JP2015117192A - SILODOSIN γ TYPE CRYSTAL AND METHOD OF PRODUCING THE SAME - Google Patents
SILODOSIN γ TYPE CRYSTAL AND METHOD OF PRODUCING THE SAME Download PDFInfo
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- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 title claims abstract description 99
- 229960004953 silodosin Drugs 0.000 title claims abstract description 98
- 238000000034 method Methods 0.000 title claims abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 165
- 239000013078 crystal Substances 0.000 claims abstract description 122
- 239000002904 solvent Substances 0.000 claims abstract description 34
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 150000001298 alcohols Chemical class 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000004519 manufacturing process Methods 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 16
- 239000006184 cosolvent Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229960004592 isopropanol Drugs 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 9
- 239000012086 standard solution Substances 0.000 description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 239000012488 sample solution Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
Description
本発明は，シロドシンγ型結晶に関し，特にトルエンを実質的に含有しないシロドシンのγ型結晶及びその製造方法に関する。 The present invention relates to a silodosin γ-type crystal, and more particularly to a silodosin γ-type crystal substantially free of toluene and a method for producing the same.
尿路選択的，特に前立腺選択的なα１−アドレナリン受容体阻害剤であるシロドシン Silodosin, a urinary tract-selective, particularly prostate-selective α 1 -adrenoceptor inhibitor
は，排尿障害治療に用いられている薬物である。シロドシンには，α型，β型，γ型，δ型等，複数の結晶形が知られている。結晶化させるための溶媒として酢酸エチルを用い温度変化により析出させて得られるα型や，微量のメタノールで溶解後に多量の石油エーテル中で析出させることができるβ型結晶に対し，γ型結晶の製造には，結晶化溶媒としてトルエンを使用することが避けられず，多量のトルエンが結晶中に残留する（特許文献１参照）。トルエンは高沸点で除去に手間を要し，結晶に残留したトルエンを十分に除去するのが困難であるなどの問題点を有すること，及び医薬品原料中のトルエンの残存量は８９０ｐｐｍ以下とすることが求められているが，γ型結晶はこの点で問題がある（特許文献１参照）。実際上，γ型結晶の製造に用いられたトルエンは，結晶中に１０００ｐｐｍ前後の濃度で残存してしまい，それ以上除去することは困難である。 Is a drug used to treat dysuria. A plurality of crystal forms such as α-type, β-type, γ-type, and δ-type are known for silodosin. In contrast to α-form obtained by precipitation with temperature change using ethyl acetate as a solvent for crystallization, and β-form crystals that can be precipitated in a large amount of petroleum ether after being dissolved in a small amount of methanol, In production, it is inevitable to use toluene as a crystallization solvent, and a large amount of toluene remains in the crystal (see Patent Document 1). Toluene has a high boiling point and requires time and effort, and it is difficult to sufficiently remove toluene remaining in the crystal. The residual amount of toluene in the pharmaceutical raw material should be 890 ppm or less. However, γ-type crystals have a problem in this respect (see Patent Document 1). In practice, the toluene used in the production of the γ-type crystal remains in the crystal at a concentration of about 1000 ppm, and it is difficult to remove it further.
トルエンは，残留溶媒についてのガイドライン（ＩＣＨ
Ｑ３Ｃ（Ｒ４）ガイドライン）において，毒性がクラス２に分類されており，人体に有害である。その点からも上記のような高濃度にトルエンを含有する結晶を医薬品原料として使用することはできないが，トルエンを用いずにシロドシンのγ型結晶を製造する手段は，これまで知られていなかった。
Toluene is a guideline for residual solvents (ICH
In Q3C (R4) guidelines), toxicity is classified as class 2 and is harmful to the human body. From this point of view, crystals containing toluene at a high concentration as described above cannot be used as a raw material for pharmaceuticals. However, no means for producing silodosin γ-type crystals without using toluene has been known. .
上記の背景において，本発明は，トルエンを実質的に含まないシロドシンのγ型結晶及びその製造方法の提供を目的とする。 In view of the above background, an object of the present invention is to provide a silodosin γ-type crystal substantially free of toluene and a method for producing the same.
本発明者は，溶媒としてトルエンを用いないシロドシンのγ型結晶の製造方法を求めて研究を重ね，その結果，アルコール系等の特定の溶媒を用いて，トルエンを使用せずにシロドシンのγ型結晶を得る方法を見出した。本発明は当該発見に基づいて完成されたものである。即ち，本発明は以下を提供する。 The present inventor has sought research for a method for producing silodosin γ-type crystals that do not use toluene as a solvent, and as a result, using a specific solvent such as an alcohol and without using toluene, the γ-type crystals of silodosin A method for obtaining crystals was found. The present invention has been completed based on the discovery. That is, the present invention provides the following.
