WO2023068253A1 - Novel crystal form of benzothiophene compound and production method therefor - Google Patents

Novel crystal form of benzothiophene compound and production method therefor Download PDF

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WO2023068253A1
WO2023068253A1 PCT/JP2022/038720 JP2022038720W WO2023068253A1 WO 2023068253 A1 WO2023068253 A1 WO 2023068253A1 JP 2022038720 W JP2022038720 W JP 2022038720W WO 2023068253 A1 WO2023068253 A1 WO 2023068253A1
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crystal
crystals
thiophen
butoxy
quinolin
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PCT/JP2022/038720
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French (fr)
Japanese (ja)
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怜 大塚
亮平 江藤
慎 深名
伸也 森
菜沙 坂本
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大塚製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the present invention relates to a novel method for producing a benzothiophene compound, a novel crystal form obtained during the method, and the like. It should be noted that the contents of all documents described in this specification (especially Patent Document 1 and Patent Document 2 below) are incorporated herein by reference.
  • brexpiprazole 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as brexpiprazole or compound (I)) is It has dopamine D2 receptor partial agonistic action, serotonin 5- HT2A receptor antagonistic action and adrenergic ⁇ 1 receptor antagonistic action. In addition to these actions, compound (I) is known to have a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) and has a wide therapeutic spectrum for central nervous system diseases (particularly schizophrenia). (Patent Document 1).
  • brexpiprazole or a dihydrate of its salt is stable and is a pharmacologically active substance that is particularly effective when used as an intramuscular injection (Patent Document 2).
  • the brexpiprazole dihydrate is a crystal that can be a better therapeutic drug for central nervous system diseases (hereinafter, the brexpiprazole dihydrate crystal is referred to as "Form I" or "hydrate form I”).
  • the brexpiprazole dihydrate is obtained by dissolving brexpiprazole in an acid (e.g., acetic acid or lactic acid)-containing solvent and neutralizing it with an alkali (e.g., sodium hydroxide) to crystallize (neutralization crystallization), low-temperature aging (for example, 5° C. or less for about 1 hour), and further high-temperature aging (for example, 20-30° C. for about 7 hours).
  • an acid e.g., acetic acid or lactic acid
  • an alkali e.g., sodium hydroxide
  • the present inventors conducted repeated studies to find a method for preparing hydrate form I crystals with a large particle size with good reproducibility. Then, brexpiprazole is dissolved in an alkali (e.g., sodium hydroxide)-containing solvent, cooled to crystallize (cooling crystallization), water is added, and then aged at high temperature to give hydrate I It was found that crystals of this type could be prepared. They also found that hydrate form I crystals having a large particle size can be obtained with good reproducibility by the production method, and that the crystals obtained by the cooling crystallization are novel crystals.
  • an alkali e.g., sodium hydroxide
  • Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 9.
  • An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 1 to 7 is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours.
  • Item 13 The powder X-ray diffraction pattern of the crystal is a pattern measured using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans).
  • EMPYREAN X-ray diffractometer
  • MHC-trans humidification measurement attachment
  • (1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one of Items 2a to 4a.
  • Item 6a Item 5a, wherein the cooling temperature in step (1) is 10 to 40°C.
  • An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 2a to 4a is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours.
  • a production method capable of reproducibly preparing crystals of brexpiprazole dihydrate having a relatively large particle size, and a novel crystal that is a precursor for preparing the stable crystal are provided.
  • the novel crystals are crystals that can be prepared during the production method. can get.
  • the large particle size of the dihydrate crystals can improve filterability and reduce operating time.
  • FIG. 4 shows the infrared absorption spectrum of brexpiprazole hydrate crystals X4 having a water content of 10.4% obtained in Production Example 4.
  • FIG. 1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X3 having a water content of 37.6% obtained in Production Example 3.
  • FIG. 1 shows the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 1.
  • FIG. 2 shows the measurement results of the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 2.
  • 1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X6 having a water content of 50.5% obtained in Production Example 6.
  • FIG. The powder X-ray diffraction pattern of the brexpiprazole hydrate crystals X6 obtained in Preparation Example 6 at 25° C. and each relative humidity (RH), measured by copper radiation with ⁇ 1.5418 ⁇ through a monochromator, is shown in FIG. show.
  • RH relative humidity
  • Crystals encompassed by the present disclosure are 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) or It is a salt hydrate crystal.
  • 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) has the following formula (I):
  • salts of compound (I) include salts described in Patent Document 1, and more specifically, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); , triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine
  • alkali metal salts e.g., sodium salts, potassium salts, etc.
  • Compound (I) or a salt thereof can be produced by a known method (for example, the method described in Patent Document 1 or 2).
  • a hydrate crystal of compound (I) or a salt thereof included in the present disclosure has at least one of the following characteristics (i) and (ii), and more preferably has both characteristics.
  • the crystal may be referred to as "the crystal of the present disclosure”.
  • diffraction angles 2 ⁇ (°) 11.4 ⁇ 0.2, 12.4 ⁇ 0.2, 15.8 ⁇ 0.2, 18.2 ⁇ 0.2, and 22.8 ⁇ 0.2
  • the crystals of the present disclosure preferably have the 5 or 6 peaks when the water content of the crystals is 30-45%, more preferably 30-40%.
  • Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS).
  • the specific peaks of these diffraction angles 2 ⁇ may shift slightly depending on the water content (moisture content).
  • the diffraction angle tends to shift slightly to the high angle side.
  • the table below shows the values of the above-mentioned specific peaks when the water values of the crystals of the present disclosure are between 30 and 45%, as well as the above-mentioned specific peak values when the water values of the crystals of the present disclosure are between 45-55%. Peak values are indicated.
  • the water content value of the crystal is the value (% by weight) measured by the Karl Fischer method (coulometric titration method).
  • Karl Fischer method coulometric titration method
  • it can be measured using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
  • Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans)).
  • EMPYREAN X-ray diffractometer manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans)
  • the measurement under a specific relative humidity means that the crystal of the present disclosure is allowed to stand under the specific temperature and relative humidity, the mass is observed, and the measurement is performed when the mass change has stabilized. means to do
  • the infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
  • an infrared spectrophotometer for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation.
  • one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption band wavenumbers (cm -1 ) may be ⁇ 10, ⁇ 9, ⁇ 8, ⁇ 7, ⁇ 6, ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1.
  • the present inventors dissolved brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent, crystallized it by cooling (cooling crystallization), added water, and then dissolved at high temperature. It was found that hydrate form I crystals can be prepared by aging, and that the production method yields hydrate form I crystals having a large particle size with good reproducibility.
  • the crystals of the present disclosure were found as crystals obtained by the cooling crystallization.
  • the crystal of the present disclosure can be preferably used as a precursor of hydrate form I crystal. By the method for preparing hydrate form I crystals using the crystals of the present disclosure, hydrate form I crystals can be obtained with good reproducibility. Furthermore, it is also possible to efficiently obtain hydrate form I crystals having a large particle size.
  • brexpiprazole can be prepared by a known method, for example, by the method described in Patent Document 1 or 2.
  • the crystals of the present disclosure are prepared, for example, by dissolving brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent and crystallizing it by cooling (cooling crystallization). can do.
  • alkali e.g., sodium hydroxide
  • the present disclosure preferably also includes methods for producing the crystals of the present disclosure.
  • the method for producing crystals of the present disclosure preferably includes (1) cooling an aqueous alcohol solution in which brexpiprazole and an alkali are dissolved.
  • the cooling temperature here is a temperature lower than the temperature at which brexpiprazole is dissolved, specifically 40° C. or less. About 10 to 40°C is preferable, and about 15 to 40°C is more preferable. Furthermore, it is preferably about 15 to 35°C.
  • alkalis examples include sodium hydroxide and potassium hydroxide, with sodium hydroxide being particularly preferred.
  • alcohols include monohydric alkyl alcohols having 1 to 4 carbon atoms, such as ethanol and propanol (n-propanol, isopropanol), with ethanol being particularly preferred.
  • the alcohol content of the alcohol aqueous solution here is preferably about 45 to 55% by mass.
  • the content of brexpiprazole is about 1 to 10% by mass, more preferably about 3 to 6% by mass, and the content of alkali is preferably about 1 to 5% by mass, more preferably about 1 to 3% by mass. is.
  • the method for producing crystals of the present disclosure includes (0) mixing brexpiprazole, alkali, alcohol, and water to obtain a solution in which brexpiprazole is dissolved before step (1).
  • the mixing ratio of each component can be the same mixing ratio as described in step (1) above.
  • brexpiprazole when dissolving brexpiprazole in an alkali-containing solvent, add 4 to 6 equivalents of sodium hydroxide to 50 to 60% by volume ethanol aqueous solution, and add an appropriate amount of brexpiprazole (for example, to the aqueous ethanol solution). about 1 to 5% by mass), mixed (preferably at a temperature of about 80 to 85° C. and stirred under reflux) to prepare a brexpiprazole solution, and the solution is cooled (dissolved at a temperature lower than the temperature at which the crystals of the present disclosure were obtained.
  • the cooling temperature is, for example, about 10 to 40.degree. C., more preferably about 15 to 40.degree.
  • the upper or lower limit of the cooling temperature may be 15, 20, 25, 30, or 35°C, for example.
  • the cooling temperature may be about 15-35°C.
  • step (1) with or without isolation of the crystals of the present disclosure, (2) further water is added to the cooled aqueous solution, and (3) high temperature aging.
  • a method for producing the dihydrate of siprazole or a salt thereof is also preferably included in the present disclosure.
  • the amount of water to be added in (2) is, for example, 0.3 to 3 times the volume of the cooled aqueous solution.
  • the upper or lower limit of the range may be, for example, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, or 2.5.
  • the range may be 0.4 to 1 volume, or 0.4 to 0.8 volume.
  • the temperature of the water to be added is preferably about the same as that of the cooled aqueous solution, such as 10 to 40°C, more preferably 15 to 40°C, and even more preferably 15 to 35°C.
  • water may be added and further stirred.
  • the stirring time can be appropriately set, for example, about 1 to 72 hours.
  • the high-temperature aging in (3) can be carried out by standing or stirring at a temperature higher than the cooling temperature (for example, 35 to 50°C, more preferably 35 to 45°C).
  • the standing or stirring time is preferably 10 minutes or longer, more preferably about 10 minutes to 19 hours.
  • the upper or lower limit of the stirring time (10 minutes to 19 hours) may be, for example, about 1, 2, 3, 5, 10, or 15 hours.
  • Dihydrate crystals (hydrate form I crystals) of brexpiprazole or a salt thereof having a large average particle size can be obtained with good reproducibility.
  • the dihydrate crystals of brexpiprazole or a salt thereof prepared as described above are sometimes referred to as "hydrate Form I crystals of the present disclosure.” It can also be said that the hydrate Form I crystals of the present disclosure can be prepared using the crystals of the present disclosure as precursors.
