JP3256311B2 - Quinolonecarboxylic acid derivative hydrate crystals - Google Patents

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】[0001]

【産業上の利用分野】本発明は、抗菌剤として有用で安
定性に優れた１−シクロプロピル−６−フルオロ−１，
４−ジヒドロ−８−メトキシ−７−（３−メチルアミノ
ピペリジン−１−イル）−４−オキソキノリン−３−カ
ルボン酸２水和物に関する。The present invention relates to 1-cyclopropyl-6-fluoro-1, which is useful as an antibacterial agent and has excellent stability.
It relates to 4-dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid dihydrate.

【０００２】[0002]

【従来の技術】特開平３−９５１７７号公報には、次式
（Ｉ） で示される１−シクロプロピル−６−フルオロ−１，４
−ジヒドロ−８−メトキシ−７−（３−メチルアミノピ
ペリジン−１−イル）−４−オキソキノリン−３−カル
ボン酸（以下「Ｑ−３５」と称する）が開示されてい
る。更に、同公報にはＱ−３５がアセトニトリルから再
結晶されたものであり、優れた抗菌性を有することが記
載されている。2. Description of the Related Art JP-A-3-95177 discloses the following formula (I). 1-cyclopropyl-6-fluoro-1,4 represented by
-Dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid (hereinafter referred to as "Q-35") is disclosed. Further, the publication describes that Q-35 is recrystallized from acetonitrile and has excellent antibacterial properties.

【０００３】[0003]

【発明が解決しようとする課題】しかし、医薬品として
の実用化研究を続けるうちに、アセトニトリルから再結
晶した上記のＱ−３５は、湿度の上昇に伴い重量が増加
するという欠点を有し、安定性が悪いことが判明した。
したがって、安定した投与量が得られないなど、上記Ｑ
−３５を医薬品として開発することは困難であることが
わかった。このため、高湿度条件下でも安定なＱ−３５
を得る手段を開発する必要があった。However, as the research on practical use as a pharmaceutical product is continued, the above-mentioned Q-35 recrystallized from acetonitrile has a drawback that its weight increases with an increase in humidity, and it is stable. It turned out to be bad.
Therefore, it is difficult to obtain a stable dose.
It has proven difficult to develop -35 as a pharmaceutical. Therefore, Q-35 is stable even under high humidity conditions.
It was necessary to develop a means to obtain

【０００４】[0004]

【課題を解決するための手段】本発明者らは、アセトニ
トリルから再結晶した上記Ｑ−３５の有する欠点を解消
すべく鋭意検討を行った結果、Ｑ−３５には、含有水分
量が一定しない結晶（以下「結晶ＩＩＩ」もしくは「Ｉ
ＩＩ型結晶」と称する）、１水和物の結晶（以下「結晶
ＩＩ」もしくは「ＩＩ型結晶」と称する）、２水和物の
結晶（以下「結晶Ｉ」もしくは「Ｉ型結晶」と称する）
及び無水物結晶の４種類の結晶形態があり、各々の形態
は再結晶溶媒の種類に左右されることを見い出した。そ
して、各結晶形態の物性について更に詳細な研究を重ね
た結果、アセトニトリルから再結晶した上記Ｑ−３５は
ＩＩＩ型結晶であること、Ｉ型結晶すなわちＱ−３５の
２水和物が高湿度条件で最も安定であり、乾燥もしくは
加熱条件で無水物に変化するものの、放置すれば２水和
物に戻ること、を見い出した。本発明は、このような知
見に基づいてなされたものである。すなわち、本発明
は、次式 を有する１−シクロプロピル−６−フルオロ−１，４−
ジヒドロ−８−メトキシ−７−（３−メチルアミノピペ
リジン−１−イル）−４−オキソキノリン−３−カルボ
ン酸２水和物である。Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to eliminate the disadvantages of the above-mentioned Q-35 recrystallized from acetonitrile. As a result, the water content of the Q-35 is not constant. Crystal (hereinafter “crystal III” or “I
Crystals of monohydrate (hereinafter referred to as "crystal II" or "type II crystals") and crystals of dihydrate (hereinafter referred to as "crystal I" or "type I crystals") )
And anhydrous crystals, and found that each form depends on the type of recrystallization solvent. Further, as a result of further detailed studies on the physical properties of each crystal form, the above-mentioned Q-35 recrystallized from acetonitrile was a type III crystal, and the type I crystal, that is, the dihydrate of Q-35 was subjected to high humidity conditions. Was found to be most stable, and changed to an anhydride under drying or heating conditions, but returned to the dihydrate when left to stand. The present invention has been made based on such findings. That is, the present invention provides the following formula: 1-cyclopropyl-6-fluoro-1,4- having
It is dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid dihydrate.

【０００５】Ｑ−３５の合成法には１−シクロプロピル
−６，７−ジフルオロ−１，４−ジヒドロ−４−オキソ
−３−キノリンカルボン酸（ＤＦＱ）に直接３−メチル
アミノピペリジン（３−ＭＡＰ）を縮合する方法（Ｉ
法）と、ＤＦＱ−ＥｔにＨＢＦ₄ を反応させてＤＦＱ−
ＢＦ₂ キレート（ＤＦＱ−ＢＦ₂ ）とし、これに３−Ｍ
ＡＰを縮合させＱ−３５ ＢＦ₂ キレート（Ｑ−３５−
ＢＦ₂ ）とした後、Ｅｔ₃ Ｎ又はＮａＯＨ水溶液等で加
水分解を行い、Ｑ−３５を得る方法（ＩＩ法）とがあ
る。ＩＩ法の方が収率が良いため大量合成には適してい
る。Ｉ法及びＩＩ法の反応径路は下記の通りである。The synthesis of Q-35 involves direct addition of 3-methylaminopiperidine (3-Q) to 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (DFQ). MAP) (I)
Method) and reacting HBF ₄ with DFQ-Et to produce DFQ-
BF ₂ chelate (DFQ-BF ₂ )
The AP is condensed to form a Q-35 BF ₂ chelate (Q-35-
After BF ₂ ), there is a method (Method II) in which hydrolysis is carried out with an Et ₃ N or NaOH aqueous solution or the like to obtain Q-35. Method II is more suitable for mass synthesis because of its better yield. The reaction routes of the methods I and II are as follows.

【０００６】 精製法としては、Ｉ法あるいはＩＩ法で得られたＱ−３
５を溶媒中で加熱還流・加熱乾燥を行い、精製用の溶媒
にて精製する。この場合、上記のいずれの結晶形が生成
するかは用いる精製溶媒によって左右される。例えば、
アセトニトリル−水ではＩＩＩ型結晶もしくはＩＩ型結
晶、メタノールではＩＩ型結晶、エタノール−水（１：
１）ではＩ型結晶がそれぞれ得られる。これら３種の結
晶形がどの様な条件で得られるかを検討したところ、エ
タノールあるいはアセトニトリルに完全に溶解した後溶
媒を減圧留去するとＩＩＩ型結晶が、メタノールに懸濁
後加熱還流するとＩＩ型結晶が、エタノール−水（１：
１）に懸濁後加熱還流するとＩ型結晶が生成することが
明らかになっている。[0006] As the purification method, Q-3 obtained by Method I or Method II was used.
5 is heated to reflux and dried by heating in a solvent, and purified with a solvent for purification. In this case, which of the above crystal forms is formed depends on the purification solvent used. For example,
In acetonitrile-water, type III crystal or type II crystal, in methanol, type II crystal, ethanol-water (1:
In 1), an I-type crystal is obtained. Investigations were made on the conditions under which these three crystal forms were obtained. After complete dissolution in ethanol or acetonitrile, the solvent was distilled off under reduced pressure. The crystals are ethanol-water (1:
It has been clarified that when the suspension is heated under reflux in 1), type I crystals are formed.

【０００７】また、結晶ＩＩは加湿及び練合（５０％エ
タノールあるいは水）により結晶Ｉへ転移する。一方、
結晶Ｉにメタノールを加えて加熱還流すると結晶ＩＩに
なるが、加湿及び練合（５０％エタノールあるいは水）
によって結晶転移はしない。更に、結晶ＩＩ及び結晶Ｉ
は、乾燥によって結晶水が失われ無水物になるが、空気
中に放置するとそれぞれ再び水和物の形に戻ることが確
認されている。The crystal II is transformed into the crystal I by humidification and kneading (50% ethanol or water). on the other hand,
When methanol is added to Crystal I and heated to reflux, it becomes Crystal II. Humidification and kneading (50% ethanol or water)
Does not cause crystal transition. Further, crystal II and crystal I
It has been confirmed that, upon drying, water of crystallization is lost to form an anhydride, but when left in the air, it returns to the hydrate form again.

【０００８】以下に本発明化合物を製造するための実施
例を示すが、本発明はこれらの実施例に限定されるもの
ではない。Examples for producing the compound of the present invention will be shown below, but the present invention is not limited to these examples.

【０００９】[0009]

【実施例１】ＤＦＱ−ＢＦ₂ エステル３．４ｇ、３−メ
チルアミノピペリジン・２ＨＣｌ（３−ＭＡＰ・２ＨＣ
ｌ）２．３ｇ、トリエチルアミン４．５ｇを塩化メチレ
ン１８ｍｌに加え、３時間加熱還流した。塩化メチレン
を減圧留去後、ＮａＯＨ２．５ｇ／水２０ｍｌの溶液を
加え、８０℃で１．５時間反応させた。反応溶液を冷却
後、６Ｎ−ＨＣｌにてｐＨ＝８〜９に調整し、晶析し
た。析出した結晶を遠心分離し、粗Ｑ−３５湿性末４．
２ｇを得た（ｄｒｙ換算３．２ｇ、収率８３．０％）。Example 1 3.4 g of DFQ-BF ₂ ester, 3-methylaminopiperidine.2HCl (3-MAP.2HC)
l) 2.3 g and 4.5 g of triethylamine were added to 18 ml of methylene chloride, and the mixture was heated under reflux for 3 hours. After distilling off methylene chloride under reduced pressure, a solution of 2.5 g of NaOH / 20 ml of water was added, and the mixture was reacted at 80 ° C. for 1.5 hours. After cooling, the reaction solution was adjusted to pH = 8-9 with 6N-HCl, and crystallized. 3. The precipitated crystals were centrifuged to obtain crude Q-35 wet powder.
2 g was obtained (dry conversion 3.2 g, yield 83.0%).

