルボニル)オキシ]-11β-ヒドロキシ-16α-メチル-3-オキソ-アンドロスタ-1,4-ジエン-17β-カルボチオ酸S-フルオロメチルエステル;ならびにナラトリプタンおよびその
塩からなる群から選択される医薬物質、またはラクトースおよびマンニトールからなる群からから選択される担体物質である請求項16に記載の方法。 - 前記物質が、フルチカゾン、ベクロメタゾン、サルメテロール、サルブタモールまたはこれらのエステル、塩もしくは溶媒和物である請求項17に記載の方法。
- 前記物質がラクトースである請求項17に記載の方法。
- 前記物質がプロピオン酸フルチカゾンである請求項18に記載の方法。
- 前記物質がキシナホ酸サルメテロールである請求項18に記載の方法。
- 前記物質が混合物である請求項1、3、16または17のいずれか1項に記載の方法。
- 前記物質が、プロピオン酸フルチカゾンとキシナホ酸サルメテロールの混合物である請求項22に記載の方法。
- 前記溶媒がアセトンであり、前記逆溶媒が水である請求項20または23に記載の方法。
- 前記溶媒がメタノールであり、前記逆溶媒が水である請求項21に記載の方法。
- 前記物質が塩酸ナラトリプタンである請求項16に記載の方法。
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GBGB0201400.9A GB0201400D0 (en) | 2002-01-22 | 2002-01-22 | Novel apparatus and process |
PCT/EP2003/000558 WO2003061816A1 (en) | 2002-01-22 | 2003-01-21 | Apparatus and process for preparing crystalline particles |
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JP2005177746A (ja) * | 2003-11-28 | 2005-07-07 | Mitsubishi Chemicals Corp | 有機化合物微粒子の製造方法 |
WO2005051511A1 (ja) * | 2003-11-28 | 2005-06-09 | Mitsubishi Chemical Corporation | 有機化合物微粒子の製造方法 |
GB0406069D0 (en) * | 2004-03-17 | 2004-04-21 | Thompson James | Process |
GB0507165D0 (en) * | 2005-04-08 | 2005-05-18 | Glaxo Group Ltd | Novel crystalline pharmaceutical product |
DE102005053862A1 (de) | 2005-11-04 | 2007-05-10 | Pharmasol Gmbh | Verfahren und Vorrichtung zur Herstellung hochfeiner Partikel sowie zur Beschichtung solcher Partikel |
JP4597107B2 (ja) * | 2006-03-02 | 2010-12-15 | 三井金属鉱業株式会社 | 砒素含有体からの砒素除去方法及び砒素除去装置 |
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GB0705159D0 (en) * | 2007-03-19 | 2007-04-25 | Prosonix Ltd | Process for making crystals |
GB0711680D0 (en) * | 2007-06-18 | 2007-07-25 | Prosonix Ltd | Process |
GB0900080D0 (en) | 2009-01-06 | 2009-02-11 | Prosonix Ltd | An apparatus and process for producing crystals |
GB0918149D0 (en) | 2009-10-16 | 2009-12-02 | Jagotec Ag | Improved medicinal aerosol formulation |
GB0918150D0 (en) * | 2009-10-16 | 2009-12-02 | Jagotec Ag | Improved formulations |
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US20010023252A1 (en) * | 1998-07-02 | 2001-09-20 | Smithkline Beecham Plc | Novel compound |
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DE60302765D1 (de) | 2006-01-19 |
EP1469938A1 (en) | 2004-10-27 |
CO5611178A2 (es) | 2006-02-28 |
IS7335A (is) | 2004-06-28 |
PL372897A1 (en) | 2005-08-08 |
NO20043444L (no) | 2004-08-18 |
CA2473059A1 (en) | 2003-07-31 |
BR0306738A (pt) | 2004-12-28 |
MXPA04007073A (es) | 2004-10-29 |
GB0201400D0 (en) | 2002-03-13 |
AR038200A1 (es) | 2005-01-05 |
US7384478B2 (en) | 2008-06-10 |
KR20040082395A (ko) | 2004-09-24 |
CN1620333A (zh) | 2005-05-25 |
JP2005525216A (ja) | 2005-08-25 |
IL162751A0 (en) | 2005-11-20 |
ES2253656T3 (es) | 2006-06-01 |
US20060096522A1 (en) | 2006-05-11 |
ATE312661T1 (de) | 2005-12-15 |
ZA200405143B (en) | 2005-12-28 |
TW200302129A (en) | 2003-08-01 |
EP1469938B1 (en) | 2005-12-14 |
RU2004120549A (ru) | 2005-05-10 |
WO2003061816A1 (en) | 2003-07-31 |
DE60302765T2 (de) | 2006-07-06 |
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