  • the hydrate form I crystal of the present disclosure preferably has an average particle size of 26 ⁇ m or more, more preferably 35 or 45 ⁇ m or more.
  • the upper limit is not particularly limited, for example, 60 ⁇ m or less is exemplified, and 55 or 50 ⁇ m or less may be exemplified.
  • the average particle size in this specification is the volume average size measured by a laser diffraction method.
  • an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
  • FT-IR IRAffinity-1S Fourier transform infrared spectrophotometer
  • the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc. .
  • the water content of crystal X3 obtained in Production Example 3 was 37.6%. Moreover, the powder X-ray diffraction pattern measurement results are shown in FIG. 1 and Table 1b. Table 1b shows characteristic peaks.
  • the crystal X4 obtained in Production Example 4 was placed in a desiccator adjusted to a relative humidity of about 7%, left to stand for 16 hours, and further dried.
  • the moisture content of the dried crystals obtained in this manner was measured in the same manner as described above and found to be 10.4%.
  • the infrared absorption spectrum of this dried crystal was also measured in the same manner as described above.
  • Figures 3a to 3b show the measurement results of the infrared absorption spectrum.
  • the moisture values for crystals X3 and X4 whose results are shown in Figures 3a-3b are given in the table below.
  • Powder X-ray diffraction pattern measurement confirms that the dihydrate crystals obtained in the above "Preparation of brexpiprazole hydrate crystals" are the same crystals as the hydrate form I crystals obtained in Patent Document 2. It was confirmed from the results and infrared absorption spectrum measurement.
  • the average particle size of the hydrate form I crystals obtained in Production Example 1 was measured using a particle size distribution analyzer (MASTERSIZER 3000) manufactured by Malvern Panalytical Co., Ltd., by a particle size measurement method based on a laser diffraction method. bottom.
  • the average particle size of the hydrate form I crystals obtained in Production Example 1 was 45.6 ⁇ m.
  • the average particle diameter here means a volume average diameter.
  • FIG. 5b the infrared absorption spectrum measurement result is shown in FIG. 5b.
  • absorption was observed near wavenumbers of 3505 cm ⁇ 1 , 2934 cm ⁇ 1 , 2810 cm ⁇ 1 , 1653 cm ⁇ 1 , 1624 cm ⁇ 1 , 1447 cm ⁇ 1 , 1223 cm ⁇ 1 and 839 cm ⁇ 1 .
  • the water content (% by weight) of the hydrate I crystals obtained in Production Example 2 was measured by the Karl Fischer method (coulometric titration method) using a water content analyzer (MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. bottom.
  • the average particle size was measured by a particle size measurement method based on a laser diffraction method using a particle size distribution analyzer (MT3300EX) manufactured by Nikkiso Co., Ltd.
  • the average particle diameter here means a volume average diameter.
  • an X-ray diffractometer (SmartLab) manufactured by Rigaku Corporation and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
  • FT-IR IRAffinity-1S Fourier transform infrared spectrophotometer
  • the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
  • the water content of crystal X6 was 50.5%.
  • 6a and Table 3 show the powder X-ray diffraction pattern measurement results. Table 3 shows characteristic peaks. Furthermore, the infrared absorption spectrum measurement result is shown in FIG. 6b.
  • the measurement was performed by a transmission method using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans).
  • Crystal X6 was allowed to stand for 24 hours in an atmosphere of 25° C. and 95% relative humidity, and subjected to powder X-ray diffraction measurement. After that, the humidity was further lowered in stages, and the relative humidity was allowed to stand for 5 hours in an atmosphere of 90% relative humidity. 3 hours each at 38, 33, and 28% humidity, 2 hours at 16% relative humidity, 3 hours at 11% relative humidity, and 5 hours at 6% relative humidity.
  • Powder X-ray diffraction measurements were performed after standing at each relative humidity.
  • Fig. 7 and Table 4 show the measurement results at relative humidity of 90%, 75%, 53%, and 33%. Table 4 shows characteristic peaks.

Abstract

Provided is a means by which a dihydrate stable crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof can be efficiently produced. Specifically, provided is a method for producing a dihydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, the method comprising: (1) cooling an alcohol aqueous solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved; (2) further adding water to the cooled aqueous solution; and (3) leaving-alone or stirring the resultant for 10 minutes to 19 hours at a temperature higher than the cooling temperature.

Description

ベンゾチオフェン化合物の新規結晶形及びその製造方法New crystal form of benzothiophene compound and method for producing the same
　本発明は、ベンゾチオフェン化合物の新規製造方法、及びその途中で得られる新規結晶形等に関する。なお、本明細書に記載される全ての文献（特に下記特許文献１及び特許文献２）の内容は参照により本明細書に組み込まれる。 The present invention relates to a novel method for producing a benzothiophene compound, a novel crystal form obtained during the method, and the like. It should be noted that the contents of all documents described in this specification (especially Patent Document 1 and Patent Document 2 below) are incorporated herein by reference.
　７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン（以下、ブレクスピプラゾール又は化合物（Ｉ）ともいう）は、ドパミンＤ２受容体パーシャルアゴニスト作用、セロトニン５－ＨＴ２Ａ受容体アンタゴニスト作用及びアドレナリンα１受容体アンタゴニスト作用を有する。また化合物（Ｉ）は、それらの作用に加えてセロトニン取り込み阻害作用（あるいはセロトニン再取り込み阻害作用）を併有し、中枢神経疾患（特に統合失調症）に対して広い治療スペクラムを有することが知られている（特許文献１）。 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (hereinafter also referred to as brexpiprazole or compound (I)) is It has dopamine D2 receptor partial agonistic action, serotonin 5- HT2A receptor antagonistic action and adrenergic α1 receptor antagonistic action. In addition to these actions, compound (I) is known to have a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) and has a wide therapeutic spectrum for central nervous system diseases (particularly schizophrenia). (Patent Document 1).
　また、ブレクスピプラゾール又はその塩の二水和物が安定であり、特に筋肉注射剤として用いるにあたって有効な薬理活性物質であることについても知られている（特許文献２）。 It is also known that brexpiprazole or a dihydrate of its salt is stable and is a pharmacologically active substance that is particularly effective when used as an intramuscular injection (Patent Document 2).
特開２００６－３１６０５２号公報JP 2006-316052 A 国際公開第２０１３／１６２０４６号WO2013/162046
　前記ブレクスピプラゾール二水和物は、中枢神経疾患に対して、より優れた治療薬になり得る結晶（以下当該ブレクスピプラゾール二水和物結晶を「ＦｏｒｍＩ」又は「水和物Ｉ形」ということがある）として調製される（特許文献２）。ただ、当該ブレクスピプラゾール二水和物は、ブレクスピプラゾールを、酸（例えば酢酸や乳酸）含有溶媒へ溶解させ、これをアルカリ（例えば水酸化ナトリウム）で中和して結晶化させ（中和晶析）、これを低温熟成（例えば５℃以下で１時間程度）させ、そしてさらに高温熟成（例えば２０～３０℃で７時間程度）させて、ようやく得られるものであり、しかも、この中和晶析を経由する方法では、粒子径の大きな水和物I形結晶を再現性良く得ることが難しく、また、効率的に製造することも難しいことから、当該製造方法は工業スケールでの大量生産に用いるには好適とは言い難い方法であった。 The brexpiprazole dihydrate is a crystal that can be a better therapeutic drug for central nervous system diseases (hereinafter, the brexpiprazole dihydrate crystal is referred to as "Form I" or "hydrate form I"). (Patent Document 2). However, the brexpiprazole dihydrate is obtained by dissolving brexpiprazole in an acid (e.g., acetic acid or lactic acid)-containing solvent and neutralizing it with an alkali (e.g., sodium hydroxide) to crystallize (neutralization crystallization), low-temperature aging (for example, 5° C. or less for about 1 hour), and further high-temperature aging (for example, 20-30° C. for about 7 hours). In a method via crystallization, it is difficult to obtain hydrate form I crystals with a large particle size with good reproducibility, and it is also difficult to produce them efficiently. It is difficult to say that this method is suitable for use in
　本発明者らは、再現性よく粒子径の大きな水和物Ｉ形結晶を調製できる方法を見いだすべく、検討を重ねた。そして、ブレクスピプラゾールを、アルカリ（例えば水酸化ナトリウム）含有溶媒へ溶解させ、これを冷却して結晶化させ（冷却晶析）、さらに水を加えたうえで高温熟成させると、水和物Ｉ形結晶が調製できることを見いだした。そして、当該製造方法であれば再現性よく粒子径の大きな水和物Ｉ形結晶が得られること、並びに、前記冷却晶析により得られる結晶が新規結晶であること、も見いだした。 The present inventors conducted repeated studies to find a method for preparing hydrate form I crystals with a large particle size with good reproducibility. Then, brexpiprazole is dissolved in an alkali (e.g., sodium hydroxide)-containing solvent, cooled to crystallize (cooling crystallization), water is added, and then aged at high temperature to give hydrate I It was found that crystals of this type could be prepared. They also found that hydrate form I crystals having a large particle size can be obtained with good reproducibility by the production method, and that the crystals obtained by the cooling crystallization are novel crystals.
　本発明は例えば以下の項に記載の主題を包含する。
項１.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有する、結晶。
項２.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、以下の（α）～（δ）の特徴のうち、１、２、３、又は４の特徴を有する、結晶。
（α）：２５℃及び相対湿度９０％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．６±０．２、１２．５±０．２、１６．０±０．２、１８．４±０．２、１９．８±０．２、及び２３．１±０．２にピークを有する。
（β）：２５℃及び相対湿度７５％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．８±０．２、１２．５±０．２、１６．０±０．２、１８．５±０．２、１９．９±０．２、及び２３．４±０．２にピークを有する。
（γ）：２５℃及び相対湿度５３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．９±０．２、１２．６±０．２、１６．３±０．２、１８．５±０．２、１９．９±０．２、及び２３．５±０．２にピークを有する。
（δ）：２５℃及び相対湿度３３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．９±０．２、１２．８±０．２、１６．６±０．２、１８．４±０．２、１９．８±０．２、及び２３．８±０．２にピークを有する。
項３.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
２５℃及び相対湿度９０％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．６±０．２、１２．５±０．２、１６．０±０．２、１８．４±０．２、１９．８±０．２、及び２３．１±０．２にピークを有する、結晶。
項４.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
２５℃及び相対湿度７５％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．８±０．２、１２．５±０．２、１６．０±０．２、１８．５±０．２、１９．９±０．２、及び２３．４±０．２にピークを有する、結晶。
項５.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
２５℃及び相対湿度５３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．９±０．２、１２．６±０．２、１６．３±０．２、１８．５±０．２、１９．９±０．２、及び２３．５±０．２にピークを有する、結晶。
項６.
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
２５℃及び相対湿度３３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝ １１．９±０．２、１２．８±０．２、１６．６±０．２、１８．４±０．２、１９．８±０．２、及び２３．８±０．２にピークを有する、結晶。
項７.
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有する、項２～６のいずれかに記載の結晶。
項８.