１．トルエンを実質的に含有しないシロドシンγ型結晶。
２．トルエンの含有量が０〜１００ｐｐｍである，上記１のシロドシンγ型結晶。
３．トルエンを含有しないものである，上記２のシロドシンγ型結晶。
４．シロドシンγ型結晶の製造方法であって，主原料とするシロドシンを，低級アルコールより選ばれる溶媒と混合し撹拌して溶解させ，溶液を冷却してシロドシンをγ型結晶として析出させることを含んでなる，製造方法。
５．上記４のシロドシンγ型結晶の製造方法であって，該溶液の冷却の過程において，結晶未析出の段階でシロドシンγ型結晶を種晶として加えることを含むものである，製造方法。
６．該低級アルコールが１価アルコールである，上記４又は５の製造方法。
７．該低級アルコールが，炭素数１〜４のものである，上記４〜６の何れかの製造方法。
８．該低級アルコールが２−プロパノールである，上記４の製造方法。
９．ｔ−ブチルメチルエーテルを共溶媒として用いることを特徴とする，上記４〜８の何れかの製造方法。
1. Silodosin γ-type crystals substantially free of toluene.
2. The silodosin γ-type crystal according to 1 above, wherein the content of toluene is 0 to 100 ppm.
3. The silodosin γ-type crystal according to 2 above, which does not contain toluene.
4). A method for producing silodosin γ-type crystals, comprising mixing silodosin as a main raw material with a solvent selected from lower alcohols, stirring and dissolving, cooling the solution and precipitating silodosin as γ-type crystals. Manufacturing method.
5. 5. The method for producing a silodosin γ-type crystal according to 4 above, which comprises adding the silodosin γ-type crystal as a seed crystal at a stage where the crystal is not precipitated in the process of cooling the solution.
6). The production method of 4 or 5 above, wherein the lower alcohol is a monohydric alcohol.
7). 7. The production method according to any one of 4 to 6, wherein the lower alcohol is one having 1 to 4 carbon atoms.
8). The production method according to 4 above, wherein the lower alcohol is 2-propanol.
9. t-butyl methyl ether is used as a co-solvent, The manufacturing method in any one of said 4-8 characterized by the above-mentioned.
本発明によれば，有害な溶媒であるトルエンを従来約１０００ｐｐｍの濃度で含有していた従来のシロドシンγ型結晶とは対照的に，トルエンを実質的に含有しないシロドシンγ型結晶を得ることが可能となる。 According to the present invention, it is possible to obtain a silodosin γ-type crystal that substantially does not contain toluene, in contrast to the conventional silodosin γ-type crystal that conventionally contained a harmful solvent of toluene at a concentration of about 1000 ppm. It becomes possible.
本発明の製造方法において主原料として用いるシロドシンは，溶媒に完全に溶解させるから，その結晶形は問わず，非晶質でもよい。また，シロドシンγ型結晶の析出を促すためのシロドシンγ型結晶を種晶として用いても，結晶化溶媒にトルエンを用いないことから，トルエンを実質的に含まないシロドシンγ型結晶を得ることができる。 Since silodosin used as a main raw material in the production method of the present invention is completely dissolved in a solvent, its crystal form is not limited and may be amorphous. In addition, even if silodosin γ-type crystals for promoting precipitation of silodosin γ-type crystals are used as seed crystals, toluene is not used as a crystallization solvent, so that silodosin γ-type crystals substantially free of toluene can be obtained. it can.
更には，そのようにして得られたシロドシンγ型結晶は，これを本発明の製造方法を実施するにおいて，主原料として又は種晶として或いはこれら双方として再度利用することもできるから，トルエン含量を更に激減させたシロドシンγ型結晶を得ることができる。従って，トルエン含有量を極限までゼロに近づけたシロドシンγ型結晶を得ることも可能となる。 Furthermore, since the silodosin γ-type crystal thus obtained can be used again as a main raw material, as a seed crystal, or both in carrying out the production method of the present invention, the toluene content can be reduced. Furthermore, silodosin γ-type crystals that are drastically reduced can be obtained. Accordingly, it is possible to obtain a silodosin γ-type crystal having a toluene content close to zero as much as possible.
本明細書において，シロドシンのγ型結晶について，「トルエンを実質的に含有しない」というときは，結晶中のトルエン含量（ｐｐｍ）が，従来のような約１０００ｐｐｍもの濃度にトルエンを含有していたシロドシンγ型結晶とは異なって，トルエンを含有するとしても含有量が最大で１００ｐｐｍ以下に止まるもの，すなわちトルエン含有量が０〜１００ｐｐｍの範囲に収まることをいう。トルエン含有量がこの範囲内に収まっていれば医薬品原料として特に問題なく許容できるため，「実質的に含有しない」として取り扱うことができる。 In the present specification, when γ-type crystals of silodosin are said to be “substantially free of toluene”, the toluene content (ppm) in the crystals contained toluene at a concentration of about 1000 ppm as in the prior art. Unlike silodosin γ-type crystals, even if toluene is contained, it means that the content is limited to 100 ppm or less at the maximum, that is, the toluene content falls within the range of 0 to 100 ppm. If the toluene content is within this range, it can be tolerated as a pharmaceutical raw material with no particular problem, and can be handled as “substantially free”.
