JP4402361B2 - Crystalline polymorph of epinastine hydrochloride - Google Patents
Crystalline polymorph of epinastine hydrochloride Download PDFInfo
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- JP4402361B2 JP4402361B2 JP2003093181A JP2003093181A JP4402361B2 JP 4402361 B2 JP4402361 B2 JP 4402361B2 JP 2003093181 A JP2003093181 A JP 2003093181A JP 2003093181 A JP2003093181 A JP 2003093181A JP 4402361 B2 JP4402361 B2 JP 4402361B2
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- Prior art keywords
- epinastine hydrochloride
- crystal
- crystals
- epinastine
- hydrochloride
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Description
【０００１】
本発明は抗アレルギーおよび抗ヒスタミン作用によって特徴付けられる治療学的に有用な塩酸エピナスチンの製造方法に関するものである。
【０００２】
【従来の技術】
３−アミノ−９，１３ｂ−ジヒドロ−１Ｈ−ジベンズ［ｃ，ｆ］イミダゾ［１，５−ａ］アゼピン・塩酸塩（以下、塩酸エピナスチンと称する）は抗アレルギー及び抗ヒスタミン作用によって特徴付けられる治療学的に有用な化合物である。結晶化法についてはメタノール−エーテル溶液から結晶化する方法が知られている（特許文献１）。この方法において得られた結晶の評価データの融点しか記載が無く、結晶多形の有無は確認されていない。またジメチルホルムアミドから結晶化する方法が知られている（特許文献２）。この方法においても結晶の評価データは融点しか記載が無く、結晶多形の有無は確認されていない。さらには水から結晶化する方法が知られている（特許文献３）。この方法においては示差走査熱量測定（以下、DSCと称する）結果から結晶多形が存在し低融点結晶、高融点結晶を判別できることが述べられている。しかしながら、純度の低い結晶では融解温度が純物質に比べ低いことから結晶化溶媒の差から生ずる不純物含量の影響を否定できず、測定対象物の純度を同一にしなければ融点による結晶多形の判別は意味を成さない。
【０００３】
【特許文献１】
特開平３−６６３１１号公報
【０００４】
【特許文献２】
特開平４−３４６９８８号公報
【０００５】
【特許文献３】
ＷＯ ０１／４０２２９
【０００６】
【発明が解決しようとする課題】
通常、結晶多形が存在する化合物は結晶形によって種々の性質が相違するため、たとえ同一化合物であっても全く異なる作用効果を持つことがある。結晶多形が存在する化合物を医薬品として用いる場合、医薬品として要求される均一な品質及び一定の作用効果を確保するためには、単一の結晶性の化合物を常に一定して提供することが必要である。
【課題を解決する為の手段】
【０００７】
本発明者らは上記の問題を解決すべく高品質の塩酸エピナスチンを使い得られた、融点が高くかつ安定性に優れた結晶を粉末Ｘ線回折法により評価した結果、2種の結晶多形が存在することを見出した。
すなわち本発明は
（１）粉末Ｘ線回折図形で回折角（２θ）において１０．３、１２．８、１３．１、１５．４、１７．２、２０．７、２１．１、２１．５度に強い回折ピークを示す塩酸エピナスチン結晶多形。
（２）高品質の塩酸エピナスチンを非プロトン性極性溶媒から結晶化することを特徴とする粉末Ｘ線回折図形で１０．３、１２．８、１３．１、１５．４、１７．２、２０．７、２１．１、２１．５に強い回折ピークを示す塩酸エピナスチン結晶多形の製造方法。
である。
【０００８】
以下本発明を詳細に説明する。
塩酸エピナスチンは特許文献２に記載の方法で製造できる化合物である。本発明者らは高品質の塩酸エピナスチンを原料とし種々の溶媒にて再結晶をおこなった結晶を粉末Ｘ線回折法により評価し、結晶多形が存在することを見出した。粉末Ｘ線回折図形で回折角（２θ）において１０．３、１２．８、１３．１、１５．４、１７．２、２０．７、２１．１、２１．５度に強い回折ピークを示す塩酸エピナスチン結晶多形は安定な結晶であり、医薬品として用いる場合、保存により品質が変化することなく常に一定した作用効果を発揮することができる。本発明の結晶多形は非プロトン性極性溶媒から再結晶することで製造できる。
【０００９】
本発明の塩酸エピナスチンの結晶多形は以下の図１に示すとおりである。
【図１】
再結晶溶媒の非プロトン性極性溶媒としてはアセトニトリル、アセトン、Ｎ−メチルピロリドン、ジメチルスルホキシド、またはこれらの混合溶媒が使用できる。
【００１１】
実施例の原料は液体クロマトグラフィー純度９９．９％の塩酸エピナスチンを使用した。また、実施例における液体クロマトグラフィー純度は、下記条件にて液体クロマトグラフィー分析を行い、各成分ピークの面積％を用いたものであり純度の指標とした。
装置：ＬＣ−２０００Ｐｌｕｓ ｓｅｒｉｅｓ（日本分光株式会社）
カラム：Ｉｎｅｒｔｓｉｌ ＯＤＳ−３
移動層：２０ｍｍｏｌ−ＫＨ２ＰＯ４（リン酸にてｐＨ＝２．５に調整）水溶液／アセトニトリル＝４０／６０の混合液に、更に２０ｍｍｏｌ濃度となる様にオクタンスルホン酸ナトリウムを加えたもの。
検出波長：２４０ｎｍ
【００１２】
【比較例】
比較例１
塩酸エピナスチン５．０ｇをメタノール１０ｍｌに加熱溶解した後、ジエチルエーテル５０ｍLを加え攪拌しながら５℃まで冷却した。析出した結晶を濾過し、乾燥することにより結晶３．８ｇを得た。得られた塩酸エピナスチンの結晶多形は以下に示すとおりである。
【図２】
【実施例】
実施例によって本発明を具体的に説明するが、本発明がこれらの実施例のみに限定されるものではない。
【００１４】
実施例１
塩酸エピナスチン５．０ｇをジメチルスルホキシド１０ｍｌに加熱溶解した後、アセトン２５ｍLを加え攪拌しながら５℃まで冷却した。析出した結晶を濾過し、乾燥することにより結晶３．６ｇを得た。得られた結晶の粉末Ｘ線回折図形は回折角（２θ）において１０．３、１２．８、１３．１、１５．４、１７．２、２０．７、２１．１、２１．５度に強い回折ピークを示した。融点は２７２℃（日本薬局方 融点測定法；第１法）、液体クロマトグラフィー純度９９．９％で原料の塩酸エピナスチンと純度は同じであった。