（１）７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリが溶解したアルコール水溶液を冷却すること
を含む、項１～７のいずれかに記載の結晶の製造方法。
項９.
（１）７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリが溶解したアルコール水溶液を冷却すること、
（２）冷却した前記水溶液にさらに水を加えること、及び
（３）前記冷却温度より高い温度で１０分～１９時間静置又は撹拌すること
を含む、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の二水和物結晶の製造方法。
項１０.
工程（２）における加水量が、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリを含有するアルコール水溶液の容量の、０．４～０．８倍容量である、項９に記載の製造方法。
項１１.
工程（１）における冷却の温度が、１０～４０℃である、項８～１０のいずれかに記載の製造方法。
項１２.
項１～７のいずれかに記載の結晶及びアルカリを含有する１０～４０℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ３５～５０℃の温度で、１０分～１９時間静置又は撹拌すること
を含む、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の二水和物結晶の製造方法。
項１３．
上記結晶の粉末Ｘ線回折パターンが、加湿測定アタッチメント（ＭＨＣ－ｔｒａｎｓ）を装着したＭａｌｖｅｒｎ　ＰＡＮａｌｙｔｉｃａｌ社製のＸ線回折装置（ＥＭＰＹＲＥＡＮ）を用い測定されるパターンである、
項２～７のいずれかに記載の結晶。
項２ａ．
７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、その水分値が３０～４５％のとき、
λ＝１．５４１８Åの銅放射線 により測定される粉末Ｘ線回折パターンにおいて、
回折角２θ（°）＝　１１．４±０．２、１２．４±０．２、１５．８±０．２、１８．２±０．２、及び２２．８±０．２にピークを有する、結晶。
項３ａ．
λ＝１．５４１８Åの銅放射線により測定される粉末Ｘ線回折パターンにおいて、
さらに、回折角２θ（°）＝１９．５±０．２にピークを有する、請求項２ａに記載の結晶。
項４ａ．
臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有する、項２ａ又は３ａに記載の結晶。
項５ａ．
（１）７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリが溶解したアルコール水溶液を冷却すること
を含む、項２ａ～４ａのいずれかに記載の結晶の製造方法。
項６ａ．
工程（１）における冷却の温度が、１０～４０℃である、項５ａに記載の製造方法。
項７ａ．
項２ａ～４ａのいずれかに記載の結晶及びアルカリを含有する１０～４０℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ３５～５０℃の温度で、１０分～１９時間静置又は撹拌すること
を含む、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の二水和物結晶の製造方法。 The invention includes, for example, the subject matter described in the following sections.
Item 1.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal with an infrared absorption band at 637±3.
Item 2.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, comprising the following ( A crystal having 1, 2, 3, or 4 of the features α) to (δ).
(α): In the powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 90% relative humidity,
Diffraction angle 2θ (°) = 11.6 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. It has a peak at 1±0.2.
(β): in the powder X-ray diffraction pattern measured by the transmission method using copper radiation of λ=1.5418 Å at 25° C. and 75% relative humidity,
Diffraction angle 2θ (°) = 11.8 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. It has a peak at 4±0.2.
(γ): powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 53% relative humidity,
Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. It has a peak at 5±0.2.
(δ): in the powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 33% relative humidity,
Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.8 ± 0.2, 16.6 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. It has a peak at 8±0.2.
Item 3.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 90% relative humidity:
Diffraction angle 2θ (°) = 11.6 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. Crystals with a peak at 1±0.2.
Item 4.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 75% relative humidity:
Diffraction angle 2θ (°) = 11.8 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. Crystals with a peak at 4±0.2.
Item 5.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 53% relative humidity:
Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. Crystals with a peak at 5±0.2.
Item 6.
A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 33% relative humidity:
Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.8 ± 0.2, 16.6 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. Crystals with a peak at 8±0.2.
Item 7.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and Item 7. The crystal according to any one of Items 2 to 6, having an infrared absorption band at 637±3.
Item 8.
(1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one of Items 1 to 7.
Item 9.
(1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved;
(2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours. ] A method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
Item 10.
Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) Item 9. The production method according to Item 9, wherein the volume is 0.4 to 0.8 times the volume of.
Item 11.
Item 11. The production method according to any one of items 8 to 10, wherein the cooling temperature in step (1) is 10 to 40°C.
Item 12.
An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 1 to 7 is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours. Dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, including standing or stirring method for producing crystals.
Item 13.
The powder X-ray diffraction pattern of the crystal is a pattern measured using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans).
Item 8. The crystal according to any one of items 2 to 7.
Item 2a.
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a hydrate crystal of a salt thereof, the water content thereof is 30 to 45%,
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
Peaks at diffraction angles 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2, 15.8 ± 0.2, 18.2 ± 0.2, and 22.8 ± 0.2 have crystals.
Item 3a.
In the powder X-ray diffraction pattern measured by copper radiation at λ=1.5418 Å,
The crystal according to claim 2a, further having a peak at diffraction angle 2θ(°)=19.5±0.2.
Item 4a.
In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and The crystal of paragraphs 2a or 3a having an infrared absorption band at 637±3.
Item 5a.
(1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , a method for producing a crystal according to any one of Items 2a to 4a.
Item 6a.
Item 5a, wherein the cooling temperature in step (1) is 10 to 40°C.
Item 7a.
An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of Items 2a to 4a is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19 hours. Dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, including standing or stirring method for producing crystals.
　比較的粒子径の大きなブレクスピプラゾール二水和物の結晶を再現性よく調製できる製造方法、及び、当該安定晶を調製するための前駆体である新規結晶が提供される。当該新規結晶は、当該製造方法の途中で調製され得る結晶であり、特に当該製造方法途中で調製される当該新規結晶が安定して得られるために、粒子径の大きな前記二水和物結晶が得られる。前記二水和物結晶の粒子径が大きいことにより、濾過性が改善され、操作時間が短縮され得る。 A production method capable of reproducibly preparing crystals of brexpiprazole dihydrate having a relatively large particle size, and a novel crystal that is a precursor for preparing the stable crystal are provided. The novel crystals are crystals that can be prepared during the production method. can get. The large particle size of the dihydrate crystals can improve filterability and reduce operating time.
モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、製造例３で得られた水分値３７．６％のブレクスピプラゾール水和物結晶Ｘ３の粉末Ｘ線回折パターンを示す。1 shows the powder X-ray diffraction pattern of brexpiprazole hydrate crystals X3 with a water content of 37.6% obtained in Preparation Example 3, measured by copper radiation at λ=1.5418 Å through a monochromator. モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、製造例1で得られたブレクスピプラゾール水和物Ｉ形結晶の、粉末Ｘ線回折パターンを示す。1 shows the powder X-ray diffraction pattern of brexpiprazole hydrate Form I crystals obtained in Preparation Example 1, measured by copper radiation at λ=1.5418 Å through a monochromator. モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、製造例５で得られたブレクスピプラゾール水和物ＩＩ形結晶の、粉末Ｘ線回折パターンを示す。1 shows the powder X-ray diffraction pattern of brexpiprazole hydrate Form II crystals obtained in Preparation Example 5, measured by λ=1.5418 Å copper radiation through a monochromator. 製造例４で得られた水分値１０．４％のブレクスピプラゾール水和物結晶Ｘ４の赤外線吸収スペクトルの測定結果を示す。4 shows the infrared absorption spectrum of brexpiprazole hydrate crystals X4 having a water content of 10.4% obtained in Production Example 4. FIG. 製造例３で得られた水分値３７．６％のブレクスピプラゾール水和物結晶Ｘ３の赤外線吸収スペクトルの測定結果を示す。1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X3 having a water content of 37.6% obtained in Production Example 3. FIG. 製造例１で得られたブレクスピプラゾール水和物Ｉ形結晶の赤外線吸収スペクトルの測定結果を示す。1 shows the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 1. FIG. モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、製造例２で得られたブレクスピプラゾール水和物Ｉ形結晶の粉末Ｘ線回折パターンを示す。1 shows the powder X-ray diffraction pattern of brexpiprazole hydrate Form I crystals obtained in Preparation Example 2, measured by copper radiation at λ=1.5418 Å through a monochromator. 製造例２で得られたブレクスピプラゾール水和物Ｉ形結晶の赤外線吸収スペクトルの測定結果を示す。2 shows the measurement results of the infrared absorption spectrum of brexpiprazole hydrate Form I crystals obtained in Production Example 2. FIG. モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、製造例６で得られた水分値５０．５％のブレクスピプラゾール水和物結晶Ｘ６の粉末Ｘ線回折パターンを示す。5 shows the powder X-ray diffraction pattern of brexpiprazole hydrate crystals X6 with a water content of 50.5% obtained in Preparation Example 6, measured by copper radiation at λ=1.5418 Å through a monochromator. 製造例６で得られた水分値５０．５％のブレクスピプラゾール水和物結晶Ｘ６の赤外線吸収スペクトルの測定結果を示す。1 shows the infrared absorption spectrum measurement results of brexpiprazole hydrate crystals X6 having a water content of 50.5% obtained in Production Example 6. FIG. モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される、２５℃、各相対湿度（ＲＨ）における製造例６で得られたブレクスピプラゾール水和物結晶Ｘ６の粉末Ｘ線回折パターンを示す。The powder X-ray diffraction pattern of the brexpiprazole hydrate crystals X6 obtained in Preparation Example 6 at 25° C. and each relative humidity (RH), measured by copper radiation with λ=1.5418 Å through a monochromator, is shown in FIG. show.
　以下、本発明の各実施形態について、さらに詳細に説明する。 Each embodiment of the present invention will be described in further detail below.
　本開示に包含される結晶は、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン（ブレクスピプラゾール）又はその塩の水和物の結晶である。７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン（ブレクスピプラゾール）は、以下の式（Ｉ）： Crystals encompassed by the present disclosure are 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) or It is a salt hydrate crystal. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one (brexpiprazole) has the following formula (I):
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
で表される化合物である。 It is a compound represented by
　本明細書では、式（Ｉ）で表される当該化合物（ブレクスピプラゾール）を化合物（Ｉ）と称することがある。また、化合物（Ｉ）の塩としては、特許文献１に記載される塩が例示され、より具体的には例えば、アルカリ金属塩（例えばナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例えばカルシウム塩、マグネシウム塩等）等の金属塩、アンモニウム塩、炭酸アルカリ金属（例えば、炭酸リチウム、炭酸カリウム、炭酸ナトリウム、炭酸セシウム等）、炭酸水素アルカリ金属（例えば、炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウム等）、アルカリ金属水酸化物（例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化セシウム等）等の無機塩基の塩；例えば、トリ（低級）アルキルアミン（例えば、トリメチルアミン、トリエチルアミン、Ｎ－エチルジイソプロピルアミン等）、ピリジン、キノリン、ピペリジン、イミダゾール、ピコリン、ジメチルアミノピリジン、ジメチルアニリン、Ｎ－（低級）アルキル－モルホリン（例えば、Ｎ－メチルモルホリン等）、１，５－ジアザビシクロ［４．３．０］ノネン－５（ＤＢＮ）、１、８－ジアザビシクロ［５．４．０］ウンデセン－７（ＤＢＵ）、１，４－ジアザビシクロ［２．２．２］オクタン（ＤＡＢＣＯ）等の有機塩基の塩；塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸の塩；ギ酸、酢酸塩、プロピオン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、乳酸塩、リンゴ酸塩、クエン酸塩、酒石酸塩、炭酸塩、ピクリン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩等の有機酸の塩等が挙げられる。  In this specification, the compound represented by formula (I) (brexpiprazole) is sometimes referred to as compound (I). Examples of salts of compound (I) include salts described in Patent Document 1, and more specifically, for example, alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), salts of inorganic bases such as alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); , triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholine (e.g., N-methylmorpholine, etc.), 1,5- diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) salts of organic bases such as; salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; formic acid, acetate, propionate, oxalate, Malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluene Salts of organic acids such as sulfonate and glutamate are included. 
