JPH05271221A - Crystals of quinolone-carboxylic acid derivative - Google Patents

Abstract

PURPOSE:To provide quinolonecarboxylic acid derivative dihydrate crystals which is obtained using a specific solvent for purification, thus shows excellent stability under the pharmacentical manufacturing conditions such as in moisture absorption, kneading or the like and is very suitable for manufacturing medicines. CONSTITUTION:1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3- methylaminopiperidin-1-yl)-4-oxoquinoline-3-carboxylic acid (Q-35) obtained from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 3- methylaminopiperidine is suspended in ethanol-water (1:1), refluxed with heat to obtain the type I crystals of Q-35 dihydrate of formula II. When methanol is used as a solvent for purification to give the type II crystals of monohydrate, further when acetonitrile is used, type III crystal of variable water content is obtained. The crystals of type I converts into type II, when it is refluxed in methanol with heat, but no transition occurs moisturization and kneading.

Description

Detailed Description of the Invention

[0001]

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]

2. Description of the Related Art Japanese Patent Application Laid-Open No. 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]

However, while continuing research into practical use as a drug, the above Q-35 recrystallized from acetonitrile has a drawback that its weight increases with an increase in humidity and is stable. It turned out to be bad.
Therefore, the above-mentioned Q
It has proven difficult to develop -35 as a drug. Therefore, Q-35 is stable even under high humidity conditions.
Needed to develop a means to obtain

[0004]

Means for Solving the Problems The inventors of the present invention have made earnest studies to eliminate the drawbacks of the above-mentioned Q-35 recrystallized from acetonitrile, and as a result, the water content in Q-35 is not constant. Crystal (hereinafter “Crystal III” or “I
II-form crystal), monohydrate crystal (hereinafter "crystal II" or "II crystal"), dihydrate crystal (hereinafter "crystal I" or "I-form crystal") )
It has been found that there are four types of crystal forms, namely, and anhydrous crystals, and each form depends on the type of recrystallization solvent. Then, as a result of further detailed studies on the physical properties of each crystal form, the above-mentioned Q-35 recrystallized from acetonitrile is a type III crystal, and the type I crystal, that is, the dihydrate of Q-35 is under high humidity conditions. It was found that although it was the most stable, it changed to an anhydrate under dry or heating conditions, but returned to a dihydrate when left to stand. The present invention has been made based on such findings. That is, the present invention is 1-cyclopropyl-6-fluoro-1,4- having
It is dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid dihydrate.

A method for synthesizing Q-35 is as follows. 1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (DFQ) is directly added to 3-methylaminopiperidine (3- MAP) condensation method (I
Method), HBF ₄ is reacted with DFQ-Et to produce DFQ-
BF ₂ chelate (DFQ-BF ₂ ) was prepared and 3-M
Q-35 BF ₂ chelate (Q-35-
BF ₂ ) and then hydrolyzing with Et ₃ N or an aqueous solution of NaOH to obtain Q-35 (method II). Method II is suitable for large-scale synthesis because the yield is better. The reaction paths for Method I and Method II are as follows.

[0006] As a purification method, Q-3 obtained by Method I or Method II
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 produced depends on the purified solvent used. For example,
Type III or type II crystals in acetonitrile-water, type II crystals in methanol, ethanol-water (1:
In 1), type I crystals are obtained respectively. When the conditions under which these three crystal forms were obtained were examined, type III crystals were obtained when completely dissolved in ethanol or acetonitrile and the solvent was distilled off under reduced pressure. The crystals are ethanol-water (1:
It has been clarified that Form I crystals are produced by heating and refluxing after suspending in 1).

Further, 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 under reflux, crystal II is obtained, but humidification and kneading (50% ethanol or water)
Does not cause crystal transition. Further, crystal II and crystal I
It has been confirmed that, when dried, the water of crystallization is lost and becomes an anhydrous substance, but when left in the air, it returns to the hydrate form again.

Examples for producing the compound of the present invention are shown below, but the present invention is not limited to these examples.

[0009]

Example 1 3.4 g of DFQ-BF ₂ ester, 3-methylaminopiperidine.2HCl (3-MAP.2HC
l) 2.3 g and triethylamine 4.5 g were added to methylene chloride 18 ml, and the mixture was heated under reflux for 3 hours. After distilling off methylene chloride under reduced pressure, a solution of NaOH 2.5 g / water 20 ml was added, and the mixture was reacted at 80 ° C. for 1.5 hours. After cooling the reaction solution, pH was adjusted to 8 to 9 with 6N-HCl and crystallization was performed. The precipitated crystals were centrifuged to give crude Q-35 moist powder 4.
2 g was obtained (3.2 g in dry conversion, yield 83.0%).