【００１０】フマル酸３．５ｇを９０％メタノール水溶
液１０２ｍｌに溶解し、そこへ粗Ｑ−３５を９．４ｇ
（ｄｒｙ換算）加えた。溶液を冷却し、析出した結晶を
遠心分離し、Ｑ−３５・フマール湿性末１２．１ｇを得
た（ｄｒｙ換算１１．０ｇ、収率９０．１％）。[0010] 3.5 g of fumaric acid was dissolved in 102 ml of 90% aqueous methanol solution, and 9.4 g of crude Q-35 was added thereto.
(Dry conversion) added. The solution was cooled, and the precipitated crystals were centrifuged to obtain 12.1 g of Q-35.fumar wet powder (11.0 g in terms of dry, yield 90.1%).

【００１１】ＮａＯＨ３．６ｇを水１００ｍｌに溶解
し、そこへＱ−３５・フマレート１１．０ｇを加え溶解
した。不溶物を濾別後、６Ｎ−ＨＣｌを加えｐＨ＝８〜
９に調整し晶析した。析出した結晶を遠心分離・乾燥
し、精製Ｑ−３５Ｉ型結晶７．７ｇ（収率８３．２％）
を得た。[0011] 3.6 g of NaOH was dissolved in 100 ml of water, and 11.0 g of Q-35.fumarate was added and dissolved therein. After filtering off the insoluble matter, 6N-HCl was added and pH = 8 to
The crystal was adjusted to 9 for crystallization. The precipitated crystals were centrifuged and dried, and 7.7 g of purified Q-35I type crystals (83.2% yield).
I got

【００１２】[0012]

【実施例２】２００ｍｌの反応容器に９．１％ｗ／ｗ−
ＭＡＰメタノール溶液６１．７ｇ（４９．３ｍｍｏｌ）
を仕込み、減圧下６０℃の温水で加熱して約５５ｍｌの
メタノールを留去した。得られた濃縮残渣に、塩化メチ
レン６５ｍｌ、トリエチルアミン７．７ｇ（７５．８ｍ
ｍｏｌ）、ＤＦＱ−ＢＦ₂ エステル１３．０ｇ（３７．
９ｍｍｏｌ）を加えて１時間還流した。次第に溶解し、
黄色の澄明溶液となった。この反応溶液の溶媒を減圧下
で留去した。濃縮残渣に水３０ｍｌ、２５％水酸化ナト
リウム水溶液３９ｇ（２４４ｍｍｏｌ）を加え、７０℃
で１時間加水分解を行った（加熱時、約５０℃から残存
していた溶媒が留去した）。加水分解混合液を水冷後、
５．５Ｎ塩酸（１／１）約３０ｍｌでｐＨを８．５に調
整し、晶析を促進するために６０℃で３０分間加熱し
た。この混合液を２５℃に冷却し、１時間攪拌した。次
いで混合液を約４５分間２４インチ遠心分離機にかけて
結晶を分離した。得られた結晶を水２０ｍｌで洗浄し、
３０分間振り切って、粗Ｑ−３５湿性末１８．２ｇ（ｎ
ｅｔ＝１３．８ｇ、収率９４％）を得た。Example 2 9.1% w / w- in a 200 ml reaction vessel
61.7 g (49.3 mmol) of MAP methanol solution
And heated with warm water at 60 ° C. under reduced pressure to distill off about 55 ml of methanol. To the obtained concentrated residue, methylene chloride (65 ml) and triethylamine (7.7 g, 75.8 m) were added.
mol), DFQ-BF ₂ ester 13.0 g (37.
9 mmol) and refluxed for 1 hour. Gradually dissolved,
A yellow clear solution resulted. The solvent of this reaction solution was distilled off under reduced pressure. 30 ml of water and 39 g (244 mmol) of a 25% aqueous sodium hydroxide solution were added to the concentrated residue,
For 1 hour (at the time of heating, the remaining solvent was distilled off from about 50 ° C.). After cooling the hydrolysis mixture with water,
The pH was adjusted to 8.5 with about 30 ml of 5.5N hydrochloric acid (1/1), and the mixture was heated at 60 ° C. for 30 minutes to promote crystallization. The mixture was cooled to 25 ° C. and stirred for 1 hour. The mixture was then centrifuged for about 45 minutes in a 24 inch centrifuge to separate the crystals. The obtained crystals are washed with 20 ml of water,
Shake off for 30 minutes to obtain 18.2 g of crude Q-35 wet powder (n
et = 13.8 g, 94% yield).

【００１３】２００ｍｌの反応容器にイオン交換水１０
０ｍｌ、濃塩酸４．３ｍｌ（４７．３ｍｍｏｌ）、上で
得られた粗Ｑ−３５湿性末１８．２ｇ（ｎｅｔ＝１３．
８ｇ（３５．５ｍｍｏｌ））を加えた（ｐＨ＝３〜
４）。酢酸エチル３０ｍｌで２回抽出した。減圧下、７
０℃の温水で加熱し、水層に溶解している酢酸エチルを
留去した（約１時間３０分）。水層に塩酸２ｍｌを加え
酸性とし、生じた若干の不溶物を濾別した。水酸化ナト
リウム水溶液（３ｇ／１０ｍｌ）約８ｍｌで濾液のｐＨ
を８．５に調整した後、晶析を促進するために６０℃で
３０分間加熱した。加熱終了後、この液を２５℃に冷却
し、１時間攪拌した。次いで濾液を約３０分間２４イン
チ遠心分離機にかけて結晶を分離した。得られた結晶を
イオン交換水２０ｍｌで洗浄し、３０分間振り切って、
結晶１３．７ｇを得た。[0013] Ion exchange water 10 in a 200 ml reaction vessel
0 ml, concentrated hydrochloric acid 4.3 ml (47.3 mmol), 18.2 g of the crude Q-35 wet powder obtained above (net = 13.
8 g (35.5 mmol)) (pH = 3 to
4). Extracted twice with 30 ml of ethyl acetate. 7 under reduced pressure
The mixture was heated with warm water at 0 ° C., and ethyl acetate dissolved in the aqueous layer was distilled off (about 1 hour and 30 minutes). 2 ml of hydrochloric acid was added to the aqueous layer to make it acidic, and some insolubles generated were filtered off. PH of the filtrate with about 8 ml of sodium hydroxide aqueous solution (3 g / 10 ml)
Was adjusted to 8.5, and then heated at 60 ° C. for 30 minutes to promote crystallization. After the heating was completed, the solution was cooled to 25 ° C. and stirred for 1 hour. The filtrate was then centrifuged for about 30 minutes in a 24 inch centrifuge to separate the crystals. The obtained crystals are washed with 20 ml of ion-exchanged water and shaken off for 30 minutes.
13.7 g of crystals were obtained.

【００１４】２００ｍｌの反応容器にエタノール８０ｍ
ｌ、水８０ｍｌ、上記結晶１３．７ｇを加え、７０℃に
加熱し、懸濁状態で３０分間攪拌した。この混合液を２
５℃に冷却し１時間攪拌した後、約３０分間２４インチ
遠心分離機にかけて結晶を分離した。得られた結晶をイ
オン交換水２０ｍｌで洗浄し、３０分間振り切って、Ｑ
−３５湿性末を得た。得られたＱ−３５湿性末を、通気
乾燥機を用いて、６０℃２時間乾燥し、更に室温で２時
間通気し、Ｑ−３５のＩ型結晶１０．１ｇ（収率７３
％）を得た。Ethanol 80 m in a 200 ml reaction vessel
1, 80 ml of water and 13.7 g of the above crystals were added, heated to 70 ° C., and stirred in a suspended state for 30 minutes. This mixture is
After cooling to 5 ° C. and stirring for 1 hour, the crystals were separated by centrifugation for about 30 minutes in a 24 inch centrifuge. The obtained crystals are washed with 20 ml of ion-exchanged water and shaken off for 30 minutes.
A -35 wet powder was obtained. The obtained Q-35 wet powder was dried using a through-air drier at 60 ° C. for 2 hours and further ventilated at room temperature for 2 hours to obtain 10.1 g of Q-35 type I crystal (yield 73
%).

【００１５】このようにして得たＱ−３５のＩ型結晶を
用いて、その構造及び２分子の結晶水の挙動を明らかに
するために下記の実験を行った。Using the thus obtained type I crystal of Q-35, the following experiment was conducted to clarify the structure and behavior of two molecules of water of crystallization.

【００１６】〔実験例〕 １）試料 赤外吸収スペクトル、粉末Ｘ線回折及び熱分析用として
は実施例の方法で製造したものを、単結晶Ｘ線解析用と
しては次のカッコ内に記載した方法によって得られた結
晶をそれぞれ使用した。[Experimental Examples] 1) Samples Samples produced by the method of the embodiment for infrared absorption spectrum, powder X-ray diffraction and thermal analysis are described in parentheses for single crystal X-ray analysis. Each of the crystals obtained by the method was used.