本発明のシロドシンγ型結晶のトルエン含有量は，好ましくは０〜８９ｐｐｍ，より好ましくは０〜７５ｐｐｍ，更に好ましくは０〜５０ｐｐｍである。本発明の製造方法を１回実施して得られるシロドシンγ型結晶を用いて，本発明の製造方法を更に実施することを反復すれば，１回の実施の毎に得られるシロドシンγ型結晶中のトルエン含有量は激減することから，本発明の製造方法をそのようにして単に数サイクル行うことで，得られるシロドシンγ型結晶のトルエン含有量を２５ｐｐｍ以下，５ｐｐｍ以下，１ｐｐｍ以下等と引き下げることも容易である。 The toluene content of the silodosin γ-type crystal of the present invention is preferably 0 to 89 ppm, more preferably 0 to 75 ppm, and still more preferably 0 to 50 ppm. If the production method of the present invention is further repeated by using the silodosin γ-type crystal obtained by carrying out the production method of the present invention once, the silodosin γ-type crystal obtained in each time of execution is repeated. Since the toluene content of sucrose is drastically reduced, the toluene content of the obtained silodosin γ-type crystals is reduced to 25 ppm or less, 5 ppm or less, 1 ppm or less, etc. by simply carrying out the production method of the present invention in several cycles as described above. Is also easy.
本明細書において，シロドシンγ型結晶について，「トルエンを含有しない」というときは，結晶のトルエン含有量が０〜５ｐｐｍの範囲に収まっていることをいう。 In the present specification, when the silodosin γ-type crystal is referred to as “does not contain toluene”, it means that the toluene content of the crystal is within the range of 0 to 5 ppm.
本明細書において，シロドシンについて，「主原料」というときは，１サイクルの結晶化プロセスにおいて，量的に主要な原料として投入され，溶媒により溶解された後に結晶化に付されることになるシロドシンを意味する。 In the present specification, when silodosin is referred to as “main raw material”, silodosin, which is introduced as a quantitative main raw material and dissolved in a solvent and then subjected to crystallization in a one-cycle crystallization process. Means.
本明細書において，シロドシンについて，「種晶」というときは，主原料のγ型での結晶化開始を促す目的で，主原料の溶液に，その冷却過程の途中でごく僅かな量添加されるシロドシン結晶（γ型）をいう。 In this specification, when referring to silodosin as a “seed crystal”, a very small amount is added to the solution of the main raw material during the cooling process in order to promote the crystallization of the main raw material in the γ-type. Silodosin crystal (γ type).
本明細書において，「低級アルコール」というときは，炭素数１，２，３，４，５又は６個のアルコールをいう。好ましくは，１価アルコールであり，そのうちでも好ましいのは，炭素数１〜４個のアルコールである。特に好ましい低級アルコールとしては，メタノール，エタノール，１−プロパノール，２−プロパノールが挙げられる。 In this specification, “lower alcohol” refers to an alcohol having 1, 2, 3, 4, 5, or 6 carbon atoms. A monohydric alcohol is preferable, and an alcohol having 1 to 4 carbon atoms is preferable among them. Particularly preferred lower alcohols include methanol, ethanol, 1-propanol and 2-propanol.
主原料とするシロドシンは，非晶質のものであっても，α型結晶やβ型結晶あってもよく，γ型結晶であってさえも（必要に応じ，本発明により結晶化を複数サイクル行うことで）用いることができる。 Silodosin as the main raw material may be amorphous, α-type crystal, β-type crystal, or even γ-type crystal. Can be used)
主原料とするシロドシンを溶媒に溶解させるときの温度は，特に制限はなく，用いた溶媒に応じて取り扱いやすい温度とすればよい。例えば，２−プロパノールを用いる場合，７０℃付近（７０±５℃等），メタノールやエタノールでは４０℃付近（４０±５℃等）とすることができるが，これらに限定されるわけではなく，シロドシンの結晶析出をもたらすに十分な温度差が後の冷却温度との間で確保できるものであればよく，そのような温度は適宜設定することができる。 The temperature at which silodosin as the main raw material is dissolved in the solvent is not particularly limited, and may be a temperature that is easy to handle depending on the solvent used. For example, when 2-propanol is used, the temperature can be around 70 ° C. (70 ± 5 ° C., etc.), and methanol or ethanol can be around 40 ° C. (40 ± 5 ° C., etc.). Any temperature difference sufficient to bring about silodosin crystal precipitation can be secured with respect to the subsequent cooling temperature, and such temperature can be appropriately set.