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 dissolved therein.
(Converted to dry) was added. The solution was cooled, and the precipitated crystals were centrifuged to obtain 12.3 g of Q-35-fumar wet powder (dry conversion 11.0 g, yield 90.1%).

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 to pH = 8-
It was adjusted to 9 and crystallized. The precipitated crystals are separated by centrifugation and dried, and 7.7 g of purified Q-35 type I crystals (yield 83.2%)
Got

[0012]

Example 2 9.1% w / w- in a 200 ml reaction vessel
61.7 g (49.3 mmol) of MAP methanol solution
Was charged and heated with warm water at 60 ° C. under reduced pressure to distill off about 55 ml of methanol. 65 ml of methylene chloride and 7.7 g of triethylamine (75.8 m) were added to the obtained concentrated residue.
mol), 13.0 g of DFQ-BF ₂ ester (37.
(9 mmol) was added and the mixture was refluxed for 1 hour. Gradually dissolves,
It became a yellow clear solution. The solvent of this reaction solution was distilled off under reduced pressure. 30 ml of water and 39 g (244 mmol) of 25% aqueous sodium hydroxide solution were added to the concentrated residue, and the mixture was heated to 70 ° C.
And hydrolyzed for 1 hour (when heated, 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 5.5 N 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 placed on a 24 inch centrifuge for about 45 minutes to separate crystals. The crystals obtained are washed with 20 ml of water,
Shake it off for 30 minutes to obtain 18.2 g (n) of coarse Q-35 wet powder.
Et = 13.8 g, yield 94%) was obtained.

Deionized water 10 was added to 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)) was added (pH = 3 ~).
4). It was extracted twice with 30 ml of ethyl acetate. Under reduced pressure, 7
The mixture was heated with warm water of 0 ° C., and ethyl acetate dissolved in the aqueous layer was distilled off (about 1 hour 30 minutes). 2 ml of hydrochloric acid was added to the aqueous layer to make it acidic, and some insoluble matter formed was filtered off. PH of 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 heating, this liquid was cooled to 25 ° C. and stirred for 1 hour. The filtrate was then placed on a 24 inch centrifuge for about 30 minutes to separate crystals. The obtained crystals are washed with 20 ml of deionized water, shaken off for 30 minutes,
13.7 g of crystals were obtained.

80 ml of ethanol in a 200 ml reaction vessel
1, 80 ml of water and 13.7 g of the above crystals were added, and the mixture was heated to 70 ° C. and stirred in a suspended state for 30 minutes. 2 this mixture
After cooling to 5 ° C. and stirring for 1 hour, the crystals were separated by a 24-inch centrifuge for about 30 minutes. The obtained crystals were washed with 20 ml of deionized water, shaken for 30 minutes, and
A -35 moist powder was obtained. The obtained Q-35 wet powder was dried at 60 ° C. for 2 hours using an aeration dryer and further aerated at room temperature for 2 hours to give 10.1 g of I-type Q-35 crystals (yield 73
%) Was obtained.

Using the type I crystal of Q-35 thus obtained, the following experiment was conducted in order to clarify its structure and the behavior of water of crystallization of two molecules.

[Experimental Examples] 1) Samples For infrared absorption spectra, powder X-ray diffraction and thermal analysis, those produced by the method of Example are described in parentheses for single crystal X-ray analysis. Each of the crystals obtained by the method was used.

(Crystal for single crystal X-ray analysis: 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-mentioned example, heated at 75 ° C. for 30 minutes and filtered while hot. The filtrate was allowed to stand at room temperature and then suction-filtered to obtain crystals (about 5.95 g).
The mixture was heated at ℃ for 5 minutes, allowed to stand at room temperature and then suction filtered, and the filtrate was allowed to stand 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 rising → temperature falling experiment (TG) Using about 10 mg of a sample (the sample is a powder, therefore, it is not crushed), and heated from room temperature to 80 ° C. at a heating rate of 5 ° C./min. Then, after holding at 80 ° C. for 30 minutes, the temperature was lowered to room temperature. At this time, the weight change 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
~ 50%).