【００１７】（単結晶Ｘ線解析用結晶：上記実施例の方
法で得たＱ−３５のＣ型結晶（８．１０ｇ）に無水エタ
ノール４５０ｍｌを加え、７５℃で３０分間加熱し熱時
濾過した。その濾液を室温放置後吸引濾過し、結晶を得
た（約５．９５ｇ）。結晶に水を３００ｍｌ加え、９５
℃で５分間加熱し、室温放置後吸引濾過し、濾液を室温
放置して結晶を得た。） ２）使用機器 ＴＧ／ＤＴＡ：セイコー電子・ＴＧ／ＤＴＡ ２００ ＤＳＣ：セイコー電子 ＤＳＣ・２１０ 赤外分光光度計：Ｎｉｃｏｌｅｔ・２０ ＤＸＢ 粉末Ｘ線回折装置：Ｐｈｉｌｉｐｓ・ＰＷ１７３０／１
０ 単結晶Ｘ線回折装置：Ｅｎｒａｆ−Ｎｏｎｉｕｓ・ＣＡ
Ｄ４ ３）実験方法 （１）熱分析 昇温→降温実験（ＴＧ） 試料約１０ｍｇを用い（試料は粉末であるため粉砕は行
わない）、室温から昇温速度５℃／ｍｉｎで８０℃まで
加熱し、８０℃で３０分ｈｏｌｄした後、室温まで降温
した。この時の加熱、降温による重量変化を観察した。
測定時はＮ₂ ガスによる乾燥の影響を防ぐため、Ｎ₂ ガ
スはｆｌｏｗさせなかった（室内の相対湿度：ＲＨ４０
〜５０％）。(Crystal for X-ray analysis of single crystal: 450 ml of anhydrous ethanol was added to the C-type crystal of Q-35 (8.10 g) obtained by the method of the above example, heated at 75 ° C. for 30 minutes and filtered while hot. The filtrate was allowed to stand at room temperature and filtered under suction to obtain crystals (approximately 5.95 g).
The mixture was heated at 5 ° C. for 5 minutes, left at room temperature, filtered by suction, and the filtrate was left at room temperature to obtain crystals. 2) Equipment used TG / DTA: Seiko Denshi, TG / DTA 200 DSC: Seiko Denshi DSC, 210 Infrared spectrophotometer: Nicolet, 20 DXB Powder X-ray diffractometer: Philips, PW1730 / 1
0 Single crystal X-ray diffractometer: Enraf-Nonius CA
D4 3) Experimental method (1) Thermal analysis Temperature rise → temperature decrease experiment (TG) Using about 10 mg of sample (pulverization is not performed because the sample is a powder), and heated from room temperature to 80 ° C. at a rate of 5 ° C./min. Then, after holding at 80 ° C. for 30 minutes, the temperature was lowered to room temperature. At this time, a change in weight due to heating and cooling was observed.
Since the measurement is to prevent the influence of drying by N ₂ gas, N ₂ gas was allowed to flow (indoor relative humidity: RH40
５０50%).

【００１８】 室温−無水雰囲気下→室内雰囲気下に
おける実験（ＴＧ） 試料約１０ｍｇを用い（粉砕は行わない）、室温でＮ₂
ガス２００ｍｌ／ｍｉｎをｆｌｏｗさせ無水雰囲気下と
して重量変化を観察した。重量変化がなくなった後、Ｎ
₂ ガスをｓｔｏｐし、室内雰囲気下とし（室内の相対湿
度：ＲＨ４０〜５０％）再度重量変化を観察した。The room temperature - under an anhydrous atmosphere → experiment under room atmosphere with (TG) sample of about 10 mg (grinding is not performed), N ₂ at room temperature
The gas was flowed at 200 ml / min and the change in weight was observed under an anhydrous atmosphere. After the weight change disappears, N
_{The two} gases were stopped, and the atmosphere was changed to an indoor atmosphere (relative humidity in the room: RH 40 to 50%), and the weight change was observed again.

【００１９】 低湿度（ＲＨ６％）下保存実験（Ｔ
Ｇ） 試料約１０ｍｇ（粉砕は行わない）を加熱、Ｎ₂ ガスｆ
ｌｏｗによる無水雰囲気下で脱水した後、室温でＲＨ６
％に調湿したＡｉｒ＊を２００ｍｌ／ｍｉｎでｆｌｏｗ
させて、その重量変化を観察した。Storage experiment under low humidity (RH 6%) (T
G) Heat about 10 mg of sample (no grinding), N ₂ gas f
After dehydration under an anhydrous atmosphere by low, RH6
% Air-conditioned at 200 ml / min.
Then, the weight change was observed.

【００２０】＊デシケーターに飽和ＮａＯＨ溶液を保存
し、ＲＨ６％に調湿し、循環させた。 昇温実験及び活性化エネルギーの算出（ＴＧ／ＤＴ
Ａ） 試料約１０ｍｇ（粉砕は行わない）を用い、室温から昇
温速度２，３，５℃／ｍｉｎで１７０℃まで加熱した。
この時の加熱による重量変化、熱的変化を観察し、重量
変化より小沢法により活性エネルギーを求めた。測定時
はＮ₂ ガスによる乾燥の影響を防ぐため、Ｎ₂ ガスはｆ
ｌｏｗさせなかった（室内の相対湿度：ＲＨ４０〜５０
％）。* Saturated NaOH solution was stored in a desiccator, RH adjusted to 6%, and circulated. Temperature rise experiment and calculation of activation energy (TG / DT
A) About 10 mg of a sample (without pulverization) was used and heated from room temperature to 170 ° C at a rate of 2, 3, 5 ° C / min.
At this time, changes in weight and heat due to heating were observed, and active energy was determined from the change in weight by the Ozawa method. Since the measurement is to prevent the influence of drying by N ₂ gas, N ₂ gas is f
(low relative humidity in the room: RH40-50)
%).

【００２１】 昇温実験（ＤＳＣ） 試料約１０ｍｇ（粉砕は行わない）を用い、サンプルパ
ンは水蒸気による加圧をさけるためクリンプせずｏｐｅ
ｎの状態で測定を行った。Ｎ₂ ガス２０ｍｌ／ｍｉｎを
ｆｌｏｗし、熱的に安定したところで（約３分間）、室
温から昇温速度３℃／ｍｉｎで１７０℃まで加熱し熱的
変化を観察した。Temperature rise experiment (DSC) About 10 mg of sample (without grinding) was used.
The measurement was performed in the state of n. 20 ml / min of N ₂ gas was flowed, and when thermally stabilized (about 3 minutes), the mixture was heated from room temperature to 170 ° C. at a rate of temperature increase of 3 ° C./min, and a thermal change was observed.

【００２２】（２）赤外吸収スペクトル 加熱（８０℃）→室内雰囲気下 試料をＫＢｒで５％に混合希釈し、粉末Ｘ線回折用加熱
セルを用いて加熱し、拡散反射法（ＤＲＡ）で測定した
（ｓｃａｎ回数：２０４８，ｇａｉｎ：１６）。加熱実
験及び室内雰囲気下における実験では、乾燥Ａｉｒによ
る影響を防ぐためＳａｍｐｌｅ室は開放状態で行い（室
内の相対湿度：ＲＨ２０〜３０％）、ｒｅｆｅｒｅｎｃ
ｅも同様に測定した。無水雰囲気下における実験では、
Ｓａｍｐｌｅ室を閉じて、乾燥Ａｉｒにより無水雰囲気
下とし、ｒｅｆｅｒｅｎｃｅも同様に測定した。(2) Infrared absorption spectrum Heating (80 ° C.) → In a room atmosphere The sample was mixed and diluted to 5% with KBr, heated using a heating cell for powder X-ray diffraction, and diffused by the reflection method (DRA). It was measured (number of scans: 2048, gain: 16). In the heating experiment and the experiment under the indoor atmosphere, the sample room was opened in order to prevent the influence of the dry air (relative humidity in the room: RH 20 to 30%).
e was measured similarly. In experiments under anhydrous atmosphere,
The sample chamber was closed, the atmosphere was changed to an anhydrous atmosphere by dry Air, and the reference was measured in the same manner.

【００２３】 室温−無水雰囲気下→室内雰囲気下 試料をＫＢｒで５％に混合希釈し、拡散反射法（ＤＲ
Ａ）で測定した（ｓｃａｎ回数：１０２４，ｇａｉｎ：
８）。セルは簡便なＤＲＡ用セルを用いて測定した。無
水雰囲気下での実験はＳａｍｐｌｅ室を閉じて、乾燥Ａ
ｉｒをｆｌｏｗし実験を行い、ｒｅｆｅｒｅｎｃｅも同
様に測定した。室内雰囲気下における実験では、Ｓａｍ
ｐｌｅ室は開放状態で行い（室内の相対湿度：ＲＨ２０
〜３０％）、ｒｅｆｅｒｅｎｃｅも同様に測定した。Room temperature—under an anhydrous atmosphere → under an indoor atmosphere A sample is mixed and diluted to 5% with KBr, and is subjected to a diffuse reflection method (DR
A) (number of scans: 1024, gain:
8). The cell was measured using a simple DRA cell. In an experiment under an anhydrous atmosphere, the sample room was closed,
The experiment was performed by flowing ir, and the reference was measured in the same manner. In an experiment in an indoor atmosphere, Sam
The ple room is opened (the relative humidity in the room: RH20).
〜30%), and the reference was measured in the same manner.

【００２４】（３）粉末Ｘ線回折スペクトル 加熱（８０℃）→室内雰囲気下 試料を粉砕し加熱用セルを用いて、昇温速度５℃／ｍｉ
ｎで８０℃まで加熱し、その後Ｎ₂ ガスをｆｌｏｗして
無水雰囲気下とした後室温まで降温した。その後Ｎ₂ ガ
スをｓｔｏｐして室内雰囲気下として測定した（室内の
相対湿度：６０〜７０％）。(3) Powder X-ray diffraction spectrum Heating (80 ° C.) → In a room atmosphere The sample is pulverized and heated at a rate of 5 ° C./mi using a heating cell.
Then, the mixture was heated to 80 ° C. with n, then N ₂ gas was flown to make the atmosphere dry, and then the temperature was lowered to room temperature. Thereafter, N ₂ gas was stopped and the measurement was performed under the indoor atmosphere (relative humidity in the room: 60 to 70%).

【００２５】 室温−無水雰囲気下→室内雰囲気下 試料を粉砕し加熱用セルを用いて、Ｎ₂ ガスをｆｌｏｗ
して無水雰囲気下とし、経時的に測定した。その後Ｎ₂
ガスをｓｔｏｐして室内雰囲気下として測定した（室内
の相対湿度：６０〜７０％）。Room temperature—under an anhydrous atmosphere → under an indoor atmosphere A sample is pulverized and N ₂ gas is flowed using a heating cell.
Then, the sample was placed in an anhydrous atmosphere and measured over time. Then N ₂
The measurement was performed under the indoor atmosphere with the gas stopped (relative humidity in the room: 60 to 70%).