　化合物（Ｉ）又はその塩は、公知の方法（例えば特許文献１又は２に記載の方法）より製造することができる。 Compound (I) or a salt thereof can be produced by a known method (for example, the method described in Patent Document 1 or 2).
　本開示に包含される化合物（Ｉ）又はその塩の水和物結晶は、以下の特徴（ｉ）及び（ｉｉ）のうち、少なくとも１つの特徴を有し、より好ましくは両方の特徴を有する。なお、当該結晶を、「本開示の結晶」ということがある。 A hydrate crystal of compound (I) or a salt thereof included in the present disclosure has at least one of the following characteristics (i) and (ii), and more preferably has both characteristics. In addition, the crystal may be referred to as "the crystal of the present disclosure".
特徴（ｉ）：特有の粉末Ｘ線回折パターン
　本開示の結晶は、モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される粉末Ｘ線回折パターンにおいて、特有のパターンを有する。例えば、回折角２θ（°）＝　１１．４±０．２、１２．４±０．２、１５．８±０．２、１８．２±０．２、及び２２．８±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。また、これら５本のピークに加えて、１９．５±０．２の回折角２θ（°）にピークを有することが、さらに好ましい。特に、本開示の結晶は、結晶の水分値が３０～４５％、より好ましくは３０～４０％のときに、前記５本若しくは６本のピークを有することが好ましい。粉末Ｘ線回折は、Ｘ線回折装置（例えばＢｒｕｋｅｒ　ＡＸＳ社製のＸ線回折装置（Ｄ８　ＡＤＶＡＮＣＥ））を用いて測定することができる。 Feature (i): Unique Powder X-Ray Diffraction Pattern The crystals of the present disclosure have a unique pattern in their powder X-ray diffraction pattern measured with λ=1.5418 Å copper radiation through a monochromator. For example, for diffraction angles 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2, 15.8 ± 0.2, 18.2 ± 0.2, and 22.8 ± 0.2 It is preferable to have a peak (especially a characteristic peak). In addition to these five peaks, it is more preferable to have a peak at a diffraction angle 2θ (°) of 19.5±0.2. In particular, the crystals of the present disclosure preferably have the 5 or 6 peaks when the water content of the crystals is 30-45%, more preferably 30-40%. Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS).
　なお、本開示の結晶は、その水分値（水分含有量）によって、若干これらの回折角２θ（°）の特有のピークが若干ずれる場合がある。特に、水分値が低下すると、回折角が高角度側に若干ずれる傾向がある。 It should be noted that, in the crystals of the present disclosure, the specific peaks of these diffraction angles 2θ (°) may shift slightly depending on the water content (moisture content). In particular, when the water content decreases, the diffraction angle tends to shift slightly to the high angle side.
　また例えば、本開示の結晶は、モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　１１．４±０．２、１２．４±０．２、１６．０±０．２、１８．３±０．２、及び２３．０±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。また、これら５本のピークに加えて、１９．６±０．２の回折角２θ（°）にピークを有することが、さらに好ましい。特に、本開示の結晶は、結晶の水分値が４５～５５％のときに、前記５本若しくは６本のピークを有することが好ましい。 Also for example, the crystals of the present disclosure have a diffraction angle 2θ (°) = 11.4 ± 0.2, 12.4 ± 0.2 in the X-ray powder diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator. It preferably has peaks (especially characteristic peaks) at 4±0.2, 16.0±0.2, 18.3±0.2, and 23.0±0.2. In addition to these five peaks, it is more preferable to have a peak at a diffraction angle 2θ (°) of 19.6±0.2. In particular, the crystal of the present disclosure preferably has the above five or six peaks when the water content of the crystal is 45-55%.
　下表に、本開示の結晶の水分値が３０～４５％のときの、上述した特有のピークの値、並びに、本開示の結晶の水分値が４５～５５％のときの、上述した特有のピークの値を示す。 The table below shows the values of the above-mentioned specific peaks when the water values of the crystals of the present disclosure are between 30 and 45%, as well as the above-mentioned specific peak values when the water values of the crystals of the present disclosure are between 45-55%. Peak values are indicated.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　また、結晶の水分値は、カールフィッシャー法（電量滴定法）により測定した値（重量％）である。例えば、日東精工アナリテック社製のカールフィッシャー微量水分測定装置（ＣＡ－２００）を用いて測定することができる。 Also, the water content value of the crystal is the value (% by weight) measured by the Karl Fischer method (coulometric titration method). For example, it can be measured using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
　また、本開示の結晶に係る、モノクロメーターを通したλ＝１．５４１８Åの銅放射線を用いた透過法により測定される特有の粉末Ｘ線回折パターンは、特定の相対湿度下で測定することでも特定することができる。粉末Ｘ線回折は、Ｘ線回折装置（例えば加湿測定アタッチメント（ＭＨＣ－ｔｒａｎｓ）を装着したＭａｌｖｅｒｎ　ＰＡＮａｌｙｔｉｃａｌ社製のＸ線回折装置（ＥＭＰＹＲＥＡＮ））を用いて測定することができる。 The characteristic X-ray powder diffraction pattern of the crystals of the present disclosure, measured by the transmission method using copper radiation at λ=1.5418 Å through a monochromator, can also be measured under a specified relative humidity. can be specified. Powder X-ray diffraction can be measured using an X-ray diffractometer (for example, an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans)).
　例えば、本開示の結晶は、２５℃、相対湿度９０％下で、モノクロメーターを通したλ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　１１．６±０．２、１２．５±０．２、１６．０±０．２、１８．４±０．２、１９．８±０．２、及び２３．１±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。 For example, crystals of the present disclosure exhibit diffraction angles 2θ (°) = 11.6±0.2, 12.5±0.2, 16.0±0.2, 18.4±0.2, 19.8±0.2, and 23.1±0 It is preferable to have a peak (particularly a characteristic peak) at .2.
　また例えば、本開示の結晶は、２５℃、相対湿度７５％下で、モノクロメーターを通したλ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　１１．８±０．２、１２．５±０．２、１６．０±０．２、１８．５±０．２、１９．９±０．２、及び２３．４±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。 Also for example, the crystals of the present disclosure exhibit a diffraction angle of 2θ (°) = 11.8±0.2, 12.5±0.2, 16.0±0.2, 18.5±0.2, 19.9±0.2, and 23.4± It is preferable to have a peak (especially a characteristic peak) at 0.2.
　また例えば、本開示の結晶は、２５℃、相対湿度５３％下で、モノクロメーターを通したλ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　１１．９±０．２、１２．６±０．２、１６．３±０．２、１８．５±０．２、１９．９±０．２、及び２３．５±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。 Also for example, the crystals of the present disclosure exhibit a diffraction angle of 2θ (°) = 11.9±0.2, 12.6±0.2, 16.3±0.2, 18.5±0.2, 19.9±0.2, and 23.5± It is preferable to have a peak (especially a characteristic peak) at 0.2.
　また例えば、本開示の結晶は、２５℃、相対湿度３３％下で、モノクロメーターを通したλ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　１１．９±０．２、１２．８±０．２、１６．６±０．２、１８．４±０．２、１９．８±０．２、及び２３．８±０．２にピーク（特に、特徴的なピーク）を有することが好ましい。 Also for example, the crystals of the present disclosure exhibit a diffraction angle of 2θ (°) = 11.9±0.2, 12.8±0.2, 16.6±0.2, 18.4±0.2, 19.8±0.2, and 23.8± It is preferable to have a peak (especially a characteristic peak) at 0.2.
　なお、特定の相対湿度下での測定とは、本開示の結晶をその（特定の温度及び）特定の相対湿度下に静置してその質量を観測して質量変化が落ち着いてきたところで測定を行うことをいう。 Note that the measurement under a specific relative humidity means that the crystal of the present disclosure is allowed to stand under the specific temperature and relative humidity, the mass is observed, and the measurement is performed when the mass change has stabilized. means to do
特徴（ｉｉ）：特有の赤外線吸収スペクトル
　本開示の結晶は、臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有することが好ましい。これらの赤外線吸収バンドのなかでも、波数（ｃｍ－１）＝１０２０±３の赤外線吸収バンドが、特に本開示の結晶に特徴的なバンドである。赤外線吸収スペクトルは、赤外分光光度計（例えば島津製作所社製のフーリエ変換赤外分光光度計（ＦＴ－ＩＲ ＩＲＡｆｆｉｎｉｔｙ－１Ｓ））を用いて、ＫＢｒ錠剤法により測定することができる。 Feature (ii): Unique Infrared Absorption Spectrum The crystal of the present disclosure has wave numbers (cm −1 )=2824±10, 1614±3, 1514±3, 1455 in the infrared absorption spectrum measured by the potassium bromide tablet method. It preferably has infrared absorption bands at ±3, 1213±3, 1020±3, 841±3, and 637±3. Among these infrared absorption bands, the infrared absorption band at wavenumber (cm −1 )=1020±3 is particularly characteristic of the crystal of the present disclosure. The infrared absorption spectrum can be measured by the KBr tablet method using an infrared spectrophotometer (for example, a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation).
　また、これらの特徴的な赤外線吸収バンドの他にも、２９４６±１０、１２４２±３、１１３６±３、及び９６８±３、からなる群より選択される１又は２以上（２、３、４、５、６、又は７）の波数（ｃｍ－１）にさらに赤外線吸収バンドを有することがより好ましい。 In addition to these characteristic infrared absorption bands, one or two or more (2, 3, 4, More preferably, it additionally has an infrared absorption band at wavenumbers (cm −1 ) of 5, 6, or 7).
　なお、当該赤外線吸収スペクトルにおいて、１又は２以上（２、３、４、５、６、７、８、９、１０、１１、１２、又は１３）の赤外線吸収バンドの波数（ｃｍ－１）の誤差は±１０、±９、±８、±７、±６、±５、±４、±３、±２、又は±１であってもよい。 In the infrared absorption spectrum, one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption band wavenumbers (cm -1 ) The error may be ±10, ±9, ±8, ±7, ±6, ±5, ±4, ±3, ±2, or ±1.