Room temperature-under anhydrous atmosphere → experimentation under indoor atmosphere (TG) Using about 10 mg of sample (without crushing), N ₂ at room temperature
The gas was allowed to flow at 200 ml / min and the weight change was observed under an anhydrous atmosphere. After the weight change disappears, N
_Two gases were stopped and placed in an indoor atmosphere (relative indoor humidity: RH 40 to 50%), and the weight change was observed again.

Storage experiments under low humidity (RH 6%) (T
G) Approximately 10 mg of sample (not crushed) is heated and N ₂ gas f
After dehydration in an anhydrous atmosphere with low, RH6 at room temperature
Flow of Air * with humidity adjusted to 100% at 200 ml / min
Then, the weight change was observed.

Saturated NaOH solution was stored in a desiccator, adjusted to RH 6%, and circulated. Temperature rising experiment and calculation of activation energy (TG / DT
A) About 10 mg of a sample (not crushed) was used and heated from room temperature to 170 ° C. at a heating rate of 2, 3, 5 ° C./min.
At this time, changes in weight and heat due to heating were observed, and the activation energy was calculated 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
Not allowed to go low (indoor relative humidity: RH 40-50
%).

Temperature rising experiment (DSC) About 10 mg of a sample (without crushing) was used, and the sample pan was not crimped in order to avoid being pressurized by steam, and ope
The measurement was performed in the state of n. 20 ml / min of N ₂ gas was allowed to flow, and when it was thermally stable (about 3 minutes), it was heated from room temperature to 170 ° C. at a temperature rising rate of 3 ° C./min and the thermal change was observed.

(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 subjected to a diffuse reflection method (DRA). The measurement was performed (scan number: 2048, gain: 16). In the heating experiment and the experiment in the indoor atmosphere, the sample chamber was opened in order to prevent the influence of the dry air (internal relative humidity: RH 20 to 30%), and the reference was performed.
Similarly, e was measured. In an experiment under anhydrous atmosphere,
The Sample chamber was closed and dried Air was placed in an anhydrous atmosphere, and the reference was measured in the same manner.

Room temperature-under anhydrous atmosphere → under room atmosphere The sample was mixed and diluted to 5% with KBr, and the diffuse reflection method (DR
A) (scan number: 1024, gain:
8). The cell was measured using a simple DRA cell. For experiments under anhydrous atmosphere, close the Sample chamber and dry.
The experiment was performed with ir flowing, and the reference was measured in the same manner. In an experiment in an indoor atmosphere, Sam
The ple room is open (relative humidity in the room: RH20
.About.30%), and the reference was similarly measured.

(3) Powder X-ray diffraction spectrum Heating (80 ° C.) → in a room atmosphere A sample was crushed and a heating cell was used to raise the temperature at 5 ° C./mi.
The mixture was heated to 80 ° C. with n, and then N ₂ gas was allowed to flow to form an anhydrous atmosphere, and then the temperature was lowered to room temperature. After that, N ₂ gas was stopped and the measurement was performed under an indoor atmosphere (relative humidity in the room: 60 to 70%).

Room temperature-under anhydrous atmosphere → under room atmosphere A sample is crushed and N ₂ gas is allowed to flow using a heating cell.
Then, it was placed in an anhydrous atmosphere and measured over time. Then N ₂
The gas was stopped and the measurement was carried out in a room atmosphere (relative humidity in the room: 60 to 70%).

(4) Single crystal X-ray analysis After measurement in a room atmosphere (relative humidity at room temperature: 60 to 70%), N ₂ gas was allowed to flow and measurement was performed in an anhydrous atmosphere. Then, it was stored again in an indoor atmosphere and measured.

4) Experimental Results and Consideration (1) Analysis of Behavior of Crystal Water by Thermal Analysis The I-form crystal of Q-35 (dihydrate) was analyzed from room temperature to 8 by TG method.
When heated to 0 ° C. (N ₂ gas is not allowed to flow in order to prevent the influence of N ₂ gas), the weight decreased as the temperature increased, and finally the amount decreased by about 8.1%. Q-
Since the theoretical water content of the 35I type crystal is 8.47%, it is estimated that the weight loss corresponds to water of crystallization. That is, the sample at the time of heating loss is considered to be dehydrated anhydride. After that, when the temperature is lowered, the weight starts to increase at the same time as the temperature is lowered.
It returned to the Initial weight in 50 minutes (Fig. 1). From these facts, it was estimated that although two molecules of crystal water of the Q-35I type crystal are desorbed by heating, they absorb water in the air at room temperature and stabilize again in the state of two molecules of crystal water. .. Confirmation that the weight change is due to crystal water is
It was performed in “(2) Structural change”.