【００１５】
実施例２
塩酸エピナスチン１．０ｇをアセトニトリル／Ｎ−メチル−２−ピロリドン（２／１）の混合液１５ｍｌに加熱溶解した後、攪拌しながら５℃まで冷却した。析出した結晶を濾過し、乾燥することにより結晶０．７ｇを得た。得られた結晶の粉末Ｘ線回折図形は回折角（２θ）において１０．３、１２．８、１３．１、１５．４、１７．２、２０．７、２１．１、２１．５度に強い回折ピークを示した。融点は２７２℃（日本薬局方 融点測定法；第１法）液体クロマトグラフィー純度９９．９％で原料の塩酸エピナスチンと純度は同じであった。
【００１６】
【発明の効果】
医薬品として優れた塩酸エピナスチン結晶多形を提供できる。[0001]
The present invention relates to a method for the production of therapeutically useful epinastine hydrochloride characterized by antiallergic and antihistamine action.
[0002]
[Prior art]
3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine hydrochloride (hereinafter referred to as epinastine hydrochloride) is a treatment characterized by antiallergic and antihistaminic activity It is a scientifically useful compound. As a crystallization method, a method of crystallization from a methanol-ether solution is known (Patent Document 1). Only the melting point of the evaluation data of the crystals obtained by this method is described, and the presence or absence of crystal polymorphism has not been confirmed. A method of crystallizing from dimethylformamide is known (Patent Document 2). Even in this method, the crystal evaluation data only describes the melting point, and the presence or absence of crystal polymorphism has not been confirmed. Furthermore, a method of crystallizing from water is known (Patent Document 3). In this method, it is stated that there are crystal polymorphs from the results of differential scanning calorimetry (hereinafter referred to as DSC), and low melting crystals and high melting crystals can be distinguished. However, since the melting temperature of low-purity crystals is lower than that of pure substances, the influence of the impurity content resulting from the difference in the crystallization solvent cannot be ruled out. Does not make sense.
[0003]
[Patent Document 1]
JP-A-3-66311
[Patent Document 2]
JP-A-4-346888
[Patent Document 3]
WO 01/40229
[0006]
[Problems to be solved by the invention]
In general, a compound having a crystal polymorph has various properties depending on the crystal form, and therefore even the same compound may have completely different effects. When using compounds with crystalline polymorphs as pharmaceuticals, it is necessary to always provide a single crystalline compound in a constant manner in order to ensure the uniform quality and certain effects that are required for pharmaceuticals. It is.
[Means for solving the problems]
[0007]
The inventors of the present invention evaluated a crystal having a high melting point and excellent stability obtained by using high-quality epinastine hydrochloride to solve the above problems by powder X-ray diffractometry. As a result, two crystal polymorphs were obtained. Found that there exists.
That is, the present invention is (1) a powder X-ray diffraction pattern with diffraction angles (2θ) of 10.3, 12.8, 13.1, 15.4, 17.2, 20.7, 21.1, 21.5. Epinastine hydrochloride crystal polymorph showing a strong diffraction peak.