シロドシン溶液の冷却温度も同様であり，例えば０℃付近（０±５℃等）から，２５℃付近（２５±５℃）とすることができるが，これらに限定されない。 The cooling temperature of the silodosin solution is also the same, and can be, for example, from around 0 ° C. (0 ± 5 ° C. or the like) to around 25 ° C. (25 ± 5 ° C.), but is not limited thereto.
主原料の溶液への種晶の添加は，主原料の結晶化がまだ開始しておらず，しかし添加される種晶が完全に溶解してしまわないよう，主原料が飽和濃度付近にある段階（飽和濃度に達するやや手前〜幾分過飽和の状態）において行えばよく，その時機は，用いる溶媒と溶液中における主原料の濃度とに依存するから，結晶化にあたり適宜作業者が決定する事項である。一度結晶化を試行して条件を定めれば，それ以降は同一条件で行うことができる。 Addition of seed crystals to the solution of the main raw material is a stage where the main raw material is near the saturation concentration so that the main raw material has not yet started to crystallize, but the added seed crystals are not completely dissolved. (Slightly before reaching the saturation concentration to a somewhat supersaturated state), and the timing depends on the solvent used and the concentration of the main raw material in the solution. is there. Once crystallization is tried and the conditions are determined, the same conditions can be used thereafter.
本発明において，主原料とするシロドシンを溶媒と混合し撹拌しつつ加熱して溶解させた後，その状態で撹拌を所定時間維持することが，溶媒として２−プロパノール又は炭素数４個以上の低級アルコールを用いた場合には好ましい。そのような撹拌によりγ型結晶生成の確実性が高まる。「所定時間」に明確な下限はないが，例えば，少なくとも５分間，より好ましくは少なくとも１０分間，更に好ましくは少なくとも２０分間であり，例えば３０分間撹拌を維持すれば十分である。より長く撹拌しても技術上の問題はないから，撹拌時間に上限はないが，設定した最小限の撹拌時間が経過した後は，何時でも溶液の冷却を開始してよい。 In the present invention, silodosin as a main raw material is mixed with a solvent, heated and dissolved while stirring, and then maintained in that state for a predetermined period of time as 2-propanol or a lower carbon number of 4 or more as a solvent. It is preferable when alcohol is used. Such agitation increases the certainty of γ-type crystal formation. There is no clear lower limit for “predetermined time”, but it is, for example, at least 5 minutes, more preferably at least 10 minutes, and even more preferably at least 20 minutes. For example, it is sufficient to maintain stirring for 30 minutes. There is no technical problem with longer stirring, so there is no upper limit on the stirring time, but after the set minimum stirring time has elapsed, the solution may be cooled at any time.
本明細書において，「共溶媒」は，シロドシンに対する貧溶媒であり，シロドシン溶液に，その冷却過程の適宜の時点で（例えば，冷却温度に達した時，又は種晶の添加の直後等），添加することができる。共溶媒の添加は必須ではないが，添加により溶媒の全体量が増すため，結晶化したシロドシンのスラリーを希釈しその粘度を低下させて，晶析槽からの抜き出しを容易にする，という効果が得られる。共溶媒の添加は，進行してゆくシロドシンγ型結晶の成長に影響を及ぼさないよう，シロドシンを含んだ液を撹拌しつつこれに滴下する形で行うことが好ましい。本発明において特に適した共溶媒は，ｔ−ブチルメチルエーテルであり，これは，共溶媒無添加の場合に得られるシロドシン結晶（γ型）に影響を及ぼすことがない。 In the present specification, the “co-solvent” is a poor solvent for silodosin, and is added to the silodosin solution at an appropriate point in the cooling process (for example, when the cooling temperature is reached or immediately after the addition of the seed crystal). Can be added. Although the addition of a co-solvent is not essential, the addition of the solvent increases the total amount of the solvent. Therefore, it has the effect of diluting the crystallized silodosin slurry to reduce its viscosity and facilitating its extraction from the crystallization tank. can get. The co-solvent is preferably added in such a manner that a liquid containing silodosin is added dropwise to the agitated liquid so as not to affect the progress of the progressing silodosin γ-type crystal. A particularly suitable cosolvent in the present invention is t-butyl methyl ether, which does not affect the silodosin crystals (γ type) obtained when no cosolvent is added.
以下，実施例を参照して本発明を更に詳細に説明するが，本発明がそれらの実施例に限定されることは意図しない。 EXAMPLES Hereinafter, although this invention is demonstrated in detail with reference to an Example, this invention is not intended to be limited to those Examples.