On the other hand, when the sample was stored at room temperature in an anhydrous atmosphere, a weight loss of about 8.0% occurred in about 700 minutes. After that, when stored in an indoor atmosphere, the weight increases rapidly,
It returned to the same weight as Initial in about 150 minutes (Fig. 2). This indicates that not only the water of crystallization of the Q-35I type crystal is desorbed by heating, but also desorption of the water of crystallization can sufficiently occur in an anhydrous atmosphere even at room temperature.

It was confirmed that dehydration corresponding to two molecules occurs even when stored at room temperature-anhydrous atmosphere, and that the dehydrated product is completely reabsorbed of water when stored in an indoor atmosphere of 40 to 50% RH. Under low humidity with a little water, Q-
What is the state of the 35I type crystal? That is, 1) two molecules of water of crystallization are taken into the crystal even under low humidity, and exist as dihydrate. 2) At a certain humidity or lower, they exist in an intermediate state such as anhydrate or monohydrate. Etc. are possible. Therefore, the dehydrated crystal was allowed to flow with Air whose humidity was adjusted to 6% at room temperature and the weight change was measured. It rapidly absorbed water despite the low humidity and returned to the weight of the dihydrate in about 60 minutes. Was confirmed, and an intermediate state such as monohydrate was not observed in the water absorption process (FIG. 3). The reason why the water absorption rate is higher in RH 6% than in the indoor atmosphere is considered to be due to the difference in the air flow rate during the measurement.

In case of dehydration by heating, TG curve (FIG. 4)
At the same time, a gradual weight loss occurs at the same time as the temperature rises, and then a rapid weight loss is observed and a plateau is reached. At this time, two peaks were observed in the DTA curve during the dehydration process, and one gentle peak of DTA, T
When the amount of G is rapidly reduced, one peak of DTA and two peaks are observed. It is considered that this is because there are two types of water that are easy to desorb and water that is difficult to desorb, so that the water that is easily desorbed first flies, and the water that is hard to desorb flies afterwards in a two-step reaction. DTA even with DSC curve
Similar to the curve, two peaks were observed during the dehydration process (Fig. 5). On the other hand, in the TG curve (FIG. 2) when N ₂ gas was allowed to flow (room temperature-anhydrous atmosphere) at room temperature, there was a slightly large amount of decrease immediately after the flow of N ₂ gas, followed by a gradual decrease, followed by a rapid decrease. Although a weight loss was observed and a plateau was reached, in this case, the water in the sample on the surface first flew, then, like the case of heating, the water that was easily desorbed first, and the water that was hard to desorb then flew 2 It is considered that the reactions of the steps are combined.

(2) Structural change Infrared absorption spectrum method i) Heating (80 ° C.) → under room atmosphere In the TG method, the Q-35I type crystal was heated (80 ° C.) to reduce the amount of crystal water equivalent to the theoretical value. It was confirmed that the initial weight was returned to the initial weight by lowering the temperature to room temperature. Since the amount of weight change agrees with the theoretical value of water of crystallization, it was estimated that the weight change was due to the desorption of two molecules of water of crystallization, and was confirmed by the infrared absorption spectroscopy method.

In the Initial spectrum, a ν _OH (H ₂ O) peak derived from water of crystallization is strongly recognized (FIG. 6). Upon heating (80 ° C.), absorption of ν _OH (H ₂ O) completely disappeared, and it was confirmed that dehydration at 80 ° C. resulted in an anhydride (FIG. 6). In addition, the spectrum on the lower wave number side than ν _{C = 0} (carboxylate, ketone: 1622 cm ^-1 ) also changed, and it is considered that some change occurred due to dehydration. Crystal water is carboxylate (Q
-35 has a betaine structure) bound to oxygen, but the carboxylate has ν _{C = 0} absorption (1622,1).
At 459 cm ^−1, a slight change in peak shape is observed. Then, lower the temperature in an anhydrous atmosphere and store at room temperature.
_No absorption of _OH (H ₂ O) was observed, which is consistent with the spectrum upon heating, and the dehydrated state is maintained (Fig. 7). However, if stored in an indoor atmosphere, Initial
Absorption of ν _OH (H ₂ O) equivalent to that of the above was observed, and the other peaks also completely matched the Initial spectrum,
It has the same molecular structure of dihydrate as Initial (FIG. 8), and it was confirmed that the dehydrated product takes up water in the presence of water at room temperature. From these results, it can be said that the Q-35 type I crystal loses its water of crystallization by heating to become an anhydride, but when it is stored in an indoor atmosphere, it absorbs water and returns to the same dihydrate molecular structure as Initial.