(2) Powder X-ray diffraction patterns characterized by crystallizing high-quality epinastine hydrochloride from an aprotic polar solvent, 10.3, 12.8, 13.1, 15.4, 17.2, 20 .7, 21.1, 21.5 Production method of epinastine hydrochloride crystal polymorph showing strong diffraction peaks.
It is.
[0008]
The present invention will be described in detail below.
Epinastine hydrochloride is a compound that can be produced by the method described in Patent Document 2. The inventors of the present invention have evaluated a crystal recrystallized from various solvents using high-quality epinastine hydrochloride as a raw material, and found that a crystal polymorph exists. X-ray powder diffraction pattern shows strong diffraction peaks at 10.3, 12.8, 13.1, 15.4, 17.2, 20.7, 21.1 and 21.5 degrees at diffraction angles (2θ). The epinastine hydrochloride polymorph is a stable crystal, and when used as a pharmaceutical, it can always exhibit a constant effect without change in quality due to storage. The crystalline polymorph of the present invention can be produced by recrystallization from an aprotic polar solvent.
[0009]
The crystal polymorph of epinastine hydrochloride of the present invention is as shown in FIG. 1 below.
[Figure 1]
As the aprotic polar solvent for the recrystallization solvent, acetonitrile, acetone, N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used.
[0011]
The raw material used in the examples was epinastine hydrochloride having a liquid chromatography purity of 99.9%. Moreover, the liquid chromatography purity in an Example performed the liquid chromatography analysis on the following conditions, and used the area% of each component peak, and made it the purity parameter | index.
Apparatus: LC-2000 Plus series (JASCO Corporation)
Column: Inertsil ODS-3
Moving layer: 20 mmol-KH 2 PO 4 (adjusted to pH = 2.5 with phosphoric acid) A mixture of aqueous solution / acetonitrile = 40/60, and sodium octanesulfonate added to a concentration of 20 mmol.
Detection wavelength: 240 nm
[0012]
[Comparative example]
Comparative Example 1
After dissolving 5.0 g of epinastine hydrochloride in 10 ml of methanol, 50 mL of diethyl ether was added and the mixture was cooled to 5 ° C. with stirring. The precipitated crystals were filtered and dried to obtain 3.8 g of crystals. The resulting crystal polymorphs of epinastine hydrochloride are as shown below.
[Figure 2]
【Example】
EXAMPLES The present invention will be specifically described with reference to examples, but the present invention is not limited only to these examples.
[0014]
Example 1
After dissolving 5.0 g of epinastine hydrochloride in 10 ml of dimethyl sulfoxide, 25 ml of acetone was added and the mixture was cooled to 5 ° C. with stirring. The precipitated crystals were filtered and dried to obtain 3.6 g of crystals. The powder X-ray diffraction pattern of the obtained crystals was 10.3, 12.8, 13.1, 15.4, 17.2, 20.7, 21.1, 21.5 degrees at diffraction angles (2θ). It showed a strong diffraction peak. The melting point was 272 ° C. (Japanese Pharmacopoeia Melting Point Measurement Method: Method 1), the liquid chromatography purity was 99.9%, and the purity was the same as that of epinastine hydrochloride as a raw material.
[0015]
Example 2
After dissolving 1.0 g of epinastine hydrochloride in 15 ml of a mixed solution of acetonitrile / N-methyl-2-pyrrolidone (2/1), the mixture was cooled to 5 ° C. with stirring. The precipitated crystals were filtered and dried to obtain 0.7 g of crystals. The powder X-ray diffraction pattern of the obtained crystals was 10.3, 12.8, 13.1, 15.4, 17.2, 20.7, 21.1, 21.5 degrees at diffraction angles (2θ). It showed a strong diffraction peak. Melting point was 272 ° C. (Japanese Pharmacopoeia Melting Point Measurement Method: Method 1) The liquid chromatography had a purity of 99.9% and was the same as the raw material epinastine hydrochloride.
[0016]
【The invention's effect】
Epinastine hydrochloride polymorphs excellent as pharmaceuticals can be provided.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003093181A JP4402361B2 (en) | 2003-03-31 | 2003-03-31 | Crystalline polymorph of epinastine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003093181A JP4402361B2 (en) | 2003-03-31 | 2003-03-31 | Crystalline polymorph of epinastine hydrochloride |
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| Publication Number | Publication Date |
|---|---|
| JP2004300042A JP2004300042A (en) | 2004-10-28 |
| JP4402361B2 true JP4402361B2 (en) | 2010-01-20 |
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| JP2003093181A Expired - Fee Related JP4402361B2 (en) | 2003-03-31 | 2003-03-31 | Crystalline polymorph of epinastine hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2985511B1 (en) * | 2012-01-05 | 2014-01-03 | Servier Lab | CRYSTALLINE DELTA FORM OF PERINOPRIL ARGININE SALT, PROCESS FOR PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| JP6428527B2 (en) * | 2015-08-06 | 2018-11-28 | 三菱瓦斯化学株式会社 | Method for producing pyrroloquinoline quinone crystals |
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