　上記の通り、本発明者らは、ブレクスピプラゾールを、アルカリ（例えば水酸化ナトリウム）含有溶媒へ溶解させ、これを冷却して結晶化させ（冷却晶析）、さらに水を加えたうえで高温熟成させると、水和物Ｉ形結晶が調製できること、そして、当該製造方法であれば再現性よく粒子径の大きな水和物Ｉ形結晶が得られることを見いだした。本開示の結晶は、前記冷却晶析により得られる結晶として見いだされたものである。また、本開示の結晶は、水和物Ｉ形結晶の前駆体として好ましく用いることができる。そして、本開示の結晶を用いる水和物Ｉ形結晶調製方法により、再現性よく水和物Ｉ形結晶が得られる。さらには、粒子径の大きな水和物Ｉ形結晶を効率よく得ることもできる。なお、ブレクスピプラゾールは、公知の方法により、調製することができ、例えば特許文献１又は２に記載の方法で調製することができる。 As described above, the present inventors dissolved brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent, crystallized it by cooling (cooling crystallization), added water, and then dissolved at high temperature. It was found that hydrate form I crystals can be prepared by aging, and that the production method yields hydrate form I crystals having a large particle size with good reproducibility. The crystals of the present disclosure were found as crystals obtained by the cooling crystallization. In addition, the crystal of the present disclosure can be preferably used as a precursor of hydrate form I crystal. By the method for preparing hydrate form I crystals using the crystals of the present disclosure, hydrate form I crystals can be obtained with good reproducibility. Furthermore, it is also possible to efficiently obtain hydrate form I crystals having a large particle size. In addition, brexpiprazole can be prepared by a known method, for example, by the method described in Patent Document 1 or 2.
　上記内容から理解できるように、本開示の結晶は、例えば、ブレクスピプラゾールを、アルカリ（例えば水酸化ナトリウム）含有溶媒へ溶解させ、これを冷却して結晶化させる（冷却晶析）ことで調製することができる。本開示は、本開示の結晶の製造方法も好ましく包含する。 As can be understood from the above content, the crystals of the present disclosure are prepared, for example, by dissolving brexpiprazole in an alkali (e.g., sodium hydroxide)-containing solvent and crystallizing it by cooling (cooling crystallization). can do. The present disclosure preferably also includes methods for producing the crystals of the present disclosure.
　本開示の結晶の製造方法は、好ましくは、（１）ブレクスピプラゾール及びアルカリが溶解したアルコール水溶液を冷却すること、を含む。ここでの冷却温度は、ブレクスピプラゾールを溶解させた温度より低い温度であり、具体的には４０℃以下が例示される。１０～４０℃程度が好ましく、１５～４０℃程度がより好ましい。更に、１５～３５℃程度が好ましい。 The method for producing crystals of the present disclosure preferably includes (1) cooling an aqueous alcohol solution in which brexpiprazole and an alkali are dissolved. The cooling temperature here is a temperature lower than the temperature at which brexpiprazole is dissolved, specifically 40° C. or less. About 10 to 40°C is preferable, and about 15 to 40°C is more preferable. Furthermore, it is preferably about 15 to 35°C.
　アルカリとしては、例えば水酸化ナトリウム又は水酸化カリウムが例示され、特に水酸化ナトリウムが好ましく挙げられる。また、アルコールとしては、炭素数１～４の一価アルキルアルコールが例示され、具体的にはエタノール、プロパノール（ｎ－プロパノール、イソプロパノール）等が挙げられ、特にエタノールが好ましく挙げられる。また、ここでのアルコール水溶液のアルコール含有量は、４５～５５質量％程度が好ましい。また、ブレクスピプラゾールの含有量は１～１０質量％程度、より好ましくは３～６質量％であり、アルカリの含有量は好ましくは１～５質量％程度、より好ましくは１～３質量％程度である。 Examples of alkalis include sodium hydroxide and potassium hydroxide, with sodium hydroxide being particularly preferred. Examples of alcohols include monohydric alkyl alcohols having 1 to 4 carbon atoms, such as ethanol and propanol (n-propanol, isopropanol), with ethanol being particularly preferred. Further, the alcohol content of the alcohol aqueous solution here is preferably about 45 to 55% by mass. In addition, the content of brexpiprazole is about 1 to 10% by mass, more preferably about 3 to 6% by mass, and the content of alkali is preferably about 1 to 5% by mass, more preferably about 1 to 3% by mass. is.
　また、本開示の結晶の製造方法では、工程（１）の前に、（０）ブレクスピプラゾール、アルカリ、アルコール、及び水を混合して、ブレクスピプラゾールを溶解した溶液を得ること、が含まれてもよい。この場合の各成分の混合割合は、上記工程（１）に記載したのと同様の混合割合を採用することができる。 In addition, the method for producing crystals of the present disclosure includes (0) mixing brexpiprazole, alkali, alcohol, and water to obtain a solution in which brexpiprazole is dissolved before step (1). may be In this case, the mixing ratio of each component can be the same mixing ratio as described in step (1) above.
　例えば、ブレクスピプラゾールをアルカリ含有溶媒へ溶解させるにあたっては、５０～６０容量％エタノール水溶液に、水酸化ナトリウムを４～６当量となるよう、及び、ブレクスピプラゾールを適当量（例えばエタノール水溶液に対して１～５質量％程度）、混合して（好ましくは温度８０～８５℃程度で還流にて撹拌して）溶解させ、ブレクスピプラゾール溶解液を調製し、当該溶解液を冷却して（溶解させた温度より低い温度とする）、本開示の結晶を得ることができる。当該冷却温度としては、例えば１０～４０℃程度、より好ましくは１５～４０℃程度が上げられる。当該冷却温度の上限又は下限は、例えば１５、２０、２５、３０、又は３５℃であってもよい。例えば、当該冷却温度は１５～３５℃程度であってもよい。 For example, when dissolving brexpiprazole in an alkali-containing solvent, add 4 to 6 equivalents of sodium hydroxide to 50 to 60% by volume ethanol aqueous solution, and add an appropriate amount of brexpiprazole (for example, to the aqueous ethanol solution). about 1 to 5% by mass), mixed (preferably at a temperature of about 80 to 85° C. and stirred under reflux) to prepare a brexpiprazole solution, and the solution is cooled (dissolved at a temperature lower than the temperature at which the crystals of the present disclosure were obtained. The cooling temperature is, for example, about 10 to 40.degree. C., more preferably about 15 to 40.degree. The upper or lower limit of the cooling temperature may be 15, 20, 25, 30, or 35°C, for example. For example, the cooling temperature may be about 15-35°C.
　なお、工程（１）の後に、本開示の結晶を単離して若しくは単離することなく、（２）冷却した前記水溶液にさらに水を加え、（３）高温熟成すること、をさらに含む、ブレクスピプラゾール又はその塩の二水和物製造方法も、本開示に好ましく包含される。（２）において加える水の量としては、例えば冷却した前記水溶液の０．３～３倍容量が挙げられる。当該範囲の上限又は下限は例えば０．４、０．５、０．６、０．７、０．８、０．９、１、１．５、２、又は２．５であってもよい。例えば、当該範囲は０．４～１倍容量であってもよく、あるいは０．４～０．８倍容量であってもよい。 It should be noted that after step (1), with or without isolation of the crystals of the present disclosure, (2) further water is added to the cooled aqueous solution, and (3) high temperature aging. A method for producing the dihydrate of siprazole or a salt thereof is also preferably included in the present disclosure. The amount of water to be added in (2) is, for example, 0.3 to 3 times the volume of the cooled aqueous solution. The upper or lower limit of the range may be, for example, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, or 2.5. For example, the range may be 0.4 to 1 volume, or 0.4 to 0.8 volume.
　また、加える水の温度としては、冷却した前記水溶液と同程度の温度であることが好ましく、１０～４０℃、より好ましくは１５～４０℃、さらに好ましくは１５～３５℃が例示される。また、水を加えてさらに攪拌してもよい。この場合、攪拌時間は適宜設定することができ、例えば１～７２時間程度が挙げられる。（３）における高温熟成は、前記冷却の温度より高い温度（例えば３５～５０℃、より好ましくは３５～４５℃）で静置又は撹拌することで行われ得る。静置又は攪拌する時間としては、１０分以上が好ましく、１０分～１９時間程度がより好ましい。当該攪拌時間（１０分から１９時間）の上限又は下限は例えば１、２、３、５、１０、又は１５時間程度であってもよい。 The temperature of the water to be added is preferably about the same as that of the cooled aqueous solution, such as 10 to 40°C, more preferably 15 to 40°C, and even more preferably 15 to 35°C. Alternatively, water may be added and further stirred. In this case, the stirring time can be appropriately set, for example, about 1 to 72 hours. The high-temperature aging in (3) can be carried out by standing or stirring at a temperature higher than the cooling temperature (for example, 35 to 50°C, more preferably 35 to 45°C). The standing or stirring time is preferably 10 minutes or longer, more preferably about 10 minutes to 19 hours. The upper or lower limit of the stirring time (10 minutes to 19 hours) may be, for example, about 1, 2, 3, 5, 10, or 15 hours.
　なお、上記のブレクスピプラゾール又はその塩の二水和物結晶（水和物Ｉ形結晶）の製造方法を用いることにより、従来の製造方法（例えば特許文献２に記載の方法）に比べて、平均粒子径の大きいブレクスピプラゾール又はその塩の二水和物結晶（水和物Ｉ形結晶）を再現性よく得ることができる。上記のようにして調製されるブレクスピプラゾール又はその塩の二水和物結晶を、「本開示の水和物Ｉ形結晶」ということがある。本開示の水和物Ｉ形結晶は、本開示の結晶を前駆体として調製され得る、ということもできる。 By using the above-described method for producing dihydrate crystals of brexpiprazole or a salt thereof (hydrate form I crystals), compared to conventional production methods (for example, the method described in Patent Document 2), Dihydrate crystals (hydrate form I crystals) of brexpiprazole or a salt thereof having a large average particle size can be obtained with good reproducibility. The dihydrate crystals of brexpiprazole or a salt thereof prepared as described above are sometimes referred to as "hydrate Form I crystals of the present disclosure." It can also be said that the hydrate Form I crystals of the present disclosure can be prepared using the crystals of the present disclosure as precursors.
　本開示の水和物Ｉ形結晶は、平均粒子径が２６μｍ以上であることが好ましく、３５、又は４５μｍ以上であることがより好ましい。また、上限は特に限定はされないが、例えば６０μｍ以下が例示され、５５、又は５０μｍ以下も例示され得る。本明細書における平均粒子径は、レーザー回折法により測定される体積平均径である。 The hydrate form I crystal of the present disclosure preferably has an average particle size of 26 µm or more, more preferably 35 or 45 µm or more. Although the upper limit is not particularly limited, for example, 60 μm or less is exemplified, and 55 or 50 μm or less may be exemplified. The average particle size in this specification is the volume average size measured by a laser diffraction method.