【００２６】（４）単結晶Ｘ線解析 室内雰囲気下（室温の相対湿度：６０〜７０％）で測定
後、Ｎ₂ ガスをｆｌｏｗして無水雰囲気下として測定し
た。その後再度室内雰囲気下に保存して測定した。(4) Single-crystal X-ray analysis After measurement in a room atmosphere (relative humidity at room temperature: 60 to 70%), the measurement was performed under an anhydrous atmosphere by flowing N ₂ gas. Thereafter, the sample was stored again in an indoor atmosphere and measured.

【００２７】４）実験結果及び考察 （１）熱分析による結晶水の挙動解析 ＴＧ法でＱ−３５のＩ形結晶（２水和物）を室温から８
０℃まで加熱（Ｎ₂ ガスによる影響を防ぐためＮ₂ ガス
はｆｌｏｗさせない）したところ、温度上昇に伴い重量
の減少が起こり、最終的に約８．１％が減量した。Ｑ−
３５Ｉ型結晶の含水量の理論値は８．４７％であるの
で、減量分は結晶水に相当すると推定される。すなわ
ち、加熱減量時の試料は脱水無水物と考えられる。その
後降温すると、降温と同時に重量が増加しはじめ、約１
５０分でＩｎｉｔｉａｌの重量に戻った（図１）。これ
らのことから、Ｑ−３５Ｉ型結晶の２分子の結晶水は加
熱により脱離するが、室温で空気中の水分を取込み、再
び２分子の結晶水の状態で安定化することが推定され
た。重量変化が結晶水によるものであることの確認は、
「（２）構造変化」で行った。4) Experimental Results and Discussion (1) Analysis of Behavior of Water of Crystalline by Thermal Analysis Form-I crystal (dihydrate) of Q-35 was obtained by TG method from room temperature to 8
When heated to 0 ° C. (the N ₂ gas was not allowed to flow to prevent the influence of the N ₂ gas), the weight was reduced with the rise in temperature, and the weight was finally reduced by about 8.1%. Q-
Since the theoretical value of the water content of the 35I type crystal is 8.47%, it is estimated that the weight loss corresponds to the water of crystallization. That is, the sample at the time of heat loss is considered to be dehydrated anhydride. When the temperature subsequently decreases, the weight begins to increase at the same time as the temperature decreases, and
It returned to the initial weight in 50 minutes (FIG. 1). From these facts, it was presumed that the water of crystallization of two molecules of the Q-35I type crystal was desorbed by heating, but the water in the air was taken in at room temperature and stabilized again in the state of water of crystallization of two molecules. . Confirmation that the weight change is due to crystal water,
This was performed in “(2) Structural change”.

【００２８】一方、試料を室温で無水雰囲気下に保存し
たところ、約７００分で約８．０％の減量が起きた。そ
の後、室内雰囲気下に保存すると急速に重量が増加し、
約１５０分でＩｎｉｔｉａｌと同じ重量に戻った（図
２）。これは、Ｑ−３５Ｉ型結晶の結晶水が加熱によっ
て脱離するだけでなく、室温においても、無水雰囲気下
で結晶水の脱離が十分起こりえることを示している。On the other hand, when the sample was stored at room temperature under an anhydrous atmosphere, a weight loss of about 8.0% occurred in about 700 minutes. Then, when stored in an indoor atmosphere, the weight rapidly increases,
It returned to the same weight as Initial in about 150 minutes (FIG. 2). This indicates that not only the crystallization water of the Q-35I type crystal is desorbed by heating but also the crystallization water can be sufficiently desorbed at room temperature under an anhydrous atmosphere.

【００２９】室温−無水雰囲気下保存でも２分子に相当
する脱水が生じ、脱水物はＲＨ４０〜５０％の室内雰囲
気下に保存することで完全に水分が再吸収されることが
確認されたが、わずかに水が存在する低湿度下ではＱ−
３５Ｉ型結晶はどのような状態で存在するのであろう
か。すなわち、１）低湿度下でも２分子の結晶水は結晶
内に取り込まれ、２水和物として存在する ２）一定湿
度以下では無水物またはと１水和物のような中間状態で
存在する こと等が考えられる。そこで一旦脱水した結
晶に、室温下ＲＨ６％に調湿したＡｉｒをｆｌｏｗし重
量変化を測定したところ、低湿度にもかかわらず急速に
吸水し、約６０分で２水和物の重量に戻ることが確認さ
れ、その吸水過程で１水和物のような中間状態は観測さ
れなかった（図３）。室内雰囲気下よりＲＨ６％の方が
吸水速度が速いのは、測定中のＡｉｒの流量の差による
ものと思われる。It was confirmed that dehydration equivalent to two molecules occurred even when stored in a room temperature-anhydrous atmosphere, and that the dehydrated product was completely reabsorbed when stored in an indoor atmosphere having an RH of 40 to 50%. Q- in low humidity where there is slight water
In what state does Form 35I crystal exist? That is, 1) Two molecules of water of crystallization are taken into the crystal and exist as dihydrate even under low humidity. 2) At a certain humidity or less, they exist in an intermediate state such as anhydrous or monohydrate. And so on. Then, once the dehydrated crystal was air-conditioned at RH 6% at room temperature and the change in weight was measured, it rapidly absorbed water despite low humidity and returned to the weight of dihydrate in about 60 minutes. Was observed, and no intermediate state such as monohydrate was observed during the water absorption process (FIG. 3). The reason why the water absorption rate is higher at RH 6% than under the indoor atmosphere is probably due to the difference in the flow rate of Air during measurement.

【００３０】加熱による脱水の場合、ＴＧ曲線（図４）
は、昇温と同時になだらかな減量が起こり、その後急激
な減量が認められプラトーに達する。この時ＤＴＡ曲線
は、脱水過程において２ピークが認められ、ＴＧにおけ
るなだらかな減量時にＤＴＡのなだらかな１ピーク、Ｔ
Ｇでの急激な減量時にＤＴＡの大きな１ピークの合わせ
て２ピークが認められる。これは、脱離しやすい水とし
にくい水の２種類が存在するため、脱離しやすい水が先
に飛び、脱離しにくい水がその後に飛ぶ２段階の反応が
合わさったためとも考えられる。ＤＳＣ曲線でもＤＴＡ
曲線と同様、脱水過程において２ピークが認められた
（図５）。一方、室温でＮ₂ ガスをｆｌｏｗ（室温−無
水雰囲気下）した場合のＴＧ曲線（図２）では、Ｎ₂ ガ
スｆｌｏｗ直後にやや大きな減量があり、その後なだら
かな減量が起こった後、急激な減量が認められプラトー
に達したが、この場合は最初に表面の試料中の水が飛
び、その後、加熱の場合と同様に脱離しやすい水が先に
飛び、脱離しにくい水がその後に飛ぶ２段階の反応が合
わさっていると考えられる。In the case of dehydration by heating, the TG curve (FIG. 4)
, A gradual weight loss occurs at the same time as the temperature rise, and then a rapid weight loss is observed and reaches a plateau. At this time, in the DTA curve, two peaks were recognized in the dehydration process.
At the time of the rapid weight loss in G, two peaks including a large peak of DTA are observed. This is considered to be due to the fact that there are two types of water that easily desorb and water that is hard to desorb, so that the two-stage reaction in which water that desorbs easily flies first, and water that hardly desorbs flies afterwards is combined. DTA in DSC curve
As with the curve, two peaks were observed during the dehydration process (FIG. 5). On the other hand, at room temperature the N ₂ gas flow - the TG curves in the case of (room temperature anhydrous atmosphere) (Fig. 2), there is little significant weight loss just after the N ₂ gas flow, after gentle weight loss occurs thereafter, rapid Weight loss was observed and reached a plateau. In this case, water in the sample on the surface flies first, and then water that is easy to desorb first jumps as in the case of heating, and water that hardly desorbs then jumps. It is considered that the reactions of the stages are combined.

【００３１】（２）構造変化 赤外吸収スペクトル法 ｉ）加熱（８０℃）→室内雰囲気下 ＴＧ法において、Ｑ−３５Ｉ型結晶は加熱（８０℃）に
より結晶水の理論値相当量の減量が認められ、その後室
温に降温することによりＩｎｉｔｉｔｉａｌの重量に戻
ることが確認された。重量変化量が結晶水の理論値と一
致することから、重量変化は２分子の結晶水の脱着によ
るものと推定し、赤外吸収スペトル法により確認した。(2) Structural change Infrared absorption spectroscopy i) Heating (80 ° C.) → In a room atmosphere In the TG method, the Q-35I type crystal loses the amount equivalent to the theoretical value of water of crystallization by heating (80 ° C.). It was confirmed that after returning to room temperature, the weight returned to Initial. Since the amount of change in weight coincides with the theoretical value of water of crystallization, the change in weight was estimated to be due to desorption of two molecules of water of crystallization, and confirmed by infrared absorption spectrometry.