〔残留トルエン濃度の測定方法〕
本明細書において，シロドシン結晶の残留トルエン濃度の測定には，以下の方法を用いた。
（ａ）１−ブタノール０．２５ｇをとり，ジメチルスルホキシドを加えて１００ｍＬとし，内標準溶液とする。内標準溶液１ｍＬを正確にとり，ジメチルスルホキシドを加えて正確に１０ｍＬとし，内標準添加液とする。
（ｂ）シロドシン０．１ｇを精密に量り，内標準添加液２ｍＬを正確に加えて，試料溶液とする。
（ｃ）トルエン約８．９ｇを精密に量り，ジメチルスルホキシドを加えて正確に１００ｍＬとし，トルエン溶液とする。この液１ｍＬを正確にとり，ジメチルスルホキシドを加えて正確に１００ｍＬとする。この液１ｍＬを正確にとり，内標準溶液２ｍＬを正確に加え，ジメチルスルホキシドを加えて正確に２０ｍＬとし，この液２ｍＬを標準溶液とする。
（ｄ）試料溶液及び標準溶液のそれぞれの容器内の気体１ｍＬにつき，次の条件でのガスクロマトグラフ法により試験を行い，内標準物質のピーク面積に対するトルエンのピーク面積の比ＱＴ及びＱＳ値よりトルエン量を求める。
[Measurement method of residual toluene concentration]
In the present specification, the following method was used to measure the residual toluene concentration of silodosin crystals.
(A) Take 0.25 g of 1-butanol, add dimethyl sulfoxide to make 100 mL, and use this as the internal standard solution. Take 1 mL of the internal standard solution accurately, add dimethyl sulfoxide to make exactly 10 mL, and use this solution as the internal standard addition solution.
(B) Weigh accurately 0.1 g of silodosin and add 2 mL of internal standard additive solution accurately to make a sample solution.
(C) Weigh accurately about 8.9 g of toluene, add dimethyl sulfoxide to make exactly 100 mL, and make a toluene solution. Take exactly 1 mL of this solution and add dimethyl sulfoxide to make exactly 100 mL. Take exactly 1 mL of this solution, add exactly 2 mL of internal standard solution, add dimethyl sulfoxide to make exactly 20 mL, and use 2 mL of this solution as the standard solution.
(D) per gas 1mL in each container of the sample solution and the standard solution were tested by gas chromatography under the following conditions, the ratio Q T and Q S value of the peak area of toluene to the peak area of the internal standard Determine the amount of toluene.
トルエン量（ｐｐｍ）＝ＭＳ×ＱＴ／ＱＳ×１／ＭＴ×１０
ここに，
ＱＴ：試料溶液中の内標準物質のピーク面積に対するトルエンのピーク面積の比
ＱＳ：標準溶液中の内標準物質のピーク面積に対するトルエンのピーク面積の比
ＭＴ：シロドシンの秤取量（ｍｇ）
ＭＳ：トルエンの秤取量（ｍｇ）
シロドシン中の残留トルエン量について，上記のようにして調製した試料溶液及び標準溶液を用い，ガスクロマトグラム法（検出器：水素炎イオン化，カラム：６％シアノプロピルフェニル−９４％ジメチルシリコンポリマー被覆）を用いて測定する。
Weight Toluene (ppm) = M S × Q T / Q S × 1 / M T × 10
here,
Q T : Ratio of peak area of toluene to peak area of internal standard substance in sample solution Q S : Ratio of peak area of toluene to peak area of internal standard substance in standard solution M T : Weighed amount of silodosin (mg )
M S : Weighed amount of toluene (mg)
Using the sample solution and standard solution prepared as described above for the amount of residual toluene in silodosin, gas chromatography (detector: flame ionization, column: 6% cyanopropylphenyl-94% dimethylsilicone polymer coating) Use to measure.
〔参考例１〕 結晶化方法のスクリーニング
シロドシンγ型結晶の製造方法を見出すための前段階として，種々の溶媒を用いて何型の結晶が得られるかを調べた（表中の「溶媒量（ｖ／ｗ）」は，シロドシンのｇ量に対する溶媒のｍＬ体積を表す）。すなわち非晶質のシロドシン５０ｍｇを次の表１に記載した溶媒のそれぞれに添加し，室温にて２４時間撹拌した後，５０℃で減圧乾燥して結晶を得た。それぞれで得られた結晶につき，粉末Ｘ線回折パターンを測定して結晶形を同定した。結果を併せて表１に示す。
[Reference Example 1] Screening of crystallization method As a preliminary step to find out a method for producing silodosin γ-type crystals, it was investigated what type of crystals could be obtained using various solvents (“solvent amount ( v / w) "represents the volume of mL of solvent relative to the amount of g of silodosin). That is, 50 mg of amorphous silodosin was added to each of the solvents described in the following Table 1, stirred at room temperature for 24 hours, and then dried under reduced pressure at 50 ° C. to obtain crystals. For each of the crystals obtained, the powder X-ray diffraction pattern was measured to identify the crystal form. The results are also shown in Table 1.