Ii) Room Temperature-Underwater Atmosphere → Indoor Atmosphere In the TG method, as in the case of heating, a reduction in the amount equivalent to the theoretical value of crystal water was recognized even under room temperature-anhydrous atmosphere, and then returned to the Initial weight in the room atmosphere. It was confirmed. It was confirmed in the infrared absorption spectrum 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 dehydrated product under heating and room temperature-anhydrous atmosphere was different. Whether or not it was observed by an infrared absorption spectrum.

When stored in an anhydrous atmosphere, absorption of ν _OH (H ₂ O) disappears as in the case of heating and completely agrees with the spectrum of heating (FIG. 9). It was found that it was dehydrated to give an anhydride and had the same molecular structure as when heated. After that, when it is stored in an indoor atmosphere, ν _{O- H} equivalent to Initial will be obtained, just as when heated.
Absorption of (H ₂ O) was observed, which was in agreement with the spectrum of Initial and was confirmed to have the same molecular structure of dihydrate as Initial (FIG. 10). Therefore,
When stored in a room temperature-anhydrous atmosphere, dehydration produces an anhydride, and the molecular structure of the dehydrated anhydride is the same as the molecular structure of dehydrated anhydride by heating. It was confirmed to return to the molecular structure of the product.

As a result of measurement of infrared absorption spectrum, Q-3
The 5I type crystal is dehydrated under heating (80 ° C.) and room temperature-anhydrous atmosphere to produce an anhydride, and the molecular structure of the dehydrated product is the same regardless of the drying conditions. It was confirmed that the desorption of water was reversible, returning to the same molecular structure of dihydrate as Initial.

Powder X-ray diffraction i) Heating (80 ° C.) → in a room atmosphere It was confirmed that water was returned again by heating in an infrared absorption spectrum, dehydration under room temperature-anhydrous atmosphere, and storage in a room atmosphere. It was Therefore, changes in the crystal structure due to dehydration were observed by powder X-ray diffraction.

The Initial spectrum is shown in FIG. When heated (80 ° C), 2 at Initial
The large peak existing at 4.2 ° C disappeared, and other spectra were changed to show completely different spectra (Fig. 12). This result means that dehydration by heating is confirmed by infrared absorption spectrum, so that not only water molecules are desorbed but also the crystal structure itself has a different structure during dehydration by heating. is doing. After this,
When the temperature was lowered to room temperature in an anhydrous atmosphere, the infrared absorption spectrum kept the dehydrated state even when the temperature was lowered in an anhydrous atmosphere and stored at room temperature. However, the crystal structure of the dehydrated product is retained (FIG. 13), and the crystal structure is the same as that of the dehydrated product during heating. However, when stored in an indoor atmosphere,
The large peak at 24.2 ° C., which was present at Initial for 14 hours, reappeared and was completely in agreement with the spectrum of Initial (FIG. 14). In the infrared absorption spectrum, water returns by being stored in an indoor atmosphere
It has been confirmed that the crystal structure of the dehydrated product is restored to the initial structure, that is, the crystal structure of the dehydrated product is restored to the Initial crystal structure, that is, the structure having two molecules of crystal water, by storing in a room atmosphere even in powder X-ray diffraction. confirmed. When the results of infrared absorption spectrum and powder X-ray diffraction are combined, dehydration by heating changes the crystal structure by dehydration, but when stored in an indoor atmosphere, water returns and the crystal structure also changes at the same time.
Return to the initial crystal structure. Desorption of water is reversible, and hydrates and dehydrated products have different crystal structures, the crystal structure changes at the same time as the desorption of water, and the change of the crystal structure is also reversible.

Ii) Room temperature-under anhydrous atmosphere → under room atmosphere In the infrared absorption spectrum, dehydration occurred even under room temperature-anhydrous atmosphere, and the change showed the same behavior as heating. Therefore, it was observed whether the powder X-ray diffraction exhibits the same behavior.