【００３２】Ｉｎｉｔｉａｌのスペクトルでは結晶水由
来のν_O-H （Ｈ₂ Ｏ）ピークが強く認められる（図
６）。加熱（８０℃）すると、ν_O-H （Ｈ₂ Ｏ）の吸収
は完全に消失しており、８０℃で脱水し無水物となって
いることが確認された（図６）。また、ν_C=0 （カルボ
キシレート、ケトン：１６２２ｃｍ^-1）より低波数側の
スペクトルも変化しており、脱水により何らかの変化が
生じていると思われる。結晶水はカルボキシレート（Ｑ
−３５はベタイン構造をとっている）の酸素に結合して
いるが、カルボキシレートのν_C=0 吸収（１６２２，１
４５９ｃｍ^-1）はわずかにピーク形状に変化が認められ
る。その後、無水雰囲気下で降温し室温保存して、ν
_O-H （Ｈ₂ Ｏ）の吸収は認められず加熱時のスペクトル
と一致し、脱水状態を保っている（図７）。しかし、室
内雰囲気下に保存すると、約２４時間でＩｎｉｔｉａｌ
と同等のν_O-H （Ｈ₂ Ｏ）の吸収が認められ、その他の
ピークも完全にＩｎｉｔｉａｌのスペクトルと一致し、
Ｉｎｉｔｉａｌと同じ２水和物の分子構造をとっており
（図８）、室温下で水が存在すると脱水物は水を取り込
むことが確認された。この結果より、Ｑ−３５Ｉ型結晶
は加熱により結晶水が脱離して無水物となるが、室内雰
囲気下に保存すると、吸水しＩｎｉｔｉａｌと同じ２水
和物の分子構造に戻るといえる。In the initial spectrum, a ν _OH (H ₂ O) peak derived from water of crystallization is strongly observed (FIG. 6). Upon heating (80 ° C.), the absorption of ν _OH (H ₂ O) completely disappeared, and it was confirmed that the product was dehydrated at 80 ° C. to become an anhydride (FIG. 6). Further, the spectrum on the lower wavenumber side than ν _{C = 0} (carboxylate, ketone: 1622 cm ⁻¹ ) also changed, and it is considered that some change was caused by dehydration. Water of crystallization is carboxylate (Q
-35 has a betaine structure) but is bound to oxygen, but ν _{C = 0} absorption of carboxylate (1622,1
459 cm ^-1 ), a slight change in peak shape is observed. Thereafter, the temperature is lowered under an anhydrous atmosphere and stored at room temperature, and ν
_No absorption of _OH (H ₂ O) was observed, which coincided with the spectrum at the time of heating, and the dehydrated state was maintained (FIG. 7). However, when stored in an indoor atmosphere, it takes about 24 hours to initialize
The absorption of ν _OH (H ₂ O) equivalent to that of was observed, and the other peaks completely coincided with the spectrum of Initial.
It has the same dihydrate molecular structure as Initial (FIG. 8), and it was confirmed that when water was present at room temperature, the dehydrated product took up water. From this result, it can be said that the Q-35I type crystal is dehydrated by elimination of water of crystallization by heating, but when stored in a room atmosphere, absorbs water and returns to the same molecular structure of dihydrate as Initial.

【００３３】ｉｉ）室温−無水雰囲気下→室内雰囲気下 ＴＧ法では加熱と同様、室温−無水雰囲気下でも結晶水
の理論値相当量の減量が認められ、その後室内雰囲気下
でＩｎｉｔｉａｌの重量に戻ることが確認された。加熱
による減量は脱水によることが赤外吸収スペクトルで確
認されたが、室温−無水雰囲気下の重量変化が水による
ものであること、また加熱と室温−無水雰囲気下の脱水
物の分子構造が異なるかどうかを、赤外吸収スペクトル
により観察した。Ii) Room temperature—under an anhydrous atmosphere → in a room atmosphere In the TG method, as in the case of heating, a reduction in the theoretical value of the amount of water of crystallization is recognized even under a room temperature—anhydrous atmosphere, and thereafter, the weight returns to the initial weight under the indoor atmosphere. It was confirmed that. The infrared absorption spectrum confirmed that the weight loss due to heating was due to dehydration, but the weight change under room temperature-anhydrous atmosphere was due to water, and the molecular structure of the dried product under heating and room temperature-anhydrous atmosphere was different Whether it was observed by infrared absorption spectrum.

【００３４】無水雰囲気下に保存すると、加熱時と同様
ν_O-H （Ｈ₂ Ｏ）の吸収が消失して完全に加熱時のスペ
クトルと一致し（図９）、室温−無水雰囲気下に保存す
るだけで脱水して無水物になり、加熱時と同じ分子構造
をとることがわかった。その後室内雰囲気下に保存する
と、加熱した時と同様、Ｉｎｉｔｉａｌと同等のν_{O- H}
（Ｈ₂ Ｏ）の吸収が認められ、Ｉｎｉｔｉａｌのスペク
トルと一致し、Ｉｎｉｔｉａｌと同じ２水和物の分子構
造をとっていることが確認された（図１０）。よって、
室温−無水雰囲気下に保存すると脱水して無水物が生
じ、その脱水無水物の分子構造は加熱による脱水無水物
の分子構造と同じであり、その後室内雰囲気下に保存す
るとＩｎｉｔｉａｌと同じ２水和物の分子構造に戻るこ
とが確認された。When stored in an anhydrous atmosphere, the absorption of ν _OH (H ₂ O) disappears as in the case of heating and completely matches the spectrum of the heated state (FIG. 9). Dehydrated to an anhydride, and it was found to have the same molecular structure as when heated. After that, when stored in an indoor atmosphere, as in the case of heating, ν _{O- H} equivalent to Initial
The absorption of (H ₂ O) was observed, which was consistent with the spectrum of Initial, and it was confirmed that it had the same molecular structure of dihydrate as Initial (FIG. 10). Therefore,
When stored at room temperature in an anhydrous atmosphere, dehydration occurs to produce an anhydride, and the molecular structure of the dehydrated anhydride is the same as the molecular structure of the dehydrated anhydride by heating, and then, when stored in an indoor atmosphere, the same dihydration as Initial It was confirmed to return to the molecular structure of the product.

【００３５】赤外吸収スペクトルの測定により、Ｑ−３
５Ｉ型結晶は加熱（８０℃）及び室温−無水雰囲気下で
脱水して無水物が生じ、脱水物の分子構造は乾燥条件に
よらず同じであり、室温雰囲気下に保存することで再び
吸湿しＩｎｉｔｉａｌと同じ２水和物の分子構造に戻
り、水の脱着は可逆的であることが確認された。According to the measurement of the infrared absorption spectrum, Q-3
The Form 5I crystal is dehydrated by heating (80 ° C.) and at room temperature in an anhydrous atmosphere to form an anhydride. The molecular structure of the dehydrated substance is the same regardless of the drying conditions. It returned to the same molecular structure of dihydrate as Initial, and it was confirmed that desorption of water was reversible.

【００３６】 粉末Ｘ線回折 ｉ）加熱（８０℃）→室内雰囲気下 赤外吸収スペクトルで加熱及び室温−無水雰囲気下で脱
水し、室内雰囲気下に保存することで再び水が戻ること
が確認された。そこで、脱水することによる結晶構造の
変化について、粉末Ｘ線回折により観察した。Powder X-ray diffraction i) Heating (80 ° C.) → in a room atmosphere It was confirmed that water was returned again by heating and dehydrating in a room temperature-free atmosphere by infrared absorption spectrum and storing in a room atmosphere. Was. Therefore, a change in crystal structure due to dehydration was observed by powder X-ray diffraction.

【００３７】Ｉｎｉｔｉａｌのスペクトルを図１１に示
す。加熱（８０℃）すると、Ｉｎｉｔｉａｌ時には２
４．２℃に存在した大きなピークが消失し、その他のス
ペクトルも変化して全く異なるスペクトルを示した（図
１２）。この結果は、加熱により脱水することが赤外吸
収スペクトルで確認されているため、加熱による脱水時
は単に水分子が脱離しているだけでなく結晶構造自体が
異なる構造をとっていることを意味している。この後、
無水雰囲気下で室温まで降温すると、赤外吸収スペクト
ルでは無水雰囲気下で降温し室温保存しても脱水状態を
保持していたが、粉末Ｘ線回折においても加熱時（脱水
時）のスペクトルと一致し、脱水物の結晶構造を保持し
ており（図１３）、結晶構造は加熱時の脱水物と同じ構
造をとっている。しかし、室内雰囲気下に保存すると、
１４時間でＩｎｉｔｉａｌ時に存在した２４．２℃の大
きなピークが再び現れ、Ｉｎｉｔｉａｌのスペクトルと
完全に一致した（図１４）。赤外吸収スペトルでは、室
内雰囲気下に保存することで水が戻ってＩｎｉｔｉａｌ
の分子構造に戻ることが確認されており、粉末Ｘ線回折
においても室内雰囲気下に保存することで脱水物の結晶
構造がＩｎｉｔｉａｌの結晶構造、すなわち２分子の結
晶水をもつ構造に戻ることが確認された。赤外吸収スペ
クトル及び粉末Ｘ線回折の結果をあわせてみると、加熱
で脱水し、脱水することで結晶構造も変化するが、室内
雰囲気下に保存すると、水は戻り、結晶構造も同時にＩ
ｎｉｔｉａｌの結晶構造に戻る。水の脱着は可逆であ
り、かつ水和物、脱水物は異なる結晶構造を持ち、水の
脱着と同時に結晶構造が変化し、結晶構造の変化も可逆
である。FIG. 11 shows the initial spectrum. When heated (80 ° C), 2
The large peak at 4.2 ° C. disappeared, and the other spectra changed to show completely different spectra (FIG. 12). This result indicates that dehydration by heating was confirmed in the infrared absorption spectrum, so that during dehydration by heating, not only water molecules were detached but also the crystal structure itself was different. are doing. After this,
When the temperature was lowered to room temperature in an anhydrous atmosphere, the infrared absorption spectrum showed that the temperature was lowered in an anhydrous atmosphere and the product was kept in a dehydrated state even when stored at room temperature. Thus, the crystal structure of the dehydrate is retained (FIG. 13), and the crystal structure is the same as that of the dehydrate during heating. However, when stored in an indoor atmosphere,
A large peak at 24.2 ° C., which was present at the time of Initial at 14 hours, reappeared and was completely consistent with the spectrum of Initial (FIG. 14). In the infrared absorption spectrum, water is returned by storing in an indoor atmosphere,
It has been confirmed that the crystal structure of the dehydrated product returns to the initial crystal structure, that is, a structure having two molecules of water of crystallization by storing in a room atmosphere in powder X-ray diffraction. confirmed. When the results of the infrared absorption spectrum and the powder X-ray diffraction are combined, dehydration by heating and dehydration change the crystal structure. However, when stored in a room atmosphere, water returns and the crystal structure is simultaneously reduced.
Return to the crystal structure of the initial. Desorption of water is reversible, and hydrates and dehydrates have different crystal structures. The crystal structure changes simultaneously with the desorption of water, and the change in the crystal structure is also reversible.