表１に見られるとおり，得られた結晶のうちγ型であったのはトルエンを溶媒に用いた場合のみであり，それ以外は全て，α型，β型，δ型やα型とβ型との混晶等，他の結晶形のものであった。 As can be seen in Table 1, the crystals obtained were γ-type only when toluene was used as a solvent, and all other cases were α-type, β-type, δ-type, α-type and β-type. And other crystal forms.
〔参考例２〕 γ型結晶の製造
シロドシン（α型結晶）３ｇにトルエン１２ｍＬを加え９０℃にて３０分間撹拌した後，２０℃まで徐冷した。生じた結晶を濾取し５０℃で乾燥させてγ型結晶２．７ｇを得た。この結晶の残留トルエン濃度は，１０１８ｐｐｍであった。
[Reference Example 2] Production of γ-type crystal 12 mL of toluene was added to 3 g of silodosin (α-type crystal), stirred at 90 ° C for 30 minutes, and then gradually cooled to 20 ° C. The resulting crystals were collected by filtration and dried at 50 ° C. to obtain 2.7 g of γ-type crystals. The residual toluene concentration of this crystal was 1018 ppm.
〔実施例１〕 γ型結晶化方法の検討−１
次いで，トルエンを使用せずにシロドシンのγ型結晶を得るための方法を求めて，検討を行った。
即ち，シロドシン（α型結晶）５０ｍｇを表２に記載したとおりにそれぞれ溶媒を加え，加熱して溶解させ，冷却を開始し，溶液に種晶としてシロドシンのγ型結晶（参考例２）を３重量％（溶液中のシロドシン量に対する重量割合）加えた。混合物を０℃に冷却し，析出した結晶を濾取して減圧乾燥した，乾燥結晶を粉末Ｘ線回折により分析した。
[Example 1] Examination of γ-type crystallization method-1
Next, a method for obtaining silodosin γ-type crystals without using toluene was obtained and examined.
That is, 50 mg of silodosin (α-type crystal) was added to each solvent as shown in Table 2, heated to dissolve, cooling was started, and γ-type crystals of silodosin (Reference Example 2) were added as seed crystals to the solution. % By weight (weight ratio to the amount of silodosin in the solution) was added. The mixture was cooled to 0 ° C., and the precipitated crystals were collected by filtration and dried under reduced pressure. The dried crystals were analyzed by powder X-ray diffraction.
＜結果＞
結果を，使用溶媒，温度条件と共に，表２に示す。
<Result>
The results are shown in Table 2 together with the solvent used and temperature conditions.
表２見られるように，溶媒としてメタノール，エタノール，１−プロパノールを使用した場合に，シロドシンのγ型結晶が得られ，２−プロパノール，１−ブタノール，２−ブタノール使用した場合にγ型とβ型の混晶が得られた。これに対し，ケトン類溶媒を用いた場合にはα型のみ，エステル類溶媒を用いた場合には主としてα型が得られ，酢酸イソプロピルでのみγ型がβ型との混晶として得られた。溶媒として水を用いた場合は，γ型結晶が得られたが，非晶質のシロドシンも含まれていた。エーテル類又は炭化水素類の溶媒では，シロドシンは還流下においてさえも不溶であった。これらの結果は，総合すると，シロドシンのγ型結晶を種晶として加えれば，メタノール，エタノール，１−プロパノール又は水の使用によりシロドシンのγ型結晶を得ることができること（但し水の場合非晶質も含まれる），及びこれら以外のアルコール類にも，条件次第でシロドシンのγ型結晶を与える潜在的可能性のあることを示唆している。 As can be seen from Table 2, γ-type crystals of silodosin are obtained when methanol, ethanol, and 1-propanol are used as solvents, and γ-type and β are obtained when 2-propanol, 1-butanol, and 2-butanol are used. A mixed crystal of the type was obtained. In contrast, only α-form was obtained when the ketone solvent was used, α-form was obtained mainly when the ester solvent was used, and γ-type was obtained as a mixed crystal with the β-type only with isopropyl acetate. . When water was used as the solvent, γ-type crystals were obtained, but amorphous silodosin was also included. In ethers or hydrocarbon solvents, silodosin was insoluble even under reflux. In summary, these results show that if γ-type crystals of silodosin are added as seed crystals, γ-type crystals of silodosin can be obtained by using methanol, ethanol, 1-propanol or water (however, in the case of water, it is amorphous). And other alcohols have the potential to give γ-type crystals of silodosin depending on the conditions.