When stored in an anhydrous atmosphere, the spectrum changes with time and the spectrum during heating (during dehydration) is shown in FIG.
(Fig. 16). In the infrared absorption spectrum,
Since it was confirmed that the sample was dehydrated at room temperature in an anhydrous atmosphere, the sample after storage in an anhydrous atmosphere by powder X-ray diffraction is a dehydrated product. It was confirmed that the dehydrated product after storage in an anhydrous atmosphere had the same crystal structure as the dehydrated product by heating, in the infrared absorption spectrum, similar to the same molecular structure under heating and room temperature-drying conditions. It was When stored in an indoor atmosphere, the powder X-ray diffraction spectrum of Initial completely coincided with that of FIG. 18 in 2 hours (FIG. 17), and when stored in an indoor atmosphere by an infrared absorption spectrum, water was returned. In diffraction as well as in heating, Ini
It was confirmed to return to the crystal structure of tial dihydrate.

From these results, the Q-35I type crystal is dehydrated by heating or storage under room temperature-anhydrous atmosphere to be an anhydride, and since these dehydrated products have the same molecular structure and crystal structure, they are the same substance, In addition, it was found that by storing the dehydrated product in a room atmosphere, the same substance having the same dihydrate molecular structure and crystal structure as Initial was recovered.

(3) Single crystal X-ray analysis From infrared absorption spectrum and powder X-ray diffraction, heating, room temperature-
It is dehydrated in an anhydrous atmosphere, and the dehydrated product has the same molecular structure and crystal structure.
It was found that the same molecular structure and crystal structure of the same dihydrate as the above were restored. To further support this fact, single crystal X-ray analysis was performed.

The Q-35I type crystal prepared for single crystal X-ray analysis was measured, and the powder X-ray diffraction synthetic spectrum obtained from the result was in agreement with the powder X-ray diffraction spectrum (FIG. 19) in an indoor atmosphere. (Fig. 20). Then room temperature-
Q prepared for single crystal X-ray analysis dried under anhydrous atmosphere
The -35I type crystal was measured, and the powder X-ray diffraction synthetic spectrum obtained from the result was in agreement with the powder X-ray diffraction spectrum FIG. 21 under heating and under room temperature-anhydrous atmosphere (FIG. 22). Therefore, it was confirmed that the dried single crystal was dehydrated. The dehydrated single crystal has a changed lattice constant (Initial: b = 12.966 (2) Å, dehydrated crystal: b = 38.34 (2) Å, a, c, β remain unchanged) The structure had changed in the body.

The crystal structure of Initial is shown in FIGS.
The crystal structure diagram of the dehydrated product is shown in FIGS. Crystals dried under a room temperature-anhydrous atmosphere were stored in a room atmosphere and measured again to confirm that they had the same crystal structure as Initial (FIGS. 27 and 28).

It was shown by powder X-ray diffraction that the hydrate and the dehydrate had different crystal structures, and it was confirmed that the structural change was reversible. The results were also supported in single crystal X-ray analysis. It was the result.

5) Conclusion From the above experimental results, the following points were clarified regarding the behavior of crystal water of the Q-35 type I crystal.

By heating or storing in a room temperature-anhydrous atmosphere, dehydration occurs with a change in crystal structure to produce an anhydride.

The molecular structure and crystal structure of the dehydrated product are the same regardless of the drying conditions of heating or storage under room temperature-anhydrous atmosphere.

The amount of dehydration quantitatively agrees with the theoretical water content of dihydrate.

By storing the dehydrated product in a room atmosphere, moisture in the air is absorbed and it returns to the Q-35I type crystal.

Desorption of water is reversible.

The water absorption of the dehydrated product quantitatively agrees with the theoretical value of two water molecules.

Since the dehydrated product changes into Q-35I type crystal even if a slight amount of water is present in the atmosphere, the water of crystallization of the Q-35I type crystal is stable in normal handling.

As mentioned above, the Q-35 type III crystal has very poor stability. On the other hand, although the Q-35 type I crystal (dihydrate) and the Q-35 type II crystal (monohydrate) are dehydrated to dryness under dry conditions, they are stored in an indoor atmosphere. Therefore, it has been confirmed that it absorbs moisture in the air again and returns to the Q-35I type crystal and the Q-35II type crystal, respectively. Therefore, the method and results of the comparative test conducted on the stability of both are described below.

