JP3256311B2 - Quinolonecarboxylic acid derivative hydrate crystals - Google Patents
Quinolonecarboxylic acid derivative hydrate crystalsInfo
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- JP3256311B2 JP3256311B2 JP01453893A JP1453893A JP3256311B2 JP 3256311 B2 JP3256311 B2 JP 3256311B2 JP 01453893 A JP01453893 A JP 01453893A JP 1453893 A JP1453893 A JP 1453893A JP 3256311 B2 JP3256311 B2 JP 3256311B2
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Description
【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νO-H (H2 O)ピークが強く認められる(図
6)。加熱(80℃)すると、νO-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、νC=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νC=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νO-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
νO-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νO- 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)
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.
Priority Applications (1)
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---|---|---|---|
JP01453893A JP3256311B2 (en) | 1992-01-31 | 1993-02-01 | Quinolonecarboxylic acid derivative hydrate crystals |
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JP1654592 | 1992-01-31 | ||
JP4-16545 | 1992-01-31 | ||
JP01453893A JP3256311B2 (en) | 1992-01-31 | 1993-02-01 | Quinolonecarboxylic acid derivative hydrate crystals |
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JPH05271221A JPH05271221A (en) | 1993-10-19 |
JP3256311B2 true JP3256311B2 (en) | 2002-02-12 |
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JPH10101674A (en) * | 1996-08-06 | 1998-04-21 | Taisho Pharmaceut Co Ltd | Paratoluene sulfonate hydrate of thiazoline compound |
JP5255183B2 (en) * | 2003-09-04 | 2013-08-07 | ウォックハート リミテッド | Benzoquinolidine-2-carboxylic acid arginine salt tetrahydrate |
JP2008003079A (en) * | 2006-05-22 | 2008-01-10 | Minebea Co Ltd | Evaluation method for lifetime of grease composition |
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