【００３８】ｉｉ）室温−無水雰囲気下→室内雰囲気下 赤外吸収スペクトルでは、室温−無水雰囲気下でも脱水
し、その変化は加熱と同様の挙動を示していた。そこ
で、粉末Ｘ線回折でも同様の挙動を示すかを観察した。Ii) Room temperature—under an anhydrous atmosphere → under a room atmosphere In the infrared absorption spectrum, dehydration was performed even under a room temperature—anhydrous atmosphere, and the change showed the same behavior as heating. Therefore, it was observed whether or not the same behavior is exhibited by powder X-ray diffraction.

【００３９】無水雰囲気下に保存すると、スペクトルが
経時的に変化し、加熱時（脱水時）のスペクトル図１５
と一致した（図１６）。赤外吸収スペクトルにおいて、
室温−無水雰囲気下で脱水することが確認されているの
で、粉末Ｘ線回折での無水雰囲気下保存後の試料は脱水
物である。無水雰囲気下保存後の脱水物は、赤外吸収ス
ペクトルで、加熱、室温−乾燥条件下いずれも同じ分子
構造を示していたのと同様、加熱による脱水物と同じ結
晶構造をもつことが確認された。室内雰囲気下に保存す
ると、２時間でＩｎｉｔｉａｌの粉末Ｘ線回折スペクト
ル図１８と完全に一致し（図１７）、赤外吸収スペクト
ルで室内雰囲気下に保存すると水が戻っていたが、粉末
Ｘ線回折においても、加熱における変化と同様、Ｉｎｉ
ｔｉａｌの２水和物の結晶構造に戻ることが確認され
た。When stored in an anhydrous atmosphere, the spectrum changes over time, and the spectrum during heating (during dehydration) is shown in FIG.
(FIG. 16). In the infrared absorption spectrum,
Since it has been confirmed that dehydration occurs at room temperature in an anhydrous atmosphere, the sample after storage in an anhydrous atmosphere by powder X-ray diffraction is a dehydrated product. In the infrared absorption spectrum, the dehydrated product after storage under an anhydrous atmosphere was confirmed to have the same crystal structure as the dehydrated product by heating, as well as showing the same molecular structure under both heating and room temperature-drying conditions. Was. When stored in an indoor atmosphere, it completely matched the initial powder X-ray diffraction spectrum of FIG. 18 in 2 hours (FIG. 17), and when stored in an indoor atmosphere in the infrared absorption spectrum, water was returned. In diffraction as well as in heating, Ini
It was confirmed that the crystal structure returned to the crystal structure of tial dihydrate.

【００４０】これらの結果より、Ｑ−３５Ｉ型結晶は加
熱あるいは室温−無水雰囲気下保存で脱水して無水物と
なり、それらの脱水物は同じ分子構造、結晶構造をとる
ことから同一物質であり、また、脱水物を室内雰囲気下
に保存することでＩｎｉｔｉａｌと同じ２水和物の分子
構造、結晶構造をとる同一物質に戻ることが判明した。From these results, the Q-35I type crystal was dehydrated by heating or storage at room temperature in an anhydrous atmosphere to become an anhydrous substance, and the dehydrated substance had the same molecular structure and crystal structure, and was the same substance. In addition, it was found that storing the dehydrated product in an indoor atmosphere returns to the same substance having the same molecular structure and crystal structure of dihydrate as Initial.

【００４１】（３）単結晶Ｘ線解析 赤外吸収スペクトル、粉末Ｘ線回折から、加熱、室温−
無水雰囲気下で脱水し、脱水物は同じ分子構造、結晶構
造をとり、また、室内雰囲気下の保存でＩｎｉｔｉａｌ
と同じ２水和物の分子構造、結晶構造に戻ることがわか
った。この事実をさらに裏付けるために、単結晶Ｘ線解
析を行った。(3) Single crystal X-ray analysis From infrared absorption spectrum and powder X-ray diffraction, heating, room temperature
After dehydration in an anhydrous atmosphere, the dehydrated product has the same molecular structure and crystal structure.
It was found that the molecular structure and the crystal structure of the same dihydrate returned to the same. To further support this fact, single crystal X-ray analysis was performed.

【００４２】単結晶Ｘ線解析用に調製したＱ−３５Ｉ型
結晶を測定し、その結果より得た粉末Ｘ線回折の合成ス
ペクトルは、室内雰囲気下における粉末Ｘ線回折スペク
トル（図１９）と合致した（図２０）。その後、室温−
無水雰囲気下で乾燥した単結晶Ｘ線解析用に調製したＱ
−３５Ｉ型結晶を測定し、その結果より得た粉末Ｘ線回
折の合成スペクトルは、加熱下及び室温−無水雰囲気下
における粉末Ｘ線回折スペクトル図２１と合致した（図
２２）。よって、乾燥した単結晶は脱水していることが
確認された。脱水した単結晶は、格子定数が変化してお
り（Ｉｎｉｔｉａｌ：ｂ＝１２．９６６（２）Å、脱水
結晶：ｂ＝３８．３４（２）Å、ａ，ｃ，βは変化な
し）三量体に構造が変化していた。The Q-35I type crystal prepared for single crystal X-ray analysis was measured, and the synthetic spectrum of the powder X-ray diffraction obtained from the measurement was in agreement with the powder X-ray diffraction spectrum in an indoor atmosphere (FIG. 19). (FIG. 20). Then, at room temperature
Q prepared for X-ray analysis of single crystal dried under anhydrous atmosphere
-35I type crystal was measured, and the synthesized spectrum of the powder X-ray diffraction obtained from the measurement was in agreement with the powder X-ray diffraction spectrum diagram 21 under heating and at room temperature in an anhydrous atmosphere (FIG. 22). Therefore, it was confirmed that the dried single crystal was dehydrated. The lattice constant of the dehydrated single crystal is changed (Initial: b = 12.966 (2) Å, dehydrated crystal: b = 38.34 (2) Å, a, c, and β are unchanged). The body had changed structure.

【００４３】Ｉｎｉｔｉａｌの結晶構造図を図２３，２
４に、脱水物の結晶構造図を図２５，２６に示す。室温
−無水雰囲気下で乾燥した結晶を室内雰囲気下に保存
し、再び測定するとＩｎｉｔｉａｌと同じ結晶構造を持
つことが確認された（図２７，２８）。The crystal structure diagram of Initial is shown in FIGS.
FIG. 4 shows the crystal structure of the dehydrated product in FIGS. The crystals dried at room temperature in an anhydrous atmosphere were stored in an indoor atmosphere and measured again to confirm that they had the same crystal structure as Initial (FIGS. 27 and 28).

【００４４】粉末Ｘ線回折で水和物と脱水物の結晶構造
が異なることが示され、その構造変化は可逆であること
が確認されていたが、その結果を単結晶Ｘ線解析におい
ても支持する結果であった。The powder X-ray diffraction showed that the crystal structures of the hydrate and the dehydrate were different, and it was confirmed that the structural change was reversible, but the results were also supported by single crystal X-ray analysis. Was the result.

【００４５】５）結論 以上の実験結果から、Ｑ−３５Ｉ型結晶の結晶水の挙動
について次の点が明らかとなった。5) Conclusion From the above experimental results, the following points became clear regarding the behavior of water of crystallization of Q-35I type crystal.

【００４６】・加熱あるいは室温−無水雰囲気下に保存
することにより、結晶構造の変化を伴った脱水がおき無
水物が生じる。Heating or storage at room temperature in an anhydrous atmosphere causes dehydration accompanied by a change in the crystal structure to produce an anhydride.

【００４７】・加熱あるいは室温−無水雰囲気下保存の
乾燥条件によらず、脱水物の分子構造及び結晶構造は同
じである。The molecular structure and crystal structure of the dehydrated product are the same regardless of the drying conditions of heating or storage at room temperature in an anhydrous atmosphere.

【００４８】・脱水量は、定量的に２水和物の含水理論
値と一致する。The amount of dehydration quantitatively agrees with the theoretical water content of dihydrate.

【００４９】・脱水物は室内雰囲気下に保存すること
で、空気中の水分が吸収しＱ−３５Ｉ型結晶に戻る。When the dehydrated product is stored in an indoor atmosphere, the moisture in the air is absorbed and returns to the Q-35I crystal.

【００５０】・水の脱着は可逆的なものである。The desorption of water is reversible.

【００５１】・脱水物の吸水量は、定量的に水２分子の
理論値と一致する。The amount of water absorbed by the dehydrated product quantitatively agrees with the theoretical value of two molecules of water.

【００５２】・脱水物は雰囲気にわずかに水が存在する
だけで、Ｑ−３５Ｉ型結晶に変化するため、通常の扱い
においては、Ｑ−３５Ｉ型結晶の結晶水は安定である。Since the dehydrated product changes to Q-35I type crystal only when water is slightly present in the atmosphere, the water of crystallization of Q-35I type crystal is stable in the usual handling.

【００５３】先に述べたように、Ｑ−３５ＩＩＩ型結晶
は非常に安定性が悪い。これに対して、Ｑ−３５Ｉ型結
晶（二水和物）及びＱ−３５ＩＩ型結晶（一水和物）は
いずれも乾燥条件下で脱水して無水物になるものの、室
内雰囲気下に保存することよって再び空気中の水分を吸
収し、それぞれＱ−３５Ｉ型結晶及びＱ−３５ＩＩ型結
晶に戻ることが確認されている。そこで、以下に両者の
安定性について行なった比較試験の方法並びに結果を記
す。As mentioned above, the Q-35III type crystal has very poor stability. On the other hand, the Q-35I crystal (dihydrate) and the Q-35II crystal (monohydrate) are both dehydrated under dry conditions to become anhydrous, but are stored in a room atmosphere. Accordingly, it has been confirmed that water in the air is absorbed again and the crystal returns to the Q-35I crystal and the Q-35II crystal, respectively. Therefore, a method and results of a comparative test performed on the stability of the two are described below.