Test Example 1 Moisture Absorption Test 4 Q-35I type crystals and 4 Q-35II type crystals were used.
0% RH, 52.4% RH, 75% R at 0 ° C
The sample was left to stand under the humidity conditions of H and 100% RH, and the weight change after 4 to 7 days was examined. The results are shown in Table 1.

Table 1 Weight change sample at 40 ° C. and humidity control (mg) 4 days 5 days 6 days 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 Type II crystals showed a slight weight loss of more than 2% at 0% RH, but at 52.4 and 75% RH the weight change was less than 1%. 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 under all other relative humidity, the change was within 1%. It is considered that the crystal water of the type I crystal is lost under low humidity.

Type II crystal was subjected to 40 ° C. 0% RH and 75% R
Powder X-ray diffraction spectrum after storage in H for 1 week (Fig. 29,
Fig. 30) was in agreement with the initial spectrum of the type II crystal, but the spectrum after storage for 1 week at 40 ° C and 100% RH (Fig. 31) did not agree with the initial spectrum of the type II crystal, and the type I crystal was observed. It was considered to be a mixed spectrum of the diffraction peaks of the crystal and the type III crystal.

On the other hand, the type I crystal was subjected to 1 at 40 ° C. and 100% RH.
The powder X-ray diffraction spectrum (FIG. 32) after storage for a week shows I
It was in agreement with the initial spectrum of the type crystals.

From the above results, although the type I crystal has a weight change due to the loss of water of crystallization under 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 the production of chemicals.

[Test Example 2] Effect of kneading Q-35 is 100 to 20 when used as a medicine.
An oral formulation of 0 mg is considered suitable. Therefore, it is considered that the preparation will have a high content of the main drug, and it is highly necessary to carry out wet granulation. Therefore, assuming wet granulation,
In order to confirm whether the crystal form is changed by kneading with water and ethanol, the type II crystal and the type I crystal were kneaded with ethanol, 50% ethanol aqueous solution and water, respectively, and then powder X The line diffraction spectrum was measured.

The kneading end of the type II crystal became a powder X-ray diffraction spectrum (FIG. 33) which coincided with the original type II crystal by kneading with ethanol, and it was found that the crystal form did not change. However, when the mixture was kneaded with a 50% ethanol aqueous solution or water, the diffraction peaks of the type II crystal and the type I crystal were mixed (FIGS. 34 and 35). Ie II
It was confirmed that the type crystals were partially transformed into crystals I by kneading with a solvent having an ethanol content of 50% or less.

On the other hand, the powder X-ray diffraction spectra of the kneading powder of the type I crystal were in agreement with those of the initial type I crystal (FIGS. 36, 37 and 38). That is, it was confirmed that even if the I-type crystal was kneaded, the I-type crystal was not transformed.

Therefore, it was found that the type I crystal is more preferable than the type II crystal when the formulation is carried out by wet granulation.

[0063]

As described above, the Q-35 of the present invention is used.
Form I crystals are excellent in stability under conditions such as moisture absorption and kneading, and thus are crystal forms that are extremely suitable for formulation.

[Brief description of drawings]

FIG. 1 Q-35I when stored in a room atmosphere after heating
It is a graph showing the weight change of a type crystal.

FIG. 2 is a graph showing the weight change of the Q-35I type crystal when stored in a room atmosphere after being stored in a room temperature-anhydrous atmosphere.

FIG. 3 is a graph showing a weight change when a dehydrated product of Q-35 type I crystal is stored in a room temperature-RH6% atmosphere.

FIG. 4 is a TG / DTA spectrum obtained when a Q-35 type I crystal was heated from room temperature to 170 ° C. at a temperature rising rate of 3 ° C./min.

FIG. 5 is a DSC spectrum of a Q-35 type I crystal heated from room temperature to 170 ° C. at a temperature rising rate of 3 ° C./min.

FIG. 6 is an infrared absorption spectrum of Q-35 type I crystal during Initial and heating.

FIG. 7 is an infrared absorption spectrum of the Q-35 type I crystal when it was heated and when the temperature was lowered and stored at room temperature in an anhydrous atmosphere.

FIG. 8 is an infrared absorption spectrum of Q-35 type I crystal when initially stored and stored in a room atmosphere after heating.

FIG. 9 is an infrared absorption spectrum of a Q-35 type I crystal when heated and stored at room temperature in an anhydrous atmosphere.