　なお、本開示の水和物Ｉ形結晶は、モノクロメーターを通したλ＝１．５４１８Åの銅放射線により測定される粉末Ｘ線回折パターンにおいて、回折角２θ（°）＝　８．１±０．２、８．９±０．２、１５．１±０．２、１５．６±０．２、及び２４．４±０．２にピークを有する。さらには、回折角２θ（°）＝１４．０±０．２、１８．０±０．２、１８．５±０．２、１８．９±０．２、１９．５±０．２、及び２４．９±０．２にもピークを好ましく有し得る。 In addition, the hydrate form I crystal of the present disclosure has a diffraction angle 2θ (°) = 8.1 ± 0.5 in a powder X-ray diffraction pattern measured by copper radiation at λ = 1.5418 Å through a monochromator. It has peaks at 2, 8.9±0.2, 15.1±0.2, 15.6±0.2, and 24.4±0.2. Furthermore, diffraction angle 2θ (°) = 14.0 ± 0.2, 18.0 ± 0.2, 18.5 ± 0.2, 18.9 ± 0.2, 19.5 ± 0.2, and preferably also peaks at 24.9±0.2.
　また、本開示の水和物Ｉ形結晶は、臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝３５０９±１０、２９３４±１０、２８１２±１０、１６５１±３、１６２６±３、１４４７±３、１２２３±３、及び８３９±３に赤外線吸収バンドを有する。　 Further, the hydrate form I crystal of the present disclosure has wave numbers (cm -1 ) = 3509 ± 10, 2934 ± 10, 2812 ± 10, 1651 ± 3, in the infrared absorption spectrum measured by the potassium bromide tablet method. It has infrared absorption bands at 1626±3, 1447±3, 1223±3, and 839±3.
　なお、本明細書において「含む」とは、「本質的にからなる」と、「からなる」をも包含する（The term "comprising" includes "consisting essentially of” and "consisting of."）。また、本発明は、本明細書に説明した構成要件を任意の組み合わせを全て包含する。 In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." In addition, the present invention encompasses all arbitrary combinations of the constituent elements described herein.
　また、上述した本発明の各実施形態について説明した各種特性（性質、構造、機能等）は、本発明に包含される主題を特定するにあたり、どのように組み合わせられてもよい。すなわち、本発明には、本明細書に記載される組み合わせ可能な各特性のあらゆる組み合わせからなる主題が全て包含される。 In addition, the various characteristics (property, structure, function, etc.) described for each of the embodiments of the present invention described above may be combined in any way to specify the subject matter included in the present invention. That is, the invention encompasses all subject matter consisting of any and all possible combinations of the features described herein.
　以下、例を示して本開示の実施形態をより具体的に説明するが、本開示の実施形態は下記の例に限定されるものではない。 Hereinafter, the embodiments of the present disclosure will be described more specifically with examples, but the embodiments of the present disclosure are not limited to the following examples.
［ブレクスピプラゾールの合成］
　特許文献２（国際公開第２０１３／１６２０４６号）の参考例１及び２に記載の方法により、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン（ブレクスピプラゾール）を調製し、以下の検討に用いた。 [Synthesis of brexpiprazole]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy] by the method described in Reference Examples 1 and 2 of Patent Document 2 (WO 2013/162046). -1H-quinolin-2-one (brexpiprazole) was prepared and used in the following studies.
［ブレクスピプラゾール水和物結晶の調製（製造例１）］
　７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン８．０ｇ、エタノール９６．０ｍＬ、水９２．０ｍＬ、水酸化ナトリウム４．０６ｇ を攪拌しながら還流することにより溶解させた（還流温度：約８２℃）。還流にて攪拌後、７０℃付近まで冷却し、熱時濾過を行い、エタノール１６ｍＬで洗浄した。熱時濾過後、還流温度まで再加熱し、攪拌を行った。攪拌後、３０℃以下まで冷却し、さらに１時間攪拌した。この段階で得られた（再結晶した）水和物結晶を以下「結晶Ｘ」と表記することがある。 [Preparation of brexpiprazole hydrate crystals (Production Example 1)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 96.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring (refluxing temperature: about 82°C). After stirring under reflux, the mixture was cooled to about 70° C., filtered while hot, and washed with 16 mL of ethanol. After hot filtration, the mixture was reheated to the reflux temperature and stirred. After stirring, the mixture was cooled to 30° C. or less and stirred for another hour. The (recrystallized) hydrate crystals obtained at this stage are hereinafter sometimes referred to as "crystal X".
　その後、３０℃以下を保ちながら水１１６ｍＬを加え、さらに６４時間攪拌した後、３８～４３℃に昇温し、６．５時間攪拌した。攪拌後、固液分離を実施し、得られた固体を水２４０ｍｌで洗浄した。洗浄後の固体をさらに水８ｍｌとエタノール８ｍｌの混合溶液にて洗浄し，得られた固体を恒量になるまで風乾し、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン二水和物（水和物Ｉ形結晶）８．２２ｇ（収率：９４．８７％，化学純度：９９．６７％）を得た。 After that, 116 mL of water was added while maintaining the temperature at 30°C or less, and after stirring for an additional 64 hours, the temperature was raised to 38 to 43°C and the mixture was stirred for 6.5 hours. After stirring, solid-liquid separation was performed, and the obtained solid was washed with 240 ml of water. The washed solid is further washed with a mixed solution of 8 ml of water and 8 ml of ethanol, and the obtained solid is air-dried to a constant weight, and 7-[4-(4-benzo[b]thiophen-4-yl-piperazine. -1-yl)-butoxy]-1H-quinolin-2-one dihydrate (hydrate form I crystals) 8.22 g (yield: 94.87%, chemical purity: 99.67%) rice field.
［特許文献２の方法による水和物結晶の調製（製造例２）］
　また、上記とは別に、特許文献２（国際公開第２０１３／１６２０４６号）の実施例１に記載の方法を参考にして、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン二水和物（水和物Ｉ形結晶）を調製した。 [Preparation of hydrate crystals by the method of Patent Document 2 (Production Example 2)]
In addition to the above, 7-[4-(4-benzo[b]thiophen-4-yl- Piperazin-1-yl)-butoxy]-1H-quinolin-2-one dihydrate (hydrate form I crystals) was prepared.
　すなわち、水１８６．０ｋｇに水酸化ナトリウム２．７５ｋｇを加え、攪拌、溶解させた。７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン９．３ｋｇ、水１３９．５ｋｇ、ＤＬ－乳酸４．２５ｋｇ、エタノール１１０．２ｋｇの懸濁液を、攪拌しながら還流することにより溶解させた（還流温度：約８２℃）。得られた溶液を５℃以下まで冷却し、１℃以下に冷却した水酸化ナトリウム水溶液へと、３℃以下を保ちながら流入した。３℃以下で３時間以上攪拌した。 That is, 2.75 kg of sodium hydroxide was added to 186.0 kg of water and stirred to dissolve. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 9.3 kg, water 139.5 kg, DL-lactic acid 4.25 kg , and 110.2 kg of ethanol were dissolved by refluxing with stirring (refluxing temperature: about 82° C.). The resulting solution was cooled to 5° C. or lower and poured into an aqueous sodium hydroxide solution cooled to 1° C. or lower while maintaining the temperature at 3° C. or lower. The mixture was stirred at 3° C. or below for 3 hours or longer.
　前記攪拌後、４０℃まで昇温した。４０℃から５０℃にて２時間以上攪拌し、固液分離した。同様の操作を合計で３回実施した。３回分を合わせて水にて洗浄後、５０％含水エタノールにて洗浄した。得られた固体を乾燥窒素及び加湿窒素を用いて４０℃で乾燥し、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン二水和物（水和物Ｉ形結晶）２９．１５ｋｇを得た。 After the stirring, the temperature was raised to 40°C. The mixture was stirred at 40° C. to 50° C. for 2 hours or longer to effect solid-liquid separation. A similar operation was performed three times in total. The three batches were combined, washed with water, and then washed with ethanol containing 50% water. The resulting solid was dried with dry nitrogen and humidified nitrogen at 40° C. to yield 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinoline. 29.15 kg of -2-one dihydrate (hydrate form I crystals) was obtained.
［結晶Ｘ３の調製（製造例３）］
　７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン８．０ｇ，エタノール１１２．０ｍＬ，水９２．０ｍＬ，水酸化ナトリウム４．０６ｇ　を攪拌しながら還流することにより溶解させた。還流にて攪拌後，３５℃まで冷却した。析出晶を一部取り出して、結晶を得た。当該結晶を結晶Ｘ３と表記することがある。 [Preparation of Crystal X3 (Production Example 3)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35°C. A part of the precipitated crystal was taken out to obtain a crystal. The crystal is sometimes referred to as crystal X3.
［結晶Ｘ４の調製（製造例４）］
　７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン８．０ｇ，エタノール１１２．０ｍＬ，水９２．０ｍＬ，水酸化ナトリウム４．０６ｇ　を攪拌しながら還流することにより溶解させた。還流にて攪拌後，３５℃まで冷却し，固液分離した。得られた固体を５０℃で４時間乾燥し，結晶を得た。当該結晶を結晶Ｘ４と表記することがある。 [Preparation of Crystal X4 (Production Example 4)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 35° C. for solid-liquid separation. The resulting solid was dried at 50°C for 4 hours to obtain crystals. The crystal is sometimes referred to as crystal X4.
［水和物ＩＩ形結晶の調製（製造例５）］
　水１８６．０ｍＬに水酸化ナトリウム３．００ｇを加え，攪拌，溶解させ，水酸化ナトリウム水溶液を得た。７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン９．３ｇ，水１３９．５ｍＬ，エタノール１３９．５ｍＬ，Ｌ－乳酸５．２２ｇの懸濁液を，攪拌しながら還流することにより溶解させた（還流温度：約８３℃）。得られた溶液を５℃以下まで冷却し，１℃以下に冷却した水酸化ナトリウム水溶液へと，３℃以下を保ちながら流入し，３℃以下で１時間攪拌し，結晶を析出させた。この段階で得られた結晶を以下「水和物ＩＩ形結晶」とも呼ぶ。 [Preparation of hydrate form II crystals (Production Example 5)]
3.00 g of sodium hydroxide was added to 186.0 mL of water, stirred and dissolved to obtain an aqueous sodium hydroxide solution. 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 9.3 g, water 139.5 mL, ethanol 139.5 mL, L - A suspension of 5.22 g of lactic acid was dissolved by refluxing with stirring (reflux temperature: about 83°C). The resulting solution was cooled to 5° C. or lower, poured into an aqueous sodium hydroxide solution cooled to 1° C. or lower while maintaining the temperature at 3° C. or lower, and stirred at 3° C. or lower for 1 hour to precipitate crystals. The crystals obtained at this stage are hereinafter also referred to as "hydrate form II crystals".