【００５４】〔試験例１〕吸湿試験 Ｑ−３５Ｉ型結晶及びＱ−３５ＩＩ型結晶をそれぞれ４
０℃において、０％ＲＨ、５２．４％ＲＨ、７５％Ｒ
Ｈ、１００％ＲＨの湿度条件下に放置し、４〜７日後の
重量変化を調べた。結果を表１に示す。Test Example 1 Moisture Absorption Test Q-35I type crystal and Q-35II type crystal
At 0 ° C., 0% RH, 52.4% RH, 75% RH
H and 100% RH, and the weight change after 4 to 7 days was examined. Table 1 shows the results.

【００５５】 表１ ４０℃、調湿条件下における重量変化 サンプル(mg) ４日後 ５日後 ６日後 ７日後(%) （ＩＩ型結晶） 0％ＲＨ 113.0 −2.57 −2.48 −2.12 −2.48 52.4％ＲＨ 129.1 0.31 −0.15 −0.08 −0.15 75％ＲＨ 113.0 0.53 0.53 0.62 0.62 100％ＲＨ 118.9 3.78 4.46 4.46 4.71 （Ｉ型結晶） 0％ＲＨ 127.9 −4.53 −8.29 −8.21 −8.05 52.4％ＲＨ 132.5 0.38 0.23 0.30 0.53 75％ＲＨ 192.5 0.42 0.47 0.26 0.42 100％ＲＨ 129.1 0.70 0.39 0.39 0.34 ＩＩ型結晶は、０％ＲＨで２％強の重量減少を認めた
が、５２．４及び７５％ＲＨでは１％以下の重量変化に
留まった。しかし、１００％ＲＨにおいては約５％重量
が増加した。一方、Ｉ型結晶は、０％ＲＨで約８％の重
量減少を認めたが、他の相対湿度下ではいずれも１％以
内の変化であった。低湿度下ではＩ型結晶の結晶水が失
われるものと考えられる。 Table 1 Weight change sample (mg) under the condition of 40 ° C. and humidity control After 4 days After 5 days After 6 days After 7 days (%) (Type II crystal) 0% RH 113.0 -2.57 -2.48 -2.12 -2.48 52.4% RH 129.1 0.31 -0.15 -0.08 -0.15 75% RH 113.0 0.53 0.53 0.62 0.62 100% RH 118.9 3.78 4.46 4.46 4.71 (I-type crystal) 0% RH 127.9 -4.53 -8.29 -8.21 -8.05 52.4% RH 132.5 0.38 0.23 0.30 0.53 75 % RH 192.5 0.42 0.47 0.26 0.42 100% RH 129.1 0.70 0.39 0.39 0.34 The type II crystal showed a weight loss of just over 2% at 0% RH, but a weight change of 1% or less at 52.4 and 75% RH. Stayed. However, at 100% RH, the weight increased by about 5%. On the other hand, the type I crystal showed a weight loss of about 8% at 0% RH, but the change was within 1% at all other relative humidity. It is considered that the water of crystallization of the type I crystal is lost under low humidity.

【００５６】ＩＩ型結晶を４０℃０％ＲＨ及び７５％Ｒ
Ｈで１週間保存後の粉末Ｘ線回折スペクトル（図２９、
図３０）は、ＩＩ型結晶の初期のスペクトルといずれも
一致したが、４０℃１００％ＲＨで１週間保存後のスペ
クトル（図３１）は、ＩＩ型結晶の初期スペクトルと一
致せず、Ｉ型結晶とＩＩＩ型結晶の回折ピークの混合ス
ペクトルと考えられた。Form II crystal was obtained at 40 ° C. with 0% RH and 75% R
H powder X-ray diffraction spectrum after one week storage (FIG. 29,
Although FIG. 30) coincided with the initial spectrum of the type II crystal, the spectrum after storage at 40 ° C. and 100% RH for one week (FIG. 31) did not agree with the initial spectrum of the type II crystal. This was considered to be a mixed spectrum of diffraction peaks of the crystal and the type III crystal.

【００５７】一方、Ｉ型結晶を４０℃１００％ＲＨで１
週間保存後の粉末Ｘ線回折スペクトル（図３２）は、Ｉ
型結晶の初期のスペクトルと一致した。On the other hand, the I-type crystal was heated at 40 ° C. and 100% RH for 1 hour.
The powder X-ray diffraction spectrum after storage for a week (FIG. 32)
It was consistent with the initial spectrum of the type crystal.

【００５８】以上の結果から、Ｉ型結晶は０％ＲＨ（乾
燥条件下）では結晶水を失うことによる重量変化がある
ものの、高湿度下では著しい吸湿を示さず、しかも結晶
転移が見られないことから、薬品製造に際してはＩＩ型
結晶よりも優れていると言える。From the above results, although the type I crystal has a weight change due to loss of water of crystallization at 0% RH (dry condition), it does not show remarkable moisture absorption under high humidity and no crystal transition is observed. Therefore, it can be said that it is superior to the type II crystal in producing a chemical.

【００５９】〔試験例２〕練合の影響 Ｑ−３５は医薬品として使用する場合に、１００〜２０
０ｍｇの経口製剤が適当であると考えられている。従っ
て、主薬含有率の高い製剤になるものと思われ、湿式造
粒を行う必要性が高い。そこで、湿式造粒を想定して、
水及びエタノールを用いて練合することにより結晶形が
変化するか否かを確認するため、ＩＩ型結晶及びＩ型結
晶をそれぞれエタノール、５０％エタノール水溶液、水
にて練合した後、粉末Ｘ線回折スペクトルを測定した。[Test Example 2] Effect of kneading Q-35 was 100 to 20 when used as a pharmaceutical.
A 0 mg oral formulation is considered suitable. Therefore, it is considered that the preparation will have a high content of the active ingredient, and it is highly necessary to perform wet granulation. Therefore, assuming wet granulation,
In order to confirm whether or not the crystal form is changed by kneading with water and ethanol, the type II crystal and the type I crystal were kneaded with ethanol, a 50% aqueous ethanol solution and water, respectively. The line diffraction spectrum was measured.

【００６０】ＩＩ型結晶の練合末は、エタノールによる
練合で当初のＩＩ型結晶と一致する粉末Ｘ線回折スペク
トル（図３３）となり、結晶形は変化していないことが
わかった。しかし、５０％エタノール水溶液あるいは水
にて練合した場合は、ＩＩ型結晶とＩ型結晶の回折ピー
クの混合となった（図３４、図３５）。すなわち、ＩＩ
型結晶はエタノール含有量５０％以下の溶媒を用いて練
合することにより結晶Ｉへ一部転移することが確認され
た。The kneaded powder of the type II crystal had a powder X-ray diffraction spectrum (FIG. 33) consistent with the original type II crystal after kneading with ethanol, and it was found that the crystal form did not change. However, when kneaded with a 50% aqueous ethanol solution or water, the diffraction peaks of the type II crystal and the type I crystal were mixed (FIGS. 34 and 35). That is, II
It was confirmed that the type crystals were partially transferred to crystal I by kneading using a solvent having an ethanol content of 50% or less.

【００６１】一方、Ｉ型結晶の練合末の粉末Ｘ線回折ス
ペクトルは、いずれも初期のＩ型結晶のスペクトルと一
致した（図３６、図３７、図３８）。すなわちＩ型結晶
を練合してもＩ型結晶から転移しないことが確認され
た。On the other hand, the powder X-ray diffraction spectrum of the kneaded I-type crystal was consistent with the spectrum of the initial I-type crystal (FIGS. 36, 37 and 38). That is, it was confirmed that even when the I-type crystal was kneaded, no transition from the I-type crystal occurred.

【００６２】したがって、湿式造粒による製剤化を行う
場合は、Ｉ型結晶の方がＩＩ型結晶よりも望ましいこと
がわかった。Therefore, it was found that in the case of formulating by wet granulation, type I crystals are more preferable than type II crystals.

【００６３】[0063]

【発明の効果】以上説明したように、本発明のＱ−３５
Ｉ型結晶は、吸湿、練合などの条件下で優れた安定性を
示すので、製剤上極めて好適な結晶形である。As described above, according to the present invention, Q-35
Form I crystal is a crystal form that is extremely suitable for preparation because it shows excellent stability under conditions such as moisture absorption and kneading.

【図面の簡単な説明】[Brief description of the drawings]

【図１】加熱後室内雰囲気下に保存した時のＱ−３５Ｉ
型結晶の重量変化を表すグラフである。FIG. 1. Q-35I when stored under indoor atmosphere after heating
4 is a graph showing a change in weight of a type crystal.

【図２】室温−無水雰囲気下保存後、室内雰囲気下に保
存した時のＱ−３５Ｉ型結晶の重量変化を表すグラフで
ある。FIG. 2 is a graph showing a change in weight of Q-35I type crystal when stored in a room atmosphere after storage at room temperature in an anhydrous atmosphere.

【図３】Ｑ−３５Ｉ型結晶の脱水物を室温−ＲＨ６％雰
囲気下に保存した時の重量変化を表すグラフである。FIG. 3 is a graph showing a weight change when a dehydrated product of Form Q-35I crystal is stored at room temperature in an atmosphere of 6% RH.

【図４】Ｑ−３５Ｉ型結晶を室温から昇温速度３℃／分
で１７０℃まで加熱した時のＴＧ／ＤＴＡスペクトルで
ある。FIG. 4 is a TG / DTA spectrum when the Q-35I crystal was heated from room temperature to 170 ° C. at a rate of temperature increase of 3 ° C./min.

【図５】Ｑ−３５Ｉ型結晶を室温から昇温速度３℃／分
で１７０℃まで加熱した時のＤＳＣスペクトルである。FIG. 5 is a DSC spectrum obtained when the Q-35I crystal was heated from room temperature to 170 ° C. at a rate of temperature increase of 3 ° C./min.