〔実施例２〕 γ型結晶化方法の検討−２
上記の結果に基づき，更に２−プロパノールを用いて，シロドシンのγ型結晶の取得を試みた。
即ち，上記実施例１と同様に，但しシロドシンを溶媒に溶解させた後に，引き続き３０分間の撹拌行った上で，冷却を開始するように変更して，結晶化を試みた。このようにすることで，溶媒として２−プロパノールを用いてもシロドシンのγ型結晶が再現性良く得られることが判明した（データ示さず）。
[Example 2] Study of γ-type crystallization method-2
Based on the above results, an attempt was made to obtain γ-type crystals of silodosin using 2-propanol.
That is, in the same manner as in Example 1, except that silodosin was dissolved in a solvent and then stirred for 30 minutes and then changed to start cooling, and crystallization was attempted. In this way, it was found that γ-type crystals of silodosin can be obtained with good reproducibility even when 2-propanol is used as a solvent (data not shown).
〔実施例３〕 ２−プロパノールからのシロドシンの結晶化の再確認
実施例２の結果に基づき，２−プロパノールを用いた結晶化について更に検討を行った。
即ち，表３に示した各条件で，主原料としてシロドシン（α型結晶）を２プロパノールに加え，加熱して溶解させた後，引き続き３０分間撹拌した。得られた溶液を冷却し，種晶としてシロドシンのγ型結晶を加えた後，更に冷却した。析出物を濾取し，減圧乾燥してシロドシンの結晶を得た。何れの結晶もγ型であった。収率を併せて表３に示す。
Example 3 Reconfirmation of Silodosin Crystallization from 2-Propanol Based on the results of Example 2, crystallization using 2-propanol was further investigated.
That is, under each condition shown in Table 3, silodosin (α-type crystal) as a main raw material was added to 2 propanol, dissolved by heating, and then stirred for 30 minutes. The obtained solution was cooled, and γ-type crystals of silodosin were added as seed crystals, followed by further cooling. The precipitate was collected by filtration and dried under reduced pressure to obtain silodosin crystals. All the crystals were γ type. The yield is also shown in Table 3.
表３に見られるとおり，試験番号１〜６の何れの条件でも，収率こそ異なるものの，安定してシロドシンγ型結晶が得られた。 As seen in Table 3, silodosin γ-type crystals were stably obtained under any of the test numbers 1 to 6 although the yields were different.
〔実施例４〕 共溶媒の検討
実施例４において，安定してシロドシンγ型結晶が得られることが確認できたことから，次いで，工業的スケールでの操作性の改善を求めて検討を行った。２−プロパノールを溶媒とするシロドシンγ型結晶のスラリーが高粘性で，晶析槽からの抜き出しの操作性に難点があったためである。
結晶化において共溶媒を用いることを着想し，共溶媒として，２−プロパノールに比べてシロドシンを溶解させにくい溶媒（水，ヘプタン，ｔ−ブチルメチルエーテル）を試みた。即ち，主原料であるシロドシン（α型結晶）０．２ｇを２−プロパノール０．６ｍＬ（３ｖ／ｗ）に加え，７０〜７３℃に加熱して溶解させた後，引き続き３０分間撹拌した。得られた溶液を４５℃に冷却し，種晶としてシロドシンのγ型結晶を２重量％（主原料に対する重量％）添加した。混合物を１０分間撹拌後，２５℃に冷却して共溶媒を滴下した。析出物を濾取し，減圧乾燥した。生成物を粉末Ｘ線回折により分析した。結果を表４に示す。
[Example 4] Examination of co-solvent In Example 4, it was confirmed that silodosin γ-type crystals could be obtained stably, and then, an examination was conducted to improve the operability on an industrial scale. . This is because the slurry of silodosin γ-type crystal using 2-propanol as a solvent is highly viscous, and there is a difficulty in operability of extraction from the crystallization tank.
The idea of using a co-solvent in crystallization was attempted, and a solvent (water, heptane, t-butyl methyl ether) in which silodosin is less soluble than 2-propanol was tried as a co-solvent. That is, 0.2 g of silodosin (α-type crystal) as the main raw material was added to 0.6 mL (3 v / w) of 2-propanol, dissolved by heating to 70 to 73 ° C., and then stirred for 30 minutes. The resulting solution was cooled to 45 ° C., and 2 wt% of silodosin γ-type crystals (wt% based on the main raw material) was added as seed crystals. The mixture was stirred for 10 minutes, then cooled to 25 ° C. and a cosolvent was added dropwise. The precipitate was collected by filtration and dried under reduced pressure. The product was analyzed by powder X-ray diffraction. The results are shown in Table 4.