［調製した結晶の解析］
　製造例３で得られた結晶Ｘ３について、モノクロメーターを通したλ＝１．５４１８Åの銅放射線（ＣｕＫα特性Ｘ線）により粉末Ｘ線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。また、製造例１で得た水和物Ｉ形結晶についても、同様の測定を行った。 [Analysis of prepared crystals]
Regarding the crystal X3 obtained in Production Example 3, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ=1.5418 Å through a monochromator, and the infrared absorption spectrum was measured by the potassium bromide tablet method. , respectively, were measured. Also, the hydrate type I crystal obtained in Production Example 1 was subjected to the same measurement.
　なお、測定には、Ｂｒｕｋｅｒ　ＡＸＳ社製のＸ線回折装置（Ｄ８　ＡＤＶＡＮＣＥ）及び島津製作所社製のフーリエ変換赤外分光光度計（ＦＴ－ＩＲ ＩＲＡｆｆｉｎｉｔｙ－１Ｓ）を用いた。また、測定に供する各結晶については、日東精工アナリテック社製のカールフィッシャー微量水分測定装置（ＣＡ－２００）を用い、カールフィッシャー法（電量滴定法）により、水分値（重量％）を測定した。 For the measurement, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used. For each crystal used for measurement, the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc. .
　製造例３で得られた結晶Ｘ３の水分値は３７．６％であった。また、粉末Ｘ線回折パターン測定結果を、図１並びに表１ｂに示す。表１ｂには特徴的なピークを示す。 The water content of crystal X3 obtained in Production Example 3 was 37.6%. Moreover, the powder X-ray diffraction pattern measurement results are shown in FIG. 1 and Table 1b. Table 1b shows characteristic peaks.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　なお、製造例１で得た水和物Ｉ形結晶、及び製造例５で得た水和物ＩＩ形結晶の粉末Ｘ線回折パターン測定結果を、それぞれ、図２ａ及び図２ｂに示す。 The powder X-ray diffraction pattern measurement results of the hydrate form I crystal obtained in Production Example 1 and the hydrate form II crystal obtained in Production Example 5 are shown in Figures 2a and 2b, respectively.
　また、製造例４で得られた結晶Ｘ４を、相対湿度約７％に調湿したデシケータに入れ、１６時間静置させて、さらに乾燥した。このようにして得られた、乾燥結晶の水分値を上記と同様にして測定したところ、１０．４％であった。この乾燥結晶についても上記と同様にして赤外線吸収スペクトルを測定した。 In addition, the crystal X4 obtained in Production Example 4 was placed in a desiccator adjusted to a relative humidity of about 7%, left to stand for 16 hours, and further dried. The moisture content of the dried crystals obtained in this manner was measured in the same manner as described above and found to be 10.4%. The infrared absorption spectrum of this dried crystal was also measured in the same manner as described above.
　赤外線吸収スペクトルの測定結果を図３ａ～３ｂに示す。図３ａ～３ｂに結果が示される結晶Ｘ３及びＸ４の水分値を下表に示す。 　Figures 3a to 3b show the measurement results of the infrared absorption spectrum. The moisture values for crystals X3 and X4 whose results are shown in Figures 3a-3b are given in the table below.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　いずれの赤外線吸収スペクトルにおいても、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３に吸収が認められた。 In any infrared absorption spectrum, absorption occurs at wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and 637 ± 3. Admitted.
　なお、製造例１で得た水和物Ｉ形結晶の赤外線吸収スペクトルの測定結果を、図４に示す。 The measurement results of the infrared absorption spectrum of the hydrate form I crystal obtained in Production Example 1 are shown in FIG.
　上記「ブレクスピプラゾール水和物結晶の調製」で得られた二水和物結晶が、特許文献２で得られた水和物Ｉ形結晶と同じ結晶であることが、粉末Ｘ線回折パターン測定結果及び赤外線吸収スペクトル測定から確認できた。特に、粉末Ｘ線回折パターン測定（図２ａ）では、回折角２θ（°）＝　８．１、８．９、１５．１、１５．６、及び２４．４に特徴的なピークが観察され、さらに回折角２θ（°）＝１４．０、１８．０、１８．５、１８．９、１９．５、及び２４．９にもピークが観察された。また、赤外線吸収スペクトル測定（図４）では、波数（ｃｍ－１）＝３５０７、２９３４、２８１０、１６５１、１６２６、１４４７、１２２３、８３９に特徴的なピークが観察された。 Powder X-ray diffraction pattern measurement confirms that the dihydrate crystals obtained in the above "Preparation of brexpiprazole hydrate crystals" are the same crystals as the hydrate form I crystals obtained in Patent Document 2. It was confirmed from the results and infrared absorption spectrum measurement. In particular, in the powder X-ray diffraction pattern measurement (Fig. 2a), characteristic peaks were observed at diffraction angles 2θ (°) = 8.1, 8.9, 15.1, 15.6, and 24.4, Furthermore, peaks were also observed at diffraction angles 2θ (°) = 14.0, 18.0, 18.5, 18.9, 19.5, and 24.9. Further, in infrared absorption spectrum measurement (FIG. 4), characteristic peaks were observed at wave numbers (cm −1 )=3507, 2934, 2810, 1651, 1626, 1447, 1223 and 839.
　またさらに、製造例１で得た水和物Ｉ形結晶について、マルバーン・パナリティカル社製の粒度分布測定装置（ＭＡＳＴＥＲＳＩＺＥＲ３０００）を用いて，レーザー回折法による粒子径測定法により，平均粒子径を測定した．その結果、製造例１で得た水和物Ｉ形結晶の平均粒子径は４５．６μｍであった。なお、ここでの平均粒子径とは体積平均径をいう。 Furthermore, the average particle size of the hydrate form I crystals obtained in Production Example 1 was measured using a particle size distribution analyzer (MASTERSIZER 3000) manufactured by Malvern Panalytical Co., Ltd., by a particle size measurement method based on a laser diffraction method. bottom. As a result, the average particle size of the hydrate form I crystals obtained in Production Example 1 was 45.6 μm. In addition, the average particle diameter here means a volume average diameter.
［製造例２で調製した結晶の解析］
　製造例２で得た水和物Ｉ結晶について、モノクロメーターを通したλ＝１．５４１８Åの銅放射線（ＣｕＫα特性Ｘ線）により粉末Ｘ線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。なお、測定には、Ｂｒｕｋｅｒ　ＡＸＳ社製のＸ線回折装置（Ｄ８　ＡＤＶＡＮＣＥ）及び島津製作所社製のフーリエ変換赤外分光光度計（ＦＴ－ＩＲ ＩＲＡｆｆｉｎｉｔｙ－１Ｓ）を用いた。 [Analysis of crystals prepared in Production Example 2]
For the hydrate I crystals obtained in Production Example 2, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ=1.5418 Å through a monochromator, and the infrared absorption by the potassium bromide tablet method. Spectra were measured respectively. For the measurement, an X-ray diffractometer (D8 ADVANCE) manufactured by Bruker AXS and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used.
　図５ａに粉末Ｘ線回折パターン測定結果を示す。図５ａに示すように，２θ＝８．１°、８．９°、１５．１°、１５．６°及び２４．４回折ピークを認めた。それ以外のピークとしては、２θ＝１２．２°、１４．０°１８．１、１８．４°、１８．９°、１９．５°、２０．６°、２２．５°、２４．９°、２６．１°、２７．１°、２８．６°、２８．９°、３０．４°及び３４．０°に回折ピークを認めた。 Fig. 5a shows the results of powder X-ray diffraction pattern measurement. As shown in FIG. 5a, 2θ=8.1°, 8.9°, 15.1°, 15.6° and 24.4 diffraction peaks were observed. Other peaks at 2θ = 12.2°, 14.0°, 18.1, 18.4°, 18.9°, 19.5°, 20.6°, 22.5°, 24.9 , 26.1°, 27.1°, 28.6°, 28.9°, 30.4° and 34.0°.
　また、図５ｂに、赤外線吸収スペクトル測定結果を示す。図５ｂに示すように、波数３５０５ｃｍ－１、２９３４ｃｍ－１、２８１０ｃｍ－１、１６５３ｃｍ－１、１６２４ｃｍ－１、１４４７ｃｍ－１、１２２３ｃｍ－１及び８３９ｃｍ－１付近に吸収を認めた。 Moreover, the infrared absorption spectrum measurement result is shown in FIG. 5b. As shown in FIG. 5b, absorption was observed near wavenumbers of 3505 cm −1 , 2934 cm −1 , 2810 cm −1 , 1653 cm −1 , 1624 cm −1 , 1447 cm −1 , 1223 cm −1 and 839 cm −1 .
　また、製造例２で得た水和物Ｉ結晶について、京都電子工業社製の水分測定装置（ＭＫＣ－６１０）を用い、カールフィッシャー法（電量滴定法）により、水分値（重量％）を測定した。また、日機装社製の粒度分布測定装置（ＭＴ３３００ＥＸ）を用いて、レーザー回折法による粒子径測定法により、平均粒子径を測定した。その結果、水分値は７．５０％、平均粒子径は７．９μｍであった。なお、ここでの平均粒子径とは体積平均径をいう。 Further, the water content (% by weight) of the hydrate I crystals obtained in Production Example 2 was measured by the Karl Fischer method (coulometric titration method) using a water content analyzer (MKC-610) manufactured by Kyoto Electronics Industry Co., Ltd. bottom. In addition, the average particle size was measured by a particle size measurement method based on a laser diffraction method using a particle size distribution analyzer (MT3300EX) manufactured by Nikkiso Co., Ltd. As a result, the water content was 7.50% and the average particle size was 7.9 μm. In addition, the average particle diameter here means a volume average diameter.
［結晶Ｘ６の調製（製造例６）］
　７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）－ブトキシ］－１Ｈ－キノリン－２－オン８．０ｇ，エタノール１１２．０ｍＬ，水９２．０ｍＬ，水酸化ナトリウム４．０６ｇ　を攪拌しながら還流することにより溶解させた。還流にて攪拌後，２５℃まで冷却した。冷却後，析出晶を固液分離した．得られた固体を水８０ｍＬでかけ洗浄を行い、１０分間脱液し，結晶を得た。当該結晶を結晶Ｘ６と表記することがある。 [Preparation of Crystal X6 (Production Example 6)]
7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one 8.0 g, ethanol 112.0 mL, water 92.0 mL, water 4.06 g of sodium oxide was dissolved by refluxing with stirring. After stirring under reflux, the mixture was cooled to 25°C. After cooling, the precipitated crystals were separated into solid and liquid. The obtained solid was washed with 80 mL of water and deliquored for 10 minutes to obtain crystals. The crystal is sometimes referred to as crystal X6.
　結晶Ｘ６について、モノクロメーターを通したλ＝１．５４１８Åの銅放射線（ＣｕＫα特性Ｘ線）により粉末Ｘ線回折パターンを、また、臭化カリウム錠剤法により赤外線吸収スペクトルを、それぞれ測定した。 For crystal X6, the powder X-ray diffraction pattern was measured by copper radiation (CuKα characteristic X-ray) of λ = 1.5418 Å through a monochromator, and the infrared absorption spectrum was measured by the potassium bromide tablet method.