【図６】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌ及び加熱時
の赤外吸収スペクトルである。FIG. 6 is an infrared absorption spectrum of Q-35I type crystal at initial and heating.

【図７】Ｑ−３５Ｉ型結晶の加熱時及び無水雰囲気下で
降温−室温保存した時の赤外吸収スペクトルである。FIG. 7 is an infrared absorption spectrum when the Q-35I crystal is heated and stored at room temperature and at room temperature under an anhydrous atmosphere.

【図８】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌ及び加熱後
室内雰囲気下に保存した時の赤外吸収スペクトルであ
る。FIG. 8 is an infrared absorption spectrum of the Q-35I type crystal at the time of initial storage and after storage under room atmosphere after heating.

【図９】Ｑ−３５Ｉ型結晶の加熱時及び室温−無水雰囲
気下に保存した時の赤外吸収スペクトルである。FIG. 9 is an infrared absorption spectrum of the Q-35I type crystal when heated and stored at room temperature in an anhydrous atmosphere.

【図１０】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌ及び室温
−無水雰囲気下に保存後室内雰囲気下に保存した時の赤
外吸収スペクトルである。FIG. 10 is an infrared absorption spectrum of Q-35I type crystal at initial and at room temperature in an anhydrous atmosphere and then stored in an indoor atmosphere.

【図１１】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌの粉末Ｘ
線回折スペクトルである。FIG. 11: Initial powder X of Q-35I crystal
It is a line diffraction spectrum.

【図１２】Ｑ−３５Ｉ型結晶の加熱時の粉末Ｘ線回折ス
ペクトルである。FIG. 12 is an X-ray powder diffraction spectrum of a Q-35I crystal during heating.

【図１３】Ｑ−３５Ｉ型結晶を加熱後無水雰囲気下で降
温し室温保存した時の粉末Ｘ線回折スペクトルである。FIG. 13 is a powder X-ray diffraction spectrum when the Q-35I crystal was heated and then cooled in an anhydrous atmosphere and stored at room temperature.

【図１４】Ｑ−３５Ｉ型結晶を加熱後無水雰囲気で降温
し、更に室内雰囲気下に保存した時の粉末Ｘ線回折スペ
クトルである。FIG. 14 is a powder X-ray diffraction spectrum when the Q-35I crystal was heated, cooled in an anhydrous atmosphere, and further stored in an indoor atmosphere.

【図１５】Ｑ−３５Ｉ型結晶の加熱時の粉末Ｘ線回折ス
ペクトルである。FIG. 15 is a powder X-ray diffraction spectrum of the Q-35I type crystal at the time of heating.

【図１６】Ｑ−３５Ｉ型結晶を室温−無水雰囲気下保存
後の粉末Ｘ線回折スペクトルである。FIG. 16 is an X-ray powder diffraction spectrum of the Q-35I crystal after storage at room temperature in an anhydrous atmosphere.

【図１７】Ｑ−３５Ｉ型結晶を室温−無水雰囲気下保存
後、引き続いて室内雰囲気下に保存した後の粉末Ｘ線回
折スペクトルである。FIG. 17 is an X-ray powder diffraction spectrum of the Q-35I type crystal after storage at room temperature in an anhydrous atmosphere and subsequently after storage in an indoor atmosphere.

【図１８】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌの粉末Ｘ
線回折スペクトルである。FIG. 18: Initial powder X of Q-35I crystal
It is a line diffraction spectrum.

【図１９】室内雰囲気下におけるＱ−３５Ｉ型結晶のＩ
ｎｉｔｉａｌの粉末Ｘ線回折スペクトルである。FIG. 19 shows the I of Q-35I crystal in a room atmosphere.
2 is a powder X-ray diffraction spectrum of a natural.

【図２０】Ｑ−３５Ｉ型結晶の単結晶Ｘ線解析結果より
得たＩｎｉｔｉａｌの粉末Ｘ線回折の合成スペクトルで
ある。FIG. 20 is a composite spectrum of Initial powder X-ray diffraction obtained from the result of single crystal X-ray analysis of Q-35I type crystal.

【図２１】加熱時におけるＱ−３５Ｉ型結晶の粉末Ｘ線
回折スペクトルである。FIG. 21 is an X-ray powder diffraction spectrum of a Q-35I crystal during heating.

【図２２】Ｑ−３５Ｉ型結晶の単結晶Ｘ線解析結果より
得た室温−無水雰囲気下における粉末Ｘ線回折の合成ス
ペクトルである。FIG. 22 is a synthetic spectrum of powder X-ray diffraction under an anhydrous atmosphere at room temperature obtained from the result of single-crystal X-ray analysis of Q-35I type crystal.

【図２３】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌの結晶構
造図である。FIG. 23 is a crystal structure diagram of Initial of Q-35I type crystal.

【図２４】Ｑ−３５Ｉ型結晶のＩｎｉｔｉａｌのステレ
オ結晶構造図である。FIG. 24 is a stereo crystal structure diagram of Initial of Q-35I type crystal.

【図２５】Ｑ−３５Ｉ型結晶の室温−無水雰囲気下（脱
水物）の結晶構造図である。FIG. 25 is a crystal structure diagram of Q-35I type crystal at room temperature in an anhydrous atmosphere (dehydrated product).

【図２６】Ｑ−３５Ｉ型結晶の室温−無水雰囲気下（脱
水物）のステレオ結晶構造図である。FIG. 26 is a stereocrystal structure diagram of Q-35I crystal at room temperature in an anhydrous atmosphere (dehydrated product).

【図２７】Ｑ−３５Ｉ型結晶を室温−無水雰囲気下保存
後、更に室内雰囲気下に保存した場合の結晶構造図であ
る。FIG. 27 is a crystal structure diagram when the Q-35I crystal is stored at room temperature in an anhydrous atmosphere and then further stored in an indoor atmosphere.

【図２８】Ｑ−３５Ｉ型結晶を室温−無水雰囲気下保存
後、更に室内雰囲気下に保存した場合のステレオ結晶構
造図である。FIG. 28 is a stereo crystal structure diagram when the Q-35I crystal is stored at room temperature in an anhydrous atmosphere and further stored in an indoor atmosphere.

【図２９】Ｑ−３５ＩＩ型結晶をａ）４０℃０％ＲＨの
条件下で１週間調湿保存後の粉末Ｘ線回折スペクトルで
ある。FIG. 29 is an X-ray powder diffraction spectrum of a Q-35II type crystal after a) conditioning storage at 40 ° C. and 0% RH for 1 week.

【図３０】Ｑ−３５ＩＩ型結晶をｂ）４０℃７５％ＲＨ
の条件下で１週間調湿保存後の粉末Ｘ線回折スペクトル
である。FIG. 30 shows b) 40 ° C. 75% RH
4 is a powder X-ray diffraction spectrum after storage for one week under the condition of (1).

【図３１】Ｑ−３５ＩＩ型結晶をｃ）４０℃１００％Ｒ
Ｈの条件下で１週間調湿保存後の粉末Ｘ線回折スペクト
ルである。FIG. 31 shows c-35II type crystal at c) 100% R at 40 ° C.
It is a powder X-ray-diffraction spectrum after humidified storage under H condition for 1 week.

【図３２】Ｑ−３５Ｉ型結晶を４０℃１００％ＲＨの条
件下で１週間保存した後の粉末Ｘ線回折スペクトルであ
る。FIG. 32 is a powder X-ray diffraction spectrum after storing the Q-35I crystal at 40 ° C. and 100% RH for one week.

【図３３】Ｑ−３５ＩＩ型結晶をエタノールで練合後の
ａ）エタノール練合末の粉末Ｘ線回折スペクトルであ
る。FIG. 33 is a powder X-ray diffraction spectrum of a) ethanol kneaded powder after kneading Form Q-35II with ethanol.

【図３４】Ｑ−３５ＩＩ型結晶を５０％エタノール水溶
液で練合後のｂ）５０％エタノール水溶液練合末の粉末
Ｘ線回折スペクトルである。FIG. 34 is a powder X-ray diffraction spectrum of b) a 50% ethanol aqueous solution after kneading the Q-35II type crystal with a 50% aqueous ethanol solution.

【図３５】Ｑ−３５ＩＩ型結晶を水で練合後のｃ）水練
合末の粉末Ｘ線回折スペクトルである。FIG. 35 is a powder X-ray diffraction spectrum of c) water-kneaded powder after kneading the Q-35II type crystal with water.

【図３６】Ｑ−３５Ｉ型結晶をエタノールで練合後の
ａ）エタノール練合末の粉末Ｘ線回折スペクトルであ
る。FIG. 36 is a powder X-ray diffraction spectrum of a) ethanol kneaded powder after kneading Form Q-35I with ethanol.

【図３７】Ｑ−３５Ｉ型結晶を５０％エタノール水溶液
で練合後のｂ）５０％エタノール水溶液練合末の粉末Ｘ
線回折スペクトルである。FIG. 37: Powder X after kneading the Q-35I crystal with a 50% aqueous ethanol solution
It is a line diffraction spectrum.

【図３８】Ｑ−３５Ｉ型結晶を水で練合後のｃ）水練合
末の粉末Ｘ線回折スペクトルである。FIG. 38 is a powder X-ray diffraction spectrum of c) water-kneaded powder after kneading Form Q-35I with water.

フロントページの続き (58)調査した分野(Int.Cl.⁷，ＤＢ名) C07D 401/04 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)Continuation of the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 401/04 CA (STN) REGISTRY (STN)

Claims (1)

(57)【特許請求の範囲】(57) [Claims] 【請求項１】 下記の式 【化１】 を有する１−シクロプロピル−６−フルオロ−１，４−
ジヒドロ−８−メトキシ−７−（３−メチルアミノピペ
リジン−１−イル）−４−オキソキノリン−３−カルボ
ン酸２水和物のＩ型結晶。1. The following formula: 1-cyclopropyl-6-fluoro-1,4- having
Form I crystal of dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid dihydrate.