表４に示すように，共溶媒としてｎ−ヘプタンを用いた場合にはα型結晶とγ型結晶との混晶が生じたが，共溶媒としｔ−ブチルメチルエーテルを用いた場合にはγ型結晶のみが得られた。共溶媒として水を用いた場合には，γ型結晶以外に非晶質のシロドシンが得られた。 As shown in Table 4, when n-heptane was used as a cosolvent, a mixed crystal of α-type crystals and γ-type crystals was formed, but when t-butyl methyl ether was used as a cosolvent, γ Only type crystals were obtained. When water was used as a cosolvent, amorphous silodosin was obtained in addition to the γ-type crystals.
〔実施例５〕 スケールアップ検討
主原料として粗シロドシン（α型結晶）（ＨＰＬＣ面積：９９．２２％）２０ｇを，２−プロパノール６０ｍＬに加え，７０℃に加熱して溶解させた後，引き続き３０分間撹拌した。得られた溶液を４５℃に冷却し，これに種晶としてシロドシンのγ型結晶４〜５重量％（表５参照）を添加した。１時間撹拌の後，ｔ−ブチルメチルエーテル５００ｍＬを約２５分かけて滴下し，その後室温まで冷却して１〜１７時間撹拌した。析出物を濾取し，ろ過器上でｔ−ブチルメチルエーテル３０ｍＬで洗浄した。湿結晶を５０℃で減圧乾燥することで，シロドシンγ型結晶を得た。得られた結晶につき，残留トルエン濃度を測定した。結果を表５に示す。
[Example 5] Scale-up study 20 g of crude silodosin (α-type crystal) (HPLC area: 99.22%) as a main raw material was added to 60 mL of 2-propanol, dissolved by heating to 70 ° C, and subsequently 30 Stir for minutes. The obtained solution was cooled to 45 ° C., and 4 to 5 wt% of silodosin γ-type crystals (see Table 5) were added as seed crystals. After stirring for 1 hour, 500 mL of t-butyl methyl ether was added dropwise over about 25 minutes, then cooled to room temperature and stirred for 1 to 17 hours. The precipitate was collected by filtration and washed with 30 mL of t-butyl methyl ether on the filter. The wet crystals were dried under reduced pressure at 50 ° C. to obtain silodosin γ-type crystals. The residual toluene concentration was measured for the obtained crystals. The results are shown in Table 5.
表５に示すように，何れの試験でもシロドシンγ型結晶の残留トルエン濃度は，５０ｐｐｍより低い３１〜３８ｐｐｍの値であった。 As shown in Table 5, the residual toluene concentration of silodosin γ-type crystals was 31 to 38 ppm lower than 50 ppm in all tests.
本発明は，α１−アドレナリン受容体阻害剤であるシロドシンのうち，そのγ型結晶を，人体に対し有害物質であり医薬品原体中の残留が規制されているものであるトルエンを実質的に含有しない形で製造すること可能にした点で，有用である。
In the present invention, among the silodosin which is an α 1 -adrenergic receptor inhibitor, its γ-type crystal is substantially converted to toluene which is a harmful substance to the human body and whose residue in the drug substance is regulated. This is useful in that it can be produced in a form that does not contain it.
Claims (9)
The production method according to claim 4, wherein t-butyl methyl ether is used as a co-solvent.
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| PCT/JP2014/083189 WO2015093456A1 (en) | 2013-12-17 | 2014-12-16 | Silodosin γ-form crystal and method for producing same |
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| JP2016147811A (en) * | 2015-02-10 | 2016-08-18 | ダイト株式会社 | METHOD FOR PRODUCING SILODOSIN γ-TYPE CRYSTAL |
| CN111410626A (en) * | 2019-01-04 | 2020-07-14 | 上海汇伦医药科技有限公司 | Preparation method of silodosin α -crystal form |
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| KR20150127996A (en) * | 2014-05-08 | 2015-11-18 | 한미정밀화학주식회사 | Method for preparing gamma crystalline form of silodosin |
| CN109824569B (en) * | 2019-04-04 | 2022-09-20 | 重庆医药高等专科学校 | Sirocalcin crystal form I and preparation method thereof |
| WO2020237643A1 (en) * | 2019-05-31 | 2020-12-03 | 上海汇伦生命科技有限公司 | Preparation method for preparing silodosin alpha-crystal form |
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| JP2016147811A (en) * | 2015-02-10 | 2016-08-18 | ダイト株式会社 | METHOD FOR PRODUCING SILODOSIN γ-TYPE CRYSTAL |
| CN111410626A (en) * | 2019-01-04 | 2020-07-14 | 上海汇伦医药科技有限公司 | Preparation method of silodosin α -crystal form |
| CN111410626B (en) * | 2019-01-04 | 2022-11-04 | 上海汇伦医药股份有限公司 | Preparation method of silodosin alpha-crystal form |
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