　なお、測定には、リガク社製のＸ線回折装置（ＳｍａｒｔＬａｂ）及び島津製作所社製のフーリエ変換赤外分光光度計（ＦＴ－ＩＲ ＩＲＡｆｆｉｎｉｔｙ－１Ｓ）を用いた。また、測定に供する結晶については、日東精工アナリテック社製のカールフィッシャー微量水分測定装置（ＣＡ－２００）を用い、カールフィッシャー法（電量滴定法）により、水分値（重量％）を測定した。 For the measurement, an X-ray diffractometer (SmartLab) manufactured by Rigaku Corporation and a Fourier transform infrared spectrophotometer (FT-IR IRAffinity-1S) manufactured by Shimadzu Corporation were used. For the crystals to be measured, the water content (% by weight) was measured by the Karl Fischer method (coulometric titration method) using a Karl Fischer trace moisture analyzer (CA-200) manufactured by Nitto Seiko Analyticc.
　結晶Ｘ６の水分値は５０．５％であった。また、粉末Ｘ線回折パターン測定結果を、図６ａ及び表３に示す。表３には特徴的なピークを示す。さらにまた、赤外線吸収スペクトル測定結果を図６ｂに示す。 The water content of crystal X6 was 50.5%. 6a and Table 3 show the powder X-ray diffraction pattern measurement results. Table 3 shows characteristic peaks. Furthermore, the infrared absorption spectrum measurement result is shown in FIG. 6b.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　図６ｂに示すように、当該赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４、１６１６、１５１４、１４５８、１２１３、１０２０、８４３、及び６３７に、吸収が認められた。 As shown in FIG. 6b, absorption was observed at wave numbers (cm −1 )=2824, 1616, 1514, 1458, 1213, 1020, 843 and 637 in the infrared absorption spectrum.
　結晶Ｘ６については、モノクロメーターを通したλ＝１．５４１８Åの銅放射線（ＣｕＫα特性Ｘ線）により２５℃での各相対湿度（ＲＨ）における粉末Ｘ線回折パターンも測定した。なお、測定については、加湿測定アタッチメント（ＭＨＣ－ｔｒａｎｓ）を装着したＭａｌｖｅｒｎ　ＰＡＮａｌｙｔｉｃａｌ社製のＸ線回折装置（ＥＭＰＹＲＥＡＮ）を用いて、透過法にて測定した。結晶Ｘ６を、２５℃、相対湿度９５％の雰囲気下で２４時間静置して粉末Ｘ線回折測定を実施した。その後、さらに湿度を段階的に下げ、相対湿度９０％の雰囲気下で５時間静置、続いて相対湿度８５、８０、７５、７０、５８、５３、４８％の雰囲気下で各２時間、相対湿度３８、３３、２８％の雰囲気下で各３時間、相対湿度１６％の雰囲気下で２時間、相対湿度１１％の雰囲気下で３時間、及び相対湿度６％の雰囲気下で５時間静置させ、各相対湿度で静置させた後に粉末Ｘ線回折測定を実施した。 For the crystal X6, the powder X-ray diffraction pattern was also measured at each relative humidity (RH) at 25°C with λ = 1.5418 Å copper radiation (CuKα characteristic X-ray) through a monochromator. The measurement was performed by a transmission method using an X-ray diffractometer (EMPYREAN) manufactured by Malvern PANalytical equipped with a humidification measurement attachment (MHC-trans). Crystal X6 was allowed to stand for 24 hours in an atmosphere of 25° C. and 95% relative humidity, and subjected to powder X-ray diffraction measurement. After that, the humidity was further lowered in stages, and the relative humidity was allowed to stand for 5 hours in an atmosphere of 90% relative humidity. 3 hours each at 38, 33, and 28% humidity, 2 hours at 16% relative humidity, 3 hours at 11% relative humidity, and 5 hours at 6% relative humidity. Powder X-ray diffraction measurements were performed after standing at each relative humidity.
　相対湿度９０％、７５％、５３％、及び３３％での測定結果を図７及び表４に示す。表４には特徴的なピークを示す。 Fig. 7 and Table 4 show the measurement results at relative humidity of 90%, 75%, 53%, and 33%. Table 4 shows characteristic peaks.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

Claims (12)

  1. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
    臭化カリウム錠剤法により測定される赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有する、結晶。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
    In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal with an infrared absorption band at 637±3.
  2. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、以下の（α）～（δ）の特徴のうち、１、２、３、又は４の特徴を有する、結晶。
    （α）：２５℃及び相対湿度９０％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．６±０．２、１２．５±０．２、１６．０±０．２、１８．４±０．２、１９．８±０．２、及び２３．１±０．２にピークを有する。
    （β）：２５℃及び相対湿度７５％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．８±０．２、１２．５±０．２、１６．０±０．２、１８．５±０．２、１９．９±０．２、及び２３．４±０．２にピークを有する。
    （γ）：２５℃及び相対湿度５３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．９±０．２、１２．６±０．２、１６．３±０．２、１８．５±０．２、１９．９±０．２、及び２３．５±０．２にピークを有する。
    （δ）：２５℃及び相対湿度３３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．９±０．２、１２．８±０．２、１６．６±０．２、１８．４±０．２、１９．８±０．２、及び２３．８±０．２にピークを有する。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof, comprising the following ( A crystal having 1, 2, 3, or 4 of the features α) to (δ).
    (α): In the powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 90% relative humidity,
    Diffraction angle 2θ (°) = 11.6 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. It has a peak at 1±0.2.
    (β): in the powder X-ray diffraction pattern measured by the transmission method using copper radiation of λ=1.5418 Å at 25° C. and 75% relative humidity,
    Diffraction angle 2θ (°) = 11.8 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. It has a peak at 4±0.2.
    (γ): powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 53% relative humidity,
    Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. It has a peak at 5±0.2.
    (δ): in the powder X-ray diffraction pattern measured by transmission method using copper radiation of λ=1.5418 Å at 25° C. and 33% relative humidity,
    Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.8 ± 0.2, 16.6 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. It has a peak at 8±0.2.
  3. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
    ２５℃及び相対湿度９０％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．６±０．２、１２．５±０．２、１６．０±０．２、１８．４±０．２、１９．８±０．２、及び２３．１±０．２にピークを有する、結晶。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
    In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 90% relative humidity:
    Diffraction angle 2θ (°) = 11.6 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. Crystals with a peak at 1±0.2.
  4. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
    ２５℃及び相対湿度７５％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．８±０．２、１２．５±０．２、１６．０±０．２、１８．５±０．２、１９．９±０．２、及び２３．４±０．２にピークを有する、結晶。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
    In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 75% relative humidity:
    Diffraction angle 2θ (°) = 11.8 ± 0.2, 12.5 ± 0.2, 16.0 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. Crystals with a peak at 4±0.2.
  5. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
    ２５℃及び相対湿度５３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．９±０．２、１２．６±０．２、１６．３±０．２、１８．５±０．２、１９．９±０．２、及び２３．５±０．２にピークを有する、結晶。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
    In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 53% relative humidity:
    Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.6 ± 0.2, 16.3 ± 0.2, 18.5 ± 0.2, 19.9 ± 0.2, and 23. Crystals with a peak at 5±0.2.
  6. ７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の水和物の結晶であって、
    ２５℃及び相対湿度３３％下で、λ＝１．５４１８Åの銅放射線を用いた透過法により測定される粉末Ｘ線回折パターンにおいて、
    回折角２θ（°）＝ １１．９±０．２、１２．８±０．２、１６．６±０．２、１８．４±０．２、１９．８±０．２、及び２３．８±０．２にピークを有する、結晶。     A hydrate crystal of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof,
    In the powder X-ray diffraction pattern measured by the transmission method using copper radiation at λ=1.5418 Å at 25° C. and 33% relative humidity:
    Diffraction angle 2θ (°) = 11.9 ± 0.2, 12.8 ± 0.2, 16.6 ± 0.2, 18.4 ± 0.2, 19.8 ± 0.2, and 23. Crystals with a peak at 8±0.2.
  7. 臭化カリウム錠剤法により測定された赤外線吸収スペクトルにおいて、波数（ｃｍ－１）＝２８２４±１０、１６１４±３、１５１４±３、１４５５±３、１２１３±３、１０２０±３、８４１±３、及び６３７±３　に赤外線吸収バンドを有する、請求項２～６のいずれかに記載の結晶。 In the infrared absorption spectrum measured by the potassium bromide tablet method, wave numbers (cm -1 ) = 2824 ± 10, 1614 ± 3, 1514 ± 3, 1455 ± 3, 1213 ± 3, 1020 ± 3, 841 ± 3, and A crystal according to any one of claims 2 to 6, having an infrared absorption band at 637±3.
  8. （１）７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリが溶解したアルコール水溶液を冷却すること
    を含む、請求項１～７のいずれかに記載の結晶の製造方法。     (1) including cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali are dissolved; , the method for producing the crystal according to any one of claims 1 to 7.
  9. （１）７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリが溶解したアルコール水溶液を冷却すること、
    （２）冷却した前記水溶液にさらに水を加えること、及び
    （３）前記冷却温度より高い温度で１０分～１９時間静置又は撹拌すること
    を含む、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の二水和物結晶の製造方法。     (1) cooling an aqueous alcohol solution in which 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and an alkali are dissolved;
    (2) adding more water to the cooled aqueous solution; and (3) standing or stirring at a temperature higher than the cooling temperature for 10 minutes to 19 hours. ] A method for producing a dihydrate crystal of thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or a salt thereof.
  10. 工程（２）における加水量が、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン及びアルカリを含有するアルコール水溶液の容量の、０．４～０．８倍容量である、請求項９に記載の製造方法。 Aqueous alcohol solution containing 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one and alkali in the amount added in step (2) The production method according to claim 9, wherein the capacity is 0.4 to 0.8 times the capacity of.
  11. 工程（１）における冷却の温度が、１０～４０℃である、請求項８～１０のいずれかに記載の製造方法。 The production method according to any one of claims 8 to 10, wherein the cooling temperature in step (1) is 10 to 40°C.
  12. 請求項１～７のいずれかに記載の結晶及びアルカリを含有する１０～４０℃のアルコール水溶液を、当該アルコール水溶液の温度より高い温度であって且つ３５～５０℃の温度で、１０分～１９時間静置又は撹拌すること
    を含む、７－［４－（４－ベンゾ［ｂ］チオフェン－４－イル－ピペラジン－１－イル）ブトキシ］－１Ｈ－キノリン－２－オン又はその塩の二水和物結晶の製造方法。      An alcohol aqueous solution of 10 to 40° C. containing the crystal and alkali according to any one of claims 1 to 7 is heated at a temperature higher than the temperature of the alcohol aqueous solution and at a temperature of 35 to 50° C. for 10 minutes to 19. Dihydrate of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one or its salt, including standing or stirring for a period of time A method for producing a hydrate crystal.
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