FIG. 10 is an infrared absorption spectrum of the Q-35 type I crystal when stored in Initial and room temperature-anhydrous atmosphere and then stored in an indoor atmosphere.

FIG. 11: Initial powder X of Q-35 type I crystal
It is a line diffraction spectrum.

FIG. 12 is a powder X-ray diffraction spectrum of a Q-35 type I crystal upon heating.

FIG. 13 is a powder X-ray diffraction spectrum of the Q-35I type crystal when heated and then cooled in an anhydrous atmosphere and stored at room temperature.

FIG. 14 is a powder X-ray diffraction spectrum when the Q-35I type crystal is heated and then cooled in an anhydrous atmosphere, and further stored in a room atmosphere.

FIG. 15 is a powder X-ray diffraction spectrum of a Q-35 type I crystal upon heating.

FIG. 16 is a powder X-ray diffraction spectrum of the Q-35I type crystal after storage at room temperature in an anhydrous atmosphere.

FIG. 17 is a powder X-ray diffraction spectrum of the Q-35I type crystal after being stored in a room temperature-anhydrous atmosphere and subsequently stored in a room atmosphere.

FIG. 18: Initial powder X of Q-35 type I crystal
It is a line diffraction spectrum.

FIG. 19: I of Q-35 type I crystal in a room atmosphere
It is a powder X-ray diffraction spectrum of the initial.

FIG. 20 is a synthetic spectrum of an initial powder X-ray diffraction obtained from a single crystal X-ray analysis result of a Q-35 type I crystal.

FIG. 21 is a powder X-ray diffraction spectrum of the Q-35I type crystal at the time of heating.

FIG. 22 is a composite spectrum of powder X-ray diffraction in a room temperature-anhydrous atmosphere obtained from the single crystal X-ray analysis result of the Q-35 type I crystal.

FIG. 23 is a crystal structure diagram of Initial of Q-35I type crystal.

FIG. 24 is an initial stereo crystal structure diagram of a Q-35 type I crystal.

FIG. 25 is a crystal structure diagram of a Q-35 type I crystal at room temperature in an anhydrous atmosphere (dehydrated product).

FIG. 26 is a stereo crystal structure diagram of a Q-35 type I crystal at room temperature in an anhydrous atmosphere (dehydrated product).

FIG. 27 is a crystal structure diagram of a Q-35I type crystal stored in a room temperature-anhydrous atmosphere and further stored in a room atmosphere.

FIG. 28 is a stereo crystal structure diagram in the case where the Q-35I type crystal is stored in a room temperature-anhydrous atmosphere and further stored in an indoor atmosphere.

FIG. 29 is a powder X-ray diffraction spectrum of the Q-35II type crystal after a) humidity storage for 1 week under the condition of 40 ° C. and 0% RH.

FIG. 30: Q-35 type II crystal b) 40 ° C. 75% RH
2 is a powder X-ray diffraction spectrum after storage under humidity control for 1 week.

FIG. 31 c) Q-35 type II crystal c) 40 ° C. 100% R
It is a powder X-ray-diffraction spectrum after humidity control storage for 1 week on H conditions.

FIG. 32 is a powder X-ray diffraction spectrum of the Q-35I type crystal after being stored under the conditions of 40 ° C. and 100% RH for 1 week.

FIG. 33 is a powder X-ray diffraction spectrum of a) an ethanol kneaded powder after kneading the Q-35II type crystal with ethanol.

FIG. 34 is a powder X-ray diffraction spectrum of b) the kneaded powder of a 50% ethanol aqueous solution after kneading the Q-35II type crystals with a 50% ethanol aqueous solution.

FIG. 35 is a powder X-ray diffraction spectrum of c) a water-kneaded powder after kneading a Q-35II type crystal with water.

FIG. 36 is a powder X-ray diffraction spectrum of a) the kneaded powder of ethanol after kneading the Q-35 type I crystal with ethanol.

FIG. 37 b) Powder X after kneading of Q-35 type I crystal with 50% ethanol aqueous solution, b) 50% ethanol aqueous solution kneading powder
It is a line diffraction spectrum.

FIG. 38 is a powder X-ray diffraction spectrum of c) a water-kneaded powder after kneading a Q-35I type crystal with water.

Claims (1)

[Claims] 1. The following formula 1-cyclopropyl-6-fluoro-1,4- having
Dihydro-8-methoxy-7- (3-methylaminopiperidin-1-yl) -4-oxoquinoline-3-carboxylic acid